TY - JOUR AB - Tissue phenotypes, such as metabolic states, inflammation, and tumor properties, emerge from both molecular states and spatial cell organization. Spatial molecular assays provide an unbiased view of tissue architecture, enabling phenotype prediction. Graph neural networks (GNNs) offer a natural framework for analyzing spatial proteomics by integrating expression profiles with structure. We apply GNNs to classify tissue phenotypes using spatial cell patterns. We show that for relatively simple classification tasks, such as tumor grading in breast cancer, incorporating spatial context does not significantly improve predictive performance over models trained on single-cell or pseudobulk representations. However, GNNs capture meaningful spatial features, retaining prognostic signals beyond tumor labels, highlighting tumor-grade-specific cell type interactions, and uncovering complex immune infiltration patterns in colorectal cancer not detectable with traditional approaches. These findings suggest that while spatial dependencies may not always enhance classification performance in small datasets, GNNs remain valuable tools for characterizing tissue organization and interactions. AU - Ali, M. AU - Richter, S. AU - Ertürk, A. AU - Fischer, D.S. AU - Theis, F.J. C1 - 75637 C2 - 58057 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Graph neural networks learn emergent tissue properties from spatial molecular profiles. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Impaired glucose uptake in the brain is an early presymptomatic manifestation of Alzheimer's disease (AD), with symptom-free periods of varying duration that likely reflect individual differences in metabolic resilience. We propose a systemic "bioenergetic capacity", the individual ability to maintain energy homeostasis under pathological conditions. Using fasting serum acylcarnitine profiles from the AD Neuroimaging Initiative as a blood-based readout for this capacity, we identified subgroups with distinct clinical and biomarker presentations of AD. Our data suggests that improving beta-oxidation efficiency can decelerate bioenergetic aging and disease progression. The estimated treatment effects of targeting the bioenergetic capacity were comparable to those of recently approved anti-amyloid therapies, particularly in individuals with specific mitochondrial genotypes linked to succinylcarnitine metabolism. Taken together, our findings provide evidence that therapeutically enhancing bioenergetic health may reduce the risk of symptomatic AD. Furthermore, monitoring the bioenergetic capacity via blood acylcarnitine measurements can be achieved using existing clinical assays. AU - Arnold, M. AU - Buyukozkan, M.* AU - Doraiswamy, P.M.* AU - Nho, K.* AU - Wu, T. AU - Gudnason, V.* AU - Launer, L.J.* AU - Wang-Sattler, R. AU - Adamski, J. AU - de Jager, P.L.* AU - Ertekin-Taner, N.* AU - Bennett, D.A.* AU - Saykin, A.J.* AU - Peters, A. AU - Suhre, K.* AU - Kaddurah-Daouk, R.* AU - Kastenmüller, G. AU - Krumsiek, J.* C1 - 73483 C2 - 56860 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Individual bioenergetic capacity as a potential source of resilience to Alzheimer's disease. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Type 2 diabetes is associated with a range of non-cardiovascular non-oncologic comorbidities. To move beyond associations and evaluate causal effects between type 2 diabetes genetic predisposition and 21 comorbidities, we apply Mendelian randomization analysis using genome-wide association studies across multiple genetic ancestries. Additionally, leveraging eight mechanistic clusters of type 2 diabetes genetic profiles, each representing distinct biological pathways, we investigate causal links between cluster-stratified type 2 diabetes genetic predisposition and comorbidity risk. We identify causal effects of type 2 diabetes genetic predisposition driven by distinct genetic clusters. For example, the risk-increasing effects of type 2 diabetes genetic predisposition on cataracts and erectile dysfunction are primarily attributed to adiposity and glucose regulation mechanisms, respectively. We observe opposing effect directions across different genetic ancestries for depression, asthma and chronic obstructive pulmonary disease. Our findings leverage the heterogeneity underpinning type 2 diabetes genetic predisposition to prioritize biological mechanisms underlying causal relationships with comorbidities. AU - Arruda, A.L. AU - Bocher, O. AU - Taylor, H.J.* AU - Cammann, D.* AU - Yoshiji, S.* AU - Yin, X.* AU - Zhao, C.* AU - Chen, J.* AU - Wood, A.C.* AU - Suzuki, K.* AU - Mercader, J.M.* AU - Spracklen, C.N.* AU - Meigs, J.B.* AU - Vujkovic, M.R.* AU - Smith, G.D.* AU - Rotter, J.I.* AU - Voight, B.F.* AU - Morris, A.P.* AU - Zeggini, E. C1 - 75753 C2 - 57974 CY - Heidelberger Platz 3, Berlin, 14197, Germany SP - 14 TI - The effect of type 2 diabetes genetic predisposition on non-cardiovascular comorbidities. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - The hypothalamus in the central nervous system (CNS) has important functions in controlling systemic metabolism. A calorie-rich diet triggers CNS immune activation, impairing metabolic control and promoting obesity and Type 2 Diabetes (T2D), but the mechanisms driving hypothalamic immune activation remain unclear. Here we identify regulatory T cells (Tregs) as key modulators of hypothalamic immune responses. In mice, calorie-rich environments activate hypothalamic CD4+ T cells, infiltrating macrophages and microglia while reducing hypothalamic Tregs. mRNA profiling of hypothalamic CD4+ T cells reveals a Th1-like activation state, with increased Tbx21, Cxcr3 and Cd226 but decreased Ccr7 and S1pr1. Importantly, results from Treg loss-of function and gain-of-function experiments show that Tregs limit hypothalamic immune activation and reverse metabolic impairments induced by hyper-caloric feeding. Our findings thus help refine the current model of Treg-centered immune-metabolic crosstalk in the brain and may contribute to the development of precision immune modulation for obesity and diabetes. AU - Becker, M. AU - Kälin, S. AU - Neubig, A.H. AU - Lauber, M. AU - Opaleva, D. AU - Hipp, H. AU - Salb, V.K. AU - Ott, V. AU - Legutko, B. AU - Kälin, R.E.* AU - Hippich, M. AU - Scherm, M.G. AU - Nascimento, L.F.R. AU - Serr, I. AU - Hosp, F.* AU - Nikolaev, A.* AU - Mohebiany, A.* AU - Krueger, M.* AU - Flachmeyer, B.* AU - Pfaffl, M.W.* AU - Haase, B.* AU - Yi, C.X.* AU - Dietzen, S.* AU - Bopp, T.* AU - Woods, S.C.* AU - Waisman, A.* AU - Weigmann, B.* AU - Mann, M.* AU - Tschöp, M.H. AU - Daniel, C. C1 - 73732 C2 - 57200 TI - Regulatory T cells in the mouse hypothalamus control immune activation and ameliorate metabolic impairments in high-calorie environments. JO - Nat. Commun. VL - 16 IS - 1 PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Normative representation learning focuses on understanding the typical anatomical distributions from large datasets of medical scans from healthy individuals. Generative Artificial Intelligence (AI) leverages this attribute to synthesize images that accurately reflect these normative patterns. This capability enables the AI allowing them to effectively detect and correct anomalies in new, unseen pathological data without the need for expert labeling. Traditional anomaly detection methods often evaluate the anomaly detection performance, overlooking the crucial role of normative learning. In our analysis, we introduce novel metrics, specifically designed to evaluate this facet in AI models. We apply these metrics across various generative AI frameworks, including advanced diffusion models, and rigorously test them against complex and diverse brain pathologies. In addition, we conduct a large multi-reader study to compare these metrics to experts' evaluations. Our analysis demonstrates that models proficient in normative learning exhibit exceptional versatility, adeptly detecting a wide range of unseen medical conditions. Our code is available at https://github.com/compai-lab/2024-ncomms-bercea.git . AU - Bercea, C.-I. AU - Wiestler, B.* AU - Rueckert, D.* AU - Schnabel, J.A. C1 - 73388 C2 - 57039 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Evaluating normative representation learning in generative AI for robust anomaly detection in brain imaging. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Closely related genes typically display common essential functions but also functional diversification, ensuring retention of both genes throughout evolution. The histone lysine acetyltransferases KAT6A (MOZ) and KAT6B (QKF/MORF), sharing identical protein domain structure, are mutually exclusive catalytic subunits of a multiprotein complex. Mutations in either KAT6A or KAT6B result in congenital intellectual disability disorders in human patients. In mice, loss of function of either gene results in distinct, severe phenotypic consequences. Here we show that, surprisingly, 4-fold overexpression of Kat6b rescues all previously described developmental defects in Kat6a mutant mice, including rescuing the absence of hematopoietic stem cells. Kat6b restores acetylation at histone H3 lysines 9 and 23 and reverses critical gene expression anomalies in Kat6a mutant mice. Our data suggest that the target gene specificity of KAT6A can be substituted by the related paralogue KAT6B, despite differences in amino acid sequence, if KAT6B is expressed at sufficiently high levels. AU - Bergamasco, M.I.* AU - Yang, Y.* AU - Garnham, A.L.* AU - Sheikh, B. AU - Smyth, G.K.* AU - Voss, A.K.* AU - Thomas, T.* C1 - 73519 C2 - 57083 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - KAT6B overexpression rescues embryonic lethality in homozygous null KAT6A mice restoring vitality and normal lifespan. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Folding of the mammalian cerebral cortex into sulcal fissures and gyral peaks is the result of complex processes that are incompletely understood. Previously we showed that genetic deletion of Flrt1/3 adhesion molecules causes folding of the smooth mouse cortex into sulci resulting from increased lateral dispersion and faster neuron migration, without progenitor expansion. Here, we show in mice that combining the Flrt1/3 double knockout with an additional genetic deletion that causes progenitor expansion, greatly enhances cortex folding. Expansion of intermediate progenitors by deletion of Cep83 leads to a relative increase in Flrt-mutant neurons resulting in enhanced formation of sulci. Expansion of apical progenitors by deletion of Fgf10 leads to a relative reduction in Flrt-mutant neurons resulting in enhanced formation of gyri. These results together with computational modeling identify key developmental mechanisms, such as adhesive properties, cell densities and migration of cortical neurons, that cooperate to promote cortical gyrification. AU - Chun, S.H.* AU - Yoon, D.E.* AU - Diaz Almeida, D.S.* AU - Todorov, M.I. AU - Straub, T.* AU - Ruff, T.* AU - Shao, W.* AU - Yang, J.* AU - Seyit-Bremer, G.* AU - Shen, Y.R.* AU - Ertürk, A. AU - Del Toro, D.* AU - Shi, S.* AU - Klein, R.* C1 - 75427 C2 - 58005 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Cortex folding by combined progenitor expansion and adhesion-controlled neuronal migration. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Cells utilize protein disaggregases to avoid abnormal protein aggregation that causes many diseases. Among these, caseinolytic peptidase B protein homolog (CLPB) is localized in the mitochondrial intermembrane space and linked to human disease. Upon CLPB loss, MICU1 and MICU2, regulators of the mitochondrial calcium uniporter complex (mtCU), and OPA1, a main mediator of mitochondrial fusion, become insoluble but the functional outcome remains unclear. In this work we demonstrate that CLPB is required to maintain mitochondrial calcium signalling and fusion dynamics. CLPB loss results in altered mtCU composition, interfering with mitochondrial calcium uptake independently of cytosolic calcium and mitochondrial membrane potential. Additionally, OPA1 decreases, and aggregation occurs, accompanied by mitochondrial fragmentation. Disease-associated mutations in the CLPB gene present in skin fibroblasts from patients also display mitochondrial calcium and structural changes. Thus, mtCU and fusion activity are dependent on CLPB, and their impairments might contribute to the disease caused by CLPB variants. AU - D'Angelo, D.* AU - Sánchez-Vázquez, V.H.* AU - Cartes-Saavedra, B.* AU - Vecellio Reane, D. AU - Cupo, R.R.* AU - Delgado De La Herran, H.C. AU - Ghirardo, G.* AU - Shorter, J.* AU - Wevers, R.A.* AU - Wortmann, S.B.* AU - Perocchi, F. AU - Rizzuto, R.* AU - Raffaello, A.* AU - Hajnóczky, G.* C1 - 73739 C2 - 57206 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Dependence of mitochondrial calcium signalling and dynamics on the disaggregase, CLPB. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - The voltage-dependent anion channel (VDAC) is the main gateway for metabolites across the mitochondrial outer membrane. VDAC oligomers are connected to apoptosis induced by various stimuli. However, the mechanistic and structural basis of apoptosis induction by VDAC remains poorly understood. Here, using cryo-EM and NMR we show that VDAC1 oligomerization or confinement in small lipid nanodiscs triggers the exposure of its N-terminal α-helix (VDAC1-N) which becomes available for partner protein binding. NMR and X-ray crystallography data show that VDAC1-N forms a complex with the BH3 binding groove of the anti-apoptotic Bcl2 protein BclxL. Biochemical assays demonstrate that VDAC1-N exhibits a pro-apoptotic function by promoting pore formation of the executor Bcl2 protein Bak via neutralization of BclxL. This mechanism is reminiscent of BH3-only sensitizer Bcl2 proteins that are efficient inducers of Bax/Bak-mediated mitochondrial outer membrane permeabilization and ultimately apoptosis. The VDAC pathway most likely responds to mitochondrial stress or damage. AU - Daniilidis, M.* AU - Günsel, U. AU - Broutzakis, G.* AU - Leitl, K.D.* AU - Janowski, R. AU - Fredriksen, K.* AU - Niessing, D. AU - Gatsogiannis, C.* AU - Hagn, F. C1 - 75880 C2 - 58173 TI - Structural basis of apoptosis induction by the mitochondrial voltage-dependent anion channel. JO - Nat. Commun. VL - 16 IS - 1 PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Diffusion-weighted MRI is critical for diagnosing and managing ischemic stroke, but variability in images and disease presentation limits the generalizability of AI algorithms. We present DeepISLES, a robust ensemble algorithm developed from top submissions to the 2022 Ischemic Stroke Lesion Segmentation challenge we organized. By combining the strengths of best-performing methods from leading research groups, DeepISLES achieves superior accuracy in detecting and segmenting ischemic lesions, generalizing well across diverse axes. Validation on a large external dataset (N = 1685) confirms its robustness, outperforming previous state-of-the-art models by 7.4% in Dice score and 12.6% in F1 score. It also excels at extracting clinical biomarkers and correlates strongly with clinical stroke scores, closely matching expert performance. Neuroradiologists prefer DeepISLES' segmentations over manual annotations in a Turing-like test. Our work demonstrates DeepISLES' clinical relevance and highlights the value of biomedical challenges in developing real-world, generalizable AI tools. DeepISLES is freely available at https://github.com/ezequieldlrosa/DeepIsles . AU - de la Rosa, E.* AU - Reyes, M.* AU - Liew, S.L.* AU - Hutton, A.* AU - Wiest, R.* AU - Kaesmacher, J.* AU - Hanning, U.* AU - Hakim, A.J.* AU - Zubal, R.* AU - Valenzuela, W.* AU - Robben, D.* AU - Sima, D.M.* AU - Anania, V.* AU - Brys, A.* AU - Meakin, J.A.* AU - Mickan, A.* AU - Broocks, G.* AU - Heitkamp, C.* AU - Gao, S.* AU - Liang, K.W.* AU - Zhang, Z.* AU - Rahman Siddiquee, M.M.* AU - Myronenko, A.* AU - Ashtari, P.* AU - Van Huffel, S.* AU - Jeong, H.* AU - Yoon, C.* AU - Kim, C.* AU - Huo, J.* AU - Ourselin, S.* AU - Sparks, R.* AU - Clèrigues, A.* AU - Oliver, A.J.* AU - Lladó, X.* AU - Chalcroft, L.* AU - Pappas, I.* AU - Bertels, J.* AU - Heylen, E.* AU - Moreau, J.* AU - Hatami, N.* AU - Frindel, C.* AU - Qayyum, A.* AU - Mazher, M.* AU - Puig, D.* AU - Lin, S.C.* AU - Juan, C.J.* AU - Hu, T.* AU - Boone, L.* AU - Goubran, M.* AU - Liu, Y.J.* AU - Wegener, S.* AU - Kofler, F. AU - Ezhov, I.* AU - Shit, S.* AU - Hernandez Petzsche, M.R.* AU - Müller, M.* AU - Menze, B.* AU - Kirschke, J.S.* AU - Wiestler, B.* C1 - 75330 C2 - 57943 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - DeepISLES: A clinically validated ischemic stroke segmentation model from the ISLES'22 challenge. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Self-organised three-dimensional (3D) cell cultures, collectively called 3D-oids, include spheroids, organoids and other co-culture models. Systematic evaluation of these models forms a critical new generation of high-content screening (HCS) systems for patient-specific drug analysis and cancer research. However, the standardisation of working with 3D-oids remains challenging and lacks convincing implementation. This study develops and tests HCS-3DX, a next-generation system for HCS analysis in 3D imaging and image evaluation. HCS-3DX is based on three main components: an automated Artificial Intelligence (AI)-driven micromanipulator for 3D-oid selection, an HCS foil multiwell plate for optimised imaging, and image-based AI software for single-cell data analysis. We validated HCS-3DX directly on 3D tumour models, including tumour-stroma co-cultures. Our data demonstrate that HCS-3DX achieves a resolution that overcomes the limitations of current systems and reliably and effectively performs 3D HCS at the single-cell level. Its application will enhance the accuracy and efficiency of drug screening processes, support personalised medicine approaches, and facilitate more detailed investigations into cellular behaviour within 3D structures. AU - Diosdi, A.* AU - Toth, T.* AU - Harmati, M.* AU - Istvan, G.* AU - Schrettner, B.* AU - Hapek, N.* AU - Kovács, F.* AU - Kriston, A.* AU - Buzas, K.* AU - Pampaloni, F.* AU - Piccinini, F.* AU - Horvath, P. C1 - 75737 C2 - 57979 CY - Heidelberger Platz 3, Berlin, 14197, Germany SP - 16 TI - HCS-3DX, a next-generation AI-driven automated 3D-oid high-content screening system. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Human plasma is routinely collected during clinical care and constitutes a rich source of biomarkers for diagnostics and patient stratification. Liquid chromatography-mass spectrometry (LC-MS)-based proteomics is a key method for plasma biomarker discovery, but the high dynamic range of plasma proteins poses significant challenges for MS analysis and data processing. To benchmark the quantitative performance of neat plasma analysis, we introduce a multispecies sample set based on a human tryptic plasma digest containing varying low level spike-ins of yeast and E. coli tryptic proteome digests, termed PYE. By analysing the sample set on state-of-the-art LC-MS platforms across twelve different sites in data-dependent (DDA) and data-independent acquisition (DIA) modes, we provide a data resource comprising a total of 1116 individual LC-MS runs. Centralized data analysis shows that DIA methods outperform DDA-based approaches regarding identifications, data completeness, accuracy, and precision. DIA achieves excellent technical reproducibility, as demonstrated by coefficients of variation (CVs) between 3.3% and 9.8% at protein level. Comparative analysis of different setups clearly shows a high overlap in identified proteins and proves that accurate and precise quantitative measurements are feasible across multiple sites, even in a complex matrix such as plasma, using state-of-the-art instrumentation. The collected dataset, including the PYE sample set and strategy presented, serves as a valuable resource for optimizing the accuracy and reproducibility of LC-MS and bioinformatic workflows for clinical plasma proteome analysis. AU - Distler, U.* AU - Yoo, H.B.* AU - Kardell, O. AU - Hein, D.* AU - Sielaff, M.* AU - Scherer, M.* AU - Jozefowicz, A.M.* AU - Leps, C.* AU - Gomez-Zepeda, D.* AU - von Toerne, C. AU - Merl-Pham, J. AU - Barth, T.K.* AU - Tüshaus, J.* AU - Giesbertz, P.* AU - Müller, T.* AU - Kliewer, G.* AU - Aljakouch, K.* AU - Helm, B.* AU - Unger, H.* AU - Frey, D.L.* AU - Helm, D.* AU - Schwarzmüller, L.E.* AU - Popp, O.* AU - Qin, D.* AU - Wudy, S.I.* AU - Sinn, L.R.* AU - Mergner, J.* AU - Ludwig, C.* AU - Imhof, A.* AU - Kuster, B.* AU - Lichtenthaler, S.F.* AU - Krijgsveld, J.* AU - Klingmüller, U.* AU - Mertins, P.* AU - Coscia, F.* AU - Ralser, M.* AU - Mülleder, M.* AU - Hauck, S.M. AU - Tenzer, S.* C1 - 75701 C2 - 58093 CY - Heidelberger Platz 3, Berlin, 14197, Germany SP - 18 TI - Multicenter evaluation of label-free quantification in human plasma on a high dynamic range benchmark set. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - The DNA-dependent protease SPRTN maintains genome stability by degrading toxic DNA-protein crosslinks (DPCs). To understand how SPRTN's promiscuous protease activity is confined to cleavage of crosslinked proteins, we reconstitute the repair of DPCs including their modification with SUMO and ubiquitin chains in vitro. We discover that DPC ubiquitylation strongly activates SPRTN independently of SPRTN's known ubiquitin-binding domains. Using protein structure prediction, MD simulations and NMR spectroscopy we reveal that ubiquitin binds to SPRTN's protease domain, promoting an open, active conformation. Replacing key interfacial residues prevents allosteric activation of SPRTN by ubiquitin, leading to genomic instability and cell cycle defects in cells expressing truncated SPRTN variants that cause premature aging and liver cancer in Ruijs-Aalfs syndrome patients. Collectively, our results reveal a ubiquitin-dependent regulatory mechanism that ensures SPRTN activity is deployed precisely when and where it is needed. AU - Dürauer, S.* AU - Kang, H.-S. AU - Wiebeler, C.* AU - Machida, Y.* AU - Schnapka, D.S.* AU - Yaneva, D.* AU - Renz, C.* AU - Götz, M.J.* AU - Weickert, P.* AU - Major, A.C.* AU - Rahmanto, A.S.* AU - Gutenthaler-Tietze, S.M.* AU - Daumann, L.J.* AU - Beli, P.* AU - Ulrich, H.D.* AU - Sattler, M. AU - Machida, Y.J.* AU - Schwierz, N.* AU - Stingele, J.* C1 - 75198 C2 - 57844 TI - Allosteric activation of the SPRTN protease by ubiquitin maintains genome stability. JO - Nat. Commun. VL - 16 IS - 1 PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Atherosclerosis is the underlying cause of myocardial infarction and ischemic stroke. It is a lipid-triggered and cytokine/chemokine-driven arterial inflammatory condition. We identify D-dopachrome tautomerase/macrophage migration-inhibitory factor-2 (MIF-2), a paralog of the cytokine MIF, as an atypical chemokine promoting both atherosclerosis and hepatic lipid accumulation. In hyperlipidemic Apoe-/- mice, Mif-2-deficiency and pharmacological MIF-2-blockade protect against lesion formation and vascular inflammation in early and advanced atherogenesis. MIF-2 promotes leukocyte migration, endothelial arrest, and foam-cell formation, and we identify CXCR4 as a receptor for MIF-2. Mif-2-deficiency in Apoe-/- mice leads to decreased plasma lipid levels and suppressed hepatic lipid accumulation, characterized by reductions in lipogenesis-related pathways, tri-/diacylglycerides, and cholesterol-esters, as revealed by hepatic transcriptomics/lipidomics. Hepatocyte cultures and FLIM-FRET-microscopy suggest that MIF-2 activates SREBP-driven lipogenic genes, mechanistically involving MIF-2-inducible CD74/CXCR4 complexes and PI3K/AKT but not AMPK signaling. MIF-2 is upregulated in unstable carotid plaques from atherosclerotic patients and its plasma concentration correlates with disease severity in patients with coronary artery disease. These findings establish MIF-2 as an atypical chemokine linking vascular inflammation to metabolic dysfunction in atherosclerosis. AU - El Bounkari, O.* AU - Zan, C.* AU - Yang, B.* AU - Ebert, S.* AU - Wagner, J.* AU - Bugar, E.* AU - Krämer, N.* AU - Bourilhon, P.* AU - Kontos, C.* AU - Zarwel, M.* AU - Sinitski, D.* AU - Milic, J.* AU - Jansen, Y.* AU - Kempf, W.E.* AU - Sachs, N.* AU - Maegdefessel, L.* AU - Ji, H.* AU - Gokce, O.* AU - Riols, F. AU - Haid, M. AU - Gerra, S.* AU - Hoffmann, A.* AU - Brandhofer, M.* AU - Avdic, M.* AU - Bucala, R.* AU - Megens, R.T.A.* AU - Willemsen, N.* AU - Messerer, D.* AU - Schulz, C.* AU - Bartelt, A. AU - Harm, T.* AU - Rath, D.* AU - Döring, Y.* AU - Gawaz, M.* AU - Weber, C.* AU - Kapurniotu, A.* AU - Bernhagen, J.* C1 - 73630 C2 - 57142 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - An atypical atherogenic chemokine that promotes advanced atherosclerosis and hepatic lipogenesis. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Lung fibrosis development utilizes alveolar macrophages, with mechanisms that are incompletely understood. Here, we fate map connective tissue during mouse lung fibrosis and observe disassembly and transfer of connective tissue macromolecules from pleuro-alveolar junctions (PAJs) into deep lung tissue, to activate fibroblasts and fibrosis. Disassembly and transfer of PAJ macromolecules into deep lung tissue occurs by alveolar macrophages, activating cysteine-type proteolysis on pleural mesothelium. The PAJ niche and the disassembly cascade is active in patient lung biopsies, persists in chronic fibrosis models, and wanes down in acute fibrosis models. Pleural-specific viral therapeutic carrying the cysteine protease inhibitor Cystatin A shuts down PAJ disassembly, reverses fibrosis and regenerates chronic fibrotic lungs. Targeting PAJ disassembly by targeting the pleura may provide a unique therapeutic avenue to treat lung fibrotic diseases. AU - Fischer, A. AU - Han, W. AU - Hu, S. AU - Mück-Häusl, M. AU - Wannemacher, J. AU - Kadri, S. AU - Lin, Y. AU - Dai, R. AU - Christ, S. AU - Su, Y. AU - Dasgupta, B. AU - Sardogan, A. AU - Deisenhofer, C. AU - Dutta, S. AU - Kadri, A. AU - Güney, T.G. AU - Correa-Gallegos, D.* AU - Mayr, C.H. AU - Hatz, R.* AU - Stoleriu, M.G.* AU - Lindner, M.* AU - Hilgendorff, A. AU - Adler, H. AU - Machens, H.G.* AU - Schiller, H.B. AU - Hauck, S.M. AU - Rinkevich, Y.* C1 - 72931 C2 - 57038 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Targeting pleuro-alveolar junctions reverses lung fibrosis in mice. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Correction to: Nature Communicationshttps://doi.org/10.1038/s41467-024-55596-x, published online 02 January 2025 In this article the author’s name Martin Mück-Häusl was incorrectly written as Martin Mück Häusl. The original article has been corrected. AU - Fischer, A. AU - Han, W. AU - Hu, S. AU - Mück-Häusl, M. AU - Wannemacher, J. AU - Kadri, S. AU - Lin, Y. AU - Dai, R. AU - Christ, S. AU - Su, Y. AU - Dasgupta, B. AU - Sardogan, A. AU - Deisenhofer, C. AU - Dutta, S. AU - Kadri, A. AU - Güney, T.G. AU - Correa-Gallegos, D.* AU - Mayr, C.H. AU - Hatz, R.* AU - Stoleriu, M.G.* AU - Lindner, M.* AU - Hilgendorff, A. AU - Adler, H. AU - Machens, H.G.* AU - Schiller, H.B. AU - Hauck, S.M. AU - Rinkevich, Y.* C1 - 73484 C2 - 57072 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Author Correction: Targeting pleuro-alveolar junctions reverses lung fibrosis in mice. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Although genome-wide association studies have provided valuable insights into the genetic basis of complex traits and diseases, translating these findings to causal genes and their downstream mechanisms remains challenging. We performed trans expression quantitative trait locus (trans-eQTL) meta-analysis in 3734 lymphoblastoid cell line samples, identifying four robust loci that replicated in an independent multi-ethnic dataset of 682 individuals. The trans-eQTL signal at the ubiquitin specific peptidase 18 (USP18) locus colocalised with a GWAS signal for systemic lupus erythematosus (SLE). USP18 is a known negative regulator of interferon signalling and the SLE risk allele increased the expression of 50 interferon-inducible genes, suggesting that the risk allele impairs USP18's ability to effectively limit the interferon response. Intriguingly, the USP18 trans-eQTL signal would not have been discovered in a meta-analysis of up to 43,301 whole blood samples, reaffirming the importance of capturing context-specific genetic effects for GWAS interpretation. AU - Freimann, K.* AU - Brümmer, A.* AU - Warmerdam, R.* AU - Rupall, T.S.* AU - Hernández-Ledesma, A.L.* AU - Chiou, J.* AU - Holzinger, E.R.* AU - Maranville, J.C.* AU - Nakić, N.* AU - Ongen, H.* AU - Stefanucci, L.* AU - Turchin, M.C.* AU - Franke, L.* AU - Võsa, U.* AU - Jones, C.P.* AU - Medina-Rivera, A.* AU - Trynka, G.* AU - Kisand, K.* AU - Bergmann, S.* AU - PRECISESADS Clinical Consortium (Farzeen, A.) AU - PRECISESADS Clinical Consortium (Prokisch, H.) AU - PRECISESADS Clinical Consortium (Gieger, C.) AU - PRECISESADS Clinical Consortium (Peters, A.) AU - PRECISESADS Clinical Consortium (Stumvoll, M.) C1 - 75712 C2 - 57993 TI - Trans-eQTL mapping prioritises USP18 as a negative regulator of interferon response at a lupus risk locus. JO - Nat. Commun. VL - 16 IS - 1 PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Longitudinal multi-view omics data offer unique insights into the temporal dynamics of individual-level physiology, which provides opportunities to advance personalized healthcare. However, the common occurrence of incomplete views makes extrapolation tasks difficult, and there is a lack of tailored methods for this critical issue. Here, we introduce LEOPARD, an innovative approach specifically designed to complete missing views in multi-timepoint omics data. By disentangling longitudinal omics data into content and temporal representations, LEOPARD transfers the temporal knowledge to the omics-specific content, thereby completing missing views. The effectiveness of LEOPARD is validated on four real-world omics datasets constructed with data from the MGH COVID study and the KORA cohort, spanning periods from 3 days to 14 years. Compared to conventional imputation methods, such as missForest, PMM, GLMM, and cGAN, LEOPARD yields the most robust results across the benchmark datasets. LEOPARD-imputed data also achieve the highest agreement with observed data in our analyses for age-associated metabolites detection, estimated glomerular filtration rate-associated proteins identification, and chronic kidney disease prediction. Our work takes the first step toward a generalized treatment of missing views in longitudinal omics data, enabling comprehensive exploration of temporal dynamics and providing valuable insights into personalized healthcare. AU - Han, S. AU - Yu, S. AU - Shi, M. AU - Harada, M. AU - Ge, J. AU - Lin, J. AU - Prehn, C. AU - Petrera, A. AU - Li, Y.* AU - Sam, F.* AU - Matullo, G.* AU - Adamski, J. AU - Suhre, K.* AU - Gieger, C. AU - Hauck, S.M. AU - Herder, C.* AU - Roden, M.* AU - Casale, F.P. AU - Cai, N. AU - Peters, A. AU - Wang-Sattler, R. C1 - 73993 C2 - 57052 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - LEOPARD: Missing view completion for multi-timepoint omics data via representation disentanglement and temporal knowledge transfer. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Despite the frequent implication of aberrant gene expression in diseases, algorithms predicting aberrantly expressed genes of an individual are lacking. To address this need, we compile an aberrant expression prediction benchmark covering 8.2 million rare variants from 633 individuals across 49 tissues. While not geared toward aberrant expression, the deleteriousness score CADD and the loss-of-function predictor LOFTEE show mild predictive ability (1-1.6% average precision). Leveraging these and further variant annotations, we next train AbExp, a model that yields 12% average precision by combining in a tissue-specific fashion expression variability with variant effects on isoforms and on aberrant splicing. Integrating expression measurements from clinically accessible tissues leads to another two-fold improvement. Furthermore, we show on UK Biobank blood traits that performing rare variant association testing using the continuous and tissue-specific AbExp variant scores instead of LOFTEE variant burden increases gene discovery sensitivity and enables improved phenotype predictions. AU - Hölzlwimmer, F.R.* AU - Lindner, J.* AU - Tsitsiridis, G.* AU - Wagner, N.* AU - Casale, F.P. AU - Yépez, V.A.* AU - Gagneur, J. C1 - 73801 C2 - 57235 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Aberrant gene expression prediction across human tissues. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Internal organs are encased by a supportive epithelial monolayer of mesodermal origin, termed mesothelium. The nature, evolution and function of mesothelial cells, and their genetic regulation impacting disease development are insufficiently understood. Here, we generate a comprehensive organ-wide single-cell transcriptomic compendium of mesothelium across healthy and diseased mouse and human organs, delineating the evolution of conserved activated states of mesothelial cells in response to disease. We uncover genetic drives behind each cell state and reveal a conserved metabolic gate into multipotent proteolytic, inflammatory and fibrotic cell differentiation, in mouse and human. Using lung injury models in mice, in combination with mesothelial cell-specific viral approaches, we show that direct metabolic reprogramming using Ifi27l2a and Crip1 on organ surfaces, blocks multipotent differentiation and protects mouse lungs from fibrotic disease. These findings place mesothelial cells as cellular exemplars and gateway to fibrotic disease, opening translational approaches to subvert fibrosis across a range of clinical indications. AU - Kadri, S. AU - Fischer, A. AU - Mück-Häusl, M. AU - Han, W. AU - Kadri, A. AU - Lin, Y. AU - Yang, L. AU - Hu, S. AU - Ye, H. AU - Ramesh, P. AU - Ansari, M. AU - Schiller, H.B. AU - Machens, H.G.* AU - Rinkevich, Y.* C1 - 75576 C2 - 58044 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - A mesothelial differentiation gateway drives fibrosis. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Human cancer cell lines are the mainstay of cancer research. Recent reports showed that highly mutated adult carcinoma cell lines (mainly HeLa and MCF-7) present striking diversity across laboratories and that long-term continuous culturing results in genomic/transcriptomic heterogeneity with strong phenotypical implications. Here, we hypothesize that oligomutated pediatric sarcoma cell lines mainly driven by a fusion transcription factor, such as Ewing sarcoma (EwS), are genetically and phenotypically more stable than the previously investigated adult carcinoma cell lines. A comprehensive molecular and phenotypic characterization of multiple EwS cell line strains, together with a simultaneous analysis during 12 months of continuous cell culture show that fusion-driven pediatric sarcoma cell line strains are genomically more stable than adult carcinoma strains, display remarkably stable and homogenous transcriptomes, and exhibit uniform and stable drug response. Additionally, the analysis of multiple EwS cell lines subjected to long-term continuous culture reveals that variable degrees of genomic/transcriptomic/phenotypic changes among fusion-driven cell lines, further exemplifying that the potential for reproducibility of in vitro scientific results may be rather understood as a spectrum, even within the same tumor entity. AU - Kasan, M.* AU - Geyer, F.H.* AU - Siebenlist, J.* AU - Sill, M.* AU - Öllinger, R.* AU - Faehling, T.* AU - de Álava, E.* AU - Surdez, D.* AU - Dirksen, U.* AU - Oehme, I.* AU - Scotlandi, K.* AU - Delattre, O.* AU - Müller-Nurasyid, M. AU - Rad, R.* AU - Strauch, K. AU - Grünewald, T.G.P.* AU - Cidre-Aranaz, F.* C1 - 72944 C2 - 56876 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Genomic and phenotypic stability of fusion-driven pediatric sarcoma cell lines. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Anti-viral immunity can vary tremendously from individual to individual but mechanistic understanding is still scarce. Here, we show that a defined, low complex bacterial community (OMM12) but not the general absence of microbes in germ-free mice leads to a more potent immune response compared to the microbiome of specific-pathogen-free (SPF) mice after a systemic viral infection with LCMV Clone-13. Consequently, gnotobiotic mice colonized with OMM12 have more severe LCMV-induced disease pathology but also enhance viral clearance in the intestinal tract. Mechanistically, single-cell RNA sequencing analysis of adoptively transferred virus-specific T helper cells and endogenous T helper cells in the intestinal tract reveal a stronger pro-inflammatory Th1 profile and a more vigorous expansion in OMM12 than SPF mice. Altogether, our work highlights the causative function of the intestinal microbiome for shaping adaptive anti-viral immunity with implications for vaccination strategies and anti-cancer treatment regimens. AU - Kolland, D. AU - Kuhlmann, M.* AU - de Almeida, G.P.* AU - Köhler, A. AU - Arifovic, A. AU - von Strempel, A.* AU - Pourjam, M.* AU - Bolsega, S.* AU - Wurmser, C.* AU - Steiger, K.* AU - Basic, M.* AU - Neuhaus, K.* AU - Schmidt-Weber, C.B. AU - Stecher, B.* AU - Zehn, D.* AU - Ohnmacht, C. C1 - 74201 C2 - 57366 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - A specific microbial consortium enhances Th1 immunity, improves LCMV viral clearance but aggravates LCMV disease pathology in mice. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - The Rnf complex is the primary respiratory enzyme of several anaerobic prokaryotes that transfers electrons from ferredoxin to NAD+ and pumps ions (Na+ or H+) across a membrane, powering ATP synthesis. Rnf is widespread in primordial organisms and the evolutionary predecessor of the Na+-pumping NADH-quinone oxidoreductase (Nqr). By running in reverse, Rnf uses the electrochemical ion gradient to drive ferredoxin reduction with NADH, providing low potential electrons for nitrogenases and CO2 reductases. Yet, the molecular principles that couple the long-range electron transfer to Na+ translocation remain elusive. Here, we resolve key functional states along the electron transfer pathway in the Na+-pumping Rnf complex from Acetobacterium woodii using redox-controlled cryo-electron microscopy that, in combination with biochemical functional assays and atomistic molecular simulations, provide key insight into the redox-driven Na+ pumping mechanism. We show that the reduction of the unique membrane-embedded [2Fe2S] cluster electrostatically attracts Na+, and in turn, triggers an inward/outward transition with alternating membrane access driving the Na+ pump and the reduction of NAD+. Our study unveils an ancient mechanism for redox-driven ion pumping, and provides key understanding of the fundamental principles governing energy conversion in biological systems. AU - Kumar, A.* AU - Roth, J.* AU - Kim, H.* AU - Saura, P.* AU - Bohn, S. AU - Reif-Trauttmansdorff, T.* AU - Schubert, A.* AU - Kaila, V.R.I.* AU - Schuller, J.M.* AU - Müller, V.* C1 - 73629 C2 - 57237 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Molecular principles of redox-coupled sodium pumping of the ancient Rnf machinery. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Lilies are economically important monocots known for their ornamental flowers, bulbs, and large genomes. The absence of their genomic information has impeded evolutionary studies and genome-based breeding efforts. Here, we present reference genomes for Lilium sargentiae (lily, 35.66 Gb) and Gloriosa superba (flame lily, 5.09 Gb). The giant lily genome is shaped by recent long terminal repeat retroelements. Phylogenetic analysis reveals diverse, independent origins of lily cultivars. Gene families involved in sucrose and starch metabolism are significantly expanded in the lily genome. Key homologs of XTH22, SOC1, and AP1/FUL-like genes regulate the development, bud growth transition, and floral bud growth transition of lily bulbs. Colchicine biosynthetic gene clusters are identified in G. superba but are absent in L. sargentiae, highlighting independent colchicine evolution in Colchicaceae. These genomic insights enhance understanding of Liliales evolution, providing a foundation for future breeding and molecular research. AU - Liang, Y.* AU - Gao, Q.* AU - Li, F.* AU - Du, Y.* AU - Wu, J.* AU - Pan, W.* AU - Wang, S.* AU - Zhang, X.* AU - Zhang, M.* AU - Song, X.* AU - Zhong, L.* AU - Zhang, F.* AU - Li, Y.* AU - Wang, Z.* AU - Li, D.* AU - Duan, Q.* AU - Li, S.* AU - Jin, C.* AU - Zhang, P.* AU - Gu, Y.* AU - Chen, Z.H.* AU - Mayer, K.F.X. AU - Zhou, X.* AU - Wang, J.* AU - Zhang, L.* C1 - 72932 C2 - 56875 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - The giant genome of lily provides insights into the hybridization of cultivated lilies. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Heatwaves are commonly simplified as binary variables in epidemiological studies, limiting the understanding of heatwave-mortality associations. Here we conduct a multi-country study across 28 East Asian cities that employed the Cumulative Excess Heatwave Index (CEHWI), which represents excess heat accumulation during heatwaves, to explore the potentially nonlinear associations of daytime-only, nighttime-only, and day-night compound heatwaves with mortality from 1981 to 2010. Populations exhibited high adaptability to daytime-only and nighttime-only heatwaves, with non-accidental mortality risks increasing only at higher CEHWI levels (75th-90th percentiles). In contrast, compound heatwaves posed a super-linear increase in mortality risks after the 25th percentile of CEHWI. Associations of heatwaves with cardiovascular mortality mirrored those with non-accidental mortality but were more pronounced at higher CEHWI levels, while significant associations with respiratory mortality emerged at low-to-moderate CEHWI levels. These results highlight the necessity of considering the nonlinear health responses to heatwaves of different types in disease burden assessments and heatwave-health warning systems amid climate change. AU - Liu, J.* AU - Kim, H.* AU - Hashizume, M.* AU - Lee, W.* AU - Honda, Y.* AU - Kim, S.E.* AU - He, C. AU - Kan, H.* AU - Chen, R.* C1 - 73033 C2 - 56903 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Nonlinear exposure-response associations of daytime, nighttime, and day-night compound heatwaves with mortality amid climate change. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Circadian disruption enhances cancer risk, and many tumors exhibit disordered circadian gene expression. We show rhythmic gene expression is unexpectedly robust in clear cell renal cell carcinoma (ccRCC). The core circadian transcription factor BMAL1 is closely related to ARNT, and we show that BMAL1-HIF2α regulates a subset of HIF2α target genes in ccRCC cells. Depletion of BMAL1 selectively reduces HIF2α chromatin association and target gene expression and reduces ccRCC growth in culture and in xenografts. Analysis of pre-existing data reveals higher BMAL1 in patient-derived xenografts that are sensitive to growth suppression by a HIF2α antagonist (PT2399). BMAL1-HIF2α is more sensitive than ARNT-HIF2α is to suppression by PT2399, and the effectiveness of PT2399 for suppressing xenograft tumor growth in vivo depends on the time of day at which it is delivered. Together, these findings indicate that an alternate HIF2α heterodimer containing the circadian partner BMAL1 influences HIF2α activity, growth, and sensitivity to HIF2α antagonist drugs in ccRCC cells. AU - Mello, R.M.* AU - Gomez Ceballos, D.* AU - Sandate, C.R.* AU - Wang, S.* AU - Jouffe, C. AU - Agudelo, D. AU - Uhlenhaut, N.H. AU - Thomä, N.H.* AU - Simon, M.C.* AU - Lamia, K.A.* C1 - 75056 C2 - 57734 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - BMAL1 and ARNT enable circadian HIF2α responses in clear cell renal cell carcinoma. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Metabolic flexibility in skeletal muscle is essential for maintaining healthy glucose and lipid metabolism, and its dysfunction is closely linked to metabolic diseases. Exercise enhances metabolic flexibility, making it an important tool for discovering mechanisms that promote metabolic health. Here we show that pantothenate kinase 4 (PanK4) is a new conserved exercise target with high abundance in muscle. Muscle-specific deletion of PanK4 impairs fatty acid oxidation which is related to higher intramuscular acetyl-CoA and malonyl-CoA levels. Elevated acetyl-CoA levels persist regardless of feeding state and are associated with whole-body glucose intolerance, reduced insulin-stimulated glucose uptake in glycolytic muscle, and impaired glucose uptake during exercise. Conversely, increasing PanK4 levels in glycolytic muscle lowers acetyl-CoA and enhances glucose uptake. Our findings highlight PanK4 as an important regulator of acetyl-CoA levels, playing a key role in both muscle lipid and glucose metabolism. AU - Miranda-Cervantes, A.* AU - Fritzen, A.M.* AU - Raun, S.H.* AU - Hodek, O.* AU - Møller, L.L.V.* AU - Johann, K.* AU - Deisen, L.* AU - Gregorevic, P.* AU - Gudiksen, A.* AU - Artati, A. AU - Adamski, J. AU - Andersen, N.R.* AU - Sigvardsen, C.M.* AU - Carl, C.S.* AU - Voldstedlund, C.T.* AU - Kjøbsted, R.* AU - Hauck, S.M. AU - Schjerling, P.* AU - Jensen, T.E.* AU - Cebrian Serrano, A. AU - Jähnert, M.* AU - Gottmann, P.* AU - Burtscher, I. AU - Lickert, H. AU - Pilegaard, H.* AU - Schürmann, A.* AU - Tschöp, M.H. AU - Moritz, T.* AU - Müller, T.D. AU - Sylow, L.* AU - Kiens, B.* AU - Richter, E.A.* AU - Kleinert, M. C1 - 72933 C2 - 56853 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Pantothenate kinase 4 controls skeletal muscle substrate metabolism. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Understanding the dynamics of marine dissolved organic carbon (DOC) is essential for predicting its role in carbon cycling and its response to climate change. Here, we unveil molecular transformations of marine chromophoric dissolved organic matter (CDOM) across the global ocean using Ultraviolet-visible spectroscopy. Significant variability in CDOM composition within the epi- and mesopelagic layers ( < 1000 m) correlates with physicochemical parameters, driven by irradiation, primary production, biological activity, transport, and riverine inputs. In the bathypelagic layer (1000-5000 m), up to 18.2% of highly conjugated molecules transform into low-molecular-weight CDOM, despite stable DOC concentrations. This dynamic process sustains biomass production and respiration in deep ocean, contributing a carbon flux of 3-24 Pg C yr-1-up to an order of magnitude more than the fast-sinking particulate organic carbon flux. Our findings offer insights into the molecular transformation of deep-ocean DOM and underscore the need to reassess the bathypelagic DOC pool's role in the global carbon cycle. AU - Mo, S.* AU - Liu, Z.* AU - Hao, Y.* AU - Hertkorn, N. AU - Wang, H.* AU - Zhang, C.* AU - Korshin, G.* AU - Ni, J.* AU - Yan, M.* C1 - 74866 C2 - 57643 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Unveiling ongoing biogeochemical dynamics of CDOM from surface to deep ocean. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - The rise in antimicrobial resistance poses a worldwide threat, reducing the efficacy of common antibiotics. Determining the antimicrobial activity of new chemical compounds through experimental methods remains time-consuming and costly. While compound-centric deep learning models promise to accelerate this search and prioritization process, current strategies require large amounts of custom training data. Here, we introduce a lightweight computational strategy for antimicrobial discovery that builds on MolE (Molecular representation through redundancy reduced Embedding), a self-supervised deep learning framework that leverages unlabeled chemical structures to learn task-independent molecular representations. By combining MolE representation learning with available, experimentally validated compound-bacteria activity data, we design a general predictive model that enables assessing compounds with respect to their antimicrobial potential. Our model correctly identifies recent growth-inhibitory compounds that are structurally distinct from current antibiotics. Using this approach, we discover de novo, and experimentally confirm, three human-targeted drugs as growth inhibitors of Staphylococcus aureus. This framework offers a viable, cost-effective strategy to accelerate antibiotic discovery. AU - Olayo-Alarcon, R. AU - Amstalden, M.K.* AU - Zannoni, A.* AU - Bajramovic, M. AU - Sharma, C.M.* AU - Brochado, A.R.* AU - Rezaei, M.* AU - Müller, C.L. C1 - 74058 C2 - 57318 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Pre-trained molecular representations enable antimicrobial discovery. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Advancements in high-throughput screenings enable the exploration of rich phenotypic readouts through high-content microscopy, expediting the development of phenotype-based drug discovery. However, analyzing large and complex high-content imaging screenings remains challenging due to incomplete sampling of perturbations and the presence of technical variations between experiments. To tackle these shortcomings, we present IMage Perturbation Autoencoder (IMPA), a generative style-transfer model predicting morphological changes of perturbations across genetic and chemical interventions. We show that IMPA accurately captures morphological and population-level changes of both seen and unseen perturbations on breast cancer and osteosarcoma cells. Additionally, IMPA accounts for batch effects and can model perturbations across various sources of technical variation, further enhancing its robustness in diverse experimental conditions. With the increasing availability of large-scale high-content imaging screens generated by academic and industrial consortia, we envision that IMPA will facilitate the analysis of microscopy data and enable efficient experimental design via in-silico perturbation prediction. AU - Palma, A. AU - Theis, F.J. AU - Lotfollahi, M. C1 - 72992 C2 - 56880 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Predicting cell morphological responses to perturbations using generative modeling. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Prions are infectious agents that initiate transmissible spongiform encephalopathies, causing devastating neuronal destruction in Creutzfeldt-Jakob and Kuru disease. Rapid cell death depends on presence of the endogenous prion protein PrPC, but its mechanistic contribution to pathogenesis is unclear. Here we investigate the molecular role of PrPC, reactive oxygen species and lipid metabolism in ferroptosis susceptibility, a regulated cell death process characterized by lipid peroxidation. We discover that elevated expression of the cellular prion PrPC creates a relaxed oxidative milieu that favors accumulation of unsaturated long-chain phospholipids responsible for ferroptotic death. This condition is sustained by the luminal protein glutathione peroxidase 8, which detoxifies reactive species produced by protein misfolding. Consequently, both PrPC and infectious Creutzfeldt-Jakob disease (CJD) prions trigger ferroptotic markers and sensitization. This lethality is further enhanced by RAC3, a small GTPase. Depletion of RAC3 is observed solely in pathologically afflicted cortices in CJD patients, revealing a synergistic modulation of lipids and reactive species that drives ferroptosis susceptibility. Together, the results show that PrPC initially suppresses oxidative stress, attenuates cellular defenses, and establishes a systemic vulnerability to the ferroptotic cascade. These results provide insight into the mechanism underlying regulation of ferroptosis in prion diseases and highlight potential therapeutic targets for diseases involving dysregulated cell death processes. AU - Peng, H. AU - Pfeiffer, S. AU - Varynskyi, B. AU - Qiu, M. AU - Srinark, C. AU - Jin, X.* AU - Zhang, X. AU - Williams, K.* AU - Groveman, B.R.* AU - Foliaki, S.T.* AU - Race, B.* AU - Thomas, T.* AU - Chen, C.* AU - Müller, C. AU - Kovács, K.J.* AU - Arzberger, T.* AU - Momma, S.* AU - Haigh, C.L.* AU - Schick, J.A. C1 - 75030 C2 - 57705 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Prion-induced ferroptosis is facilitated by RAC3. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Protection against pathogens is a major function of the gut microbiota. Although bacterial natural products have emerged as crucial components of host-microbiota interactions, their exact role in microbiota-mediated protection is largely unexplored. We addressed this knowledge gap with the nematode Caenorhabditis elegans and its microbiota isolate Pseudomonas fluorescens MYb115 that is known to protect against Bacillus thuringiensis (Bt) infection. We find that MYb115-mediated protection depends on sphingolipids (SLs) that are derived from an iterative type I polyketide synthase (PKS) cluster PfSgaAB, thereby revealing a non-canonical pathway for the production of bacterial SLs as secondary metabolites. SL production is common in eukaryotes but was thought to be limited to a few bacterial phyla that encode the serine palmitoyltransferase (SPT) enzyme, which catalyses the initial step in SL synthesis. We demonstrate that PfSgaB encodes a pyridoxal 5'-phosphate-dependent alpha-oxoamine synthase with SPT activity, and find homologous putative PKS clusters present across host-associated bacteria that are so far unknown SL producers. Moreover, we provide evidence that MYb115-derived SLs affect C. elegans defence against Bt infection by altering SL metabolism in the nematode host. This work establishes SLs as structural outputs of bacterial PKS and highlights the role of microbiota-derived SLs in host protection against pathogens. AU - Peters, L.* AU - Drechsler, M.* AU - Herrera, M.A.* AU - Liu, J.* AU - Pees, B.* AU - Jarstorff, J.* AU - Czerwinski, A.* AU - Lubbock, F.* AU - Angelidou, G.* AU - Salzer, L. AU - Moors, K.A.* AU - Paczia, N.* AU - Shi, Y.M.* AU - Schulenburg, H.* AU - Kaleta, C.* AU - Witting, M. AU - Liebeke, M.* AU - Campopiano, D.J.* AU - Bode, H.B.* AU - Dierking, K.* C1 - 74859 C2 - 57637 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Polyketide synthase-derived sphingolipids mediate microbiota protection against a bacterial pathogen in C. elegans. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Copper (Cu) is a vitally important micronutrient, whose balance between essential and toxic levels requires a tightly regulated network of proteins. Dysfunction in key components of this network leads to the disruption of Cu homeostasis, resulting in fatal disorders such as Wilson disease, which is caused by mutations in the hepatic Cu efflux transporter ATP7B. Unfortunately, the molecular targets for normalizing Cu homeostasis in Wilson disease remain poorly understood. Here, using genome-wide screening, we identified the cellular prion protein (PrP) as an important mediator of Cu toxicity in WD. Loss of ATP7B stimulates hepatic expression of PrP, which promotes endocytic Cu uptake, leading to toxic Cu overload. Suppression of PrP significantly reduces Cu toxicity in cell and animal models of Wilson disease. These findings highlight the critical regulatory role of PrP in copper metabolism and open new avenues for exploring the therapeutic potential of PrP suppression in Wilson disease. AU - Petruzzelli, R.* AU - Catalano, F.* AU - Crispino, R.* AU - Polishchuk, E.V.* AU - Elia, M.* AU - Masone, A.* AU - Lavigna, G.* AU - Grasso, A.* AU - Battipaglia, M.* AU - Sepe, L.V.* AU - Akdogan, B. AU - Reinold, Q.* AU - Del Prete, E.* AU - Carrella, D.* AU - Torella, A.* AU - Nigro, V.* AU - Caruso, E.* AU - Innocenti, N.* AU - Biasini, E.* AU - Puchkova, L.V.* AU - Indrieri, A.* AU - Ilyechova, E.Y.* AU - Piccolo, P.* AU - Zischka, H. AU - Chiesa, R.* AU - Polishchuk, R.S.* C1 - 73328 C2 - 57011 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Prion protein promotes copper toxicity in Wilson disease. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AU - Ramani, A.* AU - Pasquini, G.* AU - Gerkau, N.J.* AU - Jadhav, V.* AU - Vinchure, O.S.* AU - Altinisik, N.* AU - Windoffer, H.* AU - Muller, S.* AU - Rothenaigner, I. AU - Lin, S. AU - Mariappan, A.* AU - Rathinam, D.* AU - Mirsaidi, A.* AU - Goureau, O.* AU - Ricci-Vitiani, L.* AU - D'Alessandris, Q.G.* AU - Wollnik, B.* AU - Muotri, A.* AU - Freifeld, L.* AU - Jurisch-Yaksi, N.* AU - Pallini, R.* AU - Rose, C.R.* AU - Busskamp, V.* AU - Gabriel, E.* AU - Hadian, K. AU - Gopalakrishnan, J.* C1 - 73300 C2 - 56990 TI - Author Correction: Reliability of high-quantity human brain organoids for modeling microcephaly, glioma invasion and drug screening. JO - Nat. Commun. VL - 16 IS - 1 PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Gene enhancers often form long-range contacts with promoters, but it remains unclear if the activity of enhancers and their chromosomal contacts are mediated by the same DNA sequences and recruited factors. Here, we study the effects of expression quantitative trait loci (eQTLs) on enhancer activity and promoter contacts in primary monocytes isolated from 34 male individuals. Using eQTL-Capture Hi-C and a Bayesian approach considering both intra- and inter-individual variation, we initially detect 19 eQTLs associated with enhancer-eGene promoter contacts, most of which also associate with enhancer accessibility and activity. Capitalising on these shared effects, we devise a multi-modality Bayesian strategy, identifying 629 "trimodal QTLs" jointly associated with enhancer accessibility, eGene promoter contact, and gene expression. Causal mediation analysis and CRISPR interference reveal causal relationships between these three modalities. Many detected QTLs overlap disease susceptibility loci and influence the predicted binding of myeloid transcription factors, including SPI1, GABPB and STAT3. Additionally, a variant associated with PCK2 promoter contact directly disrupts a CTCF binding motif and impacts promoter insulation from downstream enhancers. Jointly, our findings suggest an inherent genetic coupling of enhancer activity and connectivity in gene expression control relevant to human disease and highlight the regulatory role of genetically determined chromatin boundaries. AU - Ray-Jones, H.* AU - Sung, C.K.* AU - Chan, L.T.* AU - Haglund, A.* AU - Artemov, P.* AU - Della Rosa, M.* AU - Ruje, L.* AU - Burden, F.* AU - Kreuzhuber, R.* AU - Litovskikh, A. AU - Weyenbergh, E.* AU - Brusselaers, Z.* AU - Tan, V.X.H.* AU - Frontini, M.* AU - Wallace, C.* AU - Malysheva, V.* AU - Bottolo, L.* AU - Vigorito, E.* AU - Spivakov, M.* C1 - 73196 C2 - 56955 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Genetic coupling of enhancer activity and connectivity in gene expression control. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - While the effect of amplification-induced oncogene expression in cancer is known, the impact of copy-number gains on "bystander" genes is less understood. We create a comprehensive map of dosage compensation in cancer by integrating expression and copy number profiles from over 8000 tumors in The Cancer Genome Atlas and cell lines from the Cancer Cell Line Encyclopedia. Additionally, we analyze 17 cancer open reading frame screens to identify genes toxic to cancer cells when overexpressed. Combining these approaches, we propose a class of 'Amplification-Related Gain Of Sensitivity' (ARGOS) genes located in commonly amplified regions, yet expressed at lower levels than expected by their copy number, and toxic when overexpressed. We validate RBM14 as an ARGOS gene in lung and breast cancer cells, and suggest a toxicity mechanism involving altered DNA damage response and STING signaling. We additionally observe increased patient survival in a radiation-treated cancer cohort with RBM14 amplification. AU - Rendo, V.* AU - Schubert, M. AU - Khuu, N.* AU - Suarez Peredo Rodriguez, M.F.* AU - Whyte, D.* AU - Ling, X.* AU - van den Brink, A.* AU - Huang, K.* AU - Swift, M.* AU - He, Y.* AU - Zerbib, J.* AU - Smith, R.* AU - Raaijmakers, J.* AU - Bandopadhayay, P.* AU - Guenther, L.M.* AU - Hwang, J.H.* AU - Iniguez, A.* AU - Moody, S.* AU - Seo, J.H.* AU - Stover, E.H.* AU - Garraway, L.* AU - Hahn, W.C.* AU - Stegmaier, K.* AU - Medema, R.H.* AU - Chowdhury, D.* AU - Colomé-Tatché, M. AU - Ben-David, U.* AU - Beroukhim, R.* AU - Foijer, F.* C1 - 73195 C2 - 56954 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - A compendium of Amplification-Related Gain Of Sensitivity genes in human cancer. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - The development of granulomas with central necrosis harboring Mycobacterium tuberculosis (Mtb) is the hallmark of human tuberculosis (TB). New anti-TB therapies need to effectively penetrate the cellular and necrotic compartments of these lesions and reach sufficient concentrations to eliminate Mtb. BTZ-043 is a novel antibiotic showing good bactericidal activity in humans in a phase IIa trial. Here, we report on lesional BTZ-043 concentrations severalfold above the minimal-inhibitory-concentration and the substantial local efficacy of BTZ-043 in interleukin-13-overexpressing mice, which mimic human TB pathology of granuloma necrosis. High-resolution MALDI imaging further reveals that BTZ-043 diffuses and accumulates in the cellular compartment, and fully penetrates the necrotic center. This is the first study that visualizes an efficient penetration and accumulation of a clinical-stage TB drug in human-like centrally necrotizing granulomas and that also determines its lesional activity. Our results most likely predict a substantial bactericidal effect of BTZ-043 at these hard-to-reach sites in TB patients. AU - Römpp, A.* AU - Treu, A.* AU - Kokesch-Himmelreich, J.* AU - Marwitz, F.* AU - Dreisbach, J.* AU - Aboutara, N.* AU - Hillemann, D.* AU - Garrelts, M.* AU - Converse, P.J.* AU - Tyagi, S.* AU - Gerbach, S.* AU - Gyr, L.* AU - Lemm, A.K.* AU - Volz, J.* AU - Hölscher, A.* AU - Gröschel, L.* AU - Stemp, E.M.* AU - Heinrich, N.* AU - Kloss, F.* AU - Nuermberger, E.L.* AU - Schwudke, D.* AU - Hoelscher, M. AU - Hölscher, C.* AU - Walter, K.* C1 - 73132 C2 - 56923 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - The clinical-stage drug BTZ-043 accumulates in murine tuberculosis lesions and efficiently acts against Mycobacterium tuberculosis. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Mucociliary clearance is a vital defense mechanism of the human airways, protecting against harmful particles and infections. When this process fails, it contributes to respiratory diseases like chronic obstructive pulmonary disease (COPD) and asthma. While advances in single-cell transcriptomics have revealed the complexity of airway composition, much of what we know about how airway structure impacts clearance relies on animal studies. This limits our ability to create accurate human-based models of airway diseases. Here we show that the airways in female rats and in humans exhibit species-specific differences in the distribution of ciliated and secretory cells as well as in ciliary beat, resulting in significantly higher clearance effectiveness in humans. We further reveal that standard lab-grown cultures exhibit lower clearance effectiveness compared to human airways, and we identify the underlying structural differences. By combining diverse experiments and physics-based modeling, we establish universal benchmarks to assess human airway function, interpret preclinical models, and better understand disease-specific impairments in mucociliary clearance. AU - Roth, D. AU - Sahin, A.T. AU - Ling, F. AU - Tepho, N. AU - Senger, C.N.* AU - Quiroz, E.J.* AU - Calvert, B.A.* AU - van der Does, A.M.* AU - Güney, T.G. AU - Glasl, S. AU - van Schadewijk, A.* AU - von Schledorn, L.* AU - Olmer, R.* AU - Kanso, E.* AU - Nawroth, J. AU - Ryan, A.L.* C1 - 73666 C2 - 57024 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Structure and function relationships of mucociliary clearance in human and rat airways. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Long noncoding RNAs (lncRNA) are crucial yet underexplored regulators of human immunity. Here we develop GRADR, a method integrating gradient profiling with RNA-binding proteome analysis, to map the protein interactomes of all expressed RNAs in a single experiment to study mechanisms of lncRNA-mediated regulation of human primary macrophages. Applying GRADR alongside CRISPR-multiomics, we reveal a network of NFκB-dependent lncRNAs, including LINC01215, AC022816.1 and ROCKI, which modulate distinct aspects of macrophage immunity, particularly through interactions with mRNA-processing factors, such as hnRNP proteins. We further uncover the function of ROCKI in repressing the messenger of the anti-inflammatory GATA2 transcription factor, thus promoting macrophage activation. Lastly, all data are consolidated in the SMyLR web interface, a searchable reference catalog for exploring lncRNA functions and pathway-dependencies in immune cells. Our results thus not only highlight the important functions of lncRNAs in immune regulation, but also provide a rich resource for lncRNA studies. AU - Schmerer, N.* AU - Janga, H.* AU - Aillaud, M.* AU - Hoffmann, J.* AU - Aznaourova, M.* AU - Wende, S.* AU - Steding, H.* AU - Halder, L.D.* AU - Uhl, M.* AU - Boldt, F.* AU - Stiewe, T.* AU - Nist, A.* AU - Jerrentrup, L.* AU - Kirschbaum, A.* AU - Ruppert, C.* AU - Rossbach, O.* AU - Ntini, E.* AU - Marsico, A. AU - Valasarajan, C.* AU - Backofen, R.* AU - Linne, U.* AU - Pullamsetti, S.S.* AU - Schmeck, B.* AU - Schulte, L.N.* C1 - 74781 C2 - 57575 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - A searchable atlas of pathogen-sensitive lncRNA networks in human macrophages. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Copy number variations (CNVs), the gain or loss of genomic regions, are associated with disease, especially cancer. Single cell technologies offer new possibilities to capture within-sample heterogeneity of CNVs and identify subclones relevant for tumor progression and treatment outcome. Several computational tools have been developed to identify CNVs from scRNA-seq data. However, an independent benchmarking of them is lacking. Here, we evaluate six popular methods in their ability to correctly identify ground truth CNVs, euploid cells and subclonal structures in 21 scRNA-seq datasets. We discover dataset-specific factors influencing the performance, including dataset size, the number and type of CNVs in the sample and the choice of the reference dataset. Methods which include allelic information perform more robustly for large droplet-based datasets, but require higher runtime. Furthermore, the methods differ in their additional functionalities. We offer a benchmarking pipeline to identify the optimal method for new datasets, and improve methods' performance. AU - Schmid, K.T.* AU - Symeonidi, A. AU - Hlushchenko, D.* AU - Richter, M.L.* AU - Tijhuis, A.E.* AU - Foijer, F.* AU - Colomé-Tatché, M. C1 - 75702 C2 - 58094 CY - Heidelberger Platz 3, Berlin, 14197, Germany SP - 17 TI - Benchmarking scRNA-seq copy number variation callers. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - KRAS-dependent acinar-to-ductal metaplasia (ADM) is a fundamental step in the development of pancreatic ductal adenocarcinoma (PDAC), but the involvement of cell death pathways remains unclear. Here, we show that key regulators of programmed cell death (PCD) become upregulated during KRAS-driven ADM, thereby priming transdifferentiated cells to death. Using transgenic mice and primary cell and organoid cultures, we show that transforming growth factor (TGF)-β-activated kinase 1 (TAK1), a kinase regulating cell survival and inflammatory pathways, prevents the elimination of transdifferentiated cells through receptor-interacting protein kinase 1 (RIPK1)-mediated apoptosis and necroptosis, enabling PDAC development. Accordingly, pharmacological inhibition of TAK1 induces PCD in patient-derived PDAC organoids. Importantly, cell death induction via TAK1 inhibition does not appear to elicit an overt injury-associated inflammatory response. Collectively, these findings suggest that TAK1 supports cellular plasticity by suppressing spontaneous PCD activation during ADM, representing a promising pharmacological target for the prevention and treatment of PDAC. AU - Schneider, A.T.* AU - Koppe, C.* AU - Crouchet, E.* AU - Papargyriou, A. AU - Singer, M.T.* AU - Büttner, V.* AU - Keysberg, L.S.* AU - Szydlowska, M.* AU - Jühling, F.* AU - Moehlin, J.* AU - Chen, M.C.* AU - Leone, V. AU - Mueller, S.* AU - Neuß, T.* AU - Castoldi, M.* AU - Lesina, M.* AU - Bergmann, F.* AU - Hackert, T.* AU - Steiger, K.* AU - Knoefel, W.T.* AU - Zaufel, A.* AU - Kather, J.N.* AU - Esposito, I.* AU - Gaida, M.M.* AU - Ghallab, A.* AU - Hengstler, J.G.* AU - Einwächter, H.* AU - Unger, K. AU - Algül, H.* AU - Gassler, N.* AU - Schmid, R.M.* AU - Rad, R.* AU - Baumert, T.F.* AU - Reichert, M.* AU - Heikenwalder, M.* AU - Kondylis, V.* AU - Vucur, M.* AU - Luedde, T.* C1 - 73435 C2 - 57136 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - A decision point between transdifferentiation and programmed cell death priming controls KRAS-dependent pancreatic cancer development. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Correction to: Nature Communicationshttps://doi.org/10.1038/s41467-024-53374-3, published online 29 October 2024 In this article the authors name Alicja Rączkowska was incorrectly given as Alicja Ra̧czkowska. The original article has been corrected. AU - Shafighi, S.* AU - Geras, A.* AU - Jurzysta, B.* AU - Sahaf Naeini, A.* AU - Filipiuk, I.* AU - Rączkowska, A.* AU - Toosi, H.* AU - Koperski, L.* AU - Thrane, K.* AU - Engblom, C.* AU - Mold, J.E.* AU - Chen, X.* AU - Hartman, J.* AU - Nowis, D.* AU - Carbone, A.* AU - Lagergren, J.* AU - Szczurek, E. C1 - 73738 C2 - 57205 TI - Author Correction: Integrative spatial and genomic analysis of tumor heterogeneity with Tumoroscope. JO - Nat. Commun. VL - 16 IS - 1 PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Histopathology is the reference standard for diagnosing the presence and nature of many diseases, including cancer. However, analyzing tissue samples under a microscope and summarizing the findings in a comprehensive pathology report is time-consuming, labor-intensive, and non-standardized. To address this problem, we present HistoGPT, a vision language model that generates pathology reports from a patient's multiple full-resolution histology images. It is trained on 15,129 whole slide images from 6705 dermatology patients with corresponding pathology reports. The generated reports match the quality of human-written reports for common and homogeneous malignancies, as confirmed by natural language processing metrics and domain expert analysis. We evaluate HistoGPT in an international, multi-center clinical study and show that it can accurately predict tumor subtypes, tumor thickness, and tumor margins in a zero-shot fashion. Our model demonstrates the potential of artificial intelligence to assist pathologists in evaluating, reporting, and understanding routine dermatopathology cases. AU - Tran, M. AU - Schmidle, P.* AU - Guo, R.R.* AU - Wagner, S. AU - Koch, V. AU - Lupperger, V.* AU - Novotny, B.* AU - Murphree, D.H.* AU - Hardway, H.D.* AU - D'Amato, M.* AU - Lefkes, J.* AU - Geijs, D.J.* AU - Feuchtinger, A. AU - Böhner, A.* AU - Kaczmarczyk, R.* AU - Biedermann, T.* AU - Amir, A.L.* AU - Mooyaart, A.L.* AU - Ciompi, F.* AU - Litjens, G.* AU - Wang, C.* AU - Comfere, N.I.* AU - Eyerich, K.* AU - Braun, S.A.* AU - Marr, C. AU - Peng, T. C1 - 74807 C2 - 57590 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Generating dermatopathology reports from gigapixel whole slide images with HistoGPT. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Atherosclerosis, a major cause of cardiovascular diseases, is characterized by the buildup of lipids and chronic inflammation in the arteries, leading to plaque formation and potential rupture. Despite recent advances in single-cell transcriptomics (scRNA-seq), the underlying immune mechanisms and transformations in structural cells driving plaque progression remain incompletely defined. Existing datasets often lack comprehensive coverage and consistent annotations, limiting the utility of downstream analyses. Here, we present an integrated single-cell atlas of human atherosclerotic plaques, covering roughly 250k high-quality annotated cells. We achieve robust cell type annotations validated by expert consensus and surface protein measurements. Using this atlas, we introduce distinct markers for plaque neutrophils, identify a proangiogenic endothelial cell cluster enriched in advanced lesions, and specialized macrophage subsets. We also establish that fibromyocytes are exclusive to vascular tissue. This comprehensive atlas enables accurate automatic cell type annotation of new datasets, improves experimental design by guiding sample size and detection power, and supports the deconvolution of bulk RNA-seq data. An interactive WebUI makes these resources widely accessible. AU - Träuble, K. AU - Munz, M.* AU - Pauli, J.* AU - Sachs, N.* AU - Vafadarnejad, E.* AU - Carrillo-Roa, T.* AU - Maegdefessel, L.* AU - Kastner, P.* AU - Heinig, M. C1 - 75544 C2 - 58038 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Integrated single-cell atlas of human atherosclerotic plaques. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Type 1 diabetes is a chronic, autoimmune disease characterized by the destruction of insulin-producing β-cells in the pancreas. Early detection can facilitate timely intervention, potentially delaying or preventing disease onset. Circulating proteins reflect dysregulated biological processes and offer insights into early disease mechanisms. Here, we construct a genome-wide pQTL map of 1985 proteins in 695 newborn babies (median age 2 days) at increased genetic risk of developing Type 1 diabetes. We identify 535 pQTLs (352 cis-pQTLs, 183 trans-pQTLs), 62 of which characteristic of newborns. We show colocalization of pQTLs for CTRB1, APOBR, IL7R, CPA1, and PNLIPRP1 with Type 1 diabetes GWAS signals, and Mendelian randomization causally implicates each of these five proteins in the aetiology of Type 1 diabetes. Our study illustrates the utility of newborn molecular profiles for discovering potential drug targets for childhood diseases of significant concern. AU - Tutino, M. AU - Yu, N.Y.-L. AU - Hatzikotoulas, K. AU - Park, Y.-C. AU - Kreitmaier, P. AU - Katsoula, G. AU - Berner, R.* AU - Casteels, K.* AU - Elding Larsson, H.* AU - Kordonouri, O.* AU - Ołtarzewski, M.* AU - Szypowska, A.* AU - Ott, R. AU - Weiss, A. AU - Winkler, C. AU - Zapardiel-Gonzalo, J. AU - Petrera, A. AU - Hauck, S.M. AU - Bonifacio, E. AU - Ziegler, A.-G. AU - Zeggini, E. C1 - 74169 C2 - 57361 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Genetics of circulating proteins in newborn babies at high risk of type 1 diabetes. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AU - Van Coillie, S.* AU - Van San, E.* AU - Goetschalckx, I.* AU - Wiernicki, B.* AU - Mukhopadhyay, B.* AU - Tonnus, W.* AU - Choi, S.M.* AU - Roelandt, R.* AU - Dumitrascu, C.* AU - Lamberts, L.E.* AU - Dams, G.* AU - Weyts, W.* AU - Huysentruyt, J.* AU - Hassannia, B.* AU - Ingold, I. AU - Lele, S.* AU - Meyer, E.* AU - Berg, M.* AU - Seurinck, R.* AU - Saeys, Y.* AU - Vermeulen, A.* AU - van Nuijs, A.L.N.* AU - Conrad, M. AU - Linkermann, A.* AU - Rajapurkar, M.* AU - Vandenabeele, P.* AU - Hoste, E.* AU - Augustyns, K.* AU - Vanden Berghe, T.* C1 - 75596 C2 - 58049 TI - Author Correction: Targeting ferroptosis protects against experimental (multi)organ dysfunction and death. JO - Nat. Commun. VL - 16 IS - 1 PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Mendelian randomization (MR) identifies causal relationships from observational data but has increased Type 1 error rates (T1E) when genetic instruments are limited to a single associated region, a typical scenario for molecular exposures. We developed MR-link-2, which leverages summary statistics and linkage disequilibrium (LD) to estimate causal effects and pleiotropy in a single region. We compare MR-link-2 to other cis MR methods: i) In simulations, MR-link-2 has calibrated T1E and high power. ii) We reidentify metabolic reactions from three metabolic pathway references using four independent metabolite quantitative trait locus studies. MR-link-2 often (76%) outperforms other methods in area under the receiver operator characteristic curve (AUC) (up to 0.80). iii) For canonical causal relationships between complex traits, MR-link-2 has lower per-locus T1E (0.096 vs. min. 0.142, at 5% level), identifying all but one of the true causal links, reducing cross-locus causal effect heterogeneity to almost half. iv) Testing causal direction between blood cell compositions and marker gene expression shows MR-link-2 has superior AUC (0.82 vs. 0.68). Finally, analyzing causality between metabolites not directly connected by canonical reactions, only MR-link-2 identifies the causal relationship between pyruvate and citrate ( α ̂  = 0.11, P =  7.2⋅10-7), a key citric acid cycle reaction. Overall, MR-link-2 identifies pleiotropy-robust causality from summary statistics in single associated regions, making it well suited for applications to molecular phenotypes. AU - van der Graaf, A.* AU - Warmerdam, R.* AU - Auwerx, C.* AU - Võsa, U.* AU - Borges, M.C.* AU - Franke, L.* AU - eQTLGen Consortium (Farzeen, A. AU - Gieger, C. AU - Peters, A.) C1 - 75577 C2 - 57901 TI - MR-link-2: Pleiotropy robust cis Mendelian randomization validated in three independent reference datasets of causality. JO - Nat. Commun. VL - 16 IS - 1 PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Tools available for inferring enzyme function from general sequence, fold, or evolutionary information are generally successful. However, they can lead to misclassification if a deviation in local structural features influences the function. Here, we present TopEC, a 3D graph neural network based on a localized 3D descriptor to learn chemical reactions of enzymes from enzyme structures and predict Enzyme Commission (EC) classes. Using message-passing frameworks, we include distance and angle information to significantly improve the predictive performance for EC classification (F-score: 0.72) compared to regular 2D graph neural networks. We trained networks without fold bias that can classify enzyme structures for a vast functional space (>800 ECs). Our model is robust to uncertainties in binding site locations and similar functions in distinct binding sites. We observe that TopEC networks learn from an interplay between biochemical features and local shape-dependent features. TopEC is available as a repository on GitHub: https://github.com/IBG4-CBCLab/TopEC and https://doi.org/10.25838/d5p-66. AU - van der Weg, K.* AU - Merdivan, E. AU - Piraud, M. AU - Gohlke, H.* C1 - 73808 C2 - 57240 TI - TopEC: Prediction of Enzyme Commission classes by 3D graph neural networks and localized 3D protein descriptor. JO - Nat. Commun. VL - 16 IS - 1 PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Early life stress (ELS) can increase vulnerability to psychiatric disorders, but also trigger resilience. FKBP51 has been associated with an increased risk for developing psychiatric disorders, specifically in interaction with ELS exposure. Here, the contribution of FKBP51 in glutamatergic forebrain neurons to the long-term consequences of ELS was investigated in both sexes. In female wild-type Fkbp5lox/lox mice, ELS exposure led to an anxiolytic phenotype and improved memory performance in a stressful context, however this ELS effect was absent in Fkbp5Nex mice. These interactive FKBP51 x ELS effects in female mice were also reflected in reduced brain region volumes, and on structural and electrophysiological properties of CA1 pyramidal neurons of the dorsal hippocampus. In contrast, the behavioral, structural and functional effects in male ELS mice were less pronounced and independent of FKBP51. RNA sequencing of the hippocampus revealed the transcription factor 4 (TCF4) as a potential regulator of the female interactive effects. Cre-dependent viral overexpression of TCF4 in female Nex-Cre mice led to similar beneficial effects on behavior as the ELS exposure. This study demonstrates a sex-specific role for FKBP51 in mediating the adaptive effects of ELS on emotional regulation, cognition, and neuronal function, implicating TCF4 as a downstream effector. AU - van Doeselaar, L.* AU - Abromeit, A.* AU - Stark, T.* AU - Menegaz, D.* AU - Ballmann, M.* AU - Mitra, S.* AU - Yang, H.* AU - Rehawi, G.* AU - Huettl, R.E.* AU - Bordes, J.* AU - Narayan, S.* AU - Harbich, D.* AU - Deussing, J.M.* AU - Rammes, G.* AU - Czisch, M.* AU - Knauer-Arloth, J. AU - Eder, M.* AU - Lopez, J.P.* AU - Schmidt, M.V.* C1 - 73685 C2 - 57176 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - FKBP51 in glutamatergic forebrain neurons promotes early life stress inoculation in female mice. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal disease characterized by excessive extracellular matrix deposition. Current IPF therapies slow disease progression but do not stop or reverse it. The (myo)fibroblasts are thought to be the main cellular contributors to excessive extracellular matrix production in IPF. Here we show that fibrotic alveolar type II cells regulate production and crosslinking of extracellular matrix via the co-transcriptional activator YAP. YAP leads to increased expression of Lysl oxidase (LOX) and subsequent LOX-mediated crosslinking by fibrotic alveolar type II cells. Pharmacological YAP inhibition via verteporfin reverses fibrotic alveolar type II cell reprogramming and LOX expression in experimental lung fibrosis in vivo and in human fibrotic tissue ex vivo. We thus identify YAP-TEAD/LOX inhibition in alveolar type II cells as a promising potential therapy for IPF patients. AU - Wagner, D.E. AU - Alsafadi, H.N. AU - Mitash, N.* AU - Justet, A.* AU - Hu, Q.* AU - Pineda, R.* AU - Staab-Weijnitz, C.A. AU - Korfei, M.* AU - Gvazava, N.* AU - Wannemo, K.* AU - Onwuka, U.* AU - Mozurak, M.* AU - Estrada-Bernal, A.* AU - Cala-Garcia, J.* AU - Mutze, K. AU - Costa, R. AU - Bölükbas, D.A.* AU - Stegmayr, J.* AU - Skronska-Wasek, W. AU - Klee, S. AU - Ota, C. AU - Baarsma, H.A. AU - Wang, J.* AU - Sembrat, J.* AU - Hilgendorff, A. AU - Ding, J.* AU - Günther, A.* AU - Chambers, R.* AU - Rosas, I.* AU - de Langhe, S.* AU - Kaminski, N.* AU - Lehmann, M. AU - Eickelberg, O.* AU - Königshoff, M. C1 - 75294 C2 - 57925 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Inhibition of epithelial cell YAP-TEAD/LOX signaling attenuates pulmonary fibrosis in preclinical models. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - The biomechanical properties and responses of tissues underpin a variety important of physiological functions and pathologies. In striated muscle, the actin-binding protein filamin C (FLNC) is a key protein whose variants causative for a wide range of cardiomyopathies and musculoskeletal pathologies. FLNC is a multi-functional protein that interacts with a variety of partners, however, how it is regulated at the molecular level is not well understood. Here we investigate its interaction with HSPB7, a cardiac-specific molecular chaperone whose absence is embryonically lethal. We find that FLNC and HSPB7 interact in cardiac tissue under biomechanical stress, forming a strong hetero-dimer whose structure we solve by X-ray crystallography. Our quantitative analyses show that the hetero-dimer out-competes the FLNC homo-dimer interface, potentially acting to abrogate the ability of the protein to cross-link the actin cytoskeleton, and to enhance its diffusive mobility. We show that phosphorylation of FLNC at threonine 2677, located at the dimer interface and associated with cardiac stress, acts to favour the homo-dimer. Conversely, phosphorylation at tyrosine 2683, also at the dimer interface, has the opposite effect and shifts the equilibrium towards the hetero-dimer. Evolutionary analysis and ancestral sequence reconstruction reveals this interaction and its mechanisms of regulation to date around the time primitive hearts evolved in chordates. Our work therefore shows, structurally, how HSPB7 acts as a specific molecular chaperone that regulates FLNC dimerisation. AU - Wang, Z.* AU - Cao, G.* AU - Collier, M.P.* AU - Qiu, X.* AU - Broadway-Stringer, S.* AU - Šaman, D.* AU - Ng, J.Z.Y.* AU - Sen, N.* AU - Azad, A.J.* AU - Hooper, C.* AU - Zimmermann, J.* AU - McDonough, M.A.* AU - Brem, J.* AU - Rabe, P.* AU - Song, H.* AU - Alderson, T.R. AU - Schofield, C.J.* AU - Bolla, J.R.* AU - Djinovic-Carugo, K.* AU - Fürst, D.O.* AU - Warscheid, B.* AU - Degiacomi, M.T.* AU - Allison, T.M.* AU - Hochberg, G.K.A.* AU - Robinson, C.V.* AU - Gehmlich, K.* AU - Benesch, J.L.P.* C1 - 74299 C2 - 57423 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Filamin C dimerisation is regulated by HSPB7. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Wheat is the most widely cultivated crop in the world, with over 215 million hectares grown annually. The 10+ Wheat Genomes Project recently sequenced and assembled to chromosome-level the genomes of nine wheat cultivars, uncovering genetic diversity and selection within the pan-genome of wheat. Here, we provide a wheat pan-transcriptome with de novo annotation and differential expression analysis for these wheat cultivars across multiple tissues. Using the de novo annotations we identify cultivar-specific genes and define the core and dispensable genomes. Expression analysis across cultivars and tissues reveals conservation in expression between a large core set of homeologous genes, in addition to widespread changes in subgenome homeolog expression bias between cultivars and cultivar-specific expression profiles. We utilise both the newly constructed gene-based wheat pan-genome and pan-transcriptome, demonstrating variation in the prolamin superfamily and immune-reactive proteins across cultivars. AU - White, B.* AU - Lux, T. AU - Rusholme-Pilcher, R.* AU - Juhász, A.* AU - Kaithakottil, G.* AU - Duncan, S.R.* AU - Simmonds, J.* AU - Rees, H.* AU - Wright, J.* AU - Colmer, J.* AU - Ward, S.* AU - Joynson, R.* AU - Coombes, B.* AU - Irish, N.* AU - Henderson, S.* AU - Barker, T.* AU - Chapman, H.* AU - Catchpole, L.* AU - Gharbi, K.* AU - Bose, U.* AU - Okada, M.* AU - Handa, H.* AU - Nasuda, S.* AU - Shimizu, K.K.* AU - Gundlach, H. AU - Lang, D. AU - Naamati, G.* AU - Legg, E.J.* AU - Bharti, A.K.* AU - Colgrave, M.L.* AU - Haerty, W.* AU - Uauy, C.* AU - Swarbreck, D.* AU - Poland, J.A.* AU - Krattinger, S.G.* AU - Stein, N.* AU - Mayer, K.F.X. AU - Pozniak, C.* AU - Spannagl, M. AU - Hall, A.* C1 - 75722 C2 - 57982 TI - De novo annotation reveals transcriptomic complexity across the hexaploid wheat pan-genome. JO - Nat. Commun. VL - 16 IS - 1 PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Metabolic disorders, including obesity and metabolic-associated steatohepatitis, arise from a chronic energy surplus. Thus, enhancing energy dissipation through increased respiration holds significant therapeutic potential for metabolic disorders. Through a comprehensive analysis of human and murine adipose tissues, along with a functional screen, we identify mitochondrial carrier homolog 2, a mitochondrial outer membrane protein, as a pivotal regulator of mitochondrial metabolism. Intriguingly, its expression in adipose tissue is a strong determinant of obesity in humans. Adipocyte-specific ablation of mitochondrial carrier homolog 2 improves mitochondrial function and whole-body energy expenditure, independent of uncoupling protein 1. Furthermore, mitochondrial carrier homolog 2 regulates mitochondrial influx of free fatty acids by modulating the sensitivity of carnitine palmitoyltransferase 1 to malonyl-CoA through direct physical interaction, leading to enhanced energy expenditure in adipocytes/adipose tissue. Here we show mitochondrial carrier homolog 2 functions as a negative regulator of energy metabolism in adipocytes and represents a potential target for treating obesity and related metabolic disorders. AU - Wu, C.* AU - Wang, T.* AU - Ghosh, A.* AU - Long, F.* AU - Sharma, A.K.* AU - Dahlby, T.* AU - Noé, F.* AU - Severi, I.* AU - Colleluori, G.* AU - Cinti, S.* AU - Giordano, A.* AU - Ding, L.* AU - Khandelwal, R.* AU - Kostidis, S.* AU - Giera, M.* AU - Balázová, L.* AU - Gardeux, V.* AU - Abu-Nawwas, L.* AU - Deplancke, B.* AU - Chourasia, S.* AU - Kleiner, S.* AU - Hamilton, B.S.* AU - Alcántara, J.M.A.* AU - Ruiz, J.R.* AU - Blüher, M. AU - Pekcec, A.* AU - Balaz, M.* AU - Gross, A.* AU - Neubauer, H.* AU - Wolfrum, C.* C1 - 75708 C2 - 57994 CY - Heidelberger Platz 3, Berlin, 14197, Germany SP - 18 TI - MTCH2 modulates CPT1 activity to regulate lipid metabolism of adipocytes. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Human pancreas development remains incompletely characterized due to restricted sample access. We investigate whether pigs resemble humans in pancreas development, offering a complementary large-animal model. As pig pancreas organogenesis is unexplored, we first annotate developmental hallmarks throughout its 114-day gestation. Building on this, we construct a pig single-cell multiome pancreas atlas across all trimesters. Cross-species comparisons reveal pigs resemble humans more closely than mice in developmental tempo, epigenetic and transcriptional regulation, and gene regulatory networks. This further extends to progenitor dynamics and endocrine fate acquisition. Transcription factors regulated by NEUROG3, the endocrine master regulator, are over 50% conserved between pig and human, many being validated in human stem cell models. Notably, we uncover that during embryonic development, emerging beta-cell heterogeneity coincides with a species-conserved primed endocrine cell (PEC) population alongside NEUROG3-expressing cells. Overall, our work lays the foundation for comparative investigations and offers unprecedented insights into evolutionarily conserved pancreas organogenesis mechanisms across animal models. AU - Yang, K. AU - Spitzer, H. AU - Sterr, M. AU - Hrovatin, K. AU - de la O, S.* AU - Zhang, X.* AU - Setyono, E.S.A. AU - Ud-Dean, M. AU - Walzthoeni, T. AU - Flisikowski, K.* AU - Flisikowska, T.* AU - Schnieke, A.* AU - Scheibner, K. AU - Wells, J.M.* AU - Sneddon, J.B.* AU - Kessler, B.* AU - Wolf, E.* AU - Kemter, E.* AU - Theis, F.J. AU - Lickert, H. C1 - 75837 C2 - 58132 TI - A multimodal cross-species comparison of pancreas development. JO - Nat. Commun. VL - 16 IS - 1 PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Structural variations (SVs) are diverse forms of genetic alterations and drive a wide range of human diseases. Accurately genotyping SVs, particularly occurring at repetitive genomic regions, from short-read sequencing data remains challenging. Here, we introduce SVLearn, a machine-learning approach for genotyping bi-allelic SVs. It exploits a dual-reference strategy to engineer a curated set of genomic, alignment, and genotyping features based on a reference genome in concert with an allele-based alternative genome. Using 38,613 human-derived SVs, we show that SVLearn significantly outperforms four state-of-the-art tools, with precision improvements of up to 15.61% for insertions and 13.75% for deletions in repetitive regions. On two additional sets of 121,435 cattle SVs and 113,042 sheep SVs, SVLearn demonstrates a strong generalizability to cross-species genotype SVs with a weighted genotype concordance score of up to 90%. Notably, SVLearn enables accurate genotyping of SVs at low sequencing coverage, which is comparable to the accuracy at 30× coverage. Our studies suggest that SVLearn can accelerate the understanding of associations between the genome-scale, high-quality genotyped SVs and diseases across multiple species. AU - Yang, Q.* AU - Sun, J.* AU - Wang, X.* AU - Wang, J.* AU - Liu, Q.* AU - Ru, J. AU - Zhang, X.* AU - Wang, S.* AU - Hao, R.* AU - Bian, P.* AU - Dai, X.* AU - Gong, M.* AU - Zhang, Z.* AU - Wang, A.* AU - Bai, F.* AU - Li, R.* AU - Cai, Y.* AU - Jiang, Y.* C1 - 73665 C2 - 57161 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - SVLearn: A dual-reference machine learning approach enables accurate cross-species genotyping of structural variants. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Computational competitions are the standard for benchmarking medical image analysis algorithms, but they typically use small curated test datasets acquired at a few centers, leaving a gap to the reality of diverse multicentric patient data. To this end, the Federated Tumor Segmentation (FeTS) Challenge represents the paradigm for real-world algorithmic performance evaluation. The FeTS challenge is a competition to benchmark (i) federated learning aggregation algorithms and (ii) state-of-the-art segmentation algorithms, across multiple international sites. Weight aggregation and client selection techniques were compared using a multicentric brain tumor dataset in realistic federated learning simulations, yielding benefits for adaptive weight aggregation, and efficiency gains through client sampling. Quantitative performance evaluation of state-of-the-art segmentation algorithms on data distributed internationally across 32 institutions yielded good generalization on average, albeit the worst-case performance revealed data-specific modes of failure. Similar multi-site setups can help validate the real-world utility of healthcare AI algorithms in the future. AU - Zenk, M.* AU - Baid, U.* AU - Pati, S.G.* AU - Linardos, A.* AU - Edwards, B.* AU - Sheller, M.* AU - Foley, P.* AU - Aristizabal, A.* AU - Zimmerer, D.* AU - Gruzdev, A.* AU - Martin, J.* AU - Shinohara, R.T.* AU - Reinke, A.* AU - Isensee, F.* AU - Parampottupadam, S.* AU - Parekh, K.* AU - Floca, R.O.* AU - Kassem, H.* AU - Baheti, B.* AU - Thakur, S.* AU - Chung, V.* AU - Kushibar, K.* AU - Lekadir, K.* AU - Jiang, M.* AU - Yin, Y.* AU - Yang, H.* AU - Liu, Q.* AU - Chen, C.* AU - Dou, Q.* AU - Heng, P.A.* AU - Zhang, X.* AU - Zhang, S.* AU - Khan, M.I.* AU - Azeem, M.* AU - Jafaritadi, M.* AU - Alhoniemi, E.* AU - Kontio, E.* AU - Khan, S.A.* AU - Mächler, L.* AU - Ezhov, I.* AU - Kofler, F.* AU - Shit, S.* AU - Paetzold, J.C. AU - Loehr, T.* AU - Wiestler, B.* AU - Peiris, H.* AU - Pawar, K.* AU - Zhong, S.* AU - Chen, Z.* AU - Hayat, M.A.* AU - Egan, G.* AU - Harandi, M.* AU - Isik Polat, E.* AU - Polat, G.* AU - Kocyigit, A.* AU - Temizel, A.* AU - Tuladhar, A.* AU - Tyagi, L.* AU - Souza, R.* AU - Forkert, N.D.* AU - Mouches, P.* AU - Wilms, M.* AU - Shambhat, V.* AU - Maurya, A.* AU - Danannavar, S.S.* AU - Kalla, R.* AU - Anand, V.K.* AU - Krishnamurthi, G.* AU - Nalawade, S.* AU - Ganesh, C.* AU - Wagner, B.* AU - Reddy, D.* AU - Das, Y.* AU - Yu, F.F.* AU - Fei, B.* AU - Madhuranthakam, A.J.* AU - Maldjian, J.* AU - Singh, G.* AU - Ren, J.* AU - Zhang, W.* AU - An, N.* AU - Hu, Q.* AU - Zhang, Y.* AU - Zhou, Y.* AU - Siomos, V.* AU - Tarroni, G.* AU - Passerrat-Palmbach, J.* AU - Rawat, A.A.* AU - Zizzo, G.* AU - Kadhe, S.R.* AU - Epperlein, J.P.* AU - Braghin, S.* AU - Wang, Y.* AU - Kanagavelu, R.* AU - Wei, Q.* AU - Yang, Y.* AU - Liu, Y.* AU - Kotowski, K.* AU - Adamski, S.* AU - Machura, B.* AU - Malara, W.* AU - Zarudzki, L.* AU - Nalepa, J.* AU - Shi, Y.* AU - Gao, H.* AU - Avestimehr, S.* AU - Yan, Y.* AU - Akbar, A.S.* AU - Kondrateva, E.* AU - Li, Z.* AU - Wu, H.Y.* AU - Roth, J.* AU - Saueressig, C.* AU - Milesi, A.* AU - Nguyen, Q.D.* AU - Gruenhagen, N.J.* AU - Huang, T.M.* AU - Ma, J.* AU - Singh, H.S.H.* AU - Pan, N.Y.* AU - Zhang, D.* AU - Zeineldin, R.A.* AU - Futrega, M.* AU - Yuan, Y.* AU - Conte, G.M.* AU - Feng, X.* AU - Pham, Q.D.* AU - Xia, Y.* AU - Jiang, Z.* AU - Luu, H.M.* AU - Dobko, M.* AU - Carré, A.* AU - Tuchinov, B.* AU - Mohy-Ud-Din, H.* AU - Alam, S.* AU - Singh, A.* AU - Shah, N.* AU - Wang, W.* AU - Sako, C.* AU - Bilello, M.* AU - Ghodasara, S.* AU - Mohan, S.* AU - Davatzikos, C.* AU - Calabrese, E.* AU - Rudie, J.D.* AU - Villanueva-Meyer, J.* AU - Cha, S.-C.* AU - Hess, C.* AU - Mongan, J.* AU - Ingalhalikar, M.* AU - Jadhav, M.* AU - Pandey, U.* AU - Saini, J.* AU - Huang, R.Y.* AU - Chang, K.M.* AU - To, M.S.* AU - Bhardwaj, S.* AU - Chong, C.* AU - Agzarian, M.* AU - Kozubek, M.* AU - Lux, F.* AU - Michálek, J.* AU - Matula, P.* AU - Ker Kovský, M.* AU - Kopr Ivová, T.* AU - Dostal, M.* AU - Vybíhal, V.* AU - Pinho, M.C.* AU - Holcomb, J.* AU - Metz, M.* AU - Jain, R.* AU - Lee, M.D.* AU - Lui, Y.W.* AU - Tiwari, P.* AU - Verma, R.* AU - Bareja, R.* AU - Yadav, I.* AU - Chen, J.* AU - Kumar, N.* AU - Gusev, Y.* AU - Bhuvaneshwar, K.* AU - Sayah, A.* AU - Bencheqroun, C.* AU - Belouali, A.* AU - Madhavan, S.* AU - Colen, R.R.* AU - Kotrotsou, A.* AU - Vollmuth, P.* AU - Brugnara, G.* AU - Preetha, C.J.* AU - Sahm, F.* AU - Bendszus, M.* AU - Wick, W.* AU - Mahajan, A.* AU - Balaña, C.* AU - Capellades, J.* AU - Puig, J.* AU - Choi, Y.S.* AU - Lee, S.K.* AU - Chang, J.H.* AU - Ahn, S.S.* AU - Shaykh, H.F.* AU - Herrera-Trujillo, A.* AU - Trujillo, M.* AU - Escobar, W.* AU - Abello, A.* AU - Bernal, J.* AU - Gómez, J.* AU - LaMontagne, P.* AU - Marcus, D.S.* AU - Milchenko, M.* AU - Nazeri, A.* AU - Landman, B.* AU - Ramadass, K.* AU - Xu, K.* AU - Chotai, S.* AU - Chambless, L.B.* AU - Mistry, A.* AU - Thompson, R.C.* AU - Srinivasan, A.* AU - Bapuraj, J.R.* AU - Rao, A.* AU - Wang, N.* AU - Yoshiaki, O.* AU - Moritani, T.* AU - Türk, S.* AU - Lee, J.* AU - Prabhudesai, S.* AU - Garrett, J.M.* AU - Larson, M.G.* AU - Jeraj, R.* AU - Li, H.* AU - Weiss, T.* AU - Weller, M.* AU - Bink, A.* AU - Pouymayou, B.* AU - Sharma, S.* AU - Tseng, T.C.* AU - Adabi, S.* AU - Xavier Falcão, A.* AU - Martins, S.B.* AU - Teixeira, B.C.A.* AU - Sprenger, F.* AU - Menotti, D.* AU - Lucio, D.R.* AU - Niclou, S.P.* AU - Keunen, O.* AU - Hau, A.C.* AU - Pelaez, E.* AU - Franco-Maldonado, H.* AU - Loayza, F.* AU - Quevedo, S.* AU - McKinley, R.* AU - Slotboom, J.* AU - Radojewski, P.* AU - Meier, R.* AU - Wiest, R.* AU - Trenkler, J.* AU - Pichler, J.* AU - Necker, G.* AU - Haunschmidt, A.* AU - Meckel, S.* AU - Guevara, P.* AU - Torche, E.* AU - Mendoza, C.* AU - Vera, F.* AU - Ríos, E.* AU - Lopez, E.* AU - Velastin, S.A.* AU - Choi, J.* AU - Baek, S.* AU - Kim, Y.* AU - Ismael, H.* AU - Allen, B.* AU - Buatti, J.M.* AU - Zampakis, P.* AU - Panagiotopoulos, V.* AU - Tsiganos, P.* AU - Alexiou, S.* AU - Haliassos, I.* AU - Zacharaki, E.I.* AU - Moustakas, K.* AU - Kalogeropoulou, C.* AU - Kardamakis, D.M.* AU - Luo, B.* AU - Poisson, L.M.* AU - Wen, N.* AU - Vallières, M.* AU - Loutfi, M.A.L.* AU - Fortin, D.* AU - Lepage, M.* AU - Morón, F.* AU - Mandel, J.L.* AU - Shukla, G.* AU - Liem, S.* AU - Alexandre, G.S.* AU - Lombardo, J.* AU - Palmer, J.D.* AU - Flanders, A.E.* AU - Dicker, A.P.* AU - Ogbole, G.* AU - Oyekunle, D.* AU - Odafe-Oyibotha, O.* AU - Osobu, B.* AU - Shu'aibu Hikima, M.* AU - Soneye, M.* AU - Dako, F.* AU - Dorcas, A.* AU - Murcia, D.* AU - Fu, E.* AU - Haas, R.* AU - Thompson, J.A.* AU - Ormond, D.R.* AU - Currie, S.* AU - Fatania, K.* AU - Frood, R.* AU - Simpson, A.L.* AU - Peoples, J.J.* AU - Hu, R.* AU - Cutler, D.* AU - Moraes, F.Y.* AU - Tran, A.* AU - Hamghalam, M.* AU - Boss, M.A.* AU - Gimpel, J.* AU - Kattil Veettil, D.* AU - Schmidt, K.* AU - Cimino, L.* AU - Price, C.* AU - Bialecki, B.* AU - Marella, S.* AU - Apgar, C.* AU - Jakab, A.* AU - Weber, M.A.* AU - Colak, E.* AU - Kleesiek, J.* AU - Freymann, J.B.* AU - Kirby, J.S.* AU - Maier-Hein, L.* AU - Albrecht, J.* AU - Mattson, P.* AU - Karargyris, A.* AU - Shah, P.* AU - Menze, B.* AU - Maier-Hein, K.* AU - Bakas, S.* C1 - 75111 C2 - 57774 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Towards fair decentralized benchmarking of healthcare AI algorithms with the Federated Tumor Segmentation (FeTS) challenge. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Astrocytes are not a uniform population but exhibit diverse morphological, molecular, and functional characteristics. However, how this diversity originates and becomes establishes during development, remains largely unknown. Here, using single-cell RNA sequencing and spatial transcriptomics, we identify five astrocyte subtypes with unique molecular features, spatial distributions and functions in the mouse neocortex and characterize essential regulators for their formation. Using TrackerSeq to trace clonally related astrocytes, we identify two distinct lineages that give rise to these five subtypes. One lineage derives from Emx1+ radial glial cells that initially generate neurons and later switch to astrocyte production. The other, with minimal neuronal output, predominantly produces a distinct subset of astrocytes marked by Olig2. Olig2 knockout disrupts lineage specification, leading to changes at molecular, morphological and functional levels. These findings shed light on the cellular mechanisms underlying astrocyte diversity, highlighting the presence of multiple radial glial cell subtypes responsible for generating cortical astrocyte subtypes. AU - Zhou, J.* AU - Vitali, I.* AU - Roig-Puiggros, S.* AU - Javed, A.* AU - Cantando, I.* AU - Puglisi, M. AU - Bezzi, P.* AU - Jabaudon, D.* AU - Mayer, C.* AU - Bocchi, R.* C1 - 75276 C2 - 57889 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Dual lineage origins contribute to neocortical astrocyte diversity. JO - Nat. Commun. VL - 16 IS - 1 PB - Nature Portfolio PY - 2025 SN - 2041-1723 ER - TY - JOUR AB - Sustained Notch2 signals induce trans-differentiation of Follicular B (FoB) cells into Marginal Zone B (MZB) cells in mice, but the physiology underlying this differentiation pathway is still elusive. Here, we demonstrate that most B cells receive a basal Notch signal, which is intensified in pre-MZB and MZB cells. Ablation or constitutive activation of Notch2 upon T-cell-dependent immunization reveals an interplay between antigen-induced activation and Notch2 signaling, in which FoB cells that turn off Notch2 signaling enter germinal centers (GC), while high Notch2 signaling leads to generation of MZB cells or to initiation of plasmablast differentiation. Notch2 signaling is dispensable for GC dynamics but appears to be re-induced in some centrocytes to govern expansion of IgG1+ GCB cells. Mathematical modelling suggests that antigen-activated FoB cells make a Notch2 dependent binary fate-decision to differentiate into either GCB or MZB cells. This bifurcation might serve as a mechanism to archive antigen-specific clones into functionally and spatially diverse B cell states to generate robust antibody and memory responses. AU - Babushku, T. AU - Lechner, M. AU - Ehrenberg, S. AU - Rambold, U. AU - Schmidt-Supprian, M.* AU - Yates, A.J.* AU - Rane, S.* AU - Zimber-Strobl, U. AU - Strobl, L.J. C1 - 70085 C2 - 55412 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Notch2 controls developmental fate choices between germinal center and marginal zone B cells upon immunization. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Loss-of-function mutations in the homotrimeric serine protease HTRA1 cause cerebral vasculopathy. Here, we establish independent approaches to achieve the functional correction of trimer assembly defects. Focusing on the prototypical R274Q mutation, we identify an HTRA1 variant that promotes trimer formation thus restoring enzymatic activity in vitro. Genetic experiments in Htra1R274Q mice further demonstrate that expression of this protein-based corrector in trans is sufficient to stabilize HtrA1-R274Q and restore the proteomic signature of the brain vasculature. An alternative approach employs supramolecular chemical ligands that shift the monomer-trimer equilibrium towards proteolytically active trimers. Moreover, we identify a peptidic ligand that activates HTRA1 monomers. Our findings open perspectives for tailored protein repair strategies. AU - Beaufort, N.* AU - Ingendahl, L.* AU - Merdanovic, M.* AU - Schmidt, A.* AU - Podlesainski, D.* AU - Richter, T.* AU - Neumann, T.* AU - Kuszner, M.* AU - Vetter, I.R.* AU - Stege, P.* AU - Burston, S.G.* AU - Filipovic, A.* AU - Ruiz-Blanco, Y.B.* AU - Bravo-Rodriguez, K.* AU - Mieres-Perez, J.* AU - Beuck, C.* AU - Uebel, S.* AU - Zobawa, M.* AU - Schillinger, J.* AU - Malik, R.* AU - Todorov-Völgyi, K.* AU - Rey, J.* AU - Roberti, A.* AU - Hagemeier, B.* AU - Wefers, B. AU - Müller, S.A.* AU - Wurst, W. AU - Sanchez-Garcia, E.* AU - Zimmermann, A.* AU - Hu, X.Y.* AU - Clausen, T.* AU - Huber, R.* AU - Lichtenthaler, S.F.* AU - Schmuck, C.* AU - Giese, M.* AU - Kaiser, M.* AU - Ehrmann, M.* AU - Dichgans, M.* C1 - 71194 C2 - 55924 TI - Rational correction of pathogenic conformational defects in HTRA1. JO - Nat. Commun. VL - 15 IS - 1 PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - The oxidative potential (OP) of particulate matter (PM) is a major driver of PM-associated health effects. In India, the emission sources defining PM-OP, and their local/regional nature, are yet to be established. Here, to address this gap we determine the geographical origin, sources of PM, and its OP at five Indo-Gangetic Plain sites inside and outside Delhi. Our findings reveal that although uniformly high PM concentrations are recorded across the entire region, local emission sources and formation processes dominate PM pollution. Specifically, ammonium chloride, and organic aerosols (OA) from traffic exhaust, residential heating, and oxidation of unsaturated vapors from fossil fuels are the dominant PM sources inside Delhi. Ammonium sulfate and nitrate, and secondary OA from biomass burning vapors, are produced outside Delhi. Nevertheless, PM-OP is overwhelmingly driven by OA from incomplete combustion of biomass and fossil fuels, including traffic. These findings suggest that addressing local inefficient combustion processes can effectively mitigate PM health exposure in northern India. AU - Bhattu, D.* AU - Tripathi, S.N.* AU - Bhowmik, H.S.* AU - Moschos, V.* AU - Lee, C.P.* AU - Rauber, M.M.* AU - Salazar, G.A.* AU - Abbaszade, G. AU - Cui, T.* AU - Slowik, J.G.* AU - Vats, P.* AU - Mishra, S.* AU - Lalchandani, V.* AU - Satish, R.* AU - Rai, P.* AU - Casotto, R.* AU - Tobler, A.* AU - Kumar, V.* AU - Hao, Y.* AU - Qi, L.* AU - Khare, P.* AU - Manousakas, M.I.* AU - Wang, Q.* AU - Han, Y.* AU - Tian, J.* AU - Darfeuil, S.* AU - Minguillon, M.C.* AU - Hueglin, C.* AU - Conil, S.* AU - Rastogi, N.* AU - Srivastava, A.K.* AU - Ganguly, D.* AU - Bjelic, S.* AU - Canonaco, F.* AU - Schnelle-Kreis, J. AU - Dominutti, P.A.* AU - Jaffrezo, J.L.* AU - Szidat, S.* AU - Chen, Y.* AU - Cao, J.* AU - Baltensperger, U.* AU - Uzu, G.* AU - Daellenbach, K.R.* AU - El Haddad, I.* AU - Prévôt, A.S.H.* C1 - 70558 C2 - 55685 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Local incomplete combustion emissions define the PM2.5 oxidative potential in Northern India. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Functionally relevant coronary artery disease (fCAD) can result in premature death or nonfatal acute myocardial infarction. Its early detection is a fundamentally important task in medicine. Classical detection approaches suffer from limited diagnostic accuracy or expose patients to possibly harmful radiation. Here we show how machine learning (ML) can outperform cardiologists in predicting the presence of stress-induced fCAD in terms of area under the receiver operating characteristic (AUROC: 0.71 vs. 0.64, p = 4.0E-13). We present two ML approaches, the first using eight static clinical variables, whereas the second leverages electrocardiogram signals from exercise stress testing. At a target post-test probability for fCAD of <15%, ML facilitates a potential reduction of imaging procedures by 15-17% compared to the cardiologist's judgement. Predictive performance is validated on an internal temporal data split as well as externally. We also show that combining clinical judgement with conventional ML and deep learning using logistic regression results in a mean AUROC of 0.74. AU - Bock, C.* AU - Walter, J.E.* AU - Rieck, B. AU - Strebel, I.* AU - Rumora, K.* AU - Schaefer, I.K.* AU - Zellweger, M.J.* AU - Borgwardt, K.* AU - Müller, C.* C1 - 70834 C2 - 55760 TI - Enhancing the diagnosis of functionally relevant coronary artery disease with machine learning. JO - Nat. Commun. VL - 15 IS - 1 PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Trait-based frameworks are promising tools to understand the functional consequences of community shifts in response to environmental change. The applicability of these tools to soil microbes is limited by a lack of functional trait data and a focus on categorical traits. To address this gap for an important group of soil microorganisms, we identify trade-offs underlying a fungal economics spectrum based on a large trait collection in 28 saprobic fungal isolates, derived from a common grassland soil and grown in culture plates. In this dataset, ecologically relevant trait variation is best captured by a three-dimensional fungal economics space. The primary explanatory axis represents a dense-fast continuum, resembling dominant life-history trade-offs in other taxa. A second significant axis reflects mycelial flexibility, and a third one carbon acquisition traits. All three axes correlate with traits involved in soil carbon cycling. Since stress tolerance and fundamental niche gradients are primarily related to the dense-fast continuum, traits of the 2nd (carbon-use efficiency) and especially the 3rd (decomposition) orthogonal axes are independent of tested environmental stressors. These findings suggest a fungal economics space which can now be tested at broader scales. AU - Camenzind, T.* AU - Aguilar-Trigueros, C.A.* AU - Hempel, S.* AU - Lehmann, A.* AU - Bielcik, M.* AU - Andrade Linares, D.R. AU - Bergmann, J.* AU - Dela Cruz, J.* AU - Gawronski, J.* AU - Golubeva, P.* AU - Haslwimmer, H.* AU - Lartey, L.* AU - Leifheit, E.* AU - Maas, S.* AU - Marhan, S.* AU - Pinek, L.* AU - Powell, J.R.* AU - Roy, J.* AU - Veresoglou, S.D.* AU - Wang, D.* AU - Wulf, A.* AU - Zheng, W.* AU - Rillig, M.C.* C1 - 70534 C2 - 55649 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Towards establishing a fungal economics spectrum in soil saprobic fungi. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Older adults are generally amongst the most vulnerable to heat and cold. While temperature-related health impacts are projected to increase with global warming, the influence of population aging on these trends remains unclear. Here we show that at 1.5 °C, 2 °C, and 3 °C of global warming, heat-related mortality in 800 locations across 50 countries/areas will increase by 0.5%, 1.0%, and 2.5%, respectively; among which 1 in 5 to 1 in 4 heat-related deaths can be attributed to population aging. Despite a projected decrease in cold-related mortality due to progressive warming alone, population aging will mostly counteract this trend, leading to a net increase in cold-related mortality by 0.1%-0.4% at 1.5-3 °C global warming. Our findings indicate that population aging constitutes a crucial driver for future heat- and cold-related deaths, with increasing mortality burden for both heat and cold due to the aging population. AU - Chen, K.* AU - de Schrijver, E.* AU - Sivaraj, S.* AU - Sera, F.* AU - Scovronick, N.* AU - Jiang, L.* AU - Royé, D.* AU - Lavigne, E.* AU - Kyselý, J.* AU - Urban, A.* AU - Schneider, A.E. AU - Huber, V. AU - Madureira, J.* AU - Mistry, M.N.* AU - Cvijanovic, I.* AU - Gasparrini, A.* AU - Vicedo-Cabrera, A.M.* C1 - 70111 C2 - 55215 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Impact of population aging on future temperature-related mortality at different global warming levels. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Adult behavior is commonly thought to be shaped by early-life experience, although episodes experienced during infancy appear to be forgotten. Exposing male rats during infancy to discrete spatial experience we show that these rats in adulthood are significantly better at forming a spatial memory than control rats without such infantile experience. We moreover show that the adult rats' improved spatial memory capability is mainly based on memory for context information during the infantile experiences. Infantile spatial experience increased c-Fos activity at memory testing during adulthood in the prelimbic medial prefrontal cortex (mPFC), but not in the hippocampus. Inhibiting prelimbic mPFC at testing during adulthood abolished the enhancing effect of infantile spatial experience on learning. Adult spatial memory capability only benefitted from spatial experience occurring during the sensitive period of infancy, but not when occurring later during childhood, and when sleep followed the infantile experience. In conclusion, the infantile brain, by a sleep-dependent mechanism, favors consolidation of memory for the context in which episodes are experienced. These representations comprise mPFC regions and context-dependently facilitate learning in adulthood. AU - Contreras, M.P.* AU - Mendez, M.* AU - Shan, X.* AU - Fechner, J.* AU - Sawangjit, A.* AU - Born, J. AU - Inostroza, M.* C1 - 70308 C2 - 55503 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Context memory formed in medial prefrontal cortex during infancy enhances learning in adulthood. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Insufficient functional beta-cell mass causes diabetes; however, an effective cell replacement therapy for curing diabetes is currently not available. Reprogramming of acinar cells toward functional insulin-producing cells would offer an abundant and autologous source of insulin-producing cells. Our lineage tracing studies along with transcriptomic characterization demonstrate that treatment of adult mice with a small molecule that specifically inhibits kinase activity of focal adhesion kinase results in trans-differentiation of a subset of peri-islet acinar cells into insulin producing beta-like cells. The acinar-derived insulin-producing cells infiltrate the pre-existing endocrine islets, partially restore beta-cell mass, and significantly improve glucose homeostasis in diabetic mice. These findings provide evidence that inhibition of the kinase activity of focal adhesion kinase can convert acinar cells into insulin-producing cells and could offer a promising strategy for treating diabetes. A cure for diabetes could entail an effective cell replacement therapy through generation of new insulinproducing cells. In this study, we show that inhibition of focal adhesion kinase activity results in transdifferentiation of a subset of peri-islet acinar cells into functional insulin producing beta-like cells. AU - Dahiya, S.* AU - Saleh, M.* AU - Rodriguez, U.A.* AU - Rajasundaram, D.* AU - R. Arbujas, J.* AU - Hajihassani, A.* AU - Yang, K. AU - Sehrawat, A.* AU - Kalsi, R.* AU - Yoshida, S.* AU - Prasadan, K.* AU - Lickert, H. AU - Hu, J.* AU - Piganelli, J.D.* AU - Gittes, G.K.* AU - Esni, F.* C1 - 70748 C2 - 55656 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Acinar to β-like cell conversion through inhibition of focal adhesion kinase. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Tools for predicting COVID-19 outcomes enable personalized healthcare, potentially easing the disease burden. This collaborative study by 15 institutions across Europe aimed to develop a machine learning model for predicting the risk of in-hospital mortality post-SARS-CoV-2 infection. Blood samples and clinical data from 1286 COVID-19 patients collected from 2020 to 2023 across four cohorts in Europe and Canada were analyzed, with 2906 long non-coding RNAs profiled using targeted sequencing. From a discovery cohort combining three European cohorts and 804 patients, age and the long non-coding RNA LEF1-AS1 were identified as predictive features, yielding an AUC of 0.83 (95% CI 0.82-0.84) and a balanced accuracy of 0.78 (95% CI 0.77-0.79) with a feedforward neural network classifier. Validation in an independent Canadian cohort of 482 patients showed consistent performance. Cox regression analysis indicated that higher levels of LEF1-AS1 correlated with reduced mortality risk (age-adjusted hazard ratio 0.54, 95% CI 0.40-0.74). Quantitative PCR validated LEF1-AS1's adaptability to be measured in hospital settings. Here, we demonstrate a promising predictive model for enhancing COVID-19 patient management. AU - Devaux, Y.* AU - Zhang, L.* AU - Lumley, A.I.* AU - Karaduzovic-Hadziabdic, K.* AU - Mooser, V.* AU - Rousseau, S.* AU - Shoaib, M.* AU - Satagopam, V.* AU - Adilovic, M.* AU - Srivastava, P.K.* AU - Emanueli, C.* AU - Martelli, F.* AU - Greco, S.* AU - Badimon, L.* AU - Padró, T.* AU - Lustrek, M.* AU - Scholz, M.* AU - Rosolowski, M.* AU - Jordan, M.* AU - Brandenburger, T.* AU - Benczik, B.* AU - Agg, B.* AU - Ferdinandy, P.* AU - Vehreschild, J.J.* AU - Lorenz-Depiereux, B. AU - Dörr, M.* AU - Witzke, O.* AU - Sánchez, G.* AU - Kul, S.* AU - Baker, A.H.* AU - Fagherazzi, G.* AU - Ollert, M.* AU - Wereski, R.* AU - Mills, N.L.* AU - Firat, H.* C1 - 70722 C2 - 55622 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Development of a long noncoding RNA-based machine learning model to predict COVID-19 in-hospital mortality. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - The greatly nonlinear diffraction of high-energy electron probes focused to subatomic diameters frustrates the direct inversion of ptychographic data sets to decipher the atomic structure. Several iterative algorithms have been proposed to yield atomically-resolved phase distributions within slices of a 3D specimen, corresponding to the scattering centers of the electron wave. By pixelwise phase retrieval, current approaches do not only involve orders of magnitude more free parameters than necessary, but also neglect essential details of scattering physics such as the atomistic nature of the specimen and thermal effects. Here, we introduce a parametrized, fully differentiable scheme employing neural network concepts which allows the inversion of ptychographic data by means of entirely physical quantities. Omnipresent thermal diffuse scattering in thick specimens is treated accurately using frozen phonons, and atom types, positions and partial coherence are accounted for in the inverse model as relativistic scattering theory demands. Our approach exploits 4D experimental data collected in an aberration-corrected momentum-resolved scanning transmission electron microscopy setup. Atom positions in a 20 nm thick PbZr0.2Ti0.8O3 ferroelectric are measured with picometer precision, including the discrimination of different atom types and positions in mixed columns. AU - Diederichs, B. AU - Herdegen, Z.* AU - Strauch, A.* AU - Filbir, F. AU - Muller-Caspary, K.* C1 - 69014 C2 - 55189 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Exact inversion of partially coherent dynamical electron scattering for picometric structure retrieval. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Recent advances in single-cell immune profiling have enabled the simultaneous measurement of transcriptome and T cell receptor (TCR) sequences, offering great potential for studying immune responses at the cellular level. However, integrating these diverse modalities across datasets is challenging due to their unique data characteristics and technical variations. Here, to address this, we develop the multimodal generative model mvTCR to fuse modality-specific information across transcriptome and TCR into a shared representation. Our analysis demonstrates the added value of multimodal over unimodal approaches to capture antigen specificity. Notably, we use mvTCR to distinguish T cell subpopulations binding to SARS-CoV-2 antigens from bystander cells. Furthermore, when combined with reference mapping approaches, mvTCR can map newly generated datasets to extensive T cell references, facilitating knowledge transfer. In summary, we envision mvTCR to enable a scalable analysis of multimodal immune profiling data and advance our understanding of immune responses. AU - Drost, F. AU - An, Y. AU - Bonafonte Pardás, I. AU - Dratva, L.M.* AU - Lindeboom, R.G.H.* AU - Haniffa, M.* AU - Teichmann, S.A.* AU - Theis, F.J. AU - Lotfollahi, M. AU - Schubert, B. C1 - 71044 C2 - 55871 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Multi-modal generative modeling for joint analysis of single-cell T cell receptor and gene expression data. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Autoimmune diseases result from autoantigen-mediated activation of adaptive immunity; intriguingly, autoantigen-specific T cells are also present in healthy donors. An assessment of dynamic changes of this autoreactive repertoire in both health and disease is thus warranted. Here we investigate the physiological versus pathogenic autoreactive processes in the context of Type 1 diabetes (T1D) and one of its landmark autoantigens, glutamic acid decarboxylase 65 (GAD65). Using single cell gene expression profiling and tandem T cell receptor (TCR) sequencing, we find that GAD65-specific true naïve cells are present in both health and disease, with GAD65-specific effector and memory responses showing similar ratios in healthy donors and patients. Deeper assessment of phenotype and TCR repertoire uncover differential features in GAD65-specific TCRs, including lower clonal sizes of healthy donor-derived clonotypes in patients. We thus propose a model whereby physiological autoimmunity against GAD65 is needed during early life, and that alterations of these physiological autoimmune processes in predisposed individuals trigger overt Type 1 diabetes. AU - Eugster, A.* AU - Lorenc, A.* AU - Kotrulev, M.* AU - Kamra, Y.* AU - Goel, M.* AU - Steinberg-Bains, K.* AU - Sabbah, S.* AU - Dietz, S.* AU - Bonifacio, E. AU - Peakman, M.* AU - Gomez-Tourino, I.* C1 - 72198 C2 - 56476 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Physiological and pathogenic T cell autoreactivity converge in type 1 diabetes. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Identifying cellular identities is a key use case in single-cell transcriptomics. While machine learning has been leveraged to automate cell annotation predictions for some time, there has been little progress in scaling neural networks to large data sets and in constructing models that generalize well across diverse tissues. Here, we propose scTab, an automated cell type prediction model specific to tabular data, and train it using a novel data augmentation scheme across a large corpus of single-cell RNA-seq observations (22.2 million cells). In this context, we show that cross-tissue annotation requires nonlinear models and that the performance of scTab scales both in terms of training dataset size and model size. Additionally, we show that the proposed data augmentation schema improves model generalization. In summary, we introduce a de novo cell type prediction model for single-cell RNA-seq data that can be trained across a large-scale collection of curated datasets and demonstrate the benefits of using deep learning methods in this paradigm. AU - Fischer, F. AU - Fischer, D.S. AU - Mukhin, R.* AU - Isaev, A.* AU - Biederstedt, E.* AU - Villani, A.C.* AU - Theis, F.J. C1 - 71425 C2 - 56201 TI - scTab: Scaling cross-tissue single-cell annotation models. JO - Nat. Commun. VL - 15 IS - 1 PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Import of proteins into peroxisomes depends on PEX5, PEX13 and PEX14. By combining biochemical methods and structural biology, we show that the C-terminal SH3 domain of PEX13 mediates intramolecular interactions with a proximal FxxxF motif. The SH3 domain also binds WxxxF peptide motifs in the import receptor PEX5, demonstrating evolutionary conservation of such interactions from yeast to human. Strikingly, intramolecular interaction of the PEX13 FxxxF motif regulates binding of PEX5 WxxxF/Y motifs to the PEX13 SH3 domain. Crystal structures reveal how FxxxF and WxxxF/Y motifs are recognized by a non-canonical surface on the SH3 domain. The PEX13 FxxxF motif also mediates binding to PEX14. Surprisingly, the potential PxxP binding surface of the SH3 domain does not recognize PEX14 PxxP motifs, distinct from its yeast ortholog. Our data show that the dynamic network of PEX13 interactions with PEX5 and PEX14, mediated by diaromatic peptide motifs, modulates peroxisomal matrix import. AU - Gaussmann, S. AU - Peschel, R.* AU - Ott, J.* AU - Zak, K.M. AU - Sastre, J.* AU - Delhommel, F. AU - Popowicz, G.M. AU - Boekhoven, J.* AU - Schliebs, W.* AU - Erdmann, R.* AU - Sattler, M. C1 - 70538 C2 - 55652 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Modulation of peroxisomal import by the PEX13 SH3 domain and a proximal FxxxF binding motif. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Dendritic cells (DCs) are crucial for initiating protective immune responses and have also been implicated in the generation and regulation of Foxp3+ regulatory T cells (Treg cells). Here, we show that in the lamina propria of the small intestine, the alternative NF-κB family member RelB is necessary for the differentiation of cryptopatch and isolated lymphoid follicle-associated DCs (CIA-DCs). Moreover, single-cell RNA sequencing reveals a RelB-dependent signature in migratory DCs in mesenteric lymph nodes favoring DC-Treg cell interaction including elevated expression and release of the chemokine CCL22 from RelB-deficient conventional DCs (cDCs). In line with the key role of CCL22 to facilitate DC-Treg cell interaction, RelB-deficient DCs have a selective advantage to interact with Treg cells in an antigen-specific manner. In addition, DC-specific RelB knockout animals show increased total Foxp3+ Treg cell numbers irrespective of inflammatory status. Consequently, DC-specific RelB knockout animals fail to mount protective Th2-dominated immune responses in the intestine after infection with Heligmosomoides polygyrus bakeri. Thus, RelB expression in cDCs acts as a rheostat to establish a tolerogenic set point that is maintained even during strong type 2 immune conditions and thereby is a key regulator of intestinal homeostasis. AU - Geiselhöringer, A.-L. AU - Kolland, D. AU - Patt, A.J. AU - Hammann, L.* AU - Köhler, A. AU - Kreft, L. AU - Wichmann, N. AU - Hils, M.* AU - Ruedl, C.* AU - Riemann, M.* AU - Biedermann, T.* AU - Anz, D.* AU - Diefenbach, A.* AU - Voehringer, D.* AU - Schmidt-Weber, C.B. AU - Straub, T.* AU - Szente-Pasztoi, M. AU - Ohnmacht, C. C1 - 72142 C2 - 56480 TI - Dominant immune tolerance in the intestinal tract imposed by RelB-dependent migratory dendritic cells regulates protective type 2 immunity. JO - Nat. Commun. VL - 15 IS - 1 PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) drives viral B cell transformation and oncogenesis. LMP1’s transforming activity depends on its C-terminal activation region 2 (CTAR2), which induces NF-κB and JNK by engaging TNF receptor-associated factor 6 (TRAF6). The mechanism of TRAF6 recruitment to LMP1 and its role in LMP1 signalling remains elusive. Here we demonstrate that TRAF6 interacts directly with a viral TRAF6 binding motif within CTAR2. Functional and NMR studies supported by molecular modeling provide insight into the architecture of the LMP1-TRAF6 complex, which differs from that of CD40-TRAF6. The direct recruitment of TRAF6 to LMP1 is essential for NF-κB activation by CTAR2 and the survival of LMP1-driven lymphoma. Disruption of the LMP1-TRAF6 complex by inhibitory peptides interferes with the survival of EBV-transformed B cells. In this work, we identify LMP1-TRAF6 as a critical virus-host interface and validate this interaction as a potential therapeutic target in EBV-associated cancer. AU - Giehler, F. AU - Ostertag, M.S. AU - Sommermann, T.* AU - Weidl, D.* AU - Sterz, K. AU - Kutz, H. AU - Moosmann, A. AU - Feller, S.M.* AU - Geerlof, A. AU - Biesinger, B.* AU - Popowicz, G.M. AU - Kirchmair, J.* AU - Kieser, A. C1 - 69732 C2 - 55197 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Epstein-Barr virus-driven B cell lymphoma mediated by a direct LMP1-TRAF6 complex. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Predictive coding theories propose that the brain constantly updates internal models to minimize prediction errors and optimize sensory processing. However, the neural mechanisms that link prediction error encoding and optimization of sensory representations remain unclear. Here, we provide evidence how predictive learning shapes the representational geometry of the human brain. We recorded magnetoencephalography (MEG) in humans listening to acoustic sequences with different levels of regularity. We found that the brain aligns its representational geometry to match the statistical structure of the sensory inputs, by clustering temporally contiguous and predictable stimuli. Crucially, the magnitude of this representational shift correlates with the synergistic encoding of prediction errors in a network of high-level and sensory areas. Our findings suggest that, in response to the statistical regularities of the environment, large-scale neural interactions engaged in predictive processing modulate the representational content of sensory areas to enhance sensory processing. AU - Greco, A.* AU - Moser, J. AU - Preissl, H. AU - Siegel, M.* C1 - 72315 C2 - 56592 TI - Predictive learning shapes the representational geometry of the human brain. JO - Nat. Commun. VL - 15 IS - 1 PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - In-depth multiomic phenotyping provides molecular insights into complex physiological processes and their pathologies. Here, we report on integrating 18 diverse deep molecular phenotyping (omics-) technologies applied to urine, blood, and saliva samples from 391 participants of the multiethnic diabetes Qatar Metabolomics Study of Diabetes (QMDiab). Using 6,304 quantitative molecular traits with 1,221,345 genetic variants, methylation at 470,837 DNA CpG sites, and gene expression of 57,000 transcripts, we determine (1) within-platform partial correlations, (2) between-platform mutual best correlations, and (3) genome-, epigenome-, transcriptome-, and phenome-wide associations. Combined into a molecular network of > 34,000 statistically significant trait-trait links in biofluids, our study portrays "The Molecular Human". We describe the variances explained by each omics in the phenotypes (age, sex, BMI, and diabetes state), platform complementarity, and the inherent correlation structures of multiomics data. Further, we construct multi-molecular network of diabetes subtypes. Finally, we generated an open-access web interface to "The Molecular Human" ( http://comics.metabolomix.com ), providing interactive data exploration and hypotheses generation possibilities. AU - Halama, A.* AU - Zaghlool, S.* AU - Thareja, G.* AU - Kader, S.* AU - Al Muftah, W.A.* AU - Mook-Kanamori, M.J.* AU - Sarwath, H.* AU - Mohamoud, Y.A.* AU - Stephan, N.* AU - Ameling, S.* AU - Pucic Baković, M.* AU - Krumsiek, J.* AU - Prehn, C. AU - Adamski, J. AU - Schwenk, J.M.* AU - Friedrich, N.* AU - Völker, U.* AU - Wuhrer, M.* AU - Lauc, G.* AU - Najafi-Shoushtari, S.H.* AU - Malek, J.A.* AU - Graumann, J.* AU - Mook-Kanamori, D.* AU - Schmidt, F.* AU - Suhre, K.* C1 - 71503 C2 - 56096 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - A roadmap to the molecular human linking multiomics with population traits and diabetes subtypes. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - The lncRNA Crossfirre was identified as an imprinted X-linked gene, and is transcribed antisense to the trans-acting lncRNA Firre. The Firre locus forms an inactive-X-specific interaction with Dxz4, both loci providing the platform for the largest conserved chromatin structures. Here, we characterize the epigenetic profile of these loci, revealing them as the most female-specific accessible regions genome-wide. To address their in vivo role, we perform one of the largest X-linked knockout studies by deleting Crossfirre, Firre, and Dxz4 individually and in combination. Despite their distinct epigenetic features observed on the X chromosome, our allele-specific analysis uncovers these loci as dispensable for imprinted and random X chromosome inactivation. However, we provide evidence that Crossfirre affects autosomal gene regulation but only in combination with Firre. To shed light on the functional role of these sex-specific loci, we perform an extensive standardized phenotyping pipeline and uncover diverse knockout and sex-specific phenotypes. Collectively, our study provides the foundation for exploring the intricate interplay of conserved X-linked loci in vivo. AU - Hasenbein, T.P.* AU - Hoelzl, S.* AU - Smith, Z.D.* AU - Gerhardinger, C.* AU - Gonner, M.O.C.* AU - Aguilar-Pimentel, J.A. AU - Amarie, O.V. AU - Becker, L. AU - Calzada-Wack, J. AU - Dragano, N.R.V. AU - da Silva Buttkus, P. AU - Garrett, L. AU - Hölter, S.M. AU - Kraiger, M. AU - Östereicher, M.A. AU - Rathkolb, B. AU - Sanz-Moreno, A. AU - Spielmann, N. AU - Wurst, W. AU - Gailus-Durner, V. AU - Fuchs, H. AU - Hrabě de Angelis, M. AU - Meissner, A.* AU - Engelhardt, S.* AU - Rinn, J.L.* AU - Andergassen, D.* C1 - 72673 C2 - 56673 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - X-linked deletion of Crossfirre, Firre, and Dxz4 in vivo uncovers diverse phenotypes and combinatorial effects on autosomes. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Floods have affected billions worldwide. Yet, the indirect health impacts of floods on vulnerable groups, particularly women in the developing world, remain underexplored. Here, we evaluated the risk of pregnancy loss for women exposed to floods. We analyzed 90,465 individual pregnancy loss records from 33 developing countries, cross-referencing each with spatial-temporal flood databases. We found that gestational flood exposure is associated with increased pregnancy loss with an odds ratio of 1.08 (95% confidence interval: 1.04 - 1.11). This risk is pronounced for women outside the peak reproductive age range (<21 or >35) or during the mid and late-stage of pregnancy. The risk escalated for women dependent on surface water, with lower income or education levels. We estimated that, over the 2010s, gestational flood events might be responsible for approximately 107,888 (CIs: 53,944 - 148,345) excess pregnancy losses annually across 33 developing countries. Notably, there is a consistent upward trend in annual excess pregnancy losses from 2010 to 2020, and was more prominent over Central America, the Caribbean, South America, and South Asia. Our findings underscore the disparities in maternal and child health aggravated by flood events in an evolving climate. AU - He, C. AU - Zhu, Y.* AU - Zhou, L.* AU - Bachwenkizi, J.* AU - Schneider, A.E. AU - Chen, R.* AU - Kan, H.* C1 - 69017 C2 - 55192 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Flood exposure and pregnancy loss in 33 developing countries. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Multiple omics analyzes of Vaccinia virus (VACV) infection have defined molecular characteristics of poxvirus biology. However, little is known about the monkeypox (mpox) virus (MPXV) in humans, which has a different disease manifestation despite its high sequence similarity to VACV. Here, we perform an in-depth multi-omics analysis of the transcriptome, proteome, and phosphoproteome signatures of MPXV-infected primary human fibroblasts to gain insights into the virus-host interplay. In addition to expected perturbations of immune-related pathways, we uncover regulation of the HIPPO and TGF-β pathways. We identify dynamic phosphorylation of both host and viral proteins, which suggests that MAPKs are key regulators of differential phosphorylation in MPXV-infected cells. Among the viral proteins, we find dynamic phosphorylation of H5 that influenced the binding of H5 to dsDNA. Our extensive dataset highlights signaling events and hotspots perturbed by MPXV, extending the current knowledge on poxviruses. We use integrated pathway analysis and drug-target prediction approaches to identify potential drug targets that affect virus growth. Functionally, we exemplify the utility of this approach by identifying inhibitors of MTOR, CHUK/IKBKB, and splicing factor kinases with potent antiviral efficacy against MPXV and VACV. AU - Huang, Y.* AU - Bergant, V.* AU - Grass, V.* AU - Emslander, Q.* AU - Hamad, M.S.* AU - Hubel, P.* AU - Mergner, J.* AU - Piras, A.* AU - Krey, K.* AU - Henrici, A.* AU - Öllinger, R.* AU - Tesfamariam, Y.M.* AU - Dalla Rosa, I.* AU - Bunse, T.* AU - Sutter, G.* AU - Ebert, G. AU - Schmidt, F.I.* AU - Way, M.* AU - Rad, R.* AU - Bowie, A.G.* AU - Protzer, U. AU - Pichlmair, A.* C1 - 71447 C2 - 56189 TI - Multi-omics characterization of the monkeypox virus infection. JO - Nat. Commun. VL - 15 IS - 1 PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Unlike for DNA and RNA, accurate and high-throughput sequencing methods for proteins are lacking, hindering the utility of proteomics in applications where the sequences are unknown including variant calling, neoepitope identification, and metaproteomics. We introduce Spectralis, a de novo peptide sequencing method for tandem mass spectrometry. Spectralis leverages several innovations including a convolutional neural network layer connecting peaks in spectra spaced by amino acid masses, proposing fragment ion series classification as a pivotal task for de novo peptide sequencing, and a peptide-spectrum confidence score. On spectra for which database search provided a ground truth, Spectralis surpassed 40% sensitivity at 90% precision, nearly doubling state-of-the-art sensitivity. Application to unidentified spectra confirmed its superiority and showcased its applicability to variant calling. Altogether, these algorithmic innovations and the substantial sensitivity increase in the high-precision range constitute an important step toward broadly applicable peptide sequencing. AU - Klaproth-Andrade, D.* AU - Hingerl, J.* AU - Bruns, Y.* AU - Smith, N.H.* AU - Träuble, J.* AU - Wilhelm, M.* AU - Gagneur, J. C1 - 69016 C2 - 55191 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Deep learning-driven fragment ion series classification enables highly precise and sensitive de novo peptide sequencing. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - The formation of new ribosomes is tightly coordinated with cell growth and proliferation. In eukaryotes, the correct assembly of all ribosomal proteins and RNAs follows an intricate scheme of maturation and rearrangement steps across three cellular compartments: the nucleolus, nucleoplasm, and cytoplasm. We demonstrate that usnic acid, a lichen secondary metabolite, inhibits the maturation of the large ribosomal subunit in yeast. We combine biochemical characterization of pre-ribosomal particles with a quantitative single-particle cryo-EM approach to monitor changes in nucleolar particle populations upon drug treatment. Usnic acid rapidly blocks the transition from nucleolar state B to C of Nsa1-associated pre-ribosomes, depleting key maturation factors such as Dbp10 and hindering pre-rRNA processing. This primary nucleolar block rapidly rebounds on earlier stages of the pathway which highlights the regulatory linkages between different steps. In summary, we provide an in-depth characterization of the effect of usnic acid on ribosome biogenesis, which may have implications for its reported anti-cancer activities. AU - Kofler, L.* AU - Grundmann, L.* AU - Gerhalter, M.* AU - Prattes, M.* AU - Merl-Pham, J. AU - Zisser, G.* AU - Grishkovskaya, I.* AU - Hodirnau, V.V.* AU - Vareka, M.* AU - Breinbauer, R.* AU - Hauck, S.M. AU - Haselbach, D.* AU - Bergler, H.* C1 - 71549 C2 - 56274 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - The novel ribosome biogenesis inhibitor usnic acid blocks nucleolar pre-60S maturation. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Traumatic brain injury leads to a highly orchestrated immune- and glial cell response partially responsible for long-lasting disability and the development of secondary neurodegenerative diseases. A holistic understanding of the mechanisms controlling the responses of specific cell types and their crosstalk is required to develop an efficient strategy for better regeneration. Here, we combine spatial and single-cell transcriptomics to chart the transcriptomic signature of the injured male murine cerebral cortex, and identify specific states of different glial cells contributing to this signature. Interestingly, distinct glial cells share a large fraction of injury-regulated genes, including inflammatory programs downstream of the innate immune-associated pathways Cxcr3 and Tlr1/2. Systemic manipulation of these pathways decreases the reactivity state of glial cells associated with poor regeneration. The functional relevance of the discovered shared signature of glial cells highlights the importance of our resource enabling comprehensive analysis of early events after brain injury. AU - Koupourtidou, C.* AU - Schwarz, V.* AU - Aliee, H. AU - Frerich, S.* AU - Fischer-Sternjak, J. AU - Bocchi, R. AU - Simon-Ebert, T. AU - Bai, X.* AU - Sirko, S. AU - Kirchhoff, F.* AU - Dichgans, M.* AU - Götz, M. AU - Theis, F.J. AU - Ninkovic, J. C1 - 70439 C2 - 55537 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Shared inflammatory glial cell signature after stab wound injury, revealed by spatial, temporal, and cell-type-specific profiling of the murine cerebral cortex. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Fiber-based interferometers receive significant interest as they lead to miniaturization of optoacoustic and ultrasound detectors without the quadratic loss of sensitivity common to piezoelectric elements. Nevertheless, in contrast to piezoelectric crystals, current fiber-based ultrasound detectors operate with narrow ultrasound bandwidth which limits the application range and spatial resolution achieved in imaging implementations. We port the concept of silicon waveguide etalon detection to optical fibers using a sub-acoustic reflection terminator to a Bragg grating embedded etalon resonator (EER), uniquely implementing direct and forward-looking access to incoming ultrasound waves. Precise fabrication of the terminator is achieved by continuously recording the EER spectrum during polishing and fitting the spectra to a theoretically calculated spectrum for the selected thickness. Characterization of the EER inventive design reveals a small aperture (10.1 µm) and an ultra-wide bandwidth (160 MHz) that outperforms other fiber resonators and enables an active detection area and overall form factor that is smaller by more than an order of magnitude over designs based on piezoelectric transducers. We discuss how the EER paves the way for the most adept fiber-based miniaturized sound detection today, circumventing the limitations of currently available designs. AU - La, T.A. AU - Ülgen, O. AU - Shnaiderman, R. AU - Ntziachristos, V. C1 - 71536 C2 - 56262 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Bragg grating etalon-based optical fiber for ultrasound and optoacoustic detection. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Actin mediates insulin secretion in pancreatic β-cells through remodeling. Hampered by limited resolution, previous studies have offered an ambiguous depiction as depolymerization and repolymerization. We report the in situ structure of actin remodeling in INS-1E β-cells during glucose-stimulated insulin secretion at nanoscale resolution. After remodeling, the actin filament network at the cell periphery exhibits three marked differences: 12% of actin filaments reorient quasi-orthogonally to the ventral membrane; the filament network mainly remains as cell-stabilizing bundles but partially reconfigures into a less compact arrangement; actin filaments anchored to the ventral membrane reorganize from a "netlike" to a "blooming" architecture. Furthermore, the density of actin filaments and microtubules around insulin secretory granules decreases, while actin filaments and microtubules become more densely packed. The actin filament network after remodeling potentially precedes the transport and release of insulin secretory granules. These findings advance our understanding of actin remodeling and its role in glucose-stimulated insulin secretion. AU - Li, W.* AU - Li, A.* AU - Yu, B.* AU - Zhang, X.* AU - Liu, X.* AU - White, K.L.* AU - Stevens, R.C.* AU - Baumeister, W.* AU - Sali, A.* AU - Jasnin, M. AU - Sun, L.* C1 - 73392 C2 - 56835 SP - 1311 TI - In situ structure of actin remodeling during glucose-stimulated insulin secretion using cryo-electron tomography. JO - Nat. Commun. VL - 15 IS - 1 PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - The concept of precision cell therapy targeting tumor-specific mutations is appealing but requires surface-exposed neoepitopes, which is a rarity in cancer. B cell receptors (BCR) of mature lymphoid malignancies are exceptional in that they harbor tumor-specific-stereotyped sequences in the form of point mutations that drive self-engagement of the BCR and autologous signaling. Here, we use a BCR light chain neoepitope defined by a characteristic point mutation (IGLV3-21R110) for selective targeting of a poor-risk subset of chronic lymphocytic leukemia (CLL) with chimeric antigen receptor (CAR) T cells. We develop murine and humanized CAR constructs expressed in T cells from healthy donors and CLL patients that eradicate IGLV3-21R110 expressing cell lines and primary CLL cells, but neither cells expressing the non-pathogenic IGLV3-21G110 light chain nor polyclonal healthy B cells. In vivo experiments confirm epitope-selective cytolysis in xenograft models in female mice using engrafted IGLV3-21R110 expressing cell lines or primary CLL cells. We further demonstrate in two humanized mouse models lack of cytotoxicity towards human B cells. These data provide the basis for advanced approaches of resistance-preventive and biomarker-guided cellular targeting of functionally relevant lymphoma driver mutations sparing normal B cells. AU - Märkl, F.* AU - Schultheiß, C.* AU - Ali, M.* AU - Chen, S.S.* AU - Zintchenko, M.* AU - Egli, L.* AU - Mietz, J.* AU - Chijioke, O.* AU - Paschold, L.* AU - Spajic, S.* AU - Holtermann, A.* AU - Dörr, J.* AU - Stock, S.* AU - Zingg, A.* AU - Läubli, H.* AU - Piseddu, I.* AU - Anz, D.* AU - Minden, M.D.* AU - Zhang, T.* AU - Nerreter, T.* AU - Hudecek, M.* AU - Minguet, S.* AU - Chiorazzi, N.* AU - Kobold, S. AU - Binder, M.* C1 - 69887 C2 - 55305 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Mutation-specific CAR T cells as precision therapy for IGLV3-21R110 expressing high-risk chronic lymphocytic leukemia. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - PRPF40A plays an important role in the regulation of pre-mRNA splicing by mediating protein-protein interactions in the early steps of spliceosome assembly. By binding to proteins at the 5´ and 3´ splice sites, PRPF40A promotes spliceosome assembly by bridging the recognition of the splices. The PRPF40A WW domains are expected to recognize proline-rich sequences in SF1 and SF3A1 in the early spliceosome complexes E and A, respectively. Here, we combine NMR, SAXS and ITC to determine the structure of the PRPF40A tandem WW domains in solution and characterize the binding specificity and mechanism for proline-rich motifs recognition. Our structure of the PRPF40A WW tandem in complex with a high-affinity SF1 peptide reveals contributions of both WW domains, which also enables tryptophan sandwiching by two proline residues in the ligand. Unexpectedly, a proline-rich motif in the N-terminal region of PRPF40A mediates intramolecular interactions with the WW tandem. Using NMR, ITC, mutational analysis in vitro, and immunoprecipitation experiments in cells, we show that the intramolecular interaction acts as an autoinhibitory filter for proof-reading of high-affinity proline-rich motifs in bona fide PRPF40A binding partners. We propose that similar autoinhibitory mechanisms are present in most WW tandem-containing proteins to enhance binding selectivity and regulation of WW/proline-rich peptide interaction networks. AU - Martinez Lumbreras, S. AU - Träger, L.K.* AU - Mulorz, M.M.* AU - Payr, M.* AU - Dikaya, V.* AU - Hipp, C. AU - König, J.* AU - Sattler, M. C1 - 70662 C2 - 55702 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Intramolecular autoinhibition regulates the selectivity of PRPF40A tandem WW domains for proline-rich motifs. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Under-reporting of COVID-19 and the limited information about circulating SARS-CoV-2 variants remain major challenges for many African countries. We analyzed SARS-CoV-2 infection dynamics in Addis Ababa and Jimma, Ethiopia, focusing on reinfection, immunity, and vaccination effects. We conducted an antibody serology study spanning August 2020 to July 2022 with five rounds of data collection across a population of 4723, sequenced PCR-test positive samples, used available test positivity rates, and constructed two mathematical models integrating this data. A multivariant model explores variant dynamics identifying wildtype, alpha, delta, and omicron BA.4/5 as key variants in the study population, and cross-immunity between variants, revealing risk reductions between 24% and 69%. An antibody-level model predicts slow decay leading to sustained high antibody levels. Retrospectively, increased early vaccination might have substantially reduced infections during the delta and omicron waves in the considered group of individuals, though further vaccination now seems less impactful. AU - Merkt, S.* AU - Ali, S.* AU - Gudina, E.K.* AU - Adissu, W.* AU - Gize, A.* AU - Muenchhoff, M.* AU - Graf, A.* AU - Krebs, S.* AU - Elsbernd, K.* AU - Kisch, R.* AU - Betizazu, S.S.* AU - Fantahun, B.* AU - Bekele, D.* AU - Rubio-Acero, R.* AU - Gashaw, M.* AU - Girma, E.* AU - Yilma, D.* AU - Zeynudin, A.* AU - Paunovic, I.* AU - Hoelscher, M. AU - Blum, H.* AU - Hasenauer, J. AU - Kroidl, A.* AU - Wieser, A.* C1 - 70566 C2 - 55692 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Long-term monitoring of SARS-CoV-2 seroprevalence and variants in Ethiopia provides prediction for immunity and cross-immunity. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Repeat expansions in FGF14 cause autosomal dominant late-onset cerebellar ataxia (SCA27B) with estimated pathogenic thresholds of 250 (incomplete penetrance) and 300 AAG repeats (full penetrance), but the sequence of pathogenic and non-pathogenic expansions remains unexplored. Here, we demonstrate that STRling and ExpansionHunter accurately detect FGF14 expansions from short-read genome data using outlier approaches. By combining long-range PCR and nanopore sequencing in 169 patients with cerebellar ataxia and 802 controls, we compare FGF14 expansion alleles, including interruptions and flanking regions. Uninterrupted AAG expansions are significantly enriched in patients with ataxia from a lower threshold (180-200 repeats) than previously reported based on expansion size alone. Conversely, AAGGAG hexameric expansions are equally frequent in patients and controls. Distinct 5' flanking regions, interruptions and pre-repeat sequences correlate with repeat size. Furthermore, pure AAG (pathogenic) and AAGGAG (non-pathogenic) repeats form different secondary structures. Regardless of expansion size, SCA27B is a recognizable clinical entity characterized by frequent episodic ataxia and downbeat nystagmus, similar to the presentation observed in a family with a previously unreported nonsense variant (SCA27A). Overall, this study suggests that SCA27B is a major overlooked cause of adult-onset ataxia, accounting for 23-31% of unsolved patients. We strongly recommend re-evaluating pathogenic thresholds and integrating expansion sequencing into the molecular diagnostic process. AU - Mohren, L.* AU - Erdlenbruch, F.* AU - Leitão, E.* AU - Kilpert, F.* AU - Hönes, G.S.* AU - Kaya, S.* AU - Schröder, C.* AU - Thieme, A.* AU - Sturm, M.* AU - Park, J.* AU - Schlüter, A.* AU - Ruiz, M.* AU - Morales de la Prida, M.* AU - Casasnovas, C.* AU - Becker, K.* AU - Roggenbuck, U.* AU - Pechlivanis, S. AU - Kaiser, F.J.* AU - Synofzik, M.* AU - Wirth, T.* AU - Anheim, M.* AU - Haack, T.B.* AU - Lockhart, P.J.* AU - Jöckel, K.H.* AU - Pujol, A.* AU - Klebe, S.* AU - Timmann, D.* AU - Depienne, C.* C1 - 71625 C2 - 56320 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Identification and characterisation of pathogenic and non-pathogenic FGF14 repeat expansions. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Primary cilia are sensory organelles present in many cell types, partaking in various signaling processes. Primary cilia of pancreatic beta cells play pivotal roles in paracrine signaling and their dysfunction is linked to diabetes. Yet, the structural basis for their functions is unclear. We present three-dimensional reconstructions of beta cell primary cilia by electron and expansion microscopy. These cilia are spatially confined within deep ciliary pockets or narrow spaces between cells, lack motility components and display an unstructured axoneme organization. Furthermore, we observe a plethora of beta cell cilia-cilia and cilia-cell interactions with other islet and non-islet cells. Most remarkably, we have identified and characterized axo-ciliary synapses between beta cell cilia and the cholinergic islet innervation. These findings highlight the beta cell cilia's role in islet connectivity, pointing at their function in integrating islet intrinsic and extrinsic signals and contribute to understanding their significance in health and diabetes. AU - Müller, A. AU - Klena, N.* AU - Pang, S.* AU - Galicia Garcia, L.E. AU - Topcheva, O. AU - Aurrecoechea Duran, S. AU - Sulaymankhil, D. AU - Seliskar, M. AU - Mziaut, H. AU - Schöniger, E. AU - Friedland, D. AU - Kipke, N. AU - Kretschmar, S.* AU - Münster, C. AU - Weitz, J.* AU - Distler, M.* AU - Kurth, T.* AU - Schmidt, D.* AU - Hess, H.F.* AU - Xu, C.S.* AU - Pigino, G.* AU - Solimena, M. C1 - 72156 C2 - 56479 TI - Structure, interaction and nervous connectivity of beta cell primary cilia. JO - Nat. Commun. VL - 15 IS - 1 PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Trees interact with a multitude of microbes through their roots and root symbionts such as mycorrhizal fungi and root endophytes. Here, we explore the role of fungal root symbionts as predictors of the soil and root-associated microbiomes of widespread broad-leaved trees across a European latitudinal gradient. Our results suggest that, alongside factors such as climate, soil, and vegetation properties, root colonization by ectomycorrhizal, arbuscular mycorrhizal, and dark septate endophytic fungi also shapes tree-associated microbiomes. Notably, the structure of root and soil microbiomes across our sites is more strongly and consistently associated with dark septate endophyte colonization than with mycorrhizal colonization and many abiotic factors. Root colonization by dark septate endophytes also has a consistent negative association with the relative abundance and diversity of nutrient cycling genes. Our study not only indicates that root-symbiotic interactions are an important factor structuring soil communities and functions in forest ecosystems, but also that the hitherto less studied dark septate endophytes are likely to be central players in these interactions. AU - Netherway, T.* AU - Bengtsson, J.* AU - Buegger, F. AU - Fritscher, J.* AU - Oja, J.* AU - Pritsch, K. AU - Hildebrand, F.* AU - Krab, E.J.* AU - Bahram, M.* C1 - 69015 C2 - 55190 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Pervasive associations between dark septate endophytic fungi with tree root and soil microbiomes across Europe. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Organismal functional strategies form a continuum from slow- to fast-growing organisms, in response to common drivers such as resource availability and disturbance. However, whether there is synchronisation of these strategies at the entire community level is unclear. Here, we combine trait data for >2800 above- and belowground taxa from 14 trophic guilds spanning a disturbance and resource availability gradient in German grasslands. The results indicate that most guilds consistently respond to these drivers through both direct and trophically mediated effects, resulting in a 'slow-fast' axis at the level of the entire community. Using 15 indicators of carbon and nutrient fluxes, biomass production and decomposition, we also show that fast trait communities are associated with faster rates of ecosystem functioning. These findings demonstrate that 'slow' and 'fast' strategies can be manifested at the level of whole communities, opening new avenues of ecosystem-level functional classification. AU - Neyret, M.* AU - Le Provost, G.* AU - Boesing, A.L.* AU - Schneider, F.D.* AU - Baulechner, D.* AU - Bergmann, J.* AU - de Vries, F.T.* AU - Fiore-Donno, A.M.* AU - Geisen, S.* AU - Goldmann, K.* AU - Merges, A.* AU - Saifutdinov, R.A.* AU - Simons, N.K.* AU - Tobias, J.A.* AU - Zaitsev, A.S.* AU - Gossner, M.M.* AU - Jung, K.* AU - Kandeler, E.* AU - Krauss, J.* AU - Penone, C.* AU - Schloter, M. AU - Schulz, S. AU - Staab, M.* AU - Wolters, V.* AU - Apostolakis, A.* AU - Birkhofer, K.* AU - Boch, S.* AU - Boeddinghaus, R.S.* AU - Bolliger, R.* AU - Bonkowski, M.* AU - Buscot, F.* AU - Dumack, K.* AU - Fischer, M.* AU - Gan, H.Y.* AU - Heinze, J.* AU - Hölzel, N.* AU - John, K.* AU - Klaus, V.H.* AU - Kleinebecker, T.* AU - Marhan, S.* AU - Müller, J.* AU - Renner, S.C.* AU - Rillig, M.C.* AU - Schenk, N.V.* AU - Schöning, I.* AU - Schrumpf, M.* AU - Seibold, S.* AU - Socher, S.A.* AU - Solly, E.F.* AU - Teuscher, M.* AU - van Kleunen, M.* AU - Wubet, T.* AU - Manning, P.* C1 - 69935 C2 - 55325 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - A slow-fast trait continuum at the whole community level in relation to land-use intensification. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Isolated REM Sleep Behavior Disorder (iRBD) is considered a prodrome of Parkinson's disease (PD). We investigate whether the potentially disease-modifying compound acetyl-DL-leucine (ADLL; 5 g/d) has an effect on prodromal PD progression in 2 iRBD-patients. Outcome parameters are RBD-severity sum-score (RBD-SS-3), dopamine-transporter single-photon emission computerized tomography (DAT-SPECT) and metabolic "Parkinson-Disease-related-Pattern (PDRP)"-z-score in 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). After 3 weeks ADLL-treatment, the RBD-SS-3 drops markedly in both patients and remains reduced for >18 months of ADLL-treatment. In patient 1 (female), the DAT-SPECT putaminal binding ratio (PBR) decreases in the 5 years pretreatment from normal (1.88) to pathological (1.22) and the patient's FDG-PET-PDRP-z-score rises from 1.72 to 3.28 (pathological). After 22 months of ADLL-treatment, the DAT-SPECT-PBR increases to 1.67 and the FDG-PET-PDRP-z-score stabilizes at 3.18. Similar results are seen in patient 2 (male): his DAT-SPECT-PBR rises from a pretreatment value of 1.42 to 1.72 (close to normal) and the FDG-PET-PDRP-z-score decreases from 1.02 to 0.30 after 18 months of ADLL-treatment. These results support exploration of whether ADLL may have disease-modifying properties in prodromal PD. AU - Oertel, W.H. AU - Janzen, A.* AU - Henrich, M.T.* AU - Geibl, F.F.* AU - Sittig, E.* AU - Meles, S.K.* AU - Carli, G.* AU - Leenders, K.L.* AU - Booij, J.* AU - Surmeier, D.J.* AU - Timmermann, L.* AU - Strupp, M.* C1 - 71617 C2 - 56312 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Acetyl-DL-leucine in two individuals with REM sleep behavior disorder improves symptoms, reverses loss of striatal dopamine-transporter binding and stabilizes pathological metabolic brain pattern-case reports. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Immune checkpoint blockade therapy aims to activate the immune system to eliminate cancer cells. However, clinical benefits are only recorded in a subset of patients. Here, we leverage genome-wide CRISPR/Cas9 screens in a Tumor-Immune co-Culture System focusing on triple-negative breast cancer (TNBC). We reveal that NEDD8 loss in cancer cells causes a vulnerability to nivolumab (anti-PD-1). Genetic deletion of NEDD8 only delays cell division initially but cell proliferation is unaffected after recovery. Since the NEDD8 gene is commonly essential, we validate this observation with additional CRISPR screens and uncover enhanced immunogenicity in NEDD8 deficient cells using proteomics. In female immunocompetent mice, PD-1 blockade lacks efficacy against established EO771 breast cancer tumors. In contrast, we observe tumor regression mediated by CD8+ T cells against Nedd8 deficient EO771 tumors after PD-1 blockade. In essence, we provide evidence that NEDD8 is conditionally essential in TNBC and presents as a synergistic drug target for PD-1/L1 blockade therapy. AU - Papakyriacou, I.* AU - Kutkaite, G. AU - Rúbies Bedós, M.* AU - Nagarajan, D.* AU - Alford, L.P.* AU - Menden, M.P. AU - Mao, Y.* C1 - 70548 C2 - 55667 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Loss of NEDD8 in cancer cells causes vulnerability to immune checkpoint blockade in triple-negative breast cancer. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Despite significant research, mechanisms underlying the failure of islet beta cells that result in type 2 diabetes (T2D) are still under investigation. Here, we report that Sox9, a transcriptional regulator of pancreas development, also functions in mature beta cells. Our results show that Sox9-depleted rodent beta cells have defective insulin secretion, and aging animals develop glucose intolerance, mimicking the progressive degeneration observed in T2D. Using genome editing in human stem cells, we show that beta cells lacking SOX9 have stunted first-phase insulin secretion. In human and rodent cells, loss of Sox9 disrupts alternative splicing and triggers accumulation of non-functional isoforms of genes with key roles in beta cell function. Sox9 depletion reduces expression of protein-coding splice variants of the serine-rich splicing factor arginine SRSF5, a major splicing enhancer that regulates alternative splicing. Our data highlight the role of SOX9 as a regulator of alternative splicing in mature beta cell function. AU - Puri, S.* AU - Maachi, H. AU - Nair, G.* AU - Russ, H.A.* AU - Chen, R.* AU - Pulimeno, P.* AU - Cutts, Z.* AU - Ntranos, V.* AU - Hebrok, M. C1 - 69819 C2 - 55265 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Sox9 regulates alternative splicing and pancreatic beta cell function. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Transition from traditional high-fiber to Western diets in urbanizing communities of Sub-Saharan Africa is associated with increased risk of non-communicable diseases (NCD), exemplified by colorectal cancer (CRC) risk. To investigate how urbanization gives rise to microbial patterns that may be amenable by dietary intervention, we analyzed diet intake, fecal 16 S bacteriome, virome, and metabolome in a cross-sectional study in healthy rural and urban Xhosa people (South Africa). Urban Xhosa individuals had higher intakes of energy (urban: 3,578 ± 455; rural: 2,185 ± 179 kcal/d), fat and animal protein. This was associated with lower fecal bacteriome diversity and a shift from genera favoring degradation of complex carbohydrates (e.g., Prevotella) to taxa previously shown to be associated with bile acid metabolism and CRC. Urban Xhosa individuals had higher fecal levels of deoxycholic acid, shown to be associated with higher CRC risk, but similar short-chain fatty acid concentrations compared with rural individuals. Fecal virome composition was associated with distinct gut bacterial communities across urbanization, characterized by different dominant host bacteria (urban: Bacteriodota; rural: unassigned taxa) and variable correlation with fecal metabolites and dietary nutrients. Food and skin microbiota samples showed compositional differences along the urbanization gradient. Rural-urban dietary transition in South Africa is linked to major changes in the gut microbiome and metabolome. Further studies are needed to prove cause and identify whether restoration of specific components of the traditional diet will arrest the accelerating rise in NCDs in Sub-Saharan Africa. AU - Ramaboli, M.C.* AU - Ocvirk, S.* AU - Khan Mirzaei, M. AU - Eberhart, B.L.* AU - Valdivia-Garcia, M.* AU - Metwaly, A.* AU - Neuhaus, K.* AU - Barker, G.* AU - Ru, J. AU - Nesengani, L.T.* AU - Mahdi-Joest, D.* AU - Wilson, A.S.* AU - Joni, S.K.* AU - Layman, D.C.* AU - Zheng, J.* AU - Mandal, R.* AU - Chen, Q.* AU - Perez, M.R.* AU - Fortuin, S.* AU - Gaunt, B.* AU - Wishart, D.* AU - Methé, B.* AU - Haller, D.* AU - Li, J.V.* AU - Deng, L. AU - Swart, R.* AU - O'Keefe, S.J.D.* C1 - 70529 C2 - 55645 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Diet changes due to urbanization in South Africa are linked to microbiome and metabolome signatures of Westernization and colorectal cancer. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Brain organoids offer unprecedented insights into brain development and disease modeling and hold promise for drug screening. Significant hindrances, however, are morphological and cellular heterogeneity, inter-organoid size differences, cellular stress, and poor reproducibility. Here, we describe a method that reproducibly generates thousands of organoids across multiple hiPSC lines. These High Quantity brain organoids (Hi-Q brain organoids) exhibit reproducible cytoarchitecture, cell diversity, and functionality, are free from ectopically active cellular stress pathways, and allow cryopreservation and re-culturing. Patient-derived Hi-Q brain organoids recapitulate distinct forms of developmental defects: primary microcephaly due to a mutation in CDK5RAP2 and progeria-associated defects of Cockayne syndrome. Hi-Q brain organoids displayed a reproducible invasion pattern for a given patient-derived glioma cell line. This enabled a medium-throughput drug screen to identify Selumetinib and Fulvestrant, as inhibitors of glioma invasion in vivo. Thus, the Hi-Q approach can easily be adapted to reliably harness brain organoids' application for personalized neurogenetic disease modeling and drug discovery. AU - Ramani, A.* AU - Pasquini, G.* AU - Gerkau, N.J.* AU - Jadhav, V.* AU - Vinchure, O.S.* AU - Altinisik, N.* AU - Windoffer, H.* AU - Müller, S.* AU - Rothenaigner, I. AU - Lin, S. AU - Mariappan, A.* AU - Rathinam, D.* AU - Mirsaidi, A.* AU - Goureau, O.* AU - Ricci-Vitiani, L.* AU - D'Alessandris, Q.G.* AU - Wollnik, B.* AU - Muotri, A.* AU - Freifeld, L.* AU - Jurisch-Yaksi, N.* AU - Pallini, R.* AU - Rose, C.R.* AU - Busskamp, V.* AU - Gabriel, E.* AU - Hadian, K. AU - Gopalakrishnan, J.* C1 - 72869 C2 - 56763 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Reliability of high-quantity human brain organoids for modeling microcephaly, glioma invasion and drug screening. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Endogenous retroviruses (ERVs) are an integral part of the mammalian genome. The role of immune control of ERVs in general is poorly defined as is their function as anti-cancer immune targets or drivers of autoimmune disease. Here, we generate mouse-strains where Moloney-Murine Leukemia Virus tagged with GFP (ERV-GFP) infected the mouse germline. This enables us to analyze the role of genetic, epigenetic and cell intrinsic restriction factors in ERV activation and control. We identify an autoreactive B cell response against the neo-self/ERV antigen GFP as a key mechanism of ERV control. Hallmarks of this response are spontaneous ERV-GFP+ germinal center formation, elevated serum IFN-γ levels and a dependency on Age-associated B cells (ABCs) a subclass of T-bet+ memory B cells. Impairment of IgM B cell receptor-signal in nucleic-acid sensing TLR-deficient mice contributes to defective ERV control. Although ERVs are a part of the genome they break immune tolerance, induce immune surveillance against ERV-derived self-antigens and shape the host immune response. AU - Rauch, E.* AU - Amendt, T.* AU - Lopez Krol, A.* AU - Lang, F.B.* AU - Linse, V.* AU - Hohmann, M.* AU - Keim, A.C.* AU - Kreutzer, S.* AU - Kawengian, K.* AU - Buchholz, M.* AU - Duschner, P.* AU - Grauer, S.* AU - Schnierle, B.* AU - Ruhl, A.* AU - Burtscher, I. AU - Dehnert, S.* AU - Kuria, C.* AU - Kupke, A.* AU - Paul, S.* AU - Liehr, T.* AU - Lechner, M.* AU - Schnare, M.* AU - Kaufmann, A.* AU - Huber, M.* AU - Winkler, T.H.* AU - Bauer, S.* AU - Yu, P.* C1 - 69943 C2 - 55329 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - T-bet+ B cells are activated by and control endogenous retroviruses through TLR-dependent mechanisms. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - In obesity, sustained adipose tissue (AT) inflammation constitutes a cellular memory that limits the effectiveness of weight loss interventions. Yet, the impact of fasting regimens on the regulation of AT immune infiltration is still elusive. Here we show that intermittent fasting (IF) exacerbates the lipid-associated macrophage (LAM) inflammatory phenotype of visceral AT in obese mice. Importantly, this increase in LAM abundance is strongly p53 dependent and partly mediated by p53-driven adipocyte apoptosis. Adipocyte-specific deletion of p53 prevents LAM accumulation during IF, increases the catabolic state of adipocytes, and enhances systemic metabolic flexibility and insulin sensitivity. Finally, in cohorts of obese/diabetic patients, we describe a p53 polymorphism that links to efficacy of a fasting-mimicking diet and that the expression of p53 and TREM2 in AT negatively correlates with maintaining weight loss after bariatric surgery. Overall, our results demonstrate that p53 signalling in adipocytes dictates LAM accumulation in AT under IF and modulates fasting effectiveness in mice and humans. AU - Reinisch, I.* AU - Michenthaler, H.* AU - Sulaj, A. AU - Moyschewitz, E.* AU - Krstic, J.* AU - Galhuber, M.* AU - Xu, R.* AU - Riahi, Z.* AU - Wang, T.* AU - Vujić, N.* AU - Amor, M.* AU - Zenezini Chiozzi, R.* AU - Wabitsch, M.* AU - Kolb, D.* AU - Georgiadi, A. AU - Glawitsch, L.* AU - Heitzer, E.* AU - Schulz, T.J.* AU - Schupp, M.* AU - Sun, W.* AU - Dong, H.* AU - Ghosh, A.* AU - Hoffmann, A. AU - Kratky, D.* AU - Hinte, L.C.* AU - von Meyenn, F.* AU - Heck, A.J.R.* AU - Blüher, M.* AU - Herzig, S. AU - Wolfrum, C.* AU - Prokesch, A.* C1 - 69979 C2 - 55347 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Adipocyte p53 coordinates the response to intermittent fasting by regulating adipose tissue immune cell landscape. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - A key challenge for bottom-up synthetic biology is engineering a minimal module for self-division of synthetic cells. Actin-based cytokinetic rings are considered a promising structure to produce the forces required for the controlled excision of cell-like compartments such as giant unilamellar vesicles (GUVs). Despite prior demonstrations of actin ring targeting to GUV membranes and myosin-induced constriction, large-scale vesicle deformation has been precluded due to the lacking spatial control of these contractile structures. Here we show the combined reconstitution of actomyosin rings and the bacterial MinDE protein system within GUVs. Incorporating this spatial positioning tool, able to induce active transport of membrane-attached diffusible molecules, yields self-organized equatorial assembly of actomyosin rings in vesicles. Remarkably, the synergistic effect of Min oscillations and the contractility of actomyosin bundles induces mid-vesicle deformations and vesicle blebbing. Our system showcases how functional machineries from various organisms may be combined in vitro, leading to the emergence of functionalities towards a synthetic division system. AU - Reverte-López, M.* AU - Kanwa, N.* AU - Qutbuddin, Y.* AU - Belousova, V.* AU - Jasnin, M. AU - Schwille, P.* C1 - 72586 C2 - 56652 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Self-organized spatial targeting of contractile actomyosin rings for synthetic cell division. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Complications of diabetes are often attributed to glucose and reactive dicarbonyl metabolites derived from glycolysis or gluconeogenesis, such as methylglyoxal. However, in the CNS, neurons and endothelial cells use lactate as energy source in addition to glucose, which does not lead to the formation of methylglyoxal and has previously been considered a safer route of energy consumption than glycolysis. Nevertheless, neurons and endothelial cells are hotspots for the cellular pathology underlying neurological complications in diabetes, suggesting a cause that is distinct from other diabetes complications and independent of methylglyoxal. Here, we show that in clinical and experimental diabetes plasma concentrations of dimethylglyoxal are increased. In a mouse model of diabetes, ilvb acetolactate-synthase-like (ILVBL, HACL2) is the enzyme involved in formation of increased amounts of dimethylglyoxal from lactate-derived pyruvate. Dimethylglyoxal reacts with lysine residues, forms Nε-3-hydroxy-2-butanonelysine (HBL) as an adduct, induces oxidative stress more strongly than other dicarbonyls, causes blood-brain barrier disruption, and can mimic mild cognitive impairment in experimental diabetes. These data suggest dimethylglyoxal formation as a pathway leading to neurological complications in diabetes that is distinct from other complications. Importantly, dimethylglyoxal formation can be reduced using genetic, pharmacological and dietary interventions, offering new strategies for preventing CNS dysfunction in diabetes. AU - Rhein, S.* AU - Costalunga, R.* AU - Inderhees, J.* AU - Gürtzgen, T.* AU - Faupel, T.C.* AU - Shaheryar, Z.* AU - Arrulo Pereira, A.* AU - Othman, A.* AU - Begemann, K.* AU - Binder, S.* AU - Stölting, I.* AU - Dorta, V.* AU - Nawroth, P.P.* AU - Fleming, T.* AU - Oexle, K. AU - Prévot, V.* AU - Nogueiras, R.* AU - Meyhöfer, S.* AU - Meyhöfer, S.M.* AU - Schwaninger, M.* C1 - 71096 C2 - 55913 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - The reactive pyruvate metabolite dimethylglyoxal mediates neurological consequences of diabetes. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Plant endogenous signaling peptides shape growth, development and adaptations to biotic and abiotic stress. Here, we identify C-TERMINALLY ENCODED PEPTIDEs (CEPs) as immune-modulatory phytocytokines in Arabidopsis thaliana. Our data reveals that CEPs induce immune outputs and are required to mount resistance against the leaf-infecting bacterial pathogen Pseudomonas syringae pv. tomato. We show that effective immunity requires CEP perception by tissue-specific CEP RECEPTOR 1 (CEPR1) and CEPR2. Moreover, we identify the related RECEPTOR-LIKE KINASE 7 (RLK7) as a CEP4-specific CEP receptor contributing to CEP-mediated immunity, suggesting a complex interplay of multiple CEP ligands and receptors in different tissues during biotic stress. CEPs have a known role in the regulation of root growth and systemic nitrogen (N)-demand signaling. We provide evidence that CEPs and their receptors promote immunity in an N status-dependent manner, suggesting a previously unknown molecular crosstalk between plant nutrition and cell surface immunity. We propose that CEPs and their receptors are central regulators for the adaptation of biotic stress responses to plant-available resources. AU - Rzemieniewski, J.* AU - Leicher, H.* AU - Lee, H.K.* AU - Broyart, C.* AU - Nayem, S. AU - Wiese, C.* AU - Maroschek, J.* AU - Camgöz, Z.* AU - Olsson Lalun, V.* AU - Djordjevic, M.A.* AU - Vlot, A.C. AU - Hückelhoven, R.* AU - Santiago, J.* AU - Stegmann, M.* C1 - 72840 C2 - 56744 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - CEP signaling coordinates plant immunity with nitrogen status. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Polycystic ovary syndrome (PCOS) is a heterogeneous condition, defined by oligo-/anovulation, hyper-androgenism and/or polycystic ovaries. Metabolic complications are common in patients suffering PCOS, including obesity, insulin resistance and type-2 diabetes, which severely compromise the clinical course of affected women. Yet, therapeutic options remain mostly symptomatic and of limited efficacy for the metabolic and reproductive alterations of PCOS. We report here the hormonal, metabolic and gonadal responses to the glucagon-like peptide-1 (GLP1)-based multi-agonists, GLP1/Estrogen (GLP1/E), GLP1/gastric inhibitory peptide (GLP1/GIP) and GLP1/GIP/Glucagon, in two mouse PCOS models, with variable penetrance of metabolic and reproductive traits, and their comparison with metformin. Our data illustrate the superior efficacy of GLP1/E vs. other multi-agonists and metformin in the management of metabolic complications of PCOS; GLP1/E ameliorates also ovarian cyclicity in an ovulatory model of PCOS, without direct estrogenic uterotrophic effects. In keeping with GLP1-mediated brain targeting, quantitative proteomics reveals changes in common and distinct hypothalamic pathways in response to GLP1/E between the two PCOS models, as basis for differential efficiency. Altogether, our data set the basis for the use of GLP1-based multi-agonists, and particularly GLP1/E, in the personalized management of PCOS. AU - Sanchez-Garrido, M.A.* AU - Serrano-López, V.* AU - Ruiz-Pino, F.* AU - Vázquez, M.J.* AU - Rodríguez-Martín, A.* AU - Torres, E.* AU - Velasco, I.* AU - Rodríguez, A.B.* AU - Chicano-Gálvez, E.* AU - Mora-Ortiz, M.* AU - Ohlsson, C.* AU - Poutanen, M.* AU - Pinilla, L.* AU - Gaytán, F.* AU - Douros, J.D.* AU - Yang, B.* AU - Müller, T.D. AU - DiMarchi, R.D.* AU - Tschöp, M.H. AU - Finan, B.* AU - Tena-Sempere, M.* C1 - 71901 C2 - 56486 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Superior metabolic improvement of polycystic ovary syndrome traits after GLP1-based multi-agonist therapy. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - The yellow fever 17D vaccine (YF17D) is highly effective but is frequently administered to individuals with pre-existing cross-reactive immunity, potentially impacting their immune responses. Here, we investigate the impact of pre-existing flavivirus immunity induced by the tick-borne encephalitis virus (TBEV) vaccine on the response to YF17D vaccination in 250 individuals up to 28 days post-vaccination (pv) and 22 individuals sampled one-year pv. Our findings indicate that previous TBEV vaccination does not affect the early IgM-driven neutralizing response to YF17D. However, pre-vaccination sera enhance YF17D virus infection in vitro via antibody-dependent enhancement (ADE). Following YF17D vaccination, TBEV-pre-vaccinated individuals develop high amounts of cross-reactive IgG antibodies with poor neutralizing capacity. In contrast, TBEV-unvaccinated individuals elicit a non-cross-reacting neutralizing response. Using YF17D envelope protein mutants displaying different epitopes, we identify quaternary dimeric epitopes as the primary target of neutralizing antibodies. Additionally, TBEV-pre-vaccination skews the IgG response towards the pan-flavivirus fusion loop epitope (FLE), capable of mediating ADE of dengue and Zika virus infections in vitro. Together, we propose that YF17D vaccination conceals the FLE in individuals without prior flavivirus exposure but favors a cross-reactive IgG response in TBEV-pre-vaccinated recipients directed to the FLE with potential to enhance dengue virus infection. AU - Santos-Peral, A.* AU - Luppa, F.* AU - Goresch, S.* AU - Nikolova, E.* AU - Zaucha, M.* AU - Lehmann, L.* AU - Dahlstroem, F.* AU - Karimzadeh, H.* AU - Thorn-Seshold, J.* AU - Winheim, E.* AU - Schuster, E.M.* AU - Dobler, G.* AU - Hoelscher, M.* AU - Kümmerer, B.M.* AU - Endres, S. AU - Schober, K.* AU - Krug, A.B.* AU - Pritsch, M.* AU - Barba-Spaeth, G.* AU - Rothenfußer, S. C1 - 70030 C2 - 55366 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Prior flavivirus immunity skews the yellow fever vaccine response to cross-reactive antibodies with potential to enhance dengue virus infection. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Real-time genomics through nanopore sequencing holds the promise of fast antibiotic resistance prediction directly in the clinical setting. However, concerns about the accuracy of genomics-based resistance predictions persist, particularly when compared to traditional, clinically established diagnostic methods. Here, we leverage the case of a multi-drug resistant Klebsiella pneumoniae infection to demonstrate how real-time genomics can enhance the accuracy of antibiotic resistance profiling in complex infection scenarios. Our results show that unlike established diagnostics, nanopore sequencing data analysis can accurately detect low-abundance plasmid-mediated resistance, which often remains undetected by conventional methods. This capability has direct implications for clinical practice, where such "hidden" resistance profiles can critically influence treatment decisions. Consequently, the rapid, in situ application of real-time genomics holds significant promise for improving clinical decision-making and patient outcomes. AU - Sauerborn, E. AU - Corredor, N.C.* AU - Reska, T.T.M. AU - Perlas Puente,A. AU - Vargas da Fonseca Atum, S. AU - Goldman, N.* AU - Wantia, N.* AU - Prazeres da Costa, C.U.* AU - Foster-Nyarko, E.* AU - Urban, L. C1 - 70958 C2 - 55835 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Detection of hidden antibiotic resistance through real-time genomics. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - DNA catalysts, known as DNAzymes, have arguably been limited for decades by the lack of mechanistic information. The solution structure of the 8–17 DNAzyme reported by Wieruszekska, Pwlowicz et al. reassesses the current thinking regarding the relationship between structure, dynamic, and metal ion coordination. AU - Schmuck, J.F.* AU - Borggräfe, J. AU - Etzkorn, M.* C1 - 70872 C2 - 55775 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - The dynamic world of the 8-17 DNAzyme. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Correction to: Nature Communicationshttps://doi.org/10.1038/s41467-023-40599-x, published online 24 August 2023 The original version of this Article omitted from the author list the 17th author, “Multi-Country Multi-City (MCC) collaborative research network”, which is the consortium providing the mortality data. A list of consortium authors and their affiliations are provided in the HTML version of this Correction. Part of the Author Contributions statement was incorrectly given and should have read ‘A.M.V.C., E.M.F., B.A., M.D.S.Z.S.C., Y.L.G., Y.G., Y.H., V.H., J.K., E.L., D.R., N.R., N.S., S.S., A.U., A.G. and the MCC were involved in resources and data curation.’ In addition, the primary affiliation ‘Climate Research Foundation (FIC), Madrid, Spain’ for Dominic Roye was missing. AU - Multi-Country Multi-City (MCC) Collaborative Research Network (Schneider, A.E.) C1 - 71856 C2 - 56294 TI - Correction to: Rapid increase in the risk of heat-related mortality (Nature Communications, (2023), 14, 1, (4894), 10.1038/s41467-023-40599-x). JO - Nat. Commun. VL - 15 IS - 1 PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research. AU - Scholz, M.* AU - Horn, K.* AU - Pott, J.* AU - Wuttke, M.* AU - Kühnapfel, A.* AU - Nasr, M.K.* AU - Kirsten, H.* AU - Li, Y.* AU - Hoppmann, A.* AU - Gorski, M.* AU - Ghasemi, S.* AU - Li, M.* AU - Tin, A.* AU - Chai, J.F.* AU - Cocca, M.* AU - Wang, J.* AU - Nutile, T.* AU - Akiyama, M.* AU - Åsvold, B.O.* AU - Bansal, N.* AU - Biggs, M.L.* AU - Boutin, T.* AU - Brenner, H.* AU - Brumpton, B.* AU - Burkhardt, R.* AU - Cai, J.* AU - Campbell, A.* AU - Campbell, H.* AU - Chalmers, J.* AU - Chasman, D.I.* AU - Chee, M.L.* AU - Chen, X.* AU - Cheng, C.Y.* AU - Cifkova, R.* AU - Daviglus, M.* AU - Delgado, G.* AU - Dittrich, K.* AU - Edwards, T.L.* AU - Endlich, K.* AU - Michael Gaziano, J.* AU - Giri, A.* AU - Giulianini, F.* AU - Gordon, S.D.* AU - Gudbjartsson, D.F.* AU - Hallan, S.* AU - Hamet, P.* AU - Hartman, C.A.* AU - Hayward, C.* AU - Heid, I.M.* AU - Hellwege, J.N.* AU - Holleczek, B.* AU - Holm, H.* AU - Hutri-Kähönen, N.* AU - Hveem, K.* AU - Isermann, B.* AU - Jonas, J.B.* AU - Joshi, P.K.* AU - Kamatani, Y.* AU - Kanai, M.* AU - Kastarinen, M.* AU - Khor, C.C.* AU - Kiess, W.* AU - Kleber, M.E.* AU - Körner, A. AU - Kovacs, P.* AU - Krajcoviechova, A.* AU - Kramer, H.* AU - Krämer, B.K.* AU - Kuokkanen, M.* AU - Kähönen, M.* AU - Lange, L.A.* AU - Lash, J.P.* AU - Lehtimäki, T.* AU - Li, H.* AU - Lin, B.M.* AU - Liu, J.* AU - Loeffler, M.* AU - Lyytikäinen, L.P.* AU - Magnusson, P.K.E.* AU - Martin, N.G.* AU - Matsuda, K.* AU - Milaneschi, Y.* AU - Mishra, P.P.* AU - Mononen, N.* AU - Montgomery, G.W.* AU - Mook-Kanamori, D.O.* AU - Mychaleckyj, J.C.* AU - März, W.* AU - Nauck, M.* AU - Nikus, K.* AU - Nolte, I.M.* AU - Noordam, R.* AU - Okada, Y.* AU - Olafsson, I.* AU - Oldehinkel, A.J.* AU - Penninx, B.W.J.H.* AU - Perola, M.* AU - Pirastu, N.* AU - Polasek, O.* AU - Porteous, D.J.* AU - Poulain, T.* AU - Psaty, B.M.* AU - Rabelink, T.J.* AU - Raffield, L.M.* AU - Raitakari, O.T.* AU - Rasheed, H.* AU - Reilly, D.F.* AU - Rice, K.M.* AU - Richmond, A.* AU - Ridker, P.M.* AU - Rotter, J.I.* AU - Rudan, I.* AU - Sabanayagam, C.* AU - Salomaa, V.* AU - Schneiderman, N.* AU - Schöttker, B.* AU - Sims, M.* AU - Snieder, H.* AU - Stark, K.J.* AU - Stefansson, K.* AU - Stocker, H.* AU - Stumvoll, M.* AU - Sulem, P.* AU - Sveinbjornsson, G.* AU - Svensson, P.O.* AU - Tai, E.S.* AU - Taylor, K.D.* AU - Tayo, B.O.* AU - Teren, A.* AU - Tham, Y.C.* AU - Thiery, J.* AU - Thio, C.H.L.* AU - Thomas, L.F.* AU - Tremblay, J.* AU - Tönjes, A.* AU - van der Most, P.J.* AU - Vitart, V.* AU - Völker, U.* AU - Wang, Y.X.* AU - Wang, C.* AU - Wei, W.B.* AU - Whitfield, J.B.* AU - Wild, S.H.* AU - Wilson, J.F.* AU - Winkler, T.W.* AU - Wong, T.Y.* AU - Woodward, M.* AU - Sim, X.* AU - Chu, A.Y.* AU - Feitosa, M.F.* AU - Thorsteinsdottir, U.* AU - Hung, A.M.* AU - Teumer, A.* AU - Franceschini, N.* AU - Parsa, A.* AU - Köttgen, A.* AU - Schlosser, P.* AU - Pattaro, C.* C1 - 69823 C2 - 55267 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - X-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Many enzymes assemble into homomeric protein complexes comprising multiple copies of one protein. Because structural form is usually assumed to follow function in biochemistry, these assemblies are thought to evolve because they provide some functional advantage. In many cases, however, no specific advantage is known and, in some cases, quaternary structure varies among orthologs. This has led to the proposition that self-assembly may instead vary neutrally within protein families. The extent of such variation has been difficult to ascertain because quaternary structure has until recently been difficult to measure on large scales. Here, we employ mass photometry, phylogenetics, and structural biology to interrogate the evolution of homo-oligomeric assembly across the entire phylogeny of prokaryotic citrate synthases - an enzyme with a highly conserved function. We discover a menagerie of different assembly types that come and go over the course of evolution, including cases of parallel evolution and reversions from complex to simple assemblies. Functional experiments in vitro and in vivo indicate that evolutionary transitions between different assemblies do not strongly influence enzyme catalysis. Our work suggests that enzymes can wander relatively freely through a large space of possible assembly states and demonstrates the power of characterizing structure-function relationships across entire phylogenies. AU - Sendker, F.L.* AU - Schlotthauer, T.* AU - Mais, C.N.* AU - Lo, Y.K.* AU - Girbig, M.* AU - Bohn, S. AU - Heimerl, T.* AU - Schindler, D.* AU - Weinstein, A.* AU - Metzger, B.P.H.* AU - Thornton, J.W.* AU - Pillai, A.* AU - Bange, G.* AU - Schuller, J.M.* AU - Hochberg, G.K.A.* C1 - 72620 C2 - 56668 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Frequent transitions in self-assembly across the evolution of a central metabolic enzyme. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Spatial and genomic heterogeneity of tumors are crucial factors influencing cancer progression, treatment, and survival. However, a technology for direct mapping the clones in the tumor tissue based on somatic point mutations is lacking. Here, we propose Tumoroscope, the first probabilistic model that accurately infers cancer clones and their localization in close to single-cell resolution by integrating pathological images, whole exome sequencing, and spatial transcriptomics data. In contrast to previous methods, Tumoroscope explicitly addresses the problem of deconvoluting the proportions of clones in spatial transcriptomics spots. Applied to a reference prostate cancer dataset and a newly generated breast cancer dataset, Tumoroscope reveals spatial patterns of clone colocalization and mutual exclusion in sub-areas of the tumor tissue. We further infer clone-specific gene expression levels and the most highly expressed genes for each clone. In summary, Tumoroscope enables an integrated study of the spatial, genomic, and phenotypic organization of tumors. AU - Shafighi, S.* AU - Geras, A.* AU - Jurzysta, B.* AU - Sahaf Naeini, A.* AU - Filipiuk, I.* AU - Ra Czkowska, A.* AU - Toosi, H.* AU - Koperski, L.* AU - Thrane, K.* AU - Engblom, C.* AU - Mold, J.E.* AU - Chen, X.* AU - Hartman, J.* AU - Nowis, D.* AU - Carbone, A.* AU - Lagergren, J.* AU - Szczurek, E. C1 - 72197 C2 - 56477 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Integrative spatial and genomic analysis of tumor heterogeneity with Tumoroscope. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Correction to: Nature Communicationshttps://doi.org/10.1038/s41467-018-08152-3, published online 24 January 2019 The original version of the manuscript contained errors in Figure 4 and Supplementary Figs. 1a and 2d. In detail: In Figure 4h, the sphere images “PS+Dox” and PS-Dox” were inadvertently duplicated. In Figure 4e, the label for the second row of blots should read “XBP1” instead of “XBP1s” In Supplementary Fig. 1a, the duplicated first and last bands of the IRE1α blots were due to an incorrect selection of lanes from the original full blots. In the same figure, the correct IRE1α bands of the C4-2B samples are now also shown. In Supplementary Fig. 2d, the incorrect western blot image for IRE1α and GAPDH in 22Rv1 cells were presented. In Figure 4h, the sphere images “PS+Dox” and PS-Dox” were inadvertently duplicated. In Figure 4e, the label for the second row of blots should read “XBP1” instead of “XBP1s” In Supplementary Fig. 1a, the duplicated first and last bands of the IRE1α blots were due to an incorrect selection of lanes from the original full blots. In the same figure, the correct IRE1α bands of the C4-2B samples are now also shown. In Supplementary Fig. 2d, the incorrect western blot image for IRE1α and GAPDH in 22Rv1 cells were presented. The updated Figure 4 is shown below and the updated Supplementary Information file can be found online associated with this correction. The raw data of Figure 4h and the full blots of Supplementary Fig. 1a and Supplementary Fig. 2d are also available at Figshare: https://figshare.com/articles/figure/Raw_data_for_Sheng_et_al_2019_Erratum_zip/25790655. Please also note that for all western blots, in order to analyze multiple proteins, the same samples were run on multiple gels and blotted with different antibodies. This information should have been included in the “Methods” section. AU - Sheng, X.* AU - Nenseth, H.Z.* AU - Qu, S.* AU - Kuzu, O.F.* AU - Frahnow, T. AU - Simon, L. AU - Greene, S.* AU - Zeng, Q.* AU - Fazli, L.* AU - Rennie, P.S.* AU - Mills, I.G.* AU - Danielsen, H.* AU - Theis, F.J. AU - Patterson, J.B.* AU - Jin, Y.* AU - Saatcioglu, F.* C1 - 71281 C2 - 56000 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Author Correction: IRE1α-XBP1s pathway promotes prostate cancer by activating c-MYC signaling. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases. AU - Sterenborg, R.B.T.M.* AU - Steinbrenner, I.* AU - Li, Y.* AU - Bujnis, M.N.* AU - Naito, T.* AU - Marouli, E.* AU - Galesloot, T.E.* AU - Babajide, O.* AU - Andreasen, L.* AU - Astrup, A.* AU - Asvold, B.O.* AU - Bandinelli, S.* AU - Beekman, M.* AU - Beilby, J.P.* AU - Bork-Jensen, J.* AU - Boutin, T.* AU - Brody, J.A.* AU - Brown, S.J.* AU - Brumpton, B.* AU - Campbell, P.J.* AU - Cappola, A.R.* AU - Ceresini, G.* AU - Chaker, L.* AU - Chasman, D.I.* AU - Concas, M.P.* AU - Coutinho de Almeida, R.* AU - Cross, S.M.* AU - Cucca, F.* AU - Deary, I.J.* AU - Kjaergaard, A.D.* AU - Echouffo Tcheugui, J.B.* AU - Ellervik, C.* AU - Eriksson, J.G.* AU - Ferrucci, L.* AU - Freudenberg, J.M.* AU - Fuchsberger, C.* AU - Gieger, C. AU - Giulianini, F.* AU - Gögele, M.* AU - Graham, S.E.* AU - Grarup, N.* AU - Gunjača, I.* AU - Hansen, T.* AU - Harding, B.N.* AU - Harris, S.E.* AU - Haunsø, S.* AU - Hayward, C.* AU - Hui, J.* AU - Ittermann, T.* AU - Jukema, J.W.* AU - Kajantie, E.* AU - Kanters, J.K.* AU - Kårhus, L.L.* AU - Kiemeney, L.A.L.M.* AU - Kloppenburg, M.* AU - Kühnel, B. AU - Lahti, J.* AU - Langenberg, C.* AU - Lapauw, B.* AU - Leese, G.* AU - Li, S.* AU - Liewald, D.C.M.* AU - Linneberg, A.* AU - Lominchar, J.V.T.* AU - Luan, J.* AU - Martin, N.G.* AU - Matana, A.* AU - Meima, M.E.* AU - Meitinger, T.* AU - Meulenbelt, I.* AU - Mitchell, B.D.* AU - Møllehave, L.T.* AU - Mora, S.* AU - Naitza, S.* AU - Nauck, M.* AU - Netea-Maier, R.T.* AU - Noordam, R.* AU - Nursyifa, C.* AU - Okada, Y.* AU - Onano, S.* AU - Papadopoulou, A.A.* AU - Palmer, C.N.A.* AU - Pattaro, C.* AU - Pedersen, O.* AU - Peters, A. AU - Pietzner, M.* AU - Polašek, O.* AU - Pramstaller, P.P.* AU - Psaty, B.M.* AU - Punda, A.* AU - Ray, D.* AU - Redmond, P.* AU - Richards, J.B.* AU - Ridker, P.M.* AU - Russ, T.C.* AU - Ryan, K.A.* AU - Olesen, M.S.* AU - Schultheiss, U.T.* AU - Selvin, E.* AU - Siddiqui, M.K.* AU - Sidore, C.* AU - Slagboom, P.E.* AU - Sørensen, T.I.A.* AU - Soto-Pedre, E.* AU - Spector, T.D.* AU - Spedicati, B.* AU - Srinivasan, S.* AU - Starr, J.M.* AU - Stott, D.J.* AU - Tanaka, T.* AU - Torlak, V.* AU - Trompet, S.* AU - Tuhkanen, J.* AU - Uitterlinden, A.G.* AU - van den Akker, E.B.* AU - van den Eynde, T.* AU - van der Klauw, M.M.* AU - van Heemst, D.* AU - Verroken, C.* AU - Visser, W.E.* AU - Vojinovic, D.* AU - Völzke, H.* AU - Waldenberger, M. AU - Walsh, J.P.* AU - Wareham, N.J.* AU - Weiss, S.* AU - Willer, C.J.* AU - Wilson, S.G.* AU - Wolffenbuttel, B.H.R.* AU - Wouters, H.J.C.M.* AU - Wright, M.J.* AU - Yang, Q.* AU - Zemunik, T.* AU - Zhou, W.* AU - Zhu, G.* AU - Zöllner, S.* AU - Smit, J.W.A.* AU - Peeters, R.P.* AU - Köttgen, A.* AU - Teumer, A.* AU - Medici, M.* C1 - 69900 C2 - 55212 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - The biomedical research community addresses reproducibility challenges in animal studies through standardized nomenclature, improved experimental design, transparent reporting, data sharing, and centralized repositories. The ARRIVE guidelines outline documentation standards for laboratory animals in experiments, but genetic information is often incomplete. To remedy this, we propose the Laboratory Animal Genetic Reporting (LAG-R) framework. LAG-R aims to document animals' genetic makeup in scientific publications, providing essential details for replication and appropriate model use. While verifying complete genetic compositions may be impractical, better reporting and validation efforts enhance reliability of research. LAG-R standardization will bolster reproducibility, peer review, and overall scientific rigor. AU - Teboul, L.* AU - Amos-Landgraf, J.* AU - Benavides, F.J.* AU - Birling, M.C.* AU - Brown, S.D.M.* AU - Bryda, E.* AU - Bunton-Stasyshyn, R.* AU - Chin, H.-J.* AU - Crispo, M.* AU - Delerue, F.* AU - Dobbie, M.* AU - Franklin, C.L.* AU - Fuchtbauer, E.-M.* AU - Gao, X.* AU - Golzio, C.* AU - Haffner, R.* AU - Hérault, Y.* AU - Hrabě de Angelis, M. AU - Lloyd, K.C.K.* AU - Magnuson, T.R.* AU - Montoliu, L.* AU - Murray, S.A.* AU - Nam, K.H.* AU - Nutter, L.M.J.* AU - Pailhoux, E.* AU - Pardo Manuel de Villena, F.* AU - Peterson, K.* AU - Reinholdt, L.* AU - Sedlacek, R.* AU - Seong, J.K.* AU - Shiroishi, T.* AU - Smith, C.* AU - Takeo, T.* AU - Tinsley, L.* AU - Vilotte, J.L.* AU - Warming, S.* AU - Wells, S.* AU - Whitelaw, C.B.* AU - Yoshiki, A.* AU - Pavlovic, G.* C1 - 71041 C2 - 55830 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Improving laboratory animal genetic reporting: LAG-R guidelines. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - In this community effort, we compare measurements between 34 laboratories from 19 countries, utilizing mixtures of labelled authentic synthetic standards, to quantify by mass spectrometry four clinically used ceramide species in the NIST (National Institute of Standards and Technology) human blood plasma Standard Reference Material (SRM) 1950, as well as a set of candidate plasma reference materials (RM 8231). Participants either utilized a provided validated method and/or their method of choice. Mean concentration values, and intra- and inter-laboratory coefficients of variation (CV) were calculated using single-point and multi-point calibrations, respectively. These results are the most precise (intra-laboratory CVs ≤ 4.2%) and concordant (inter-laboratory CVs < 14%) community-derived absolute concentration values reported to date for four clinically used ceramides in the commonly analyzed SRM 1950. We demonstrate that calibration using authentic labelled standards dramatically reduces data variability. Furthermore, we show how the use of shared RM can correct systematic quantitative biases and help in harmonizing lipidomics. Collectively, the results from the present study provide a significant knowledge base for translation of lipidomic technologies to future clinical applications that might require the determination of reference intervals (RIs) in various human populations or might need to estimate reference change values (RCV), when analytical variability is a key factor for recall during multiple testing of individuals. AU - Torta, F.* AU - Hoffmann, N.* AU - Burla, B.* AU - Alecu, I.* AU - Arita, M.* AU - Bamba, T.* AU - Bennett, S.A.L.* AU - Bertrand-Michel, J.* AU - Brügger, B.* AU - Cala, M.P.* AU - Camacho-Muñoz, D.* AU - Checa, A.* AU - Chen, M.* AU - Chocholoušková, M.* AU - Cinel, M.* AU - Chu-Van, E.* AU - Colsch, B.* AU - Coman, C.* AU - Connell, L.* AU - Sousa, B.C.* AU - Dickens, A.M.* AU - Fedorova, M.* AU - Eiriksson, F.F.* AU - Gallart-Ayala, H.* AU - Ghorasaini, M.* AU - Giera, M.* AU - Guan, X.L.* AU - Haid, M. AU - Hankemeier, T.* AU - Harms, A.C.* AU - Höring, M.* AU - Holcapek, M.* AU - Hornemann, T.* AU - Hu, C.* AU - Hülsmeier, A.J.* AU - Huynh, K.* AU - Jones, C.M.* AU - Ivanisevic, J.* AU - Izumi, Y.* AU - Köfeler, H.C.* AU - Lam, S.M.* AU - Lange, M.* AU - Lee, J.C.* AU - Liebisch, G.* AU - Lippa, K.* AU - Lopez-Clavijo, A.F.* AU - Manzi, M.* AU - Martinefski, M.R.* AU - Math, R.G.H.* AU - Mayor, S.* AU - Meikle, P.J.* AU - Monge, M.E.* AU - Moon, M.H.* AU - Muralidharan, S.* AU - Nicolaou, A.* AU - Nguyen-Tran, T.* AU - O'Donnell, V.B.* AU - Oresič, M.* AU - Ramanathan, A.* AU - Riols, F. AU - Saigusa, D.* AU - Schock, T.B.* AU - Schwartz-Zimmermann, H.* AU - Shui, G.* AU - Singh, M.* AU - Takahashi, M.* AU - Thorsteinsdóttir, M.* AU - Tomiyasu, N.* AU - Tournadre, A.* AU - Tsugawa, H.* AU - Tyrrell, V.J.* AU - van der Gugten, G.* AU - Wakelam, M.O.* AU - Wheelock, C.E.* AU - Wolrab, D.* AU - Xu, G.* AU - Xu, T.* AU - Bowden, J.A.* AU - Ekroos, K.* AU - Ahrends, R.* AU - Wenk, M.R.* C1 - 71912 C2 - 56535 TI - Concordant inter-laboratory derived concentrations of ceramides in human plasma reference materials via authentic standards. JO - Nat. Commun. VL - 15 IS - 1 PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Stratified medicine holds great promise to tailor treatment to the needs of individual patients. While genetics holds great potential to aid patient stratification, it remains a major challenge to operationalize complex genetic risk factor profiles to deconstruct clinical heterogeneity. Contemporary approaches to this problem rely on polygenic risk scores (PRS), which provide only limited clinical utility and lack a clear biological foundation. To overcome these limitations, we develop the CASTom-iGEx approach to stratify individuals based on the aggregated impact of their genetic risk factor profiles on tissue specific gene expression levels. The paradigmatic application of this approach to coronary artery disease or schizophrenia patient cohorts identified diverse strata or biotypes. These biotypes are characterized by distinct endophenotype profiles as well as clinical parameters and are fundamentally distinct from PRS based groupings. In stark contrast to the latter, the CASTom-iGEx strategy discovers biologically meaningful and clinically actionable patient subgroups, where complex genetic liabilities are not randomly distributed across individuals but rather converge onto distinct disease relevant biological processes. These results support the notion of different patient biotypes characterized by partially distinct pathomechanisms. Thus, the universally applicable approach presented here has the potential to constitute an important component of future personalized medicine paradigms. AU - Trastulla, L.* AU - Dolgalev, G.* AU - Moser, S.* AU - Jiménez-Barrón, L.T.* AU - Andlauer, T.F.M.* AU - von Scheidt, M.* AU - Budde, M.* AU - Heilbronner, U.* AU - Papiol, S.* AU - Teumer, A.* AU - Homuth, G.* AU - Völzke, H.* AU - Dörr, M.* AU - Falkai, P.* AU - Schulze, T.G.* AU - Gagneur, J. AU - Iorio, F.* AU - Müller-Myhsok, B.* AU - Schunkert, H.* AU - Ziller, M.J.* C1 - 71031 C2 - 55869 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Distinct genetic liability profiles define clinically relevant patient strata across common diseases. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - The development of functional neurons is a complex orchestration of multiple signaling pathways controlling cell proliferation and differentiation. Because the balance of antioxidants is important for neuronal survival and development, we hypothesized that ferroptosis must be suppressed to gain neurons. We find that removal of antioxidants diminishes neuronal development and laminar organization of cortical organoids, which is fully restored when ferroptosis is inhibited by ferrostatin-1 or when neuronal differentiation occurs in the presence of vitamin A. Furthermore, iron-overload-induced developmental growth defects in C. elegans are ameliorated by vitamin E and A. We determine that all-trans retinoic acid activates the Retinoic Acid Receptor, which orchestrates the expression of anti-ferroptotic genes. In contrast, retinal and retinol show radical-trapping antioxidant activity. Together, our study reveals an unexpected function of vitamin A in coordinating the expression of essential cellular gatekeepers of ferroptosis, and demonstrates that suppression of ferroptosis by radical-trapping antioxidants or by vitamin A is required to obtain mature neurons and proper laminar organization in cortical organoids. AU - Tschuck, J. AU - Padmanabhan Nair, V. AU - Galhoz, A. AU - Zaratiegui, C. AU - Tai, H.-M. AU - Ciceri, G.* AU - Rothenaigner, I. AU - Tchieu, J.* AU - Stockwell, B.R.* AU - Studer, L.* AU - Cabianca, D.S. AU - Menden, M.P. AU - Vincendeau, M. AU - Hadian, K. C1 - 71614 C2 - 56183 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Suppression of ferroptosis by vitamin A or radical-trapping antioxidants is essential for neuronal development. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - In 2015, we launched the mesoSPIM initiative, an open-source project for making light-sheet microscopy of large cleared tissues more accessible. Meanwhile, the demand for imaging larger samples at higher speed and resolution has increased, requiring major improvements in the capabilities of such microscopes. Here, we introduce the next-generation mesoSPIM ("Benchtop") with a significantly increased field of view, improved resolution, higher throughput, more affordable cost, and simpler assembly compared to the original version. We develop an optical method for testing detection objectives that enables us to select objectives optimal for light-sheet imaging with large-sensor cameras. The improved mesoSPIM achieves high spatial resolution (1.5 µm laterally, 3.3 µm axially) across the entire field of view, magnification up to 20×, and supports sample sizes ranging from sub-mm up to several centimeters while being compatible with multiple clearing techniques. The microscope serves a broad range of applications in neuroscience, developmental biology, pathology, and even physics. AU - Vladimirov, N.* AU - Voigt, F.F.* AU - Naert, T.* AU - Araujo, G.R.* AU - Cai, R. AU - Reuss, A.M.* AU - Zhao, S.* AU - Schmid, P.* AU - Hildebrand, S.* AU - Schaettin, M.* AU - Groos, D.* AU - Mateos, J.M.* AU - Bethge, P.* AU - Yamamoto, T.N.* AU - Aerne, V.* AU - Roebroeck, A.* AU - Ertürk, A. AU - Aguzzi, A.* AU - Ziegler, U.* AU - Stoeckli, E.* AU - Baudis, L.* AU - Lienkamp, S.S.* AU - Helmchen, F.* C1 - 70384 C2 - 55402 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Benchtop mesoSPIM: A next-generation open-source light-sheet microscope for cleared samples. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Innate immune responses are linked to key metabolic pathways, yet the proximal signaling events that connect these systems remain poorly understood. Here we show that phosphofructokinase 1, liver type (PFKL), a rate-limiting enzyme of glycolysis, is phosphorylated at Ser775 in macrophages following several innate stimuli. This phosphorylation increases the catalytic activity of PFKL, as shown by biochemical assays and glycolysis monitoring in cells expressing phosphorylation-defective PFKL variants. Using a genetic mouse model in which PFKL Ser775 phosphorylation cannot take place, we observe that upon activation, glycolysis in macrophages is lower than in the same cell population of wild-type animals. Consistent with their higher glycolytic activity, wild-type cells have higher levels of HIF1α and IL-1β than PfklS775A/S775A after LPS treatment. In an in vivo inflammation model, PfklS775A/S775A mice show reduced levels of MCP-1 and IL-1β. Our study thus identifies a molecular link between innate immune activation and early induction of glycolysis. AU - Wang, M.* AU - Flaswinkel, H.* AU - Joshi, A.* AU - Napoli, M.* AU - Masgrau-Alsina, S.* AU - Kamper, J.M.* AU - Henne, A.* AU - Heinz, A.* AU - Berouti, M.* AU - Schmacke, N.A.* AU - Hiller, K.* AU - Kremmer, E.* AU - Wefers, B. AU - Wurst, W. AU - Sperandio, M.* AU - Ruland, J.* AU - Fröhlich, T.* AU - Hornung, V.* C1 - 71384 C2 - 56086 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Phosphorylation of PFKL regulates metabolic reprogramming in macrophages following pattern recognition receptor activation. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Enhancing thermogenic brown adipose tissue (BAT) function is a promising therapeutic strategy for metabolic disease. However, predominantly thermoneutral modern human living conditions deactivate BAT. We demonstrate that selective adipocyte deficiency of the oxygen-sensor HIF-prolyl hydroxylase (PHD2) gene overcomes BAT dormancy at thermoneutrality. Adipocyte-PHD2-deficient mice maintain higher energy expenditure having greater BAT thermogenic capacity. In human and murine adipocytes, a PHD inhibitor increases Ucp1 levels. In murine brown adipocytes, antagonising the major PHD2 target, hypoxia-inducible factor-(HIF)-2a abolishes Ucp1 that cannot be rescued by PHD inhibition. Mechanistically, PHD2 deficiency leads to HIF2 stabilisation and binding of HIF2 to the Ucp1 promoter, thus enhancing its expression in brown adipocytes. Serum proteomics analysis of 5457 participants in the deeply phenotyped Age, Gene and Environment Study reveal that serum PHD2 associates with increased risk of metabolic disease. Here we show that adipose-PHD2-inhibition is a therapeutic strategy for metabolic disease and identify serum PHD2 as a disease biomarker. AU - Wang, R.* AU - Gomez Salazar, M.* AU - Pruñonosa Cervera, I.* AU - Coutts, A.* AU - French, K.* AU - Pinto, M.M.* AU - Gohlke, S.* AU - Garcia-Martin, R.* AU - Blüher, M. AU - Schofield, C.J.* AU - Kourtzelis, I.* AU - Stimson, R.H.* AU - Bénézech, C.* AU - Christian, M.* AU - Schulz, T.J.* AU - Gudmundsson, E.F.* AU - Jennings, L.L.* AU - Gudnason, V.G.* AU - Chavakis, T. AU - Morton, N.M.* AU - Emilsson, V.* AU - Michailidou, Z.* C1 - 71548 C2 - 56273 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Adipocyte deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Understanding the genetics of kidney function decline, or trait change in general, is hampered by scarce longitudinal data for GWAS (longGWAS) and uncertainty about how to analyze such data. We use longitudinal UK Biobank data for creatinine-based estimated glomerular filtration rate from 348,275 individuals to search for genetic variants associated with eGFR-decline. This search was performed both among 595 variants previously associated with eGFR in cross-sectional GWAS and genome-wide. We use seven statistical approaches to analyze the UK Biobank data and simulated data, finding that a linear mixed model is a powerful approach with unbiased effect estimates which is viable for longGWAS. The linear mixed model identifies 13 independent genetic variants associated with eGFR-decline, including 6 novel variants, and links them to age-dependent eGFR-genetics. We demonstrate that age-dependent and age-independent eGFR-genetics exhibit a differential pattern regarding clinical progression traits and kidney-specific gene expression regulation. Overall, our results provide insights into kidney aging and linear mixed model-based longGWAS generally. AU - Wiegrebe, S.* AU - Gorski, M.* AU - Herold, J.M.* AU - Stark, K.J.* AU - Thorand, B. AU - Gieger, C. AU - Böger, C.A.* AU - Schödel, J.* AU - Härtig, F.* AU - Chen, H.* AU - Winkler, T.W.* AU - Küchenhoff, H.* AU - Heid, I.M.* C1 - 72466 C2 - 56585 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Analyzing longitudinal trait trajectories using GWAS identifies genetic variants for kidney function decline. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Members of the leucine rich repeat (LRR) and PDZ domain (LAP) protein family are essential for animal development and histogenesis. Densin-180, encoded by LRRC7, is the only LAP protein selectively expressed in neurons. Densin-180 is a postsynaptic scaffold at glutamatergic synapses, linking cytoskeletal elements with signalling proteins such as the α-subunit of Ca2+/calmodulin-dependent protein kinase II. We have previously observed an association between high impact variants in LRRC7 and Intellectual Disability; also three individual cases with variants in LRRC7 had been described. We identify here 33 individuals (one of them previously described) with a dominant neurodevelopmental disorder due to heterozygous missense or loss-of-function variants in LRRC7. The clinical spectrum involves intellectual disability, autism, ADHD, aggression and, in several cases, hyperphagia-associated obesity. A PDZ domain variant interferes with synaptic targeting of Densin-180 in primary cultured neurons. Using in vitro systems (two hybrid, BioID, coimmunoprecipitation of tagged proteins from 293T cells) we identified new candidate interaction partners for the LRR domain, including protein phosphatase 1 (PP1), and observed that variants in the LRR reduced binding to these proteins. We conclude that LRRC7 encodes a major determinant of intellectual development and behaviour. AU - Willim, J.* AU - Woike, D.* AU - Greene, D.* AU - Das, S.* AU - Pfeifer, K.* AU - Yuan, W.* AU - Lindsey, A.* AU - Itani, O.* AU - Böhme, A.L.* AU - Tibbe, D.* AU - Hönck, H.H.* AU - Hassani Nia, F.* AU - Zech, M. AU - Brunet, T. AU - Faivre, L.* AU - Sorlin, A.* AU - Vitobello, A.* AU - Smol, T.* AU - Colson, C.* AU - Baranano, K.* AU - Schatz, K.* AU - Bayat, A.* AU - Schoch, K.* AU - Spillmann, R.C.* AU - Davis, E.E.* AU - Conboy, E.* AU - Vetrini, F.* AU - Platzer, K.* AU - Neuser, S.* AU - Gburek-Augustat, J.* AU - Grace, A.N.* AU - Mitchell, B.D.* AU - Stegmann, A.P.* AU - Sinnema, M.* AU - Meeks, N.* AU - Saunders, C.* AU - Cadieux-Dion, M.* AU - Hoyer, J.* AU - Van-Gils, J.* AU - de Sainte-Agathe, J.M.* AU - Thompson, M.L.* AU - Bebin, E.M.* AU - Weisz-Hubshman, M.* AU - Tabet, A.C.* AU - Verloes, A.* AU - Lévy, J.* AU - Latypova, X.* AU - Harder, S.* AU - Silverman, G.A.* AU - Pak, S.C.* AU - Schedl, T.* AU - Freson, K.* AU - Mumford, A.* AU - Turro, E.* AU - Schlein, C.* AU - Shashi, V.* AU - Kreienkamp, H.J.* C1 - 71667 C2 - 56376 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Variants in LRRC7 lead to intellectual disability, autism, aggression and abnormal eating behaviors. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Oligodendrocytes extend numerous cellular processes that wrap multiple times around axons to generate lipid-rich myelin sheaths. Myelin biogenesis requires an enormously productive biosynthetic machinery for generating and delivering these large amounts of newly synthesized lipids. Yet, a complete understanding of this process remains elusive. Utilizing volume electron microscopy, we demonstrate that the oligodendroglial endoplasmic reticulum (ER) is enriched in developing myelin, extending into and making contact with the innermost myelin layer where growth occurs. We explore the possibility of transfer of lipids from the ER to myelin, and find that the glycolipid transfer protein (GLTP), implicated in nonvesicular lipid transport, is highly enriched in the growing myelin sheath. Mice with a specific knockout of Gltp in oligodendrocytes exhibit ER pathology, hypomyelination and a decrease in myelin glycolipid content. In summary, our results demonstrate a role for nonvesicular lipid transport in CNS myelin growth, revealing a cellular pathway in developmental myelination. AU - Wu, J.* AU - Kislinger, G.* AU - Duschek, J.* AU - Durmaz, A.D.* AU - Wefers, B.* AU - Feng, R.* AU - Nalbach, K.* AU - Wurst, W. AU - Behrends, C.* AU - Schifferer, M.* AU - Simons, M.* C1 - 72302 C2 - 56564 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Nonvesicular lipid transfer drives myelin growth in the central nervous system. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - The regulation of thymocyte development by RNA-binding proteins (RBPs) is largely unexplored. We identify 642 RBPs in the thymus and focus on Arpp21, which shows selective and dynamic expression in early thymocytes. Arpp21 is downregulated in response to T cell receptor (TCR) and Ca2+ signals. Downregulation requires Stim1/Stim2 and CaMK4 expression and involves Arpp21 protein phosphorylation, polyubiquitination and proteasomal degradation. Arpp21 directly binds RNA through its R3H domain, with a preference for uridine-rich motifs, promoting the expression of target mRNAs. Analysis of the Arpp21-bound transcriptome reveals strong interactions with the Rag1 3'-UTR. Arpp21-deficient thymocytes show reduced Rag1 expression, delayed TCR rearrangement and a less diverse TCR repertoire. This phenotype is recapitulated in Rag1 3'-UTR mutant mice harboring a deletion of the Arpp21 response region. These findings show how thymocyte-specific Arpp21 promotes Rag1 expression to enable TCR repertoire diversity until signals from the TCR terminate Arpp21 and Rag1 activities. AU - Xu, M. AU - Ito-Kureha, T.* AU - Kang, H.-S. AU - Chernev, A.* AU - Raj, T.* AU - Hoefig, K.P. AU - Hohn, C.* AU - Giesert, F. AU - Wang, Y.* AU - Pan, W.* AU - Ziętara, N.* AU - Straub, T.* AU - Feederle, R.* AU - Daniel, C. AU - Adler, B.* AU - König, J.* AU - Feske, S.* AU - Tsokos, G.C.* AU - Wurst, W. AU - Urlaub, H.* AU - Sattler, M. AU - Kisielow, J.* AU - Wulczyn, F.G.* AU - Łyszkiewicz, M. AU - Heissmeyer, V. C1 - 70265 C2 - 55478 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - The thymocyte-specific RNA-binding protein Arpp21 provides TCR repertoire diversity by binding to the 3'-UTR and promoting Rag1 mRNA expression. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Correction to: Nature Communicationshttps://doi.org/10.1038/s41467-024-46371-z, published online 11 March 2024 The original version of this Article contained errors in Fig. 6, in which the panel labels were misplaced, causing mismatches between the panels and legend. This has been corrected in both the PDF and HTML versions of the Article. AU - Xu, M. AU - Ito-Kureha, T.* AU - Kang, H.-S. AU - Chernev, A.* AU - Raj, T.* AU - Hoefig, K.P. AU - Hohn, C.* AU - Giesert, F. AU - Wang, Y.* AU - Pan, W.* AU - Ziętara, N.* AU - Straub, T.* AU - Feederle, R. AU - Daniel, C. AU - Adler, B.* AU - König, J.* AU - Feske, S.* AU - Tsokos, G.C.* AU - Wurst, W. AU - Urlaub, H.* AU - Sattler, M. AU - Kisielow, J.* AU - Wulczyn, F.G.* AU - Łyszkiewicz, M. AU - Heissmeyer, V. C1 - 71431 C2 - 56170 TI - Correction to "The thymocyte-specific RNA-binding protein Arpp21 provides TCR repertoire diversity by binding to the 3'-UTR and promoting Rag1 mRNA expression". JO - Nat. Commun. VL - 15 IS - 1 PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Genetic mechanisms of blood pressure (BP) regulation remain poorly defined. Using kidney-specific epigenomic annotations and 3D genome information we generated and validated gene expression prediction models for the purpose of transcriptome-wide association studies in 700 human kidneys. We identified 889 kidney genes associated with BP of which 399 were prioritised as contributors to BP regulation. Imputation of kidney proteome and microRNAome uncovered 97 renal proteins and 11 miRNAs associated with BP. Integration with plasma proteomics and metabolomics illuminated circulating levels of myo-inositol, 4-guanidinobutanoate and angiotensinogen as downstream effectors of several kidney BP genes (SLC5A11, AGMAT, AGT, respectively). We showed that genetically determined reduction in renal expression may mimic the effects of rare loss-of-function variants on kidney mRNA/protein and lead to an increase in BP (e.g., ENPEP). We demonstrated a strong correlation (r = 0.81) in expression of protein-coding genes between cells harvested from urine and the kidney highlighting a diagnostic potential of urinary cell transcriptomics. We uncovered adenylyl cyclase activators as a repurposing opportunity for hypertension and illustrated examples of BP-elevating effects of anticancer drugs (e.g. tubulin polymerisation inhibitors). Collectively, our studies provide new biological insights into genetic regulation of BP with potential to drive clinical translation in hypertension. AU - Xu, X.* AU - Khunsriraksakul, C.* AU - Eales, J.M.* AU - Rubin, S.* AU - Scannali, D.* AU - Saluja, S.* AU - Talavera, D.* AU - Markus, H.* AU - Wang, L.* AU - Drzal, M.* AU - Maan, A.* AU - Lay, A.C.* AU - Prestes, P.R.* AU - Regan, J.* AU - Diwadkar, A.R.* AU - Denniff, M.* AU - Rempega, G.* AU - Ryszawy, J.* AU - Król, R.* AU - Dormer, J.P.* AU - Szulinska, M.* AU - Walczak, M.* AU - Antczak, A.* AU - Matias-Garcia, P.R. AU - Waldenberger, M. AU - Woolf, A.S.* AU - Keavney, B.* AU - Zukowska-Szczechowska, E.* AU - Wystrychowski, W.* AU - Zywiec, J.* AU - Bogdanski, P.* AU - Danser, A.H.J.* AU - Samani, N.J.* AU - Guzik, T.J.* AU - Morris, A.P.* AU - Liu, D.J.* AU - Charchar, F.J.* AU - Tomaszewski, M.* C1 - 70311 C2 - 55224 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Genetic imputation of kidney transcriptome, proteome and multi-omics illuminates new blood pressure and hypertension targets. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Recent evidence indicates ferroptosis is implicated in the pathophysiology of various liver diseases; however, the organ-specific regulation mechanism is poorly understood. Here, we demonstrate 7-dehydrocholesterol reductase (DHCR7), the terminal enzyme of cholesterol biosynthesis, as a regulator of ferroptosis in hepatocytes. Genetic and pharmacological inhibition (with AY9944) of DHCR7 suppress ferroptosis in human hepatocellular carcinoma Huh-7 cells. DHCR7 inhibition increases its substrate, 7-dehydrocholesterol (7-DHC). Furthermore, exogenous 7-DHC supplementation using hydroxypropyl β-cyclodextrin suppresses ferroptosis. A 7-DHC-derived oxysterol metabolite, 3β,5α-dihydroxycholest-7-en-6-one (DHCEO), is increased by the ferroptosis-inducer RSL-3 in DHCR7-deficient cells, suggesting that the ferroptosis-suppressive effect of DHCR7 inhibition is associated with the oxidation of 7-DHC. Electron spin resonance analysis reveals that 7-DHC functions as a radical trapping agent, thus protecting cells from ferroptosis. We further show that AY9944 inhibits hepatic ischemia-reperfusion injury, and genetic ablation of Dhcr7 prevents acetaminophen-induced acute liver failure in mice. These findings provide new insights into the regulatory mechanism of liver ferroptosis and suggest a potential therapeutic option for ferroptosis-related liver diseases. AU - Yamada, N. AU - Karasawa, T.* AU - Ito, J.* AU - Yamamuro, D.* AU - Morimoto, K.* AU - Nakamura, T. AU - Komada, T.* AU - Baatarjav, C.* AU - Saimoto, Y.* AU - Jinnouchi, Y.* AU - Watanabe, K.* AU - Miura, K.* AU - Yahagi, N.* AU - Nakagawa, K.* AU - Matsumura, T.* AU - Yamada, K.i.* AU - Ishibashi, S.* AU - Sata, N.* AU - Conrad, M. AU - Takahashi, M.* C1 - 70260 C2 - 55473 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Inhibition of 7-dehydrocholesterol reductase prevents hepatic ferroptosis under an active state of sterol synthesis. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - DNA methylation is an essential epigenetic chromatin modification, and its maintenance in mammals requires the protein UHRF1. It is yet unclear if UHRF1 functions solely by stimulating DNA methylation maintenance by DNMT1, or if it has important additional functions. Using degron alleles, we show that UHRF1 depletion causes a much greater loss of DNA methylation than DNMT1 depletion. This is not caused by passive demethylation as UHRF1-depleted cells proliferate more slowly than DNMT1-depleted cells. Instead, bioinformatics, proteomics and genetics experiments establish that UHRF1, besides activating DNMT1, interacts with DNMT3A and DNMT3B and promotes their activity. In addition, we show that UHRF1 antagonizes active DNA demethylation by TET2. Therefore, UHRF1 has non-canonical roles that contribute importantly to DNA methylation homeostasis; these findings have practical implications for epigenetics in health and disease. AU - Yamaguchi, K.* AU - Chen, X.* AU - Rodgers, B.* AU - Miura, F.* AU - Bashtrykov, P.* AU - Bonhomme, F.* AU - Salinas-Luypaert, C.* AU - Haxholli, D.* AU - Gutekunst, N.* AU - Özdemir Aygenli, B. AU - Ferry, L.* AU - Kirsh, O.* AU - Laisné, M.* AU - Scelfo, A.* AU - Ugur, E.* AU - Arimondo, P.B.* AU - Leonhardt, H.* AU - Kanemaki, M.T.* AU - Bartke, T. AU - Fachinetti, D.* AU - Jeltsch, A.* AU - Ito, T.* AU - Defossez, P.A.* C1 - 70426 C2 - 55616 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Non-canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Targeted (nano-)drug delivery is essential for treating respiratory diseases, which are often confined to distinct lung regions. However, spatio-temporal profiling of drugs or nanoparticles (NPs) and their interactions with lung macrophages remains unresolved. Here, we present LungVis 1.0, an AI-powered imaging ecosystem that integrates light sheet fluorescence microscopy with deep learning-based image analysis pipelines to map NP deposition and dosage holistically and quantitatively across bronchial and alveolar (acinar) regions in murine lungs for widely-used bulk-liquid and aerosol-based delivery methods. We demonstrate that bulk-liquid delivery results in patchy NP distribution with elevated bronchial doses, whereas aerosols achieve uniform deposition reaching distal alveoli. Furthermore, we reveal that lung tissue-resident macrophages (TRMs) are dynamic, actively patrolling and redistributing NPs within alveoli, contesting the conventional paradigm of TRMs as static entities. LungVis 1.0 provides an advanced framework for exploring pulmonary delivery dynamics and deepening insights into TRM-mediated lung immunity. AU - Yang, L. AU - Liu, Q. AU - Kumar, P. AU - Sengupta, A. AU - Farnoud, A. AU - Shen, R. AU - Trofimova, D.* AU - Ziegler, S.* AU - Davoudi, N.* AU - Doryab, A. AU - Yildirim, A.Ö. AU - Diefenbacher, M. AU - Schiller, H. AU - Razansky, D.* AU - Piraud, M. AU - Burgstaller, G. AU - Kreyling, W.G. AU - Isensee, F.* AU - Rehberg, M. AU - Stöger, T. AU - Schmid, O. C1 - 72565 C2 - 56656 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - LungVis 1.0: An automatic AI-powered 3D imaging ecosystem unveils spatial profiling of nanoparticle delivery and acinar migration of lung macrophages. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Floods are becoming more frequent and severe in the context of climate change, with major impacts on human health. However, their effect on infant mortality remains unknown, particularly in low- and middle-income countries. We conducted a sibling-matched case-control study using individual-level data from Demographic and Health Surveys in Africa during 1990-2020. Individual flood experience was determined by matching the residential coordinates with flood events from the Dartmouth Flood Observatory database. Using data from 514,760 newborns, we found increased risks of infant mortality associated with flood exposure across multiple periods, with the risks remaining elevated for up to four years after the flood event. Overall, flood exposure was associated with 3.42 infant deaths per 1000 births in Africa from 2000 to 2020, approximately 1.7 times the burden associated with life-period exposure. This multi-country study in Africa provides novel evidence that flood events may increase infant mortality risk and burden, even over years after exposure. AU - Zhu, Y.* AU - He, C. AU - Bachwenkizi, J.* AU - Fatmi, Z.* AU - Zhou, L.* AU - Lei, J.* AU - Liu, C.* AU - Kan, H.* AU - Chen, R.* C1 - 72497 C2 - 56614 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Burden of infant mortality associated with flood in 37 African countries. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Marburg virus (MARV) causes lethal hemorrhagic fever in humans, posing a threat to global health. We determined by cryogenic electron microscopy (cryo-EM) the MARV helical ribonucleoprotein (RNP) complex structure in single-layered conformation, which differs from the previously reported structure of a double-layered helix. Our findings illuminate novel RNP interactions and expand knowledge on MARV genome packaging and nucleocapsid assembly, both processes representing attractive targets for the development of antiviral therapeutics against MARV disease. AU - Zinzula, L.* AU - Beck, F.* AU - Camasta, M.* AU - Bohn, S. AU - Liu, C.* AU - Morado, D.* AU - Bracher, A.* AU - Plitzko, J.M.* AU - Baumeister, W.* C1 - 72566 C2 - 56651 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Cryo-EM structure of single-layered nucleoprotein-RNA complex from Marburg virus. JO - Nat. Commun. VL - 15 IS - 1 PB - Nature Portfolio PY - 2024 SN - 2041-1723 ER - TY - JOUR AB - Short-wave infrared (SWIR) fluorescence could become the new gold standard in optical imaging for biomedical applications due to important advantages such as lack of autofluorescence, weak photon absorption by blood and tissues, and reduced photon scattering coefficient. Therefore, contrary to the visible and NIR regions, tissues become translucent in the SWIR region. Nevertheless, the lack of bright and biocompatible probes is a key challenge that must be overcome to unlock the full potential of SWIR fluorescence. Although rare-earth-based core-shell nanocrystals appeared as promising SWIR probes, they suffer from limited photoluminescence quantum yield (PLQY). The lack of control over the atomic scale organization of such complex materials is one of the main barriers limiting their optical performance. Here, the growth of either homogeneous (α-NaYF4) or heterogeneous (CaF2) shell domains on optically-active α-NaYF4:Yb:Er (with and without Ce3+ co-doping) core nanocrystals is reported. The atomic scale organization can be controlled by preventing cation intermixing only in heterogeneous core-shell nanocrystals with a dramatic impact on the PLQY. The latter reached 50% at 60 mW/cm2; one of the highest reported PLQY values for sub-15 nm nanocrystals. The most efficient nanocrystals were utilized for in vivo imaging above 1450 nm. AU - Arteaga Cardona, F.* AU - Jain, N.* AU - Popescu, R.* AU - Busko, D.* AU - Madirov, E.* AU - Arus, B.A. AU - Gerthsen, D.* AU - De Backer, A.* AU - Bals, S.* AU - Bruns, O.T. AU - Chmyrov, A. AU - Van Aert, S.* AU - Richards, B.S.* AU - Hudry, D.* C1 - 68069 C2 - 54547 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Preventing cation intermixing enables 50% quantum yield in sub-15 nm short-wave infrared-emitting rare-earth based core-shell nanocrystals. JO - Nat. Commun. VL - 14 IS - 1 PB - Nature Portfolio PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - YAP is a key transcriptional co-activator of TEADs, it regulates cell growth and is frequently activated in cancer. In Malignant Pleural Mesothelioma (MPM), YAP is activated by loss-of-function mutations in upstream components of the Hippo pathway, while, in Uveal Melanoma (UM), YAP is activated in a Hippo-independent manner. To date, it is unclear if and how the different oncogenic lesions activating YAP impact its oncogenic program, which is particularly relevant for designing selective anti-cancer therapies. Here we show that, despite YAP being essential in both MPM and UM, its interaction with TEAD is unexpectedly dispensable in UM, limiting the applicability of TEAD inhibitors in this cancer type. Systematic functional interrogation of YAP regulatory elements in both cancer types reveals convergent regulation of broad oncogenic drivers in both MPM and UM, but also strikingly selective programs. Our work reveals unanticipated lineage-specific features of the YAP regulatory network that provide important insights to guide the design of tailored therapeutic strategies to inhibit YAP signaling across different cancer types. AU - Barbosa, I.A.M.* AU - Gopalakrishnan, R.* AU - Mercan, S.* AU - Mourikis, T.P.* AU - Martin, T.* AU - Wengert, S. AU - Sheng, C.* AU - Ji, F.* AU - Lopes, R.* AU - Knehr, J.* AU - Altorfer, M.* AU - Lindeman, A.* AU - Russ, C.* AU - Naumann, U.* AU - Golji, J.* AU - Sprouffske, K.* AU - Barys, L.* AU - Tordella, L.* AU - Schübeler, D.* AU - Schmelzle, T.* AU - Galli, G.G.* C1 - 68444 C2 - 54633 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Cancer lineage-specific regulation of YAP responsive elements revealed through large-scale functional epigenomic screens. JO - Nat. Commun. VL - 14 IS - 1 PB - Nature Portfolio PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - Recent studies of severe acute inflammatory lung disease including COVID-19 identify macrophages to drive pulmonary hyperinflammation and long-term damage such as fibrosis. Here, we report on the development of a first-in-class, carbohydrate-coupled inhibitor of microRNA-21 (RCS-21), as a therapeutic means against pulmonary hyperinflammation and fibrosis. MicroRNA-21 is among the strongest upregulated microRNAs in human COVID-19 and in mice with acute inflammatory lung damage, and it is the strongest expressed microRNA in pulmonary macrophages. Chemical linkage of a microRNA-21 inhibitor to trimannose achieves rapid and specific delivery to macrophages upon inhalation in mice. RCS-21 reverses pathological activation of macrophages and prevents pulmonary dysfunction and fibrosis after acute lung damage in mice. In human lung tissue infected with SARS-CoV-2 ex vivo, RCS-21 effectively prevents the exaggerated inflammatory response. Our data imply trimannose-coupling for effective and selective delivery of inhaled oligonucleotides to pulmonary macrophages and report on a first mannose-coupled candidate therapeutic for COVID-19. AU - Beck, C.* AU - Ramanujam, D.* AU - Vaccarello, P.* AU - Widenmeyer, F.* AU - Feuerherd, M. AU - Cheng, C.C.* AU - Bomhard, A.* AU - Abikeeva, T.* AU - Schädler, J.* AU - Sperhake, J.P.* AU - Graw, M.* AU - Safi, S.* AU - Hoffmann, H.* AU - Staab-Weijnitz, C.A. AU - Rad, R.* AU - Protzer, U. AU - Frischmuth, T.* AU - Engelhardt, S.* C1 - 68056 C2 - 54534 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Trimannose-coupled antimiR-21 for macrophage-targeted inhalation treatment of acute inflammatory lung damage. JO - Nat. Commun. VL - 14 IS - 1 PB - Nature Portfolio PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - Whole genome sequencing has enabled new insights into the genetic architecture of complex traits, especially through access to low-frequency and rare variation. This Comment highlights the key contributions from this technology and discusses considerations for its use and future perspectives. AU - Bocher, O. AU - Willer, C.J.* AU - Zeggini, E. C1 - 68527 C2 - 54695 TI - Unravelling the genetic architecture of human complex traits through whole genome sequencing. JO - Nat. Commun. VL - 14 IS - 1 PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - We evaluate the shared genetic regulation of mRNA molecules, proteins and metabolites derived from whole blood from 3029 human donors. We find abundant allelic heterogeneity, where multiple variants regulate a particular molecular phenotype, and pleiotropy, where a single variant associates with multiple molecular phenotypes over multiple genomic regions. The highest proportion of share genetic regulation is detected between gene expression and proteins (66.6%), with a further median shared genetic associations across 49 different tissues of 78.3% and 62.4% between plasma proteins and gene expression. We represent the genetic and molecular associations in networks including 2828 known GWAS variants, showing that GWAS variants are more often connected to gene expression in trans than other molecular phenotypes in the network. Our work provides a roadmap to understanding molecular networks and deriving the underlying mechanism of action of GWAS variants using different molecular phenotypes in an accessible tissue. AU - Brown, A.A.* AU - Fernandez-Tajes, J.J.* AU - Hong, M.G.* AU - Brorsson, C.A.* AU - Koivula, R.W.* AU - Davtian, D.* AU - Dupuis, T.* AU - Sartori, A.* AU - Michalettou, T.D.* AU - Forgie, I.M.* AU - Adam, J. AU - Allin, K.H.* AU - Caiazzo, R.* AU - Cederberg, H.* AU - De Masi, F.* AU - Elders, P.J.M.* AU - Giordano, G.N.* AU - Haid, M. AU - Hansen, T.* AU - Hansen, T.H.* AU - Hattersley, A.T.* AU - Heggie, A.J.* AU - Howald, C.* AU - Jones, A.G.* AU - Kokkola, T.* AU - Laakso, M.* AU - Mahajan, A.* AU - Mari, A.* AU - McDonald, T.J.* AU - McEvoy, D.* AU - Mourby, M.* AU - Musholt, P.B.* AU - Nilsson, B.* AU - Pattou, F.* AU - Penet, D.* AU - Raverdy, V.* AU - Ridderstråle, M.* AU - Romano, L.* AU - Rutters, F.* AU - Sharma, S. AU - Teare, H.* AU - 't Hart, L.* AU - Tsirigos, K.D.* AU - Vangipurapu, J.* AU - Vestergaard, H.* AU - Brunak, S.* AU - Franks, P.W.* AU - Frost, G.* AU - Grallert, H. AU - Jablonka, B.* AU - McCarthy, M.I.* AU - Pavo, I.* AU - Pedersen, O.* AU - Ruetten, H.* AU - Walker, M.* AU - Adamski, J. AU - Schwenk, J.M.* AU - Pearson, E.R.* AU - Dermitzakis, E.T.* AU - Viñuela, A.* AU - DIRECT Consortium (Thorand, B. AU - Fritsche, A. AU - Artati, A. AU - Prehn, C.) C1 - 67974 C2 - 54452 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits. JO - Nat. Commun. VL - 14 IS - 1 PB - Nature Portfolio PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities. AU - Budu-Aggrey, A.* AU - Kilanowski, A. AU - Sobczyk, M.K.* AU - Shringarpure, S.S.* AU - Mitchell, R.* AU - Reis, K.* AU - Reigo, A.* AU - Mägi, R.* AU - Nelis, M.* AU - Tanaka, N.* AU - Brumpton, B.M.* AU - Thomas, L.F.* AU - Sole-Navais, P.* AU - Flatley, C.* AU - Espuela-Ortiz, A.* AU - Herrera-Luis, E.* AU - Lominchar, J.V.T.* AU - Bork-Jensen, J.* AU - Marenholz, I.* AU - Arnau-Soler, A.* AU - Jeong, A.* AU - Fawcett, K.A.* AU - Baurecht, H.* AU - Rodriguez, E.* AU - Alves, A.C.* AU - Kumar, A.* AU - Sleiman, P.M.* AU - Chang, X.* AU - Medina-Gomez, C.* AU - Hu, C.* AU - Xu, C.J.* AU - Qi, C.* AU - El-Heis, S.* AU - Titcombe, P.* AU - Antoun, E.* AU - Fadista, J.* AU - Wang, C.A.* AU - Thiering, E. AU - Wu, B.* AU - Kress, S.* AU - Kothalawala, D.M.* AU - Kadalayil, L.* AU - Duan, J.* AU - Zhang, H.* AU - Hadebe, S.* AU - Hoffmann, T.* AU - Jorgenson, E.* AU - Choquet, H.* AU - Risch, N.* AU - Njølstad, P.* AU - Andreassen, O.A.* AU - Johansson, S.* AU - Almqvist, C.* AU - Gong, T.* AU - Ullemar, V.* AU - Karlsson, R.* AU - Magnusson, P.K.E.* AU - Szwajda, A.* AU - Burchard, E.G.* AU - Thyssen, J.P.* AU - Hansen, T.* AU - Kårhus, L.L.* AU - Dantoft, T.M.* AU - Jeanrenaud, A.C.S.N.* AU - Ghauri, A.* AU - Arnold, A.* AU - Homuth, G.* AU - Lau, S.* AU - Nöthen, M.M.* AU - Hubner, N.* AU - Imboden, M.* AU - Visconti, A.* AU - Falchi, M.* AU - Bataille, V.* AU - Hysi, P.* AU - Ballardini, N.* AU - Boomsma, D.I.* AU - Hottenga, J.J.* AU - Müller-Nurasyid, M. AU - Ahluwalia, T.S.* AU - Stokholm, J.* AU - Chawes, B.* AU - Schoos, A.M.* AU - Esplugues, A.* AU - Bustamante, M.* AU - Raby, B.* AU - Arshad, S.* AU - German, C.* AU - Esko, T.* AU - Milani, L.A.* AU - Metspalu, A.* AU - Terao, C.* AU - Abuabara, K.* AU - Løset, M.* AU - Hveem, K.* AU - Jacobsson, B.* AU - Pino-Yanes, M.* AU - Strachan, D.P.* AU - Grarup, N.* AU - Linneberg, A.* AU - Lee, Y.A.* AU - Probst-Hensch, N.* AU - Weidinger, S.* AU - Jarvelin, M.R.* AU - Melén, E.* AU - Hakonarson, H.* AU - Irvine, A.D.* AU - Jarvis, D.* AU - Nijsten, T.* AU - Duijts, L.* AU - Vonk, J.M.* AU - Koppelmann, G.H.* AU - Godfrey, K.M.* AU - Barton, S.J.* AU - Feenstra, B.* AU - Pennell, C.E.* AU - Sly, P.D.* AU - Holt, P.G.* AU - Williams, L.K.* AU - Bisgaard, H.* AU - Bønnelykke, K.* AU - Curtin, J.* AU - Simpson, A.* AU - Murray, C.* AU - Schikowski, T.* AU - Bunyavanich, S.* AU - Weiss, S.T.* AU - Holloway, J.W.* AU - Min, J.L.* AU - Brown, S.J.* AU - Standl, M. AU - Paternoster, L.* C1 - 68632 C2 - 54812 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation. JO - Nat. Commun. VL - 14 IS - 1 PB - Nature Portfolio PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - Finger millet is a key food security crop widely grown in eastern Africa, India and Nepal. Long considered a ‘poor man’s crop’, finger millet has regained attention over the past decade for its climate resilience and the nutritional qualities of its grain. To bring finger millet breeding into the 21st century, here we present the assembly and annotation of a chromosome-scale reference genome. We show that this ~1.3 million years old allotetraploid has a high level of homoeologous gene retention and lacks subgenome dominance. Population structure is mainly driven by the differential presence of large wild segments in the pericentromeric regions of several chromosomes. Trait mapping, followed by variant analysis of gene candidates, reveals that loss of purple coloration of anthers and stigma is associated with loss-of-function mutations in the finger millet orthologs of the maize R1/B1 and Arabidopsis GL3/EGL3 anthocyanin regulatory genes. Proanthocyanidin production in seed is not affected by these gene knockouts. AU - Devos, K.M.* AU - Qi, P.* AU - Bahri, B.A.* AU - Gimode, D.M.* AU - Jenike, K.* AU - Manthi, S.J.* AU - Lulé, D.* AU - Lux, T. AU - Martinez-Bello, L.* AU - Pendergast, T.H.* AU - Plott, C.* AU - Saha, D.* AU - Sidhu, G.S.* AU - Sreedasyam, A.* AU - Wang, X.* AU - Wang, H.* AU - Wright, H.* AU - Zhao, J.* AU - Deshpande, S.* AU - de Villiers, S.* AU - Dida, M.M.* AU - Grimwood, J.* AU - Jenkins, J.* AU - Lovell, J.* AU - Mayer, K.F.X. AU - Mneney, E.E.* AU - Ojulong, H.F.* AU - Schatz, M.C.* AU - Schmutz, J.* AU - Song, B.* AU - Tesfaye, K.* AU - Odeny, D.A.* C1 - 68486 C2 - 54671 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Genome analyses reveal population structure and a purple stigma color gene candidate in finger millet. JO - Nat. Commun. VL - 14 IS - 1 PB - Nature Portfolio PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - SMNDC1 is a Tudor domain protein that recognizes di-methylated arginines and controls gene expression as an essential splicing factor. Here, we study the specific contributions of the SMNDC1 Tudor domain to protein-protein interactions, subcellular localization, and molecular function. To perturb the protein function in cells, we develop small molecule inhibitors targeting the dimethylarginine binding pocket of the SMNDC1 Tudor domain. We find that SMNDC1 localizes to phase-separated membraneless organelles that partially overlap with nuclear speckles. This condensation behavior is driven by the unstructured C-terminal region of SMNDC1, depends on RNA interaction and can be recapitulated in vitro. Inhibitors of the protein's Tudor domain drastically alter protein-protein interactions and subcellular localization, causing splicing changes for SMNDC1-dependent genes. These compounds will enable further pharmacological studies on the role of SMNDC1 in the regulation of nuclear condensates, gene regulation and cell identity. AU - Enders, L.* AU - Siklos, M.* AU - Borggräfe, J. AU - Gaussmann, S. AU - Koren, A.* AU - Malik, M.* AU - Tomek, T.* AU - Schuster, M.* AU - Reiniš, J.* AU - Hahn, E.* AU - Rukavina, A.* AU - Reicher, A.* AU - Casteels, T.* AU - Bock, C.* AU - Winter, G.E.* AU - Hannich, J.T.* AU - Sattler, M. AU - Kubicek, S.* C1 - 67994 C2 - 54472 TI - Pharmacological perturbation of the phase-separating protein SMNDC1. JO - Nat. Commun. VL - 14 IS - 1 PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - Despite intensive research since the emergence of SARS-CoV-2, it has remained unclear precisely which components of the early immune response protect against the development of severe COVID-19. Here, we perform a comprehensive immunogenetic and virologic analysis of nasopharyngeal and peripheral blood samples obtained during the acute phase of infection with SARS-CoV-2. We find that soluble and transcriptional markers of systemic inflammation peak during the first week after symptom onset and correlate directly with upper airways viral loads (UA-VLs), whereas the contemporaneous frequencies of circulating viral nucleocapsid (NC)-specific CD4+ and CD8+ T cells correlate inversely with various inflammatory markers and UA-VLs. In addition, we show that high frequencies of activated CD4+ and CD8+ T cells are present in acutely infected nasopharyngeal tissue, many of which express genes encoding various effector molecules, such as cytotoxic proteins and IFN-γ. The presence of IFNG mRNA-expressing CD4+ and CD8+ T cells in the infected epithelium is further linked with common patterns of gene expression among virus-susceptible target cells and better local control of SARS-CoV-2. Collectively, these results identify an immune correlate of protection against SARS-CoV-2, which could inform the development of more effective vaccines to combat the acute and chronic illnesses attributable to COVID-19. AU - Eser, T.M.* AU - Baranov, O.* AU - Huth, M. AU - Ahmed, M.I.M.* AU - Deák, F.* AU - Held, K.* AU - Lin, L.* AU - Pekayvaz, K.* AU - Leunig, A.* AU - Nicolai, L.* AU - Pollakis, G.* AU - Buggert, M.* AU - Price, D.A.* AU - Rubio-Acero, R.* AU - Reich, J.* AU - Falk, P.* AU - Markgraf, A.* AU - Puchinger, K.* AU - Castelletti, N.* AU - Olbrich, L.* AU - Vanshylla, K.* AU - Klein, F.* AU - Wieser, A.* AU - Hasenauer, J. AU - Kroidl, I.* AU - Hoelscher, M.* AU - Geldmacher, C.* C1 - 67899 C2 - 54377 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Nucleocapsid-specific T cell responses associate with control of SARS-CoV-2 in the upper airways before seroconversion. JO - Nat. Commun. VL - 14 IS - 1 PB - Nature Portfolio PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - Diseases change over time, both phenotypically and in their underlying molecular processes. Though understanding disease progression dynamics is critical for diagnostics and treatment, capturing these dynamics is difficult due to their complexity and the high heterogeneity in disease development between individuals. We present TimeAx, an algorithm which builds a comparative framework for capturing disease dynamics using high-dimensional, short time-series data. We demonstrate the utility of TimeAx by studying disease progression dynamics for multiple diseases and data types. Notably, for urothelial bladder cancer tumorigenesis, we identify a stromal pro-invasion point on the disease progression axis, characterized by massive immune cell infiltration to the tumor microenvironment and increased mortality. Moreover, the continuous TimeAx model differentiates between early and late tumors within the same tumor subtype, uncovering molecular transitions and potential targetable pathways. Overall, we present a powerful approach for studying disease progression dynamics-providing improved molecular interpretability and clinical benefits for patient stratification and outcome prediction. AU - Frishberg, A. AU - Milman, N.* AU - Alpert, A.* AU - Spitzer, H. AU - Asani, B.* AU - Schiefelbein, J.B.* AU - Bakin, E.* AU - Regev-Berman, K.* AU - Priglinger, S.G.* AU - Schultze, J.L.* AU - Theis, F.J. AU - Shen-Orr, S.S.* C1 - 68690 C2 - 54899 TI - Reconstructing disease dynamics for mechanistic insights and clinical benefit. JO - Nat. Commun. VL - 14 IS - 1 PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - Across the globe, 2-3% of humans carry the p.Ser132Pro single nucleotide polymorphism in MLKL, the terminal effector protein of the inflammatory form of programmed cell death, necroptosis. Here we show that this substitution confers a gain in necroptotic function in human cells, with more rapid accumulation of activated MLKLS132P in biological membranes and MLKLS132P overriding pharmacological and endogenous inhibition of MLKL. In mouse cells, the equivalent Mlkl S131P mutation confers a gene dosage dependent reduction in sensitivity to TNF-induced necroptosis in both hematopoietic and non-hematopoietic cells, but enhanced sensitivity to IFN-β induced death in non-hematopoietic cells. In vivo, Mlkl S131P homozygosity reduces the capacity to clear Salmonella from major organs and retards recovery of hematopoietic stem cells. Thus, by dysregulating necroptosis, the S131P substitution impairs the return to homeostasis after systemic challenge. Present day carriers of the MLKL S132P polymorphism may be the key to understanding how MLKL and necroptosis modulate the progression of complex polygenic human disease. AU - Garnish, S.E.* AU - Martin, K.R.* AU - Kauppi, M.* AU - Jackson, V.E.* AU - Ambrose, R.* AU - Eng, V.V.* AU - Chiou, S.* AU - Meng, Y.* AU - Frank, D.* AU - Tovey Crutchfield, E.C.* AU - Patel, K.M.* AU - Jacobsen, A.V.* AU - Atkin-Smith, G.K.* AU - Di Rago, L.* AU - Doerflinger, M.* AU - Horne, C.R.* AU - Hall, C.* AU - Young, S.N.* AU - Cook, M.* AU - Athanasopoulos, V.* AU - Vinuesa, C.G.* AU - Lawlor, K.E.* AU - Wicks, I.P.* AU - Ebert, G. AU - Ng, A.P.* AU - Slade, C.A.* AU - Pearson, J.S.* AU - Samson, A.L.* AU - Silke, J.* AU - Murphy, J.M.* AU - Hildebrand, J.M.* C1 - 68197 C2 - 54825 TI - A common human MLKL polymorphism confers resistance to negative regulation by phosphorylation. JO - Nat. Commun. VL - 14 IS - 1 PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - Mammalian circadian clocks respond to feeding and light cues, adjusting internal rhythms with day/night cycles. Astrocytes serve as circadian timekeepers, driving daily physiological rhythms; however, it's unknown how they ensure precise cycle-to-cycle rhythmicity. This is critical for understanding why mistimed or erratic feeding, as in shift work, disrupts circadian physiology- a condition linked to type 2 diabetes and obesity. Here, we show that astrocytic insulin signaling sets the free-running period of locomotor activity in female mice and food entrainment in male mice. Additionally, ablating the insulin receptor in hypothalamic astrocytes alters cyclic energy homeostasis differently in male and female mice. Remarkably, the mutants exhibit altered dopamine metabolism, and the pharmacological modulation of dopaminergic signaling partially restores distinct circadian traits in both male and female mutant mice. Our findings highlight the role of astrocytic insulin-dopaminergic signaling in conveying time-of-feeding or lighting cues to the astrocyte clock, thus governing circadian behavior in a sex-specific manner. AU - González-Vila, A.* AU - Luengo-Mateos, M.* AU - Silveira-Loureiro, M.* AU - Garrido-Gil, P.* AU - Ohinska, N.* AU - González-Domínguez, M.* AU - Labandeira-García, J.L.* AU - García-Cáceres, C. AU - López, M.* AU - Barca-Mayo, O.* C1 - 68927 C2 - 53771 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Astrocytic insulin receptor controls circadian behavior via dopamine signaling in a sexually dimorphic manner. JO - Nat. Commun. VL - 14 IS - 1 PB - Nature Portfolio PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - pH alterations are a hallmark of many pathologies including cancer and kidney disease. Here, we introduce [1,5-13C2]Z-OMPD as a hyperpolarized extracellular pH and perfusion sensor for MRI which allows to generate a multiparametric fingerprint of renal disease status and to detect local tumor acidification. Exceptional long T1 of two minutes at 1 T, high pH sensitivity of up to 1.9 ppm per pH unit and suitability of using the C1-label as internal frequency reference enables pH imaging in vivo of three pH compartments in healthy rat kidneys. Spectrally selective targeting of both 13C-resonances enables simultaneous imaging of perfusion and filtration in 3D and pH in 2D within one minute to quantify renal blood flow, glomerular filtration rates and renal pH in healthy and hydronephrotic kidneys with superior sensitivity compared to clinical routine methods. Imaging multiple biomarkers within a single session renders [1,5-13C2]Z-OMPD a promising new hyperpolarized agent for oncology and nephrology. AU - Grashei, M.* AU - Wodtke, P.* AU - Skinner, J.G.* AU - Sühnel, S.* AU - Setzer, N.* AU - Metzler, T.* AU - Gulde, S. AU - Park, M.* AU - Witt, D.* AU - Mohr, H. AU - Hundshammer, C.* AU - Strittmatter, N.* AU - Pellegata, N.S. AU - Steiger, K.* AU - Schilling, F.* C1 - 67975 C2 - 54453 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Simultaneous magnetic resonance imaging of pH, perfusion and renal filtration using hyperpolarized 13C-labelled Z-OMPD. JO - Nat. Commun. VL - 14 IS - 1 PB - Nature Portfolio PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - The origins of wound myofibroblasts and scar tissue remains unclear, but it is assumed to involve conversion of adipocytes into myofibroblasts. Here, we directly explore the potential plasticity of adipocytes and fibroblasts after skin injury. Using genetic lineage tracing and live imaging in explants and in wounded animals, we observe that injury induces a transient migratory state in adipocytes with vastly distinct cell migration patterns and behaviours from fibroblasts. Furthermore, migratory adipocytes, do not contribute to scar formation and remain non-fibrogenic in vitro, in vivo and upon transplantation into wounds in animals. Using single-cell and bulk transcriptomics we confirm that wound adipocytes do not convert into fibrogenic myofibroblasts. In summary, the injury-induced migratory adipocytes remain lineage-restricted and do not converge or reprogram into a fibrosing phenotype. These findings broadly impact basic and translational strategies in the regenerative medicine field, including clinical interventions for wound repair, diabetes, and fibrotic pathologies. AU - Kalgudde Gopal, S. AU - Dai, R. AU - Stefanska, A.M. AU - Ansari, M. AU - Zhao, J. AU - Ramesh, P. AU - Bagnoli, J.W.* AU - Correa-Gallegos, D. AU - Lin, Y. AU - Christ, S. AU - Angelidis, I. AU - Lupperger, V. AU - Marr, C. AU - Davies, L.C.* AU - Enard, W.* AU - Machens, H.G.* AU - Schiller, H. AU - Jiang, D. AU - Rinkevich, Y. C1 - 67892 C2 - 54370 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Wound infiltrating adipocytes are not myofibroblasts. JO - Nat. Commun. VL - 14 IS - 1 PB - Nature Portfolio PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - Most genome-wide association studies (GWAS) for lipid traits focus on the separate analysis of lipid traits. Moreover, there are limited GWASs evaluating the genetic variants associated with multiple lipid traits in African ancestry. To further identify and localize loci with pleiotropic effects on lipid traits, we conducted a genome-wide meta-analysis, multi-trait analysis of GWAS (MTAG), and multi-trait fine-mapping (flashfm) in 125,000 individuals of African ancestry. Our meta-analysis and MTAG identified four and 14 novel loci associated with lipid traits, respectively. flashfm yielded an 18% mean reduction in the 99% credible set size compared to single-trait fine-mapping with JAM. Moreover, we identified more genetic variants with a posterior probability of causality >0.9 with flashfm than with JAM. In conclusion, we identified additional novel loci associated with lipid traits, and flashfm reduced the 99% credible set size to identify causal genetic variants associated with multiple lipid traits in African ancestry. AU - Kamiza, A.B.* AU - Touré, S.M.* AU - Zhou, F.* AU - Soremekun, O.* AU - Cissé, C.* AU - Wélé, M.* AU - Touré, A.M.* AU - Nashiru, O.* AU - Corpas, M.* AU - Nyirenda, M.* AU - Crampin, A.* AU - Shaffer, J.* AU - Doumbia, S.* AU - Zeggini, E. AU - Morris, A.P.* AU - Asimit, J.L.* AU - Chikowore, T.* AU - Fatumo, S. C1 - 68324 C2 - 54743 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Multi-trait discovery and fine-mapping of lipid loci in 125,000 individuals of African ancestry. JO - Nat. Commun. VL - 14 IS - 1 PB - Nature Portfolio PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - Adipocyte-derived extracellular vesicles (AdEVs) are membranous nanoparticles that convey communication from adipose tissue to other organs. Here, to delineate their role as messengers with glucoregulatory nature, we paired fluorescence AdEV-tracing and SILAC-labeling with (phospho)proteomics, and revealed that AdEVs transfer functional insulinotropic protein cargo into pancreatic β-cells. Upon transfer, AdEV proteins were subjects for phosphorylation, augmented insulinotropic GPCR/cAMP/PKA signaling by increasing total protein abundances and phosphosite dynamics, and ultimately enhanced 1st-phase glucose-stimulated insulin secretion (GSIS) in murine islets. Notably, insulinotropic effects were restricted to AdEVs isolated from obese and insulin resistant, but not lean mice, which was consistent with differential protein loads and AdEV luminal morphologies. Likewise, in vivo pre-treatment with AdEVs from obese but not lean mice amplified insulin secretion and glucose tolerance in mice. This data suggests that secreted AdEVs can inform pancreatic β-cells about insulin resistance in adipose tissue in order to amplify GSIS in times of increased insulin demand. AU - Kulaj, K. AU - Harger, A. AU - Bauer, M. AU - Caliskan, Ö.S. AU - Gupta, T.K.* AU - Chiang, D.M.* AU - Milbank, E. AU - Reber, J. AU - Karlas, A. AU - Kotzbeck, P. AU - Sailer, D.N. AU - Volta, F. AU - Lutter, D. AU - Prakash, S. AU - Merl-Pham, J. AU - Ntziachristos, V. AU - Hauner, H.* AU - Pfaffl, M.W.* AU - Tschöp, M.H. AU - Müller, T.D. AU - Hauck, S.M. AU - Engel, B.D. AU - Gerdes, J.M. AU - Pfluger, P.T. AU - Krahmer, N. AU - Stemmer, K. C1 - 67434 C2 - 54145 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Adipocyte-derived extracellular vesicles increase insulin secretion through transport of insulinotropic protein cargo. JO - Nat. Commun. VL - 14 IS - 1 PB - Nature Portfolio PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - Mast cells are central players in allergy and asthma, and their dysregulated responses lead to reduced quality of life and life-threatening conditions such as anaphylaxis. The RNA modification N6-methyladenosine (m6A) has a prominent impact on immune cell functions, but its role in mast cells remains unexplored. Here, by optimizing tools to genetically manipulate primary mast cells, we reveal that the m6A mRNA methyltransferase complex modulates mast cell proliferation and survival. Depletion of the catalytic component Mettl3 exacerbates effector functions in response to IgE and antigen complexes, both in vitro and in vivo. Mechanistically, deletion of Mettl3 or Mettl14, another component of the methyltransferase complex, lead to the enhanced expression of inflammatory cytokines. By focusing on one of the most affected mRNAs, namely the one encoding the cytokine IL-13, we find that it is methylated in activated mast cells, and that Mettl3 affects its transcript stability in an enzymatic activity-dependent manner, requiring consensus m6A sites in the Il13 3’-untranslated region. Overall, we reveal that the m6A machinery is essential in mast cells to sustain growth and to restrain inflammatory responses. AU - Leoni, C.* AU - Bataclan, M.* AU - Ito-Kureha, T.* AU - Heissmeyer, V. AU - Monticelli, S.* C1 - 68441 C2 - 54645 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - The mRNA methyltransferase Mettl3 modulates cytokine mRNA stability and limits functional responses in mast cells. JO - Nat. Commun. VL - 14 IS - 1 PB - Nature Portfolio PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - To date, single-cell studies of human white adipose tissue (WAT) have been based on small cohort sizes and no cellular consensus nomenclature exists. Herein, we performed a comprehensive meta-analysis of publicly available and newly generated single-cell, single-nucleus, and spatial transcriptomic results from human subcutaneous, omental, and perivascular WAT. Our high-resolution map is built on data from ten studies and allowed us to robustly identify >60 subpopulations of adipocytes, fibroblast and adipogenic progenitors, vascular, and immune cells. Using these results, we deconvolved spatial and bulk transcriptomic data from nine additional cohorts to provide spatial and clinical dimensions to the map. This identified cell-cell interactions as well as relationships between specific cell subtypes and insulin resistance, dyslipidemia, adipocyte volume, and lipolysis upon long-term weight changes. Altogether, our meta-map provides a rich resource defining the cellular and microarchitectural landscape of human WAT and describes the associations between specific cell types and metabolic states. AU - Massier, L.* AU - Jalkanen, J.* AU - Elmastas, M.* AU - Zhong, J.* AU - Wang, T.* AU - Nono Nankam, P.A. AU - Frendo-Cumbo, S.* AU - Bäckdahl, J.* AU - Subramanian, N.* AU - Sekine, T.* AU - Kerr, A.G.* AU - Tseng, B.T.P.* AU - Laurencikiene, J.* AU - Buggert, M.* AU - Lourda, M.* AU - Kublickiene, K.* AU - Bhalla, N.* AU - Andersson, A.* AU - Valsesia, A.* AU - Astrup, A.* AU - Blaak, E.E.* AU - Ståhl, P.L.* AU - Viguerie, N.* AU - Langin, D.* AU - Wolfrum, C.* AU - Blüher, M. AU - Rydén, M.* AU - Mejhert, N.* C1 - 67722 C2 - 54030 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - An integrated single cell and spatial transcriptomic map of human white adipose tissue. JO - Nat. Commun. VL - 14 IS - 1 PB - Nature Portfolio PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - In 2020, almost half a million individuals developed rifampicin-resistant tuberculosis (RR-TB). We estimated the global burden of RR-TB over the lifetime of affected individuals. We synthesized data on incidence, case detection, and treatment outcomes in 192 countries (99.99% of global tuberculosis). Using a mathematical model, we projected disability-adjusted life years (DALYs) over the lifetime for individuals developing tuberculosis in 2020 stratified by country, age, sex, HIV, and rifampicin resistance. Here we show that incident RR-TB in 2020 was responsible for an estimated 6.9 (95% uncertainty interval: 5.5, 8.5) million DALYs, 44% (31, 54) of which accrued among TB survivors. We estimated an average of 17 (14, 21) DALYs per person developing RR-TB, 34% (12, 56) greater than for rifampicin-susceptible tuberculosis. RR-TB burden per 100,000 was highest in former Soviet Union countries and southern African countries. While RR-TB causes substantial short-term morbidity and mortality, nearly half of the overall disease burden of RR-TB accrues among tuberculosis survivors. The substantial long-term health impacts among those surviving RR-TB disease suggest the need for improved post-treatment care and further justify increased health expenditures to prevent RR-TB transmission. AU - Menzies, N.A.* AU - Allwood, B.W.* AU - Dean, A.S.* AU - Dodd, P.J.* AU - Houben, R.M.G.J.* AU - James, L.P.* AU - Knight, G.M.* AU - Meghji, J.* AU - Nguyen, L.N.* AU - Rachow, A. AU - Schumacher, S.G.* AU - Mirzayev, F.* AU - Cohen, T.* C1 - 68191 C2 - 54811 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Global burden of disease due to rifampicin-resistant tuberculosis: A mathematical modeling analysis. JO - Nat. Commun. VL - 14 IS - 1 PB - Nature Portfolio PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - Under-utilised orphan crops hold the key to diversified and climate-resilient food systems. Here, we report on orphan crop genomics using the case of Lablab purpureus (L.) Sweet (lablab) - a legume native to Africa and cultivated throughout the tropics for food and forage. Our Africa-led plant genome collaboration produces a high-quality chromosome-scale assembly of the lablab genome. Our assembly highlights the genome organisation of the trypsin inhibitor genes - an important anti-nutritional factor in lablab. We also re-sequence cultivated and wild lablab accessions from Africa confirming two domestication events. Finally, we examine the genetic and phenotypic diversity in a comprehensive lablab germplasm collection and identify genomic loci underlying variation of important agronomic traits in lablab. The genomic data generated here provide a valuable resource for lablab improvement. Our inclusive collaborative approach also presents an example that can be explored by other researchers sequencing indigenous crops, particularly from low and middle-income countries (LMIC). AU - Njaci, I.* AU - Waweru, B.* AU - Kamal, N. AU - Muktar, M.S.* AU - Fisher, D.* AU - Gundlach, H. AU - Muli, C.* AU - Muthui, L.* AU - Maranga, M.* AU - Kiambi, D.* AU - Maass, B.L.* AU - Emmrich, P.M.F.* AU - Domelevo Entfellner, J.B.* AU - Spannagl, M. AU - Chapman, M.A.* AU - Shorinola, O.* AU - Jones, C.S.* C1 - 67596 C2 - 53904 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Chromosome-level genome assembly and population genomic resource to accelerate orphan crop lablab breeding. JO - Nat. Commun. VL - 14 IS - 1 PB - Nature Portfolio PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - It is well established that maternal thyroid hormones play an important role for the developing fetus; however, the consequences of maternal hyperthyroidism for the offspring remain poorly understood. Here we show in mice that maternal 3,3',5-triiodothyronine (T3) treatment during pregnancy leads to improved glucose tolerance in the adult male offspring and hyperactivity of brown adipose tissue (BAT) thermogenesis in both sexes starting early after birth. The activated BAT provides advantages upon cold exposure, reducing the strain on other thermogenic organs like muscle. This maternal BAT programming requires intact maternal thyroid hormone receptor β (TRβ) signaling, as offspring of mothers lacking this receptor display the opposite phenotype. On the molecular level, we identify distinct T3 induced alterations in maternal serum metabolites, including choline, a key metabolite for healthy pregnancy. Taken together, our results connect maternal TRβ activation to the fetal programming of a thermoregulatory phenotype in the offspring. AU - Oelkrug, R.* AU - Harder, L.* AU - Pedaran, M.* AU - Hoffmann, A. AU - Kolms, B.* AU - Inderhees, J.* AU - Gachkar, S.* AU - Resch, J.* AU - Johann, K.* AU - Jöhren, O.* AU - Krause, K.* AU - Mittag, J.* C1 - 68701 C2 - 54910 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Maternal thyroid hormone receptor β activation in mice sparks brown fat thermogenesis in the offspring. JO - Nat. Commun. VL - 14 IS - 1 PB - Nature Portfolio PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - Precision medicine has revolutionised cancer treatments; however, actionable biomarkers remain scarce. To address this, we develop the Oncology Biomarker Discovery (OncoBird) framework for analysing the molecular and biomarker landscape of randomised controlled clinical trials. OncoBird identifies biomarkers based on single genes or mutually exclusive genetic alterations in isolation or in the context of tumour subtypes, and finally, assesses predictive components by their treatment interactions. Here, we utilise the open-label, randomised phase III trial (FIRE-3, AIO KRK-0306) in metastatic colorectal carcinoma patients, who received either cetuximab or bevacizumab in combination with 5-fluorouracil, folinic acid and irinotecan (FOLFIRI). We systematically identify five biomarkers with predictive components, e.g., patients with tumours that carry chr20q amplifications or lack mutually exclusive ERK signalling mutations benefited from cetuximab compared to bevacizumab. In summary, OncoBird characterises the molecular landscape and outlines actionable biomarkers, which generalises to any molecularly characterised randomised controlled trial. AU - Ohnmacht, A. AU - Stahler, A.* AU - Stintzing, S.* AU - Modest, D.P.* AU - Holch, J.W.* AU - Westphalen, C.B.* AU - Hölzel, L. AU - Schübel, M.K. AU - Galhoz, A. AU - Farnoud, A. AU - Ud-Dean, M. AU - Vehling-Kaiser, U.* AU - Decker, T.* AU - Moehler, M.* AU - Heinig, M. AU - Heinemann, V.* AU - Menden, M.P. C1 - 68325 C2 - 54746 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - The Oncology Biomarker Discovery framework reveals cetuximab and bevacizumab response patterns in metastatic colorectal cancer. JO - Nat. Commun. VL - 14 IS - 1 PB - Nature Portfolio PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix®. AU - Ollila, H.M.* AU - Sharon, E.* AU - Lin, L.* AU - Sinnott-Armstrong, N.* AU - Ambati, A.* AU - Yogeshwar, S.M.* AU - Hillary, R.P.* AU - Jolanki, O.* AU - Faraco, J.* AU - Einen, M.* AU - Luo, G.* AU - Zhang, J.* AU - Han, F.* AU - Yan, H.* AU - Dong, X.S.* AU - Li, J.* AU - Hong, S.C.* AU - Kim, T.W.* AU - Dauvilliers, Y.* AU - Barateau, L.* AU - Lammers, G.J.* AU - Fronczek, R.* AU - Mayer, G.* AU - Santamaría, J.* AU - Arnulf, I.* AU - Knudsen-Heier, S.* AU - Bredahl, M.K.L.* AU - Thorsby, P.M.* AU - Plazzi, G.* AU - Pizza, F.* AU - Moresco, M.* AU - Crowe, C.* AU - Van den Eeden, S.K.* AU - Lecendreux, M.* AU - Bourgin, P.* AU - Kanbayashi, T.* AU - Martínez-Orozco, F.J.* AU - Peraita-Adrados, R.* AU - Benetó, A.* AU - Montplaisir, J.* AU - Desautels, A.* AU - Huang, Y.S.* AU - Jennum, P.* AU - Nevsimalova, S.* AU - Kemlink, D.* AU - Iranzo, A.* AU - Overeem, S.* AU - Wierzbicka, A.* AU - Geisler, P.* AU - Sonka, K.* AU - Honda, M.* AU - Högl, B.* AU - Stefani, A.* AU - Coelho, F.M.* AU - Mantovani, V.* AU - Feketeova, E.* AU - Wadelius, M.* AU - Eriksson, N.* AU - Smedje, H.* AU - Hallberg, P.* AU - Hesla, P.E.* AU - Rye, D.* AU - Pelin, Z.* AU - Ferini-Strambi, L.* AU - Bassetti, C.L.* AU - Mathis, J.* AU - Khatami, R.* AU - Aran, A.* AU - Nampoothiri, S.* AU - Olsson, T.* AU - Kockum, I.* AU - Partinen, M.* AU - Perola, M.* AU - Kornum, B.R.* AU - Rüeger, S.* AU - Winkelmann, J. AU - Miyagawa, T.* AU - Toyoda, H.* AU - Khor, S.S.* AU - Shimada, M.* AU - Tokunaga, K.* AU - Rivas, M.* AU - Pritchard, J.K.* AU - Risch, N.* AU - Kutalik, Z.* AU - O'Hara, R.* AU - Hallmayer, J.* AU - Ye, C.J.* AU - Mignot, E.J.* C1 - 67795 C2 - 54273 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy. JO - Nat. Commun. VL - 14 IS - 1 PB - Nature Portfolio PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - Plants have benefited from interactions with symbionts for coping with challenging environments since the colonisation of land. The mechanisms of symbiont-mediated beneficial effects and similarities and differences to pathogen strategies are mostly unknown. Here, we use 106 (effector-) proteins, secreted by the symbiont Serendipita indica (Si) to modulate host physiology, to map interactions with Arabidopsis thaliana host proteins. Using integrative network analysis, we show significant convergence on target-proteins shared with pathogens and exclusive targeting of Arabidopsis proteins in the phytohormone signalling network. Functional in planta screening and phenotyping of Si effectors and interacting proteins reveals previously unknown hormone functions of Arabidopsis proteins and direct beneficial activities mediated by effectors in Arabidopsis. Thus, symbionts and pathogens target a shared molecular microbe-host interface. At the same time Si effectors specifically target the plant hormone network and constitute a powerful resource for elucidating the signalling network function and boosting plant productivity. AU - Osborne, R.* AU - Rehneke, L.* AU - Lehmann, S.* AU - Roberts, J.* AU - Altmann, M. AU - Altmann, S. AU - Zhang, Y.* AU - Köpff, E.* AU - Dominguez-Ferreras, A.* AU - Okechukwu, E.* AU - Sergaki, C.* AU - Rich-Griffin, C.* AU - Ntoukakis, V.* AU - Eichmann, R.* AU - Shan, W.* AU - Falter-Braun, P. AU - Schäfer, P.* C1 - 68126 C2 - 54604 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Symbiont-host interactome mapping reveals effector-targeted modulation of hormone networks and activation of growth promotion. JO - Nat. Commun. VL - 14 IS - 1 PB - Nature Portfolio PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - Systemic antibody light chain (AL) amyloidosis is characterized by deposition of amyloid fibrils. Prior to fibril formation, soluble oligomeric AL protein has a direct cytotoxic effect on cardiomyocytes. We focus on the patient derived λ-III AL variable domain FOR005 which is mutated at five positions with respect to the closest germline protein. Using solution-state NMR spectroscopy, we follow the individual steps involved in protein misfolding from the native to the amyloid fibril state. Unfavorable mutations in the complementary determining regions introduce a strain in the native protein structure which yields partial unfolding. Driven by electrostatic interactions, the protein converts into a high molecular weight, oligomeric, molten globule. The high local concentration of aggregation prone regions in the oligomer finally catalyzes the conversion into fibrils. The topology is determined by balanced electrostatic interactions in the fibril core implying a 180° rotational switch of the beta-sheets around the conserved disulfide bond. AU - Pradhan, T. AU - Sarkar, R. AU - Meighen-Berger, K.M.* AU - Feige, M.J.* AU - Zacharias, M.* AU - Reif, B. C1 - 68489 C2 - 54662 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Mechanistic insights into the aggregation pathway of the patient-derived immunoglobulin light chain variable domain protein FOR005. JO - Nat. Commun. VL - 14 IS - 1 PB - Nature Portfolio PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - Single-cell open chromatin profiling via scATAC-seq has become a mainstream measurement of open chromatin in single-cells. Here we present epiAneufinder, an algorithm that exploits the read count information from scATAC-seq data to extract genome-wide copy number alterations (CNAs) for individual cells, allowing the study of CNA heterogeneity present in a sample at the single-cell level. Using different cancer scATAC-seq datasets, we show that epiAneufinder can identify intratumor clonal heterogeneity in populations of single cells based on their CNA profiles. We demonstrate that these profiles are concordant with the ones inferred from single-cell whole genome sequencing data for the same samples. EpiAneufinder allows the inference of single-cell CNA information from scATAC-seq data, without the need of additional experiments, unlocking a layer of genomic variation which is otherwise unexplored. AU - Ramakrishnan, A. AU - Symeonidi, A. AU - Hanel, P. AU - Schmid, K.T.* AU - Richter, M.L.* AU - Schubert, M.* AU - Colomé-Tatché, M. C1 - 68244 C2 - 54780 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - epiAneufinder identifies copy number alterations from single-cell ATAC-seq data. JO - Nat. Commun. VL - 14 IS - 1 PB - Nature Portfolio PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - Understanding phenotype-to-genotype relationships is a grand challenge of 21st century biology with translational implications. The recently proposed "omnigenic" model postulates that effects of genetic variation on traits are mediated by core-genes and -proteins whose activities mechanistically influence the phenotype, whereas peripheral genes encode a regulatory network that indirectly affects phenotypes via core gene products. Here, we develop a positive-unlabeled graph representation-learning ensemble-approach based on a nested cross-validation to predict core-like genes for diverse diseases using Mendelian disorder genes for training. Employing mouse knockout phenotypes for external validations, we demonstrate that core-like genes display several key properties of core genes: Mouse knockouts of genes corresponding to our most confident predictions give rise to relevant mouse phenotypes at rates on par with the Mendelian disorder genes, and all candidates exhibit core gene properties like transcriptional deregulation in disease and loss-of-function intolerance. Moreover, as predicted for core genes, our candidates are enriched for drug targets and druggable proteins. In contrast to Mendelian disorder genes the new core-like genes are enriched for druggable yet untargeted gene products, which are therefore attractive targets for drug development. Interpretation of the underlying deep learning model suggests plausible explanations for our core gene predictions in form of molecular mechanisms and physical interactions. Our results demonstrate the potential of graph representation learning for the interpretation of biological complexity and pave the way for studying core gene properties and future drug development. AU - Ratajczak, F. AU - Joblin, M.* AU - Hildebrandt, M.* AU - Ringsquandl, M.* AU - Falter-Braun, P. AU - Heinig, M. C1 - 68755 C2 - 54965 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Speos: An ensemble graph representation learning framework to predict core gene candidates for complex diseases. JO - Nat. Commun. VL - 14 IS - 1 PB - Nature Portfolio PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - Sporadic Parkinson's Disease (sPD) is a progressive neurodegenerative disorder caused by multiple genetic and environmental factors. Mitochondrial dysfunction is one contributing factor, but its role at different stages of disease progression is not fully understood. Here, we showed that neural precursor cells and dopaminergic neurons derived from induced pluripotent stem cells (hiPSCs) from sPD patients exhibited a hypometabolism. Further analysis based on transcriptomics, proteomics, and metabolomics identified the citric acid cycle, specifically the α-ketoglutarate dehydrogenase complex (OGDHC), as bottleneck in sPD metabolism. A follow-up study of the patients approximately 10 years after initial biopsy demonstrated a correlation between OGDHC activity in our cellular model and the disease progression. In addition, the alterations in cellular metabolism observed in our cellular model were restored by interfering with the enhanced SHH signal transduction in sPD. Thus, inhibiting overactive SHH signaling may have potential as neuroprotective therapy during early stages of sPD. AU - Schmidt, S. AU - Stautner, C. AU - Vu, D.T.* AU - Heinz, A.* AU - Regensburger, M.* AU - Karayel, O.* AU - Trümbach, D. AU - Artati, A. AU - Kaltenhäuser, S.* AU - Nassef, M.Z.* AU - Hembach, S. AU - Steinert, L. AU - Winner, B.* AU - Jürgen, W.* AU - Jastroch, M.* AU - Luecken, M. AU - Theis, F.J. AU - Westmeyer, G.G. AU - Adamski, J. AU - Mann, M.* AU - Hiller, K.* AU - Giesert, F. AU - Vogt Weisenhorn, D.M. AU - Wurst, W. C1 - 68870 C2 - 53678 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - A reversible state of hypometabolism in a human cellular model of sporadic Parkinson's disease. JO - Nat. Commun. VL - 14 IS - 1 PB - Nature Portfolio PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - The sample from the near-Earth carbonaceous asteroid (162173) Ryugu is analyzed in the context of carbonaceous meteorites soluble organic matter. The analysis of soluble molecules of samples collected by the Hayabusa2 spacecraft shines light on an extremely high molecular diversity on the C-type asteroid. Sequential solvent extracts of increasing polarity of Ryugu samples are analyzed using mass spectrometry with complementary ionization methods and structural information confirmed by nuclear magnetic resonance spectroscopy. Here we show a continuum in the molecular size and polarity, and no organomagnesium molecules are detected, reflecting a low temperature and water-rich environment on the parent body approving earlier mineralogical and chemical data. High abundance of sulfidic and nitrogen rich compounds as well as high abundance of ammonium ions confirm the water processing. Polycyclic aromatic hydrocarbons are also detected in a structural continuum of carbon saturations and oxidations, implying multiple origins of the observed organic complexity, thus involving generic processes such as earlier carbonization and serpentinization with successive low temperature aqueous alteration. AU - Schmitt-Kopplin, P. AU - Hertkorn, N. AU - Harir, M. AU - Moritz, F. AU - Lucio, M. AU - Bonal, L.* AU - Quirico, E.* AU - Takano, Y.* AU - Dworkin, J.P.* AU - Naraoka, H.* AU - Tachibana, S.* AU - Nakamura, T.* AU - Noguchi, T.* AU - Okazaki, R.* AU - Yabuta, H.* AU - Yurimoto, H.* AU - Sakamoto, K.* AU - Yada, T.* AU - Nishimura, M.* AU - Nakato, A.* AU - Miyazaki, A.* AU - Yogata, K.* AU - Abe, M.* AU - Usui, T.* AU - Yoshikawa, M.* AU - Saiki, T.* AU - Tanaka, S.* AU - Terui, F.* AU - Nakazawa, S.* AU - Okada, T.* AU - Watanabe, S.i.* AU - Tsuda, Y.* C1 - 68648 C2 - 54851 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Soluble organic matter molecular atlas of Ryugu reveals cold hydrothermalism on C-type asteroid parent body. JO - Nat. Commun. VL - 14 IS - 1 PB - Nature Portfolio PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - Selenium homeostasis depends on hepatic biosynthesis of selenoprotein P (SELENOP) and SELENOP-mediated transport from the liver to e.g. the brain. In addition, the liver maintains copper homeostasis. Selenium and copper metabolism are inversely regulated, as increasing copper and decreasing selenium levels are observed in blood during aging and inflammation. Here we show that copper treatment increased intracellular selenium and SELENOP in hepatocytes and decreased extracellular SELENOP levels. Hepatic accumulation of copper is a characteristic of Wilson’s disease. Accordingly, SELENOP levels were low in serum of Wilson’s disease patients and Wilson’s rats. Mechanistically, drugs targeting protein transport in the Golgi complex mimicked some of the effects observed, indicating a disrupting effect of excessive copper on intracellular SELENOP transport resulting in its accumulation in the late Golgi. Our data suggest that hepatic copper levels determine SELENOP release from the liver and may affect selenium transport to peripheral organs such as the brain. AU - Schwarz, M.* AU - Meyer, C.E.* AU - Löser, A.* AU - Lossow, K.* AU - Hackler, J.* AU - Ott, C.* AU - Jager, S.* AU - Mohr, I.* AU - Eklund, E.A.* AU - Patel, A.A.H.* AU - Gul, N.* AU - Alvarez, S.* AU - Altinonder, I.* AU - Wiel, C.* AU - Maares, M.* AU - Haase, H.* AU - Härtlova, A.* AU - Grune, T.* AU - Schulze, M.B.* AU - Schwerdtle, T.* AU - Merle, U.* AU - Zischka, H. AU - Sayin, V.I.* AU - Schomburg, L.* AU - Kipp, A.P.* C1 - 68523 C2 - 54699 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Excessive copper impairs intrahepatocyte trafficking and secretion of selenoprotein P. JO - Nat. Commun. VL - 14 IS - 1 PB - Nature Portfolio PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - Therapeutic antibodies are widely used to treat severe diseases. Most of them alter immune cells and act within the immunological synapse; an essential cell-to-cell interaction to direct the humoral immune response. Although many antibody designs are generated and evaluated, a high-throughput tool for systematic antibody characterization and prediction of function is lacking. Here, we introduce the first comprehensive open-source framework, scifAI (single-cell imaging flow cytometry AI), for preprocessing, feature engineering, and explainable, predictive machine learning on imaging flow cytometry (IFC) data. Additionally, we generate the largest publicly available IFC dataset of the human immunological synapse containing over 2.8 million images. Using scifAI, we analyze class frequency and morphological changes under different immune stimulation. T cell cytokine production across multiple donors and therapeutic antibodies is quantitatively predicted in vitro, linking morphological features with function and demonstrating the potential to significantly impact antibody design. scifAI is universally applicable to IFC data. Given its modular architecture, it is straightforward to incorporate into existing workflows and analysis pipelines, e.g., for rapid antibody screening and functional characterization. AU - Shetab Boushehri, S. AU - Essig, K.* AU - Chlis, N.K.* AU - Herter, S.* AU - Bacac, M.* AU - Theis, F.J. AU - Glasmacher, E.* AU - Marr, C. AU - Schmich, F.* C1 - 68886 C2 - 53744 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Explainable machine learning for profiling the immunological synapse and functional characterization of therapeutic antibodies. JO - Nat. Commun. VL - 14 IS - 1 PB - Nature Portfolio PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (Pinteraction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications. AU - Shi, J.* AU - Shiraishi, K.* AU - Choi, J.* AU - Matsuo, K.* AU - Chen, T.Y.* AU - Dai, J.* AU - Hung, R.J.* AU - Chen, K.* AU - Shu, X.O.* AU - Kim, Y.T.* AU - Landi, M.T.* AU - Lin, D.* AU - Zheng, W.* AU - Yin, Z.* AU - Zhou, B.* AU - Song, B.* AU - Wang, J.* AU - Seow, W.J.* AU - Song, L.* AU - Chang, I.S.* AU - Hu, W.* AU - Chien, L.H.* AU - Cai, Q.* AU - Hong, Y.C.* AU - Kim, H.N.* AU - Wu, Y.L.* AU - Wong, M.P.* AU - Richardson, B.D.* AU - Funderburk, K.M.* AU - Li, S.* AU - Zhang, T.* AU - Breeze, C.* AU - Wang, Z.* AU - Blechter, B.* AU - Bassig, B.A.* AU - Kim, J.H.* AU - Albanes, D.* AU - Wong, J.Y.Y.* AU - Shin, M.H.* AU - Chung, L.P.* AU - Yang, Y.* AU - An, S.J.* AU - Zheng, H.* AU - Yatabe, Y.* AU - Zhang, X.C.* AU - Kim, Y.C.* AU - Caporaso, N.E.* AU - Chang, J.* AU - Ho, J.C.M.* AU - Kubo, M.* AU - Daigo, Y.* AU - Song, M.* AU - Momozawa, Y.* AU - Kamatani, Y.* AU - Kobayashi, M.* AU - Okubo, K.* AU - Honda, T.* AU - Hosgood, D.H.* AU - Kunitoh, H.* AU - Patel, H.* AU - Watanabe, S.i.* AU - Miyagi, Y.* AU - Nakayama, H.* AU - Matsumoto, S.* AU - Horinouchi, H.* AU - Tsuboi, M.* AU - Hamamoto, R.* AU - Goto, K.* AU - Ohe, Y.* AU - Takahashi, A.* AU - Goto, A.* AU - Minamiya, Y.* AU - Hara, M.* AU - Nishida, Y.* AU - Takeuchi, K.* AU - Wakai, K.* AU - Matsuda, K.* AU - Murakami, Y.* AU - Shimizu, K.* AU - Suzuki, H.* AU - Saito, M.* AU - Ohtaki, Y.* AU - Tanaka, K.* AU - Wu, T.* AU - Wei, F.* AU - Dai, H.* AU - Machiela, M.J.* AU - Su, J.* AU - Kim, Y.H.* AU - Oh, I.J.* AU - Lee, V.H.F.* AU - Chang, G.C.* AU - Tsai, Y.H.* AU - Chen, K.Y.* AU - Huang, M.S.* AU - Su, W.C.* AU - Chen, Y.M.* AU - Seow, A.* AU - Park, J.Y.* AU - Kweon, S.S.* AU - Chen, K.C.* AU - Gao, Y.T.* AU - Qian, B.* AU - Wu, C.* AU - Lu, D.* AU - Liu, J.* AU - Schwartz, A.G.* AU - Houlston, R.* AU - Spitz, M.R.* AU - Gorlov, I.P.* AU - Wu, X.* AU - Yang, P.* AU - Lam, S.* AU - Tardón, A.* AU - Chen, C.* AU - Bojesen, S.E.* AU - Johansson, M.* AU - Risch, A.* AU - Bickeböller, H.* AU - Ji, B.T.* AU - Wichmann, H.-E. AU - Christiani, D.C.* AU - Rennert, G.* AU - Arnold, S.* AU - Brennan, P.* AU - Mckay, J.* AU - Field, J.K.* AU - Shete, S.S.* AU - Le Marchand, L.* AU - Liu, G.* AU - Andrew, A.* AU - Kiemeney, L.A.* AU - Zienolddiny-Narui, S.* AU - Grankvist, K.* AU - Cox, A.* AU - Taylor, F.* AU - Yuan, J.M.* AU - Lazarus, P.* AU - Schabath, M.B.* AU - Aldrich, M.C.* AU - Jeon, H.S.* AU - Jiang, S.S.* AU - Sung, J.S.* AU - Chen, C.H.* AU - Hsiao, C.F.* AU - Jung, Y.J.* AU - Guo, H.* AU - Hu, Z.* AU - Burdett, L.* AU - Yeager, M.* AU - Hutchinson, A.* AU - Hicks, B.* AU - Zhu, B.* AU - Berndt, S.I.* AU - Wu, W.* AU - Li, Y.* AU - Choi, J.E.* AU - Park, K.H.* AU - Sung, S.W.* AU - Liu, L.* AU - Kang, C.H.* AU - Wang, W.C.* AU - Xu, J.* AU - Guan, P.* AU - Tan, W.* AU - Yu, C.J.* AU - Yang, G.* AU - Sihoe, A.D.L.* AU - Chen, Y.* AU - Choi, Y.Y.* AU - Kim, J.S.* AU - Yoon, H.I.* AU - Park, I.K.* AU - Xu, P.* AU - He, Q.* AU - Wang, C.L.* AU - Hung, H.H.* AU - Vermeulen, R.C.H.* AU - Cheng, I.* AU - Wu, J.* AU - Lim, W.Y.* AU - Tsai, F.Y.* AU - Chan, J.K.C.* AU - Li, J.* AU - Chen, H.* AU - Lin, H.C.* AU - Jin, L.* AU - Sawada, N.* AU - Yamaji, T.* AU - Wyatt, K.* AU - Li, S.A.* AU - Ma, H.* AU - Zhu, M.* AU - Wang, Z.* AU - Cheng, S.* AU - Li, X.* AU - Ren, Y.* AU - Chao, A.* AU - Iwasaki, M.* AU - Zhu, J.* AU - Jiang, G.* AU - Fei, K.* AU - Wu, G.* AU - Chen, C.Y.* AU - Chen, C.J.* AU - Yang, P.C.* AU - Yu, J.* AU - Stevens, V.L.* AU - Fraumeni, J.F.* AU - Chatterjee, N.* AU - Gorlova, O.Y.* AU - Hsiung, C.A.* AU - Amos, C.I.* AU - Shen, H.* AU - Chanock, S.J.* AU - Rothman, N.* AU - Kohno, T.* AU - Lan, Q.* C1 - 67884 C2 - 54362 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population. JO - Nat. Commun. VL - 14 IS - 1 PB - Nature Portfolio PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - Spatial transcriptomics of histological sections have revolutionized research in life sciences and enabled unprecedented insights into genetic processes involved in tissue reorganization. However, in contrast to genomic analysis, the actual biomolecular composition of the sample has fallen behind, leaving a gap of potentially highly valuable information. Raman microspectroscopy provides untargeted spatiomolecular information at high resolution, capable of filling this gap. In this study we demonstrate spatially resolved Raman “spectromics” to reveal homogeneity, heterogeneity and dynamics of cell matrix on molecular levels by repurposing state-of-the-art bioinformatic analysis tools commonly used for transcriptomic analyses. By exploring sections of murine myocardial infarction and cardiac hypertrophy, we identify myocardial subclusters when spatially approaching the pathology, and define the surrounding metabolic and cellular (immune-) landscape. Our innovative, label-free, non-invasive “spectromics” approach could therefore open perspectives for a profound characterization of histological samples, while additionally allowing the combination with consecutive downstream analyses of the very same specimen. AU - Sigle, M.* AU - Rohlfing, A.K.* AU - Kenny, M.* AU - Scheuermann, S.* AU - Sun, N. AU - Graeßner, U.* AU - Haug, V.* AU - Sudmann, J.* AU - Seitz, C.M.* AU - Heinzmann, D.* AU - Schenke-Layland, K.* AU - Maguire, P.B.* AU - Walch, A.* AU - Marzi, J.* AU - Gawaz, M.P.* C1 - 68254 C2 - 54782 CY - Heidelberger Platz 3, Berlin, 14197, Germany SP - 16 TI - Translating genomic tools to Raman spectroscopy analysis enables high-dimensional tissue characterization on molecular resolution. JO - Nat. Commun. VL - 14 IS - 1 PB - Nature Portfolio PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - We identify biomarkers for disease progression in three type 2 diabetes cohorts encompassing 2,973 individuals across three molecular classes, metabolites, lipids and proteins. Homocitrulline, isoleucine and 2-aminoadipic acid, eight triacylglycerol species, and lowered sphingomyelin 42:2;2 levels are predictive of faster progression towards insulin requirement. Of ~1,300 proteins examined in two cohorts, levels of GDF15/MIC-1, IL-18Ra, CRELD1, NogoR, FAS, and ENPP7 are associated with faster progression, whilst SMAC/DIABLO, SPOCK1 and HEMK2 predict lower progression rates. In an external replication, proteins and lipids are associated with diabetes incidence and prevalence. NogoR/RTN4R injection improved glucose tolerance in high fat-fed male mice but impaired it in male db/db mice. High NogoR levels led to islet cell apoptosis, and IL-18R antagonised inflammatory IL-18 signalling towards nuclear factor kappa-B in vitro. This comprehensive, multi-disciplinary approach thus identifies biomarkers with potential prognostic utility, provides evidence for possible disease mechanisms, and identifies potential therapeutic avenues to slow diabetes progression. AU - Slieker, R.C.* AU - Donnelly, L.A.* AU - Akalestou, E.* AU - Lopez-Noriega, L.* AU - Melhem, R.* AU - Güneş, A.* AU - Abou Azar, F.* AU - Efanov, A.* AU - Georgiadou, E.* AU - Muniangi-Muhitu, H.* AU - Sheikh, M.* AU - Giordano, G.N.* AU - Åkerlund, M.* AU - Ahlqvist, E.* AU - Ali, A.* AU - Banasik, K.* AU - Brunak, S.* AU - Barovic, M. AU - Bouland, G.A.* AU - Burdet, F.* AU - Canouil, M.* AU - Dragan, I.* AU - Elders, P.J.M.* AU - Fernandez, C.* AU - Festa, A.* AU - Fitipaldi, H.* AU - Froguel, P.* AU - Gudmundsdottir, V.* AU - Gudnason, V.* AU - Gerl, M.J.* AU - van der Heijden, A.A.* AU - Jennings, L.L.* AU - Hansen, M.K.* AU - Kim, M.* AU - Leclerc, I.* AU - Klose, C.* AU - Kuznetsov, D.* AU - Mansour Aly, D.* AU - Mehl, F.* AU - Marek, D.* AU - Melander, O.* AU - Niknejad, A.* AU - Ottosson, F.* AU - Pavo, I.* AU - Duffin, K.C.* AU - Syed, S.K.* AU - Shaw, J.L.* AU - Cabrera, O.* AU - Pullen, T.J.* AU - Simons, K.* AU - Solimena, M. AU - Suvitaival, T.* AU - Wretlind, A.* AU - Rossing, P.* AU - Lyssenko, V.* AU - Legido Quigley, C.* AU - Groop, L.* AU - Thorens, B.* AU - Franks, P.W.* AU - Lim, G.E.* AU - Estall, J.* AU - Ibberson, M.* AU - Beulens, J.W.J.* AU - ’t Hart, L.M.* AU - Pearson, E.R.* AU - Rutter, G.A.* C1 - 68571 C2 - 53569 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Identification of biomarkers for glycaemic deterioration in type 2 diabetes. JO - Nat. Commun. VL - 14 IS - 1 PB - Nature Portfolio PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - The RNA-binding motif protein RBM5 belongs to a family of multi-domain RNA binding proteins that regulate alternative splicing of genes important for apoptosis and cell proliferation and have been implicated in cancer. RBM5 harbors structural modules for RNA recognition, such as RRM domains and a Zn finger, and protein-protein interactions such as an OCRE domain. Here, we characterize binding of the RBM5 RRM1-ZnF1-RRM2 domains to cis-regulatory RNA elements. A structure of the RRM1-ZnF1 region in complex with RNA shows how the tandem domains cooperate to sandwich target RNA and specifically recognize a GG dinucleotide in a non-canonical fashion. While the RRM1-ZnF1 domains act as a single structural module, RRM2 is connected by a flexible linker and tumbles independently. However, all three domains participate in RNA binding and adopt a closed architecture upon RNA binding. Our data highlight how cooperativity and conformational modularity of multiple RNA binding domains enable the recognition of distinct RNA motifs, thereby contributing to the regulation of alternative splicing. Remarkably, we observe surprising differences in coupling of the RNA binding domains between the closely related homologs RBM5 and RBM10. AU - Soni, K. AU - Jagtap, P.K. AU - Martinez Lumbreras, S. AU - Bonnal, S.* AU - Geerlof, A. AU - Stehle, R. AU - Simon, B.* AU - Valcárcel, J.* AU - Sattler, M. C1 - 68100 C2 - 54578 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Structural basis for specific RNA recognition by the alternative splicing factor RBM5. JO - Nat. Commun. VL - 14 IS - 1 PB - Nature Portfolio PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - Mammalian spermatogenesis shows prominent chromatin and transcriptomic switches in germ cells, but it is unclear how such dynamics are controlled. Here we identify RNA helicase DDX43 as an essential regulator of the chromatin remodeling process during spermiogenesis. Testis-specific Ddx43 knockout mice show male infertility with defective histone-to-protamine replacement and post-meiotic chromatin condensation defects. The loss of its ATP hydrolysis activity by a missense mutation replicates the infertility phenotype in global Ddx43 knockout mice. Single-cell RNA sequencing analyses of germ cells depleted of Ddx43 or expressing the Ddx43 ATPase-dead mutant reveals that DDX43 regulates dynamic RNA regulatory processes that underlie spermatid chromatin remodeling and differentiation. Transcriptomic profiling focusing on early-stage spermatids combined with enhanced crosslinking immunoprecipitation and sequencing further identifies Elfn2 as DDX43-targeted hub gene. These findings illustrate an essential role for DDX43 in spermiogenesis and highlight the single-cell-based strategy to dissect cell-state-specific regulation of male germline development. AU - Tan, H.* AU - Wang, W. AU - Zhou, C.* AU - Wang, Y.* AU - Zhang, S.* AU - Yang, P.* AU - Guo, R.* AU - Chen, W.* AU - Zhang, J.* AU - Ye, L.* AU - Cui, Y.* AU - Ni, T.* AU - Zheng, K.* C1 - 70291 C2 - 55154 TI - Single-cell RNA-seq uncovers dynamic processes orchestrated by RNA-binding protein DDX43 in chromatin remodeling during spermiogenesis. JO - Nat. Commun. VL - 14 IS - 1 PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - Although beta-endorphinergic neurons in the hypothalamic arcuate nucleus (ARC) synthesize beta-endorphin (β-EP) to alleviate nociceptive behaviors, the underlying regulatory mechanisms remain unknown. Here, we elucidated an epigenetic pathway driven by microRNA regulation of β-EP synthesis in ARC neurons to control neuropathic pain. In pain-injured rats miR-203a-3p was the most highly upregulated miRNA in the ARC. A similar increase was identified in the cerebrospinal fluid of trigeminal neuralgia patients. Mechanistically, we found histone deacetylase 9 was downregulated following nerve injury, which decreased deacetylation of histone H3 lysine-18, facilitating the binding of NR4A2 transcription factor to the miR-203a-3p gene promoter, thereby upregulating miR-203a-3p expression. Further, increased miR-203a-3p was found to maintain neuropathic pain by targeting proprotein convertase 1, an endopeptidase necessary for the cleavage of proopiomelanocortin, the precursor of β-EP. The identified mechanism may provide an avenue for the development of new therapeutic targets for neuropathic pain treatment. AU - Tao, Y.* AU - Zhang, Y.* AU - Jin, W.* AU - Hua, N.* AU - Liu, H.* AU - Qi, R.* AU - Huang, Z.* AU - Sun, Y.* AU - Jiang, D. AU - Snutch, T.P.* AU - Jiang, X.* AU - Tao, J.* C1 - 68758 C2 - 54968 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Epigenetic regulation of beta-endorphin synthesis in hypothalamic arcuate nucleus neurons modulates neuropathic pain in a rodent pain model. JO - Nat. Commun. VL - 14 IS - 1 PB - Nature Portfolio PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - Culture techniques have associated colonization with pathogenic bacteria in the airways of neonates with later risk of childhood asthma, whereas more recent studies utilizing sequencing techniques have shown the same phenomenon with specific anaerobic taxa. Here, we analyze nasopharyngeal swabs from 1 month neonates in the COPSAC2000 prospective birth cohort by 16S rRNA gene sequencing of the V3-V4 region in relation to asthma risk throughout childhood. Results are compared with previous culture results from hypopharyngeal aspirates from the same cohort and with hypopharyngeal sequencing data from the later COPSAC2010 cohort. Nasopharyngeal relative abundance values of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis are associated with the same species in the hypopharyngeal cultures. A combined pathogen score of these bacteria's abundance values is associated with persistent wheeze/asthma by age 7. No other taxa are associated. Compared to the hypopharyngeal aspirates from the COPSAC2010 cohort, the anaerobes Veillonella and Prevotella, which have previously been implicated in asthma development, are less commonly detected in the COPSAC2000 nasopharyngeal samples, but correlate with the pathogen score, hinting at latent community structures that bridge current and previous results. These findings have implications for future asthma prevention efforts. AU - Thorsen, J.* AU - Li, X.J.* AU - Peng, S.* AU - Sunde, R.B.* AU - Shah, S.A.* AU - Bhattacharyya, M.* AU - Poulsen, C.S.* AU - Poulsen, C.E.* AU - Leal Rodríguez, C.* AU - Widdowson, M.* AU - Neumann, A.U. AU - Trivedi, U.* AU - Chawes, B.* AU - Bønnelykke, K.* AU - Bisgaard, H.* AU - Sørensen, S.J.* AU - Stokholm, J.* C1 - 68713 C2 - 54922 TI - The airway microbiota of neonates colonized with asthma-associated pathogenic bacteria. JO - Nat. Commun. VL - 14 IS - 1 PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - Ferroptosis is a regulated cell death modality that occurs upon iron-dependent lipid peroxidation. Recent research has identified many regulators that induce or inhibit ferroptosis; yet, many regulatory processes and networks remain to be elucidated. In this study, we performed a chemical genetics screen using small molecules with known mode of action and identified two agonists of the nuclear receptor Farnesoid X Receptor (FXR) that suppress ferroptosis, but not apoptosis or necroptosis. We demonstrate that in liver cells with high FXR levels, knockout or inhibition of FXR sensitized cells to ferroptotic cell death, whereas activation of FXR by bile acids inhibited ferroptosis. Furthermore, FXR inhibited ferroptosis in ex vivo mouse hepatocytes and human hepatocytes differentiated from induced pluripotent stem cells. Activation of FXR significantly reduced lipid peroxidation by upregulating the ferroptosis gatekeepers GPX4, FSP1, PPARα, SCD1, and ACSL3. Together, we report that FXR coordinates the expression of ferroptosis-inhibitory regulators to reduce lipid peroxidation, thereby acting as a guardian of ferroptosis. AU - Tschuck, J. AU - Theilacker, L. AU - Rothenaigner, I. AU - Weiß, S.A.I. AU - Akdogan, B. AU - Lam, T.V. AU - Müller, C. AU - Graf, R. AU - Brandner, S. AU - Pütz, C. AU - Rieder, T.* AU - Schmitt-Kopplin, P. AU - Vincendeau, M. AU - Zischka, H. AU - Schorpp, K. AU - Hadian, K. C1 - 68740 C2 - 54950 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Farnesoid X receptor activation by bile acids suppresses lipid peroxidation and ferroptosis. JO - Nat. Commun. VL - 14 IS - 1 PB - Nature Portfolio PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development. AU - van de Vegte, Y.J.* AU - Eppinga, R.N.* AU - van der Ende, M.Y.* AU - Hagemeijer, Y.P.* AU - Mahendran, Y.* AU - Salfati, E.* AU - Smith, A.V.* AU - Tan, V.Y.* AU - Arking, D.E.* AU - Ntalla, I.* AU - Appel, E.V.* AU - Schurmann, C.* AU - Brody, J.A.* AU - Rueedi, R.* AU - Polasek, O.* AU - Sveinbjornsson, G.* AU - Lecoeur, C.* AU - Ladenvall, C.* AU - Zhao, J.H.* AU - Isaacs, A.* AU - Wang, W.* AU - Luan, J.* AU - Hwang, S.J.* AU - Mononen, N.* AU - Auro, K.* AU - Jackson, A.U.* AU - Bielak, L.F.* AU - Zeng, L.* AU - Shah, N.* AU - Nethander, M.* AU - Campbell, A.* AU - Rankinen, T.* AU - Pechlivanis, S.* AU - Qi, L.* AU - Zhao, W.* AU - Rizzi, F.* AU - Tanaka, T.* AU - Robino, A.* AU - Cocca, M.* AU - Lange, L.* AU - Müller-Nurasyid, M. AU - Roselli, C. AU - Zhang, W.* AU - Kleber, M.E.* AU - Guo, X.* AU - Lin, H.J.* AU - Pavani, F.* AU - Galesloot, T.E.* AU - Noordam, R.* AU - Milaneschi, Y.* AU - Schraut, K.E.* AU - den Hoed, M.* AU - Degenhardt, F.* AU - Trompet, S.* AU - van den Berg, M.E.* AU - Pistis, G.* AU - Tham, Y.C.* AU - Weiss, S.* AU - Sim, X.S.* AU - Li, H.L.* AU - van der Most, P.J.* AU - Nolte, I.M.* AU - Lyytikäinen, L.P.* AU - Said, M.A.* AU - Witte, D.R.* AU - Iribarren, C.* AU - Launer, L.* AU - Ring, S.M.* AU - de Vries, P.S.* AU - Sever, P.* AU - Linneberg, A.* AU - Bottinger, E.P.* AU - Padmanabhan, S.* AU - Psaty, B.M.* AU - Sotoodehnia, N.* AU - Kolcic, I.* AU - Arnar, D.O.* AU - Gudbjartsson, D.F.* AU - Holm, H.* AU - Balkau, B.* AU - Silva, C.T.* AU - Newton-Cheh, C.H.* AU - Nikus, K.* AU - Salo, P.* AU - Mohlke, K.L.* AU - Peyser, P.A.* AU - Schunkert, H.* AU - Lorentzon, M.* AU - Lahti, J.* AU - Rao, D.C.* AU - Cornelis, M.C.* AU - Faul, J.D.* AU - Smith, J.A.* AU - Stolarz-Skrzypek, K.* AU - Bandinelli, S.* AU - Concas, M.P.* AU - Sinagra, G.* AU - Meitinger, T. AU - Waldenberger, M. AU - Sinner, M.F.* AU - Strauch, K. AU - Delgado, G.E.* AU - Taylor, K.D.* AU - Yao, J.* AU - Foco, L.* AU - Melander, O.* AU - de Graaf, J.* AU - de Mutsert, R.* AU - de Geus, E.J.C.* AU - Johansson, * AU - Joshi, P.K.* AU - Lind, L.* AU - Franke, A.* AU - Macfarlane, P.W.* AU - Tarasov, K.V.* AU - Tan, N.* AU - Felix, S.B.* AU - Tai, E.S.* AU - Quek, D.Q.* AU - Snieder, H.* AU - Ormel, J.* AU - Ingelsson, M.* AU - Lindgren, C.* AU - Morris, A.P.* AU - Raitakari, O.T.* AU - Hansen, T.* AU - Assimes, T.* AU - Gudnason, V.* AU - Timpson, N.J.* AU - Morrison, A.C.* AU - Munroe, P.B.* AU - Strachan, D.P.* AU - Grarup, N.* AU - Loos, R.J.F.* AU - Heckbert, S.R.* AU - Vollenweider, P.* AU - Hayward, C.* AU - Stefansson, K.* AU - Froguel, P.* AU - Groop, L.* AU - Wareham, N.J.* AU - van Duijn, C.M.* AU - Feitosa, M.F.* AU - O'Donnell, C.J.* AU - Kähönen, M.* AU - Perola, M.* AU - Boehnke, M.* AU - Kardia, S.L.R.* AU - Erdmann, J.* AU - Palmer, C.N.A.* AU - Ohlsson, C.* AU - Porteous, D.J.* AU - Eriksson, J.G.* AU - Bouchard, C.* AU - Moebus, S.* AU - Kraft, P.* AU - Weir, D.R.* AU - Cusi, D.* AU - Ferrucci, L.* AU - Ulivi, S.* AU - Girotto, G.* AU - Correa, A.* AU - Kääb, S.* AU - Peters, A. AU - Chambers, J.C.* AU - Kooner, J.S.* AU - Marz, W.* AU - Rotter, J.I.* AU - Hicks, A.A.* AU - Smith, J.G.* AU - Kiemeney, L.A.L.M.* AU - Mook-Kanamori, D.O.* AU - Penninx, B.W.J.H.* AU - Gyllensten, U.* AU - Wilson, J.F.* AU - Burgess, S.* AU - Sundström, J.* AU - Lieb, W.* AU - Jukema, J.W.* AU - Eijgelsheim, M.* AU - Lakatta, E.L.M.* AU - Cheng, C.Y.* AU - Dörr, M.* AU - Wong, T.Y.* AU - Sabanayagam, C.* AU - Oldehinkel, A.J.* AU - Riese, H.* AU - Lehtimäki, T.* AU - Verweij, N.* AU - van der Harst, P.* C1 - 68039 C2 - 54517 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Genetic insights into resting heart rate and its role in cardiovascular disease. JO - Nat. Commun. VL - 14 IS - 1 PB - Nature Portfolio PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - Spatially resolved transcriptomics of tissue sections enables advances in fundamental and applied biomedical research. Here, we present Multiplexed Deterministic Barcoding in Tissue (xDBiT) to acquire spatially resolved transcriptomes of nine tissue sections in parallel. New microfluidic chips were developed to spatially encode mRNAs over a total tissue area of 1.17 cm2 with a 50 µm resolution. Optimization of the biochemical protocol increased read and gene counts per spot by one order of magnitude compared to previous reports. Furthermore, the introduction of alignment markers allowed seamless registration of images and spatial transcriptomic spots. Together with technological advances, we provide an open-source computational pipeline to prepare raw sequencing data for downstream analysis. The functionality of xDBiT was demonstrated by acquiring 16 spatially resolved transcriptomic datasets from five different murine organs, including the cerebellum, liver, kidney, spleen, and heart. Factor analysis and deconvolution of spatial transcriptomes allowed for in-depth characterization of the murine kidney. AU - Wirth, J. AU - Huber, N. AU - Yin, K. AU - Brood, S. AU - Chang, S.C.-E. AU - Martinez Jimenez, C.P. AU - Meier, M. C1 - 67712 C2 - 54020 TI - Spatial transcriptomics using multiplexed deterministic barcoding in tissue. JO - Nat. Commun. VL - 14 IS - 1 PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - Samples from the carbonaceous asteroid (162173) Ryugu provide information on the chemical evolution of organic molecules in the early solar system. Here we show the element partitioning of the major component ions by sequential extractions of salts, carbonates, and phyllosilicate-bearing fractions to reveal primordial brine composition of the primitive asteroid. Sodium is the dominant electrolyte of the salt fraction extract. Anions and NH4+ are more abundant in the salt fraction than in the carbonate and phyllosilicate fractions, with molar concentrations in the order SO42−> Cl−> S2O32−> NO3−> NH4+. The salt fraction extracts contain anionic soluble sulfur-bearing species such as S n-polythionic acids (n < 6), C n-alkylsulfonates, alkylthiosulfonates, hydroxyalkylsulfonates, and hydroxyalkylthiosulfonates (n < 7). The sulfur-bearing soluble compounds may have driven the molecular evolution of prebiotic organic material transforming simple organic molecules into hydrophilic, amphiphilic, and refractory S allotropes. AU - Yoshimura, T.* AU - Takano, Y.* AU - Naraoka, H.* AU - Koga, T.* AU - Araoka, D.* AU - Ogawa, N.O.* AU - Schmitt-Kopplin, P. AU - Hertkorn, N. AU - Oba, Y.* AU - Dworkin, J.P.* AU - Aponte, J.C.* AU - Yoshikawa, T.* AU - Tanaka, S.* AU - Ohkouchi, N.* AU - Hashiguchi, M.* AU - McLain, H.* AU - Parker, E.T.* AU - Sakai, S.* AU - Yamaguchi, M.* AU - Suzuki, T.* AU - Yokoyama, T.* AU - Yurimoto, H.* AU - Nakamura, T.* AU - Noguchi, T.* AU - Okazaki, R.* AU - Yabuta, H.* AU - Sakamoto, K.* AU - Yada, T.* AU - Nishimura, M.* AU - Nakato, A.* AU - Miyazaki, A.* AU - Yogata, K.* AU - Abe, M.* AU - Okada, T.* AU - Usui, T.* AU - Yoshikawa, M.* AU - Saiki, T.* AU - Terui, F.* AU - Nakazawa, S.* AU - Watanabe, S.i.* AU - Tsuda, Y.* AU - Tachibana, S.* AU - Hamase, K.* AU - Furusho, A.* AU - Fukushima, K.* AU - Aoki, D.* AU - Glavin, D.P.* AU - Mclain, H.L.* AU - Elsila, J.E.* AU - Graham, H.V.* AU - Eiler, J.M.* AU - Ruf, A.* AU - Orthous-Daunay, F.R.* AU - Wolters, C.* AU - Isa, J.* AU - Vuitton, V.* AU - Thissen, R.* AU - Sugahara, H.* AU - Mita, H.* AU - Furukawa, Y.* AU - Chikaraishi, Y.* AU - Morita, M.* AU - Onose, M.* AU - Kabashima, F.* AU - Fujishima, K.* AU - Sato, H.* AU - Sasaki, K.* AU - Kano, K.* AU - Nomura, S.i.M.* AU - Aoki, J.* AU - Yamazaki, T.* AU - Kimura, Y.* C1 - 68260 C2 - 54785 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Chemical evolution of primordial salts and organic sulfur molecules in the asteroid 162173 Ryugu. JO - Nat. Commun. VL - 14 IS - 1 PB - Nature Portfolio PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - The median eminence (ME) is a circumventricular organ at the base of the brain that controls body homeostasis. Tanycytes are its specialized glial cells that constitute the ventricular walls and regulate different physiological states, however individual signaling pathways in these cells are incompletely understood. Here, we identify a functional tanycyte subpopulation that expresses key taste transduction genes including bitter taste receptors, the G protein gustducin and the gustatory ion channel TRPM5 (M5). M5 tanycytes have access to blood-borne cues via processes extended towards diaphragmed endothelial fenestrations in the ME and mediate bidirectional communication between the cerebrospinal fluid and blood. This subpopulation responds to metabolic signals including leptin and other hormonal cues and is transcriptionally reprogrammed upon fasting. Acute M5 tanycyte activation induces insulin secretion and acute diphtheria toxin-mediated M5 tanycyte depletion results in impaired glucose tolerance in diet-induced obese mice. We provide a cellular and molecular framework that defines how bitter taste cells in the ME integrate chemosensation with metabolism. AU - Yu, Q.* AU - Gamayun, I.* AU - Wartenberg, P.* AU - Zhang, Q. AU - Qiao, S.* AU - Kusumakshi, S.* AU - Candlish, S.* AU - Götz, V.* AU - Wen, S.* AU - Das, D.* AU - Wyatt, A.* AU - Wahl, V.* AU - Ectors, F.* AU - Kattler, K.* AU - Yildiz, D.* AU - Prévot, V.* AU - Schwaninger, M.* AU - Ternier, G.* AU - Giacobini, P.* AU - Ciofi, P.* AU - Müller, T.D. AU - Boehm, U.* C1 - 67698 C2 - 54005 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Bitter taste cells in the ventricular walls of the murine brain regulate glucose homeostasis. JO - Nat. Commun. VL - 14 IS - 1 PB - Nature Portfolio PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - Humans and other tetrapods are considered to require apical-ectodermal-ridge (AER) cells for limb development, and AER-like cells are suggested to be re-formed to initiate limb regeneration. Paradoxically, the presence of AER in the axolotl, a primary model organism for regeneration, remains controversial. Here, by leveraging a single-cell transcriptomics-based multi-species atlas, composed of axolotl, human, mouse, chicken, and frog cells, we first establish that axolotls contain cells with AER characteristics. Further analyses and spatial transcriptomics reveal that axolotl limbs do not fully re-form AER cells during regeneration. Moreover, the axolotl mesoderm displays part of the AER machinery, revealing a program for limb (re)growth. These results clarify the debate about the axolotl AER and the extent to which the limb developmental program is recapitulated during regeneration. AU - Zhong, J.* AU - Aires, R.* AU - Tsissios, G.* AU - Skoufa, E.* AU - Brandt, K. AU - Sandoval-Guzmán, T. AU - Aztekin, C.* C1 - 68673 C2 - 54878 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Multi-species atlas resolves an axolotl limb development and regeneration paradox. JO - Nat. Commun. VL - 14 IS - 1 PB - Nature Portfolio PY - 2023 SN - 2041-1723 ER - TY - JOUR AB - A major obstacle in diabetes is the metabolic or hyperglycemic memory, which lacks specific therapies. Here we show that glucose-mediated changes in gene expression largely persist in diabetic kidney disease (DKD) despite reversing hyperglycemia. The senescence-associated cyclin-dependent kinase inhibitor p21 (Cdkn1a) was the top hit among genes persistently induced by hyperglycemia and was associated with induction of the p53-p21 pathway. Persistent p21 induction was confirmed in various animal models, human samples and in vitro models. Tubular and urinary p21-levels were associated with DKD severity and remained elevated despite improved blood glucose levels in humans. Mechanistically, sustained tubular p21 expression in DKD is linked to demethylation of its promoter and reduced DNMT1 expression. Two disease resolving agents, protease activated protein C (3K3A-aPC) and parmodulin-2, reversed sustained tubular p21 expression, tubular senescence, and DKD. Thus, p21-dependent tubular senescence is a pathway contributing to the hyperglycemic memory, which can be therapeutically targeted. AU - Al-Dabet, M.M.* AU - Shahzad, K.* AU - Elwakiel, A.* AU - Sulaj, A.* AU - Kopf, S.* AU - Bock, F.* AU - Gadi, I.* AU - Zimmermann, S.* AU - Rana, R.* AU - Krishnan, S.* AU - Gupta, D.* AU - Manoharan, J.* AU - Fatima, S.* AU - Nazir, S.* AU - Schwab, C.* AU - Baber, R.* AU - Scholz, M.* AU - Geffers, R.* AU - Mertens, P.R.* AU - Nawroth, P.P.* AU - Griffin, J.H.* AU - Keller, M. AU - Dockendorff, C.* AU - Kohli, S.* AU - Isermann, B.* C1 - 65966 C2 - 53017 TI - Reversal of the renal hyperglycemic memory in diabetic kidney disease by targeting sustained tubular p21 expression. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - The extraction of meaningful biological knowledge from high-throughput mass spectrometry data relies on limiting false discoveries to a manageable amount. For targeted approaches in metabolomics a main challenge is the detection of false positive metabolic features in the low signal-to-noise ranges of data-independent acquisition results and their filtering. Another factor is that the creation of assay libraries for data-independent acquisition analysis and the processing of extracted ion chromatograms have not been automated in metabolomics. Here we present a fully automated open-source workflow for high-throughput metabolomics that combines data-dependent and data-independent acquisition for library generation, analysis, and statistical validation, with rigorous control of the false-discovery rate while matching manual analysis regarding quantification accuracy. Using an experimentally specific data-dependent acquisition library based on reference substances allows for accurate identification of compounds and markers from data-independent acquisition data in low concentrations, facilitating biomarker quantification. AU - Alka, O.* AU - Shanthamoorthy, P.* AU - Witting, M. AU - Kleigrewe, K.* AU - Kohlbacher, O.* AU - Röst, H.L.* C1 - 64639 C2 - 51930 TI - DIAMetAlyzer allows automated false-discovery rate-controlled analysis for data-independent acquisition in metabolomics. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - Genome-wide association studies (GWAS) for atrial fibrillation (AF) have uncovered numerous disease-associated variants. Their underlying molecular mechanisms, especially consequences for mRNA and protein expression remain largely elusive. Thus, refined multi-omics approaches are needed for deciphering the underlying molecular networks. Here, we integrate genomics, transcriptomics, and proteomics of human atrial tissue in a cross-sectional study to identify widespread effects of genetic variants on both transcript (cis-eQTL) and protein (cis-pQTL) abundance. We further establish a novel targeted trans-QTL approach based on polygenic risk scores to determine candidates for AF core genes. Using this approach, we identify two trans-eQTLs and five trans-pQTLs for AF GWAS hits, and elucidate the role of the transcription factor NKX2-5 as a link between the GWAS SNP rs9481842 and AF. Altogether, we present an integrative multi-omics method to uncover trans-acting networks in small datasets and provide a rich resource of atrial tissue-specific regulatory variants for transcript and protein levels for cardiovascular disease gene prioritization. AU - Assum, I. AU - Krause, J.* AU - Scheinhardt, M.O.* AU - Müller, C.* AU - Hammer, E.* AU - Börschel, C.S.* AU - Völker, U.* AU - Conradi, L.* AU - Geelhoed, B.* AU - Zeller, T.* AU - Schnabel, R.B.* AU - Heinig, M. C1 - 64196 C2 - 51802 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Tissue-specific multi-omics analysis of atrial fibrillation. JO - Nat. Commun. VL - 13 IS - 1 PB - Nature Portfolio PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - Fungal infections are a major health problem that often begin in the gastrointestinal tract. Gut microbe interactions in early childhood are critical for proper immune responses, yet there is little known about the development of the fungal population from infancy into childhood. Here, as part of the TEDDY (The Environmental Determinants of Diabetes in the Young) study, we examine stool samples of 888 children from 3 to 48 months and find considerable differences between fungi and bacteria. The metagenomic relative abundance of fungi was extremely low but increased while weaning from milk and formula. Overall fungal diversity remained constant over time, in contrast with the increase in bacterial diversity. Fungal profiles had high temporal variation, but there was less variation from month-to-month in an individual than among different children of the same age. Fungal composition varied with geography, diet, and the use of probiotics. Multiple Candida spp. were at higher relative abundance in children than adults, while Malassezia and certain food-associated fungi were lower in children. There were only subtle fungal differences associated with the subset of children that developed islet autoimmunity or type 1 diabetes. Having proper fungal exposures may be crucial for children to establish appropriate responses to fungi and limit the risk of infection: the data here suggests those gastrointestinal exposures are limited and variable. AU - Auchtung, T.A.* AU - Stewart, C.J.* AU - Smith, D.P.* AU - Triplett, E.W.* AU - Agardh, D.* AU - Hagopian, W.A.* AU - Ziegler, A.-G. AU - Rewers, M.J.* AU - She, J.X.* AU - Toppari, J.* AU - Lernmark, Å.* AU - Akolkar, B.* AU - Krischer, J.P.* AU - Vehik, K.* AU - Auchtung, J.M.* AU - Ajami, N.J.* AU - Petrosino, J.F.* C1 - 65455 C2 - 52303 TI - Temporal changes in gastrointestinal fungi and the risk of autoimmunity during early childhood: The TEDDY study. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - During pancreas development endocrine cells leave the ductal epithelium to form the islets of Langerhans, but the morphogenetic mechanisms are incompletely understood. Here, we identify the Ca2+-independent atypical Synaptotagmin-13 (Syt13) as a key regulator of endocrine cell egression and islet formation. We detect specific upregulation of the Syt13 gene and encoded protein in endocrine precursors and the respective lineage during islet formation. The Syt13 protein is localized to the apical membrane of endocrine precursors and to the front domain of egressing endocrine cells, marking a previously unidentified apical-basal to front-rear repolarization during endocrine precursor cell egression. Knockout of Syt13 impairs endocrine cell egression and skews the α-to-β-cell ratio. Mechanistically, Syt13 is a vesicle trafficking protein, transported via the microtubule cytoskeleton, and interacts with phosphatidylinositol phospholipids for polarized localization. By internalizing a subset of plasma membrane proteins at the front domain, including α6β4 integrins, Syt13 modulates cell-matrix adhesion and allows efficient endocrine cell egression. Altogether, these findings uncover an unexpected role for Syt13 as a morphogenetic driver of endocrinogenesis and islet formation. AU - Bakhti, M. AU - Bastidas-Ponce, A. AU - Tritschler, S. AU - Czarnecki, O. AU - Tarquis Medina, M. AU - Nedvedova, E.* AU - Jaki, J. AU - Willmann, S. AU - Scheibner, K. AU - Cota, P. AU - Salinno, C. AU - Boldt, K.* AU - Horn, N.* AU - Ueffing, M.* AU - Burtscher, I. AU - Theis, F.J. AU - Coskun, Ü. AU - Lickert, H. C1 - 65853 C2 - 52491 TI - Synaptotagmin-13 orchestrates pancreatic endocrine cell egression and islet morphogenesis. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - Hepatitis B virus has infected a third of the world's population, and 296 million people are living with chronic infection. Chronic infection leads to progressive liver disease, including hepatocellular carcinoma and liver failure, and there remains no reliable curative therapy. These gaps in our understanding are due, in large part, to a paucity of animal models of HBV infection. Here, we show that rhesus macaques regularly clear acute HBV infection, similar to adult humans, but can develop long-term infection if immunosuppressed. Similar to patients, we longitudinally detected HBV DNA, HBV surface antigen, and HBV e antigen in the serum of experimentally infected animals. In addition, we discovered hallmarks of HBV infection in the liver, including RNA transcription, HBV core and HBV surface antigen translation, and covalently closed circular DNA biogenesis. This pre-clinical animal model will serve to accelerate emerging HBV curative therapies into the clinic. AU - Biswas, S.* AU - Rust, L.N.* AU - Wettengel, J.M. AU - Yusova, S.* AU - Fischer, M.* AU - Carson, J.N.* AU - Johnson, J.* AU - Wei, L.* AU - Thode, T.* AU - Kaadige, M.R.* AU - Sharma, S.* AU - Agbaria, M.* AU - Bimber, B.N.* AU - Tu, T.* AU - Protzer, U. AU - Ploss, A.* AU - Smedley, J.V.* AU - Golomb, G.* AU - Sacha, J.B.* AU - Burwitz, B.J.* C1 - 65400 C2 - 52285 TI - Long-term hepatitis B virus infection of rhesus macaques requires suppression of host immunity. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - Back pain is a common and debilitating disorder with largely unknown underlying biology. Here we report a genome-wide association study of back pain using diagnoses assigned in clinical practice; dorsalgia (119,100 cases, 909,847 controls) and intervertebral disc disorder (IDD) (58,854 cases, 922,958 controls). We identify 41 variants at 33 loci. The most significant association (ORIDD = 0.92, P = 1.6 × 10-39; ORdorsalgia = 0.92, P = 7.2 × 10-15) is with a 3'UTR variant (rs1871452-T) in CHST3, encoding a sulfotransferase enzyme expressed in intervertebral discs. The largest effects on IDD are conferred by rare (MAF = 0.07 - 0.32%) loss-of-function (LoF) variants in SLC13A1, encoding a sodium-sulfate co-transporter (LoF burden OR = 1.44, P = 3.1 × 10-11); variants that also associate with reduced serum sulfate. Genes implicated by this study are involved in cartilage and bone biology, as well as neurological and inflammatory processes. AU - Bjornsdottir, G.* AU - Stefansdottir, L.* AU - Thorleifsson, G.* AU - Sulem, P.* AU - Norland, K.* AU - Ferkingstad, E.* AU - Oddsson, A.* AU - Zink, F.* AU - Lund, S.H.* AU - Nawaz, M.S.* AU - Bragi Walters, G.* AU - Skuladottir, A.T.* AU - Gudjonsson, S.A.* AU - Einarsson, G.* AU - Halldorsson, G.H.* AU - Bjarnadottir, V.* AU - Sveinbjornsson, G.* AU - Helgadottir, A.* AU - Styrkarsdottir, U.* AU - Gudmundsson, L.J.* AU - Pedersen, O.B.* AU - Hansen, T.F.* AU - Werge, T.* AU - Banasik, K.* AU - Troelsen, A.* AU - Skou, S.T.* AU - Thørner, L.W.* AU - Erikstrup, C.* AU - Nielsen, K.R.* AU - Mikkelsen, S.* AU - Jonsdottir, I.* AU - Björnsson, A.* AU - Olafsson, I.H.* AU - Ulfarsson, E.* AU - Blondal, J.* AU - Vikingsson, A.* AU - Brunak, S.* AU - Ostrowski, S.R.* AU - Ullum, H.* AU - Thorsteinsdottir, U.* AU - Stefansson, H.* AU - Gudbjartsson, D.F.* AU - Thorgeirsson, T.E.* AU - Stefansson, K.* AU - GO Consortium (Zeggini, E.) AU - GO Consortium (Hatzikotoulas, K.) AU - GO Consortium (Southam, L.) AU - GO Consortium (Gilly, A.) AU - GO Consortium (Barysenska, A.) AU - GO Consortium (Steinberg, J.) C1 - 67024 C2 - 53376 TI - Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AU - Bjornsdottir, G.* AU - Stefansdottir, L.* AU - Thorleifsson, G.* AU - Sulem, P.* AU - Norland, K.* AU - Ferkingstad, E.* AU - Oddsson, A.* AU - Zink, F.* AU - Lund, S.H.* AU - Nawaz, M.S.* AU - Bragi Walters, G.* AU - Skuladottir, A.T.* AU - Gudjonsson, S.A.* AU - Einarsson, G.* AU - Halldorsson, G.H.* AU - Bjarnadottir, V.* AU - Sveinbjornsson, G.* AU - Helgadottir, A.* AU - Styrkarsdottir, U.* AU - Gudmundsson, L.J.* AU - Pedersen, O.B.* AU - Hansen, T.F.* AU - Werge, T.* AU - Banasik, K.* AU - Troelsen, A.* AU - Skou, S.T.* AU - Thørner, L.W.* AU - Erikstrup, C.* AU - Nielsen, K.R.* AU - Mikkelsen, S.* AU - Jonsdottir, I.* AU - Björnsson, A.* AU - Olafsson, I.H.* AU - Ulfarsson, E.* AU - Blondal, J.* AU - Vikingsson, A.* AU - Brunak, S.* AU - Ostrowski, S.R.* AU - Ullum, H.* AU - Thorsteinsdottir, U.* AU - Stefansson, H.* AU - Gudbjartsson, D.F.* AU - Thorgeirsson, T.E.* AU - Stefansson, K.* AU - GO Consortium (Zeggini, E. AU - Hatzikotoulas, K. AU - Southam, L. AU - Gilly, A. AU - Barysenska, A. AU - Steinberg, J.) C1 - 67025 C2 - 53421 TI - Author Correction: Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - We integrated lipidomics and genomics to unravel the genetic architecture of lipid metabolism and identify genetic variants associated with lipid species putatively in the mechanistic pathway for coronary artery disease (CAD). We quantified 596 lipid species in serum from 4,492 individuals from the Busselton Health Study. The discovery GWAS identified 3,361 independent lipid-loci associations, involving 667 genomic regions (479 previously unreported), with validation in two independent cohorts. A meta-analysis revealed an additional 70 independent genomic regions associated with lipid species. We identified 134 lipid endophenotypes for CAD associated with 186 genomic loci. Associations between independent lipid-loci with coronary atherosclerosis were assessed in ∼456,000 individuals from the UK Biobank. Of the 53 lipid-loci that showed evidence of association (P < 1 × 10-3), 43 loci were associated with at least one lipid endophenotype. These findings illustrate the value of integrative biology to investigate the aetiology of atherosclerosis and CAD, with implications for other complex diseases. AU - Cadby, G.* AU - Giles, C.* AU - Melton, P.E.* AU - Huynh, K.* AU - Mellett, N.A.* AU - Duong, T.* AU - Nguyen, A.* AU - Cinel, M.* AU - Smith, A.* AU - Olshansky, G.* AU - Wang, T.* AU - Brozynska, M.* AU - Inouye, M.* AU - McCarthy, N.S.* AU - Ariff, A.* AU - Hung, J.* AU - Hui, J.* AU - Beilby, J.* AU - Dubé, M.P.* AU - Watts, G.F.* AU - Shah, S.* AU - Wray, N.R.* AU - Lim, W.L.F.* AU - Chatterjee, P.* AU - Martins, I.* AU - Laws, S.M.* AU - Porter, T.* AU - Vacher, M.* AU - Bush, A.I.* AU - Rowe, C.C.* AU - Villemagne, V.L.* AU - Ames, D.* AU - Masters, C.L.* AU - Taddei, K.* AU - Arnold, M. AU - Kastenmüller, G. AU - Nho, K.* AU - Saykin, A.J.* AU - Han, X.* AU - Kaddurah-Daouk, R.* AU - Martins, R.N.* AU - Blangero, J.* AU - Meikle, P.J.* AU - Moses, E.K.* C1 - 65461 C2 - 52310 TI - Comprehensive genetic analysis of the human lipidome identifies loci associated with lipid homeostasis with links to coronary artery disease. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - The high plasticity of lung epithelial cells, has for many years, confounded the correct identification of the cell-of-origin of lung adenocarcinoma (LUAD), one of the deadliest malignancies worldwide. Here, we employ lineage-tracing mouse models to investigate the cell of origin of Eml4-Alk LUAD, and show that Club and Alveolar type 2 (AT2) cells give rise to tumours. We focus on Club cell originated tumours and find that Club cells experience an epigenetic switch by which they lose their lineage fidelity and gain an AT2-like phenotype after oncogenic transformation. Single-cell transcriptomic analyses identified two trajectories of Club cell evolution which are similar to the ones used during lung regeneration, suggesting that lung epithelial cells leverage on their plasticity and intrinsic regeneration mechanisms to give rise to a tumour. Together, this study highlights the role of Club cells in LUAD initiation, identifies the mechanism of Club cell lineage infidelity, confirms the presence of these features in human tumours, and unveils key mechanisms conferring LUAD heterogeneity. AU - Chen, Y.* AU - Toth, R.* AU - Chocarro, S.* AU - Weichenhan, D.* AU - Hey, J.* AU - Lutsik, P.* AU - Sawall, S.* AU - Stathopoulos, G.T. AU - Plass, C.* AU - Sotillo, R.* C1 - 65900 C2 - 52968 TI - Club cells employ regeneration mechanisms during lung tumorigenesis. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - Lipids are a structurally diverse class of biomolecules which can undergo a variety of chemical modifications. Among them, lipid (per)oxidation attracts most of the attention due to its significance in the regulation of inflammation, cell proliferation and death programs. Despite their apparent regulatory significance, the molecular repertoire of oxidized lipids remains largely elusive as accurate annotation of lipid modifications is complicated by their low abundance and often unknown, biological context-dependent structural diversity. Here, we provide a workflow based on the combination of bioinformatics and LC-MS/MS technologies to support identification and relative quantification of oxidized complex lipids in a modification type- and position-specific manner. The developed methodology is used to identify epilipidomics signatures of lean and obese individuals with and without type 2 diabetes. The characteristic signature of lipid modifications in lean individuals, dominated by the presence of modified octadecanoid acyl chains in phospho- and neutral lipids, is drastically shifted towards lipid peroxidation-driven accumulation of oxidized eicosanoids, suggesting significant alteration of endocrine signalling by oxidized lipids in metabolic disorders. AU - Criscuolo, A.* AU - Nepachalovich, P.* AU - Garcia-Del Rio, D.F.* AU - Lange, M.* AU - Ni, Z.* AU - Baroni, M.L.* AU - Cruciani, G.* AU - Goracci, L.* AU - Blüher, M. AU - Fedorova, M.* C1 - 66621 C2 - 53250 TI - Analytical and computational workflow for in-depth analysis of oxidized complex lipids in blood plasma. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - Traumatic brain injury (TBI) results in deficits that are often followed by recovery. The contralesional cortex can contribute to this process but how distinct contralesional neurons and circuits respond to injury remains to be determined. To unravel adaptations in the contralesional cortex, we used chronic in vivo two-photon imaging. We observed a general decrease in spine density with concomitant changes in spine dynamics over time. With retrograde co-labeling techniques, we showed that callosal neurons are uniquely affected by and responsive to TBI. To elucidate circuit connectivity, we used monosynaptic rabies tracing, clearing techniques and histology. We demonstrate that contralesional callosal neurons adapt their input circuitry by strengthening ipsilateral connections from pre-connected areas. Finally, functional in vivo two-photon imaging demonstrates that the restoration of pre-synaptic circuitry parallels the restoration of callosal activity patterns. Taken together our study thus delineates how callosal neurons structurally and functionally adapt following a contralateral murine TBI. AU - Empl, L.* AU - Chovsepian, A.* AU - Chahin, M.* AU - Kan, W.Y.V.* AU - Fourneau, J.* AU - Van Steenbergen, V.* AU - Weidinger, S.* AU - Marcantoni, M.* AU - Ghanem, A.* AU - Bradley, P.* AU - Conzelmann, K.K.* AU - Cai, R. AU - Ghasemigharagoz, A. AU - Ertürk, A. AU - Wagner, I.* AU - Kreutzfeldt, M.* AU - Merkler, D.* AU - Liebscher, S.* AU - Bareyre, F.M.* C1 - 65001 C2 - 52125 TI - Selective plasticity of callosal neurons in the adult contralesional cortex following murine traumatic brain injury. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - Trans-activation response DNA-binding protein of 43 kDa (TDP-43) regulates RNA processing and forms neuropathological aggregates in patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Investigating TDP-43 post-translational modifications, we discovered that K84 acetylation reduced nuclear import whereas K136 acetylation impaired RNA binding and splicing capabilities of TDP-43. Such failure of RNA interaction triggered TDP-43 phase separation mediated by the C-terminal low complexity domain, leading to the formation of insoluble aggregates with pathologically phosphorylated and ubiquitinated TDP-43. Introduction of acetyl-lysine at the identified sites via amber suppression confirmed the results from site-directed mutagenesis. K84-acetylated TDP-43 showed cytoplasmic mislocalization, and the aggregation propensity of K136-acetylated TDP-43 was confirmed. We generated antibodies selective for TDP-43 acetylated at these lysines, and found that sirtuin-1 can potently deacetylate K136-acetylated TDP-43 and reduce its aggregation propensity. Thus, distinct lysine acetylations modulate nuclear import, RNA binding and phase separation of TDP-43, suggesting regulatory mechanisms for TDP-43 pathogenesis. AU - Garcia Morato, J.* AU - Hans, F.* AU - von Zweydorf, F.* AU - Feederle, R. AU - Elsässer, S.J.* AU - Skodras, A.A.* AU - Gloeckner, C.J.* AU - Buratti, E.* AU - Neumann, M.* AU - Kahle, P.J.* C1 - 64611 C2 - 51931 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Sirtuin-1 sensitive lysine-136 acetylation drives phase separation and pathological aggregation of TDP-43. JO - Nat. Commun. VL - 13 IS - 1 PB - Nature Portfolio PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - Extravasation of monocytes into tissue and to the site of injury is a fundamental immunological process, which requires rapid responses via post translational modifications (PTM) of proteins. Protein arginine methyltransferase 7 (PRMT7) is an epigenetic factor that has the capacity to mono-methylate histones on arginine residues. Here we show that in chronic obstructive pulmonary disease (COPD) patients, PRMT7 expression is elevated in the lung tissue and localized to the macrophages. In mouse models of COPD, lung fibrosis and skin injury, reduced expression of PRMT7 associates with decreased recruitment of monocytes to the site of injury and hence less severe symptoms. Mechanistically, activation of NF-κB/RelA in monocytes induces PRMT7 transcription and consequential mono-methylation of histones at the regulatory elements of RAP1A, which leads to increased transcription of this gene that is responsible for adhesion and migration of monocytes. Persistent monocyte-derived macrophage accumulation leads to ALOX5 over-expression and accumulation of its metabolite LTB4, which triggers expression of ACSL4 a ferroptosis promoting gene in lung epithelial cells. Conclusively, inhibition of arginine mono-methylation might offer targeted intervention in monocyte-driven inflammatory conditions that lead to extensive tissue damage if left untreated. AU - Günsel, G.G. AU - Conlon, T.M. AU - Jeridi, A. AU - Kim, R. AU - Ertüz, Z. AU - Lang, N.J. AU - Ansari, M. AU - Novikova, M. AU - Jiang, D. AU - Strunz, M. AU - Gaianova, M. AU - Hollauer, C. AU - Gabriel, C. AU - Angelidis, I. AU - Doll, S. AU - Pestoni, J. AU - Edelmann, S.L. AU - Kohlhepp, M.S.* AU - Guillot, A.* AU - Bassler, K.* AU - Van Eeckhoutte, H.P.* AU - Kayalar, Ö.* AU - Konyalilar, N.* AU - Kanashova, T.* AU - Rodius, S.* AU - Ballester-Lopez, C. AU - Genes Robles, C.M. AU - Smirnova, N.F. AU - Rehberg, M. AU - Agarwal, C. AU - Krikki, I. AU - Piavaux, B.* AU - Verleden, S.E.* AU - Vanaudenaerde, B.* AU - Königshoff, M.* AU - Dittmar, G.* AU - Bracke, K.R.* AU - Schultze, J.L.* AU - Watz, H.* AU - Eickelberg, O.* AU - Stöger, T. AU - Burgstaller, G. AU - Tacke, F.* AU - Heissmeyer, V. AU - Rinkevich, Y. AU - Bayram, H.* AU - Schiller, H. B. AU - Conrad, M. AU - Schneider, R. AU - Yildirim, A.Ö. C1 - 64607 C2 - 51963 TI - The arginine methyltransferase PRMT7 promotes extravasation of monocytes resulting in tissue injury in COPD. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - Chronic hyperglycaemia causes a dramatic decrease in mitochondrial metabolism and insulin content in pancreatic β-cells. This underlies the progressive decline in β-cell function in diabetes. However, the molecular mechanisms by which hyperglycaemia produces these effects remain unresolved. Using isolated islets and INS-1 cells, we show here that one or more glycolytic metabolites downstream of phosphofructokinase and upstream of GAPDH mediates the effects of chronic hyperglycemia. This metabolite stimulates marked upregulation of mTORC1 and concomitant downregulation of AMPK. Increased mTORC1 activity causes inhibition of pyruvate dehydrogenase which reduces pyruvate entry into the tricarboxylic acid cycle and partially accounts for the hyperglycaemia-induced reduction in oxidative phosphorylation and insulin secretion. In addition, hyperglycaemia (or diabetes) dramatically inhibits GAPDH activity, thereby impairing glucose metabolism. Our data also reveal that restricting glucose metabolism during hyperglycaemia prevents these changes and thus may be of therapeutic benefit. In summary, we have identified a pathway by which chronic hyperglycaemia reduces β-cell function. AU - Haythorne, E.* AU - Lloyd, M.* AU - Walsby-Tickle, J.* AU - Tarasov, A.I.* AU - Sandbrink, J.* AU - Portillo, I.* AU - Terron Exposito, R. AU - Sachse, G.* AU - Cyranka, M.* AU - Rohm, M. AU - Rorsman, P.* AU - McCullagh, J.* AU - Ashcroft, F.M.* C1 - 66670 C2 - 53253 TI - Altered glycolysis triggers impaired mitochondrial metabolism and mTORC1 activation in diabetic β-cells. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - Heat-induced labor loss is a major economic cost related to climate change. Here, we use hourly heat stress data modeled with a regional climate model to investigate the heat-induced labor loss in 231 Chinese cities. Results indicate that future urban heat stress is projected to cause an increase in labor losses exceeding 0.20% of the total account gross domestic product (GDP) per year by the 2050s relative to the 2010s. In this process, certain lower-paid sectors could be disproportionately impacted. The implementation of various urban adaptation strategies could offset 10% of the additional economic loss per year and help reduce the inequality-related impact on lower-paid sectors. So future urban warming can not only damage cities as a whole but can also contribute to income inequality. The implication of adaptation strategies should be considered in regard to not only cooling requirements but also environmental justice. AU - He, C.* AU - Zhang, Y.* AU - Schneider, A.E. AU - Chen, R.* AU - Kinney, P.L.* AU - Kan, H.* C1 - 65630 C2 - 52391 TI - The inequality labor loss risk from future urban warming and adaptation strategies. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - Melanoma is associated with angiogenesis and vascular changes that may extend through the entire skin depth. Three-dimensional imaging of vascular characteristics in skin lesions could therefore allow diagnostic insights not available by conventional visual inspection. Raster-scan optoacoustic mesoscopy (RSOM) images microvasculature through the entire skin depth with resolutions of tens of micrometers; however, current RSOM implementations are too slow to overcome the strong breathing motions on the upper torso where melanoma lesions commonly occur. To enable high-resolution imaging of melanoma vasculature in humans, we accelerate RSOM scanning using an illumination scheme that is coaxial with a high-sensitivity ultrasound detector path, yielding 15 s single-breath-hold scans that minimize motion artifacts. We apply this Fast RSOM to image 10 melanomas and 10 benign nevi in vivo, showing marked differences between malignant and benign lesions, supporting the possibility to use biomarkers extracted from RSOM imaging of vasculature for lesion characterization to improve diagnostics. AU - He, H. AU - Schönmann, C.* AU - Schwarz, M.* AU - Hindelang, B.* AU - Berezhnoi, A. AU - Steimle-Grauer, S.A.* AU - Darsow, U.* AU - Aguirre Bueno, J. AU - Ntziachristos, V. C1 - 65081 C2 - 52130 TI - Fast raster-scan optoacoustic mesoscopy enables assessment of human melanoma microvasculature in vivo. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - Diabetes is a multifactorial disorder characterized by loss or dysfunction of pancreatic β-cells. β-cells are heterogeneous, exhibiting different glucose sensing, insulin secretion and gene expression. They communicate with other endocrine cell types via paracrine signals and between β-cells via gap junctions. Here, we identify the importance of signaling between β-cells via the extracellular signal WNT4. We show heterogeneity in Wnt4 expression, most strikingly in the postnatal maturation period, Wnt4-positive cells, being more mature while Wnt4-negative cells are more proliferative. Knock-out in adult β-cells shows that WNT4 controls the activation of calcium signaling in response to a glucose challenge, as well as metabolic pathways converging to lower ATP/ADP ratios, thereby reducing insulin secretion. These results reveal that paracrine signaling between β-cells is important in addition to gap junctions in controling insulin secretion. Together with previous reports of WNT4 up-regulation in obesity our observations suggest an adaptive insulin response coordinating β-cells. AU - Katsumoto, K.* AU - Yennek, S.* AU - Chen, C. AU - Silva, L.F.D.* AU - Traikov, S.* AU - Sever, D.* AU - Azad, A.* AU - Shan, J.* AU - Vainio, S.* AU - Ninov, N. AU - Speier, S. AU - Grapin-Botton, A. C1 - 66466 C2 - 52839 TI - Wnt4 is heterogeneously activated in maturing β-cells to control calcium signaling, metabolism and function. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - A subset of patients has long-lasting symptoms after mild to moderate Coronavirus disease 2019 (COVID-19). In a prospective observational cohort study, we analyze clinical and laboratory parameters in 42 post-COVID-19 syndrome patients (29 female/13 male, median age 36.5 years) with persistent moderate to severe fatigue and exertion intolerance six months following COVID-19. Further we evaluate an age- and sex-matched postinfectious non-COVID-19 myalgic encephalomyelitis/chronic fatigue syndrome cohort comparatively. Most post-COVID-19 syndrome patients are moderately to severely impaired in daily live. 19 post-COVID-19 syndrome patients fulfill the 2003 Canadian Consensus Criteria for myalgic encephalomyelitis/chronic fatigue syndrome. Disease severity and symptom burden is similar in post-COVID-19 syndrome/myalgic encephalomyelitis/chronic fatigue syndrome and non-COVID-19/myalgic encephalomyelitis/chronic fatigue syndrome patients. Hand grip strength is diminished in most patients compared to normal values in healthy. Association of hand grip strength with hemoglobin, interleukin 8 and C-reactive protein in post-COVID-19 syndrome/non-myalgic encephalomyelitis/chronic fatigue syndrome and with hemoglobin, N-terminal prohormone of brain natriuretic peptide, bilirubin, and ferritin in post-COVID-19 syndrome/myalgic encephalomyelitis/chronic fatigue syndrome may indicate low level inflammation and hypoperfusion as potential pathomechanisms. AU - Kedor, C.* AU - Freitag, H.* AU - Meyer-Arndt, L.* AU - Wittke, K.* AU - Hanitsch, L.G.* AU - Zöller, T.* AU - Steinbeis, F.* AU - Haffke, M.* AU - Rudolf, G.* AU - Heidecker, B.* AU - Bobbert, T.* AU - Spranger, J.* AU - Volk, H.D.* AU - Skurk, C.* AU - Konietschke, F.* AU - Paul, F.* AU - Behrends, U. AU - Bellmann-Strobl, J.* AU - Scheibenbogen, C.* C1 - 66069 C2 - 52841 TI - A prospective observational study of post-COVID-19 chronic fatigue syndrome following the first pandemic wave in Germany and biomarkers associated with symptom severity. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - In the author list of this article, the names of the authorswere incorrectly listed with initials and family name only. The incorrect author list read as “C. Kedor, H. Freitag, L. Meyer-Arndt, K. Wittke, L. G. Hanitsch, T. Zoller, F. Steinbeis, M. Haffke, G. Rudolf, B. Heidecker, T. Bobbert, J. Spranger, H. D. Volk, C. Skurk, F. Konietschke, F. Paul, U. Behrends, J. Bellmann-Strobl and C. Scheibenbogen”. The author list has now been amended to include the given and family names in the HTML and PDF versions of the article. The corrected author list reads as “Claudia Kedor, Helma Freitag, Lil Meyer-Arndt, Kirsten Wittke, Leif G. Hanitsch, Thomas Zoller, Fridolin Steinbeis, Milan Haffke, Gordon Rudolf, Bettina Heidecker, Thomas Bobbert, Joachim Spranger, Hans- Dieter Volk, Carsten Skurk, Frank Konietschke, Friedemann Paul, Uta Behrends, Judith Bellmann-Strobl and Carmen Scheibenbogen”. AU - Kedor, C.* AU - Freitag, H.* AU - Meyer-Arndt, L.* AU - Wittke, K.* AU - Hanitsch, L.G.* AU - Zöller, T.* AU - Steinbeis, F.* AU - Haffke, M.* AU - Rudolf, G.* AU - Heidecker, B.* AU - Bobbert, T.* AU - Spranger, J.* AU - Volk, H.D.* AU - Skurk, C.* AU - Konietschke, F.* AU - Paul, F.* AU - Behrends, U. AU - Bellmann-Strobl, J.* AU - Scheibenbogen, C.* C1 - 66441 C2 - 52842 TI - Author Correction: A prospective observational study of post-COVID-19 chronic fatigue syndrome following the first pandemic wave in Germany and biomarkers associated with symptom severity (Nature Communications, (2022), 13, 1, (5104), 10.1038/s41467-022-32507-6). JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - CDK4/6 inhibitors (CDK4/6i) and oncolytic viruses are promising therapeutic agents for the treatment of various cancers. As single agents, CDK4/6 inhibitors that are approved for the treatment of breast cancer in combination with endocrine therapy cause G1 cell cycle arrest, whereas adenoviruses induce progression into S-phase in infected cells as an integral part of the their life cycle. Both CDK4/6 inhibitors and adenovirus replication target the Retinoblastoma protein albeit for different purposes. Here we show that in combination CDK4/6 inhibitors potentiate the anti-tumor effect of the oncolytic adenovirus XVir-N-31 in bladder cancer and murine Ewing sarcoma xenograft models. This increase in oncolytic potency correlates with an increase in virus-producing cancer cells, enhanced viral genome replication, particle formation and consequently cancer cell killing. The molecular mechanism that regulates this response is fundamentally based on the reduction of Retinoblastoma protein expression levels by CDK4/6 inhibitors. AU - Koch, J.* AU - Schober, S.J.* AU - Hindupur, S.V.* AU - Klein, F.G.* AU - Mantwill, K.* AU - Ehrenfeld, M.* AU - Schillinger, U.* AU - Hohnecker, T.* AU - Qi, P.* AU - Steiger, K.* AU - Aichler, M. AU - Gschwend, J.E.* AU - Nawroth, R.* AU - Holm, P.S.* C1 - 65915 C2 - 52979 TI - Targeting the Retinoblastoma/E2F repressive complex by CDK4/6 inhibitors amplifies oncolytic potency of an oncolytic adenovirus. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - Anti-viral immunity continuously declines over time after SARS-CoV-2 infection. Here, we characterize the dynamics of anti-viral immunity during long-term follow-up and after BNT162b2 mRNA-vaccination in convalescents after asymptomatic or mild SARS-CoV-2 infection. Virus-specific and virus-neutralizing antibody titers rapidly declined in convalescents over 9 months after infection, whereas virus-specific cytokine-producing polyfunctional T cells persisted, among which IL-2-producing T cells correlated with virus-neutralizing antibody titers. Among convalescents, 5% of individuals failed to mount long-lasting immunity after infection and showed a delayed response to vaccination compared to 1% of naïve vaccinees, but successfully responded to prime/boost vaccination. During the follow-up period, 8% of convalescents showed a selective increase in virus-neutralizing antibody titers without accompanying increased frequencies of circulating SARS-CoV-2-specific T cells. The same convalescents, however, responded to vaccination with simultaneous increase in antibody and T cell immunity revealing the strength of mRNA-vaccination to increase virus-specific immunity in convalescents. AU - Körber, N. AU - Priller, A.* AU - Yazici, S.* AU - Bauer, T. AU - Cheng, C.-C. AU - Mijočević, H. AU - Wintersteller, H.* AU - Jeske, S. AU - Vogel, E. AU - Feuerherd, M. AU - Tinnefeld, K. AU - Winter, C.* AU - Ruland, J.* AU - Gerhard, M.* AU - Haller, B.* AU - Christa, C. AU - Zelger, O.* AU - Roggendorf, H.* AU - Halle, M.* AU - Erber, J.* AU - Lingor, P.* AU - Keppler, O.* AU - Zehn, D.* AU - Protzer, U. AU - Knolle, P.A.* C1 - 63988 C2 - 51791 TI - Dynamics of spike-and nucleocapsid specific immunity during long-term follow-up and vaccination of SARS-CoV-2 convalescents. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - Development of islet autoimmunity precedes the onset of type 1 diabetes in children, however, the presence of autoantibodies does not necessarily lead to manifest disease and the onset of clinical symptoms is hard to predict. Here we show, by longitudinal sampling of islet autoantibodies (IAb) to insulin, glutamic acid decarboxylase and islet antigen-2 that disease progression follows distinct trajectories. Of the combined Type 1 Data Intelligence cohort of 24662 participants, 2172 individuals fulfill the criteria of two or more follow-up visits and IAb positivity at least once, with 652 progressing to type 1 diabetes during the 15 years course of the study. Our Continuous-Time Hidden Markov Models, that are developed to discover and visualize latent states based on the collected data and clinical characteristics of the patients, show that the health state of participants progresses from 11 distinct latent states as per three trajectories (TR1, TR2 and TR3), with associated 5-year cumulative diabetes-free survival of 40% (95% confidence interval [CI], 35% to 47%), 62% (95% CI, 57% to 67%), and 88% (95% CI, 85% to 91%), respectively (p < 0.0001). Age, sex, and HLA-DR status further refine the progression rates within trajectories, enabling clinically useful prediction of disease onset. AU - Kwon, B.C.* AU - Anand, V.* AU - Achenbach, P. AU - Dunne, J.L.* AU - Hagopian, W.* AU - Hu, J.* AU - Koski, E.* AU - Lernmark, Å.* AU - Lundgren, M.* AU - Ng, K.* AU - Toppari, J.* AU - Veijola, R.* AU - Frohnert, B.I.* C1 - 64621 C2 - 51942 TI - Progression of type 1 diabetes from latency to symptomatic disease is predicted by distinct autoimmune trajectories. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - Primary aldosteronism affects up to 10% of hypertensive patients and is responsible for treatment resistance and increased cardiovascular risk. Here we perform a genome-wide association study in a discovery cohort of 562 cases and 950 controls and identify three main loci on chromosomes 1, 13 and X; associations on chromosome 1 and 13 are replicated in a second cohort and confirmed by a meta-analysis involving 1162 cases and 3296 controls. The association on chromosome 13 is specific to men and stronger in bilateral adrenal hyperplasia than aldosterone producing adenoma. Candidate genes located within the two loci, CASZ1 and RXFP2, are expressed in human and mouse adrenals in different cell clusters. Their overexpression in adrenocortical cells suppresses mineralocorticoid output under basal and stimulated conditions, without affecting cortisol biosynthesis. Our study identifies the first risk loci for primary aldosteronism and highlights new mechanisms for the development of aldosterone excess. AU - Le Floch, E.* AU - Cosentino, T.* AU - Larsen, C.K.* AU - Beuschlein, F.* AU - Reincke, M.* AU - Amar, L.* AU - Rossi, G.P.* AU - De Sousa, K.* AU - Baron, S.* AU - Chantalat, S.* AU - Saintpierre, B.* AU - Lenzini, L.* AU - Frouin, A.* AU - Giscos-Douriez, I.* AU - Ferey, M.* AU - Abdellatif, A.B.* AU - Meatchi, T.* AU - Empana, J.P.* AU - Jouven, X.* AU - Gieger, C. AU - Waldenberger, M. AU - Peters, A. AU - Cusi, D.* AU - Salvi, E.* AU - Meneton, P.* AU - Touvier, M.* AU - Deschasaux, M.* AU - Druesne-Pecollo, N.* AU - Boulkroun, S.* AU - Fernandes-Rosa, F.L.* AU - Deleuze, J.F.* AU - Jeunemaitre, X.* AU - Zennaro, M.C.* C1 - 66110 C2 - 52632 TI - Identification of risk loci for primary aldosteronism in genome-wide association studies. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - DNA methylation (DNAm) patterns in peripheral blood have been shown to be associated with aging related health outcomes. We perform an epigenome-wide screening to identify CpGs related to frailty, defined by a frailty index (FI), in a large population-based cohort of older adults from Germany, the ESTHER study. Sixty-five CpGs are identified as frailty related methylation loci. Using LASSO regression, 20 CpGs are selected to derive a DNAm based algorithm for predicting frailty, the epigenetic frailty risk score (eFRS). The eFRS exhibits strong associations with frailty at baseline and after up to five-years of follow-up independently of established frailty risk factors. These associations are confirmed in another independent population-based cohort study, the KORA-Age study, conducted in older adults. In conclusion, we identify 65 CpGs as frailty-related loci, of which 20 CpGs are used to calculate the eFRS with predictive performance for frailty over long-term follow-up. AU - Li, X.* AU - Delerue, T. AU - Schöttker, B.* AU - Holleczek, B.* AU - Grill, E.* AU - Peters, A. AU - Waldenberger, M. AU - Thorand, B.* AU - Brenner, H.* C1 - 66169 C2 - 52630 TI - Derivation and validation of an epigenetic frailty risk score in population-based cohorts of older adults. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AU - Lin, W.Y.* AU - Fordham, S.E.* AU - Hungate, E.* AU - Sunter, N.J.* AU - Elstob, C.* AU - Xu, Y.* AU - Park, C.* AU - Quante, A.S. AU - Strauch, K. AU - Gieger, C.* AU - Skol, A.* AU - Rahman, T.* AU - Sucheston-Campbell, L.* AU - Wang, J.* AU - Hahn, T.* AU - Clay-Gilmour, A.I.* AU - Jones, G.L.* AU - Marr, H.J.* AU - Jackson, G.H.* AU - Menne, T.* AU - Collin, M.* AU - Ivey, A.* AU - Hills, R.K.* AU - Burnett, A.K.* AU - Russell, N.H.* AU - Fitzgibbon, J.* AU - Larson, R.A.* AU - Le Beau, M.M.* AU - Stock, W.* AU - Heidenreich, O.* AU - Alharbi, A.* AU - Allsup, D.J.* AU - Houlston, R.S.* AU - Norden, J.* AU - Dickinson, A.M.* AU - Douglas, E.* AU - Lendrem, C.* AU - Daly, A.K.* AU - Palm, L.* AU - Piechocki, K.* AU - Jeffries, S.* AU - Bornhäuser, M.* AU - Röllig, C.* AU - Altmann, H.* AU - Ruhnke, L.* AU - Kunadt, D.* AU - Wagenführ, L.* AU - Cordell, H.J.* AU - Darlay, R.* AU - Andersen, M.K.* AU - Fontana, M.C.* AU - Martinelli, G.* AU - Marconi, G.* AU - Sanz, M.A.* AU - Cervera, J.* AU - Gómez-Seguí, I.* AU - Cluzeau, T.* AU - Moreilhon, C.* AU - Raynaud, S.* AU - Sill, H.* AU - Voso, M.T.* AU - Lo-Coco, F.* AU - Dombret, H.* AU - Cheok, M.* AU - Preudhomme, C.* AU - Gale, R.E.* AU - Linch, D.* AU - Gaal-Wesinger, J.* AU - Masszi, A.* AU - Nowak, D.* AU - Hofmann, W.K.* AU - Gilkes, A.* AU - Porkka, K.* AU - Milosevic Feenstra, J.D.* AU - Kralovics, R.* AU - Grimwade, D.* AU - Meggendorfer, M.* AU - Haferlach, T.* AU - Krizsán, S.* AU - Bödör, C.* AU - Stölzel, F.* AU - Onel, K.* AU - Allan, J.M.* C1 - 64016 C2 - 51832 TI - Author Correction: Genome-wide association study identifies susceptibility loci for acute myeloid leukemia. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - Plasmacytoid and conventional dendritic cells (pDC and cDC) are generated from progenitor cells in the bone marrow and commitment to pDCs or cDC subtypes may occur in earlier and later progenitor stages. Cells within the CD11c+MHCII-/loSiglec-H+CCR9lo DC precursor fraction of the mouse bone marrow generate both pDCs and cDCs. Here we investigate the heterogeneity and commitment of subsets in this compartment by single-cell transcriptomics and high-dimensional flow cytometry combined with cell fate analysis: Within the CD11c+MHCII-/loSiglec-H+CCR9lo DC precursor pool cells expressing high levels of Ly6D and lacking expression of transcription factor Zbtb46 contain CCR9loB220hi immediate pDC precursors and CCR9loB220lo (lo-lo) cells which still generate pDCs and cDCs in vitro and in vivo under steady state conditions. cDC-primed cells within the Ly6DhiZbtb46- lo-lo precursors rapidly upregulate Zbtb46 and pass through a Zbtb46+Ly6D+ intermediate stage before acquiring cDC phenotype after cell division. Type I IFN stimulation limits cDC and promotes pDC output from this precursor fraction by arresting cDC-primed cells in the Zbtb46+Ly6D+ stage preventing their expansion and differentiation into cDCs. Modulation of pDC versus cDC output from precursors by external factors may allow for adaptation of DC subset composition at later differentiation stages. AU - Lutz, K.* AU - Musumeci, A.* AU - Sie, C.* AU - Dursun, E.* AU - Winheim, E.* AU - Bagnoli, J.* AU - Ziegenhain, C.* AU - Rausch, L.* AU - Bergen, V. AU - Luecken, M. AU - Oostendorp, R.A.J.* AU - Schraml, B.U.* AU - Theis, F.J. AU - Enard, W.* AU - Korn, T.* AU - Krug, A.B.* C1 - 65565 C2 - 52218 TI - Ly6D+Siglec-H+ precursors contribute to conventional dendritic cells via a Zbtb46+Ly6D+ intermediary stage. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - Maldevelopment of the pharyngeal endoderm, an embryonic tissue critical for patterning of the pharyngeal region and ensuing organogenesis, ultimately contributes to several classes of human developmental syndromes and disorders. Such syndromes are characterized by a spectrum of phenotypes that currently cannot be fully explained by known mutations or genetic variants due to gaps in characterization of critical drivers of normal and dysfunctional development. Despite the disease-relevance of pharyngeal endoderm, we still lack a comprehensive and integrative view of the molecular basis and gene regulatory networks driving pharyngeal endoderm development. To close this gap, we apply transcriptomic and chromatin accessibility single-cell sequencing technologies to generate a multi-omic developmental resource spanning pharyngeal endoderm patterning to the emergence of organ-specific epithelia in the developing mouse embryo. We identify cell-type specific gene regulation, distill GRN models that define developing organ domains, and characterize the role of an immunodeficiency-associated forkhead box transcription factor. AU - Magaletta, M.E.* AU - Lobo, M.* AU - Kernfeld, E.M.* AU - Aliee, H. AU - Huey, J.D.* AU - Parsons, T.J.* AU - Theis, F.J. AU - Maehr, R.* C1 - 64195 C2 - 51803 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Integration of single-cell transcriptomes and chromatin landscapes reveals regulatory programs driving pharyngeal organ development. JO - Nat. Commun. VL - 13 IS - 1 PB - Nature Portfolio PY - 2022 SN - 2041-1723 ER - TY - JOUR AU - Mertes, C.* AU - Scheller, I.F. AU - Yépez, V.A.* AU - Çelik, M.H.* AU - Liang, Y.* AU - Kremer, L.S. AU - Gusic, M. AU - Prokisch, H. AU - Gagneur, J. C1 - 65561 C2 - 52274 TI - Author Correction: Detection of aberrant splicing events in RNA-seq data using FRASER. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - Despite the increasing knowledge about factors shaping the human microbiome, the host genetic factors that modulate the skin-microbiome interactions are still largely understudied. This contrasts with recent efforts to characterize host genes that influence the gut microbiota. Here, we investigated the effect of genetics on skin microbiota across three different skin microenvironments through meta-analyses of genome-wide association studies (GWAS) of two population-based German cohorts. We identified 23 genome-wide significant loci harboring 30 candidate genes involved in innate immune signaling, environmental sensing, cell differentiation, proliferation and fibroblast activity. However, no locus passed the strict threshold for study-wide significance (P < 6.3 × 10-10 for 80 features included in the analysis). Mendelian randomization (MR) analysis indicated the influence of staphylococci on eczema/dermatitis and suggested modulating effects of the microbiota on other skin diseases. Finally, transcriptional profiles of keratinocytes significantly changed after in vitro co-culturing with Staphylococcus epidermidis, chosen as a representative of skin commensals. Seven candidate genes from the GWAS were found overlapping with differential expression in the co-culturing experiments, warranting further research of the skin commensal and host genetic makeup interaction. AU - Moitinho-Silva, L.* AU - Degenhardt, F.* AU - Rodriguez, E.* AU - Emmert, H.* AU - Juzenas, S.* AU - Möbus, L.* AU - Uellendahl-Werth, F.* AU - Sander, N.* AU - Baurecht, H.* AU - Tittmann, L.* AU - Lieb, W.* AU - Gieger, C. AU - Peters, A. AU - Ellinghaus, D.* AU - Bang, C.* AU - Franke, A.* AU - Weidinger, S.* AU - Rühlemann, M.C.* C1 - 66475 C2 - 52838 TI - Host genetic factors related to innate immunity, environmental sensing and cellular functions are associated with human skin microbiota. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - Progressive respiratory failure and hyperinflammatory response is the primary cause of death in the coronavirus disease 2019 (COVID-19) pandemic. Despite mounting evidence of disruption of the hypothalamus-pituitary-adrenal axis in COVID-19, relatively little is known about the tropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to adrenal glands and associated changes. Here we demonstrate adrenal viral tropism and replication in COVID-19 patients. Adrenal glands showed inflammation accompanied by inflammatory cell death. Histopathologic analysis revealed widespread microthrombosis and severe adrenal injury. In addition, activation of the glycerophospholipid metabolism and reduction of cortisone intensities were characteristic for COVID-19 specimens. In conclusion, our autopsy series suggests that SARS-CoV-2 facilitates the induction of adrenalitis. Given the central role of adrenal glands in immunoregulation and taking into account the significant adrenal injury observed, monitoring of developing adrenal insufficiency might be essential in acute SARS-CoV-2 infection and during recovery. AU - Paul, T.* AU - Ledderose, S.* AU - Bartsch, H.* AU - Sun, N. AU - Soliman, S.* AU - Märkl, B.* AU - Ruf, V.* AU - Herms, J.* AU - Stern, M.* AU - Keppler, O.T.* AU - Delbridge, C.* AU - Müller, S.* AU - Piontek, G.* AU - Kimoto, Y.S.* AU - Schreiber, F.* AU - Williams, T.A.* AU - Neumann, J.* AU - Knösel, T.* AU - Schulz, H.* AU - Spallek, R.* AU - Graw, M.* AU - Kirchner, T.* AU - Walch, A.K. AU - Rudelius, M.* C1 - 64695 C2 - 51945 TI - Adrenal tropism of SARS-CoV-2 and adrenal findings in a post-mortem case series of patients with severe fatal COVID-19. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - The development dynamics and self-organization of glandular branched epithelia is of utmost importance for our understanding of diverse processes ranging from normal tissue growth to the growth of cancerous tissues. Using single primary murine pancreatic ductal adenocarcinoma (PDAC) cells embedded in a collagen matrix and adapted media supplementation, we generate organoids that self-organize into highly branched structures displaying a seamless lumen connecting terminal end buds, replicating in vivo PDAC architecture. We identify distinct morphogenesis phases, each characterized by a unique pattern of cell invasion, matrix deformation, protein expression, and respective molecular dependencies. We propose a minimal theoretical model of a branching and proliferating tissue, capturing the dynamics of the first phases. Observing the interaction of morphogenesis, mechanical environment and gene expression in vitro sets a benchmark for the understanding of self-organization processes governing complex organoid structure formation processes and branching morphogenesis. AU - Randriamanantsoa, S.* AU - Papargyriou, A. AU - Maurer, H.C.* AU - Peschke, K.* AU - Schuster, M.* AU - Zecchin, G.* AU - Steiger, K.* AU - Öllinger, R.* AU - Saur, D.* AU - Scheel, C. AU - Rad, R.* AU - Hannezo, E.* AU - Bausch, A.R.* C1 - 66106 C2 - 53087 TI - Spatiotemporal dynamics of self-organized branching in pancreas-derived organoids. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - Abundant heterogeneous immune cells infiltrate lesions in chronic inflammatory diseases and characterization of these cells is needed to distinguish disease-promoting from bystander immune cells. Here, we investigate the landscape of non-communicable inflammatory skin diseases (ncISD) by spatial transcriptomics resulting in a large repository of 62,000 spatially defined human cutaneous transcriptomes from 31 patients. Despite the expected immune cell infiltration, we observe rather low numbers of pathogenic disease promoting cytokine transcripts (IFNG, IL13 and IL17A), i.e. >125 times less compared to the mean expression of all other genes over lesional skin sections. Nevertheless, cytokine expression is limited to lesional skin and presented in a disease-specific pattern. Leveraging a density-based spatial clustering method, we identify specific responder gene signatures in direct proximity of cytokines, and confirm that detected cytokine transcripts initiate amplification cascades of up to thousands of specific responder transcripts forming localized epidermal clusters. Thus, within the abundant and heterogeneous infiltrates of ncISD, only a low number of cytokine transcripts and their translated proteins promote disease by initiating an inflammatory amplification cascade in their local microenvironment. AU - Schäbitz, A.* AU - Hillig, C. AU - Mubarak, M. AU - Jargosch, M. AU - Farnoud, A. AU - Scala, E.* AU - Kurzen, N. AU - Pilz, A.C.* AU - Bhalla, N.* AU - Thomas, J. AU - Stahle, M.* AU - Biedermann, T.* AU - Schmidt-Weber, C.B. AU - Theis, F.J. AU - Garzorz-Stark, N.* AU - Eyerich, K.* AU - Menden, M.P. AU - Eyerich, S. C1 - 66990 C2 - 53398 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Spatial transcriptomics landscape of lesions from non-communicable inflammatory skin diseases. JO - Nat. Commun. VL - 13 IS - 1 PB - Nature Portfolio PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - Parkinson's disease (PD) as a progressive neurodegenerative disorder arises from multiple genetic and environmental factors. However, underlying pathological mechanisms remain poorly understood. Using multiplexed single-cell transcriptomics, we analyze human neural precursor cells (hNPCs) from sporadic PD (sPD) patients. Alterations in gene expression appear in pathways related to primary cilia (PC). Accordingly, in these hiPSC-derived hNPCs and neurons, we observe a shortening of PC. Additionally, we detect a shortening of PC in PINK1-deficient human cellular and mouse models of familial PD. Furthermore, in sPD models, the shortening of PC is accompanied by increased Sonic Hedgehog (SHH) signal transduction. Inhibition of this pathway rescues the alterations in PC morphology and mitochondrial dysfunction. Thus, increased SHH activity due to ciliary dysfunction may be required for the development of pathoetiological phenotypes observed in sPD like mitochondrial dysfunction. Inhibiting overactive SHH signaling may be a potential neuroprotective therapy for sPD. AU - Schmidt, S. AU - Luecken, M. AU - Trümbach, D. AU - Hembach, S. AU - Niedermeier, K.M. AU - Wenck, N. AU - Pflügler, K. AU - Stautner, C. AU - Böttcher, A. AU - Lickert, H. AU - Ramirez Suastegui, C. AU - Ahmad, R.* AU - Ziller, M.J.* AU - Fitzgerald, J.C.* AU - Ruf, V.* AU - van de Berg, W.D.J.* AU - Jonker, A.J.* AU - Gasser, T.* AU - Winner, B.* AU - Winkler, J.* AU - Weisenhorn, D.M. AU - Giesert, F. AU - Theis, F.J. AU - Wurst, W. C1 - 65925 C2 - 52634 TI - Primary cilia and SHH signaling impairments in human and mouse models of Parkinson's disease. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - Phytosterol serum concentrations are under tight genetic control. The relationship between phytosterols and coronary artery disease (CAD) is controversially discussed. We perform a genome-wide meta-analysis of 32 phytosterol traits reflecting resorption, cholesterol synthesis and esterification in six studies with up to 9758 subjects and detect ten independent genome-wide significant SNPs at seven genomic loci. We confirm previously established associations at ABCG5/8 and ABO and demonstrate an extended locus heterogeneity at ABCG5/8 with different functional mechanisms. New loci comprise HMGCR, NPC1L1, PNLIPRP2, SCARB1 and APOE. Based on these results, we perform Mendelian Randomization analyses (MR) revealing a risk-increasing causal relationship of sitosterol serum concentrations and CAD, which is partly mediated by cholesterol. Here we report that phytosterols are polygenic traits. MR add evidence of both, direct and indirect causal effects of sitosterol on CAD. AU - Scholz, M.* AU - Horn, K.* AU - Pott, J.* AU - Gross, A.* AU - Kleber, M.E.* AU - Delgado, G.E.* AU - Mishra, P.P.* AU - Kirsten, H.* AU - Gieger, C. AU - Müller-Nurasyid, M. AU - Tönjes, A.* AU - Kovacs, P.* AU - Lehtimäki, T.* AU - Raitakari, O.* AU - Kähönen, M.* AU - Gylling, H.* AU - Baber, R.* AU - Isermann, B.* AU - Stumvoll, M.* AU - Loeffler, M.* AU - März, W.* AU - Meitinger, T.* AU - Peters, A. AU - Thiery, J.* AU - Teupser, D.* AU - Ceglarek, U.* C1 - 63987 C2 - 51790 TI - Genome-wide meta-analysis of phytosterols reveals five novel loci and a detrimental effect on coronary atherosclerosis. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - In this article the affiliation details for Helena Gylling were incorrectly given as Department of Internal Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland but this should have been Heart and Lung Center, Cardiology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. The original article has been corrected. AU - Scholz, M.* AU - Horn, K.* AU - Pott, J.* AU - Gross, A.* AU - Kleber, M.E.* AU - Delgado, G.E.* AU - Mishra, P.P.* AU - Kirsten, H.* AU - Gieger, C. AU - Müller-Nurasyid, M. AU - Tönjes, A.* AU - Kovacs, P.* AU - Lehtimäki, T.* AU - Raitakari, O.* AU - Kähönen, M.* AU - Gylling, H.* AU - Baber, R.* AU - Isermann, B.* AU - Stumvoll, M.* AU - Loeffler, M.* AU - März, W.* AU - Meitinger, T.* AU - Peters, A. AU - Thiery, J.* AU - Teupser, D.* AU - Ceglarek, U.* C1 - 64497 C2 - 51886 TI - Author Correction: Genome-wide meta-analysis of phytosterols reveals five novel loci and a detrimental effect on coronary atherosclerosis (Nature Communications, (2022), 13, 1, (143), 10.1038/s41467-021-27706-6). JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - Lung emphysema and chronic bronchitis are the two most common causes of chronic obstructive pulmonary disease. Excess macrophage elastase MMP-12, which is predominantly secreted from alveolar macrophages, is known to mediate the development of lung injury and emphysema. Here, we discovered the endolysosomal cation channel mucolipin 3 (TRPML3) as a regulator of MMP-12 reuptake from broncho-alveolar fluid, driving in two independently generated Trpml3-/- mouse models enlarged lung injury, which is further exacerbated after elastase or tobacco smoke treatment. Mechanistically, using a Trpml3IRES-Cre/eR26-τGFP reporter mouse model, transcriptomics, and endolysosomal patch-clamp experiments, we show that in the lung TRPML3 is almost exclusively expressed in alveolar macrophages, where its loss leads to defects in early endosomal trafficking and endocytosis of MMP-12. Our findings suggest that TRPML3 represents a key regulator of MMP-12 clearance by alveolar macrophages and may serve as therapeutic target for emphysema and chronic obstructive pulmonary disease. AU - Spix, B.* AU - Butz, E.S.* AU - Chen, C.C.* AU - Rosato, A.S.* AU - Tang, R.* AU - Jeridi, A. AU - Kudrina, V.* AU - Plesch, E.* AU - Wartenberg, P.* AU - Arlt, E.* AU - Briukhovetska, D.* AU - Ansari, M. AU - Günsel, G.G. AU - Conlon, T.M. AU - Wyatt, A.* AU - Wetzel, S.* AU - Teupser, D.* AU - Holdt, L.M.* AU - Ectors, F.* AU - Boekhoff, I.* AU - Boehm, U.* AU - García-Añoveros, J.* AU - Saftig, P.* AU - Giera, M.* AU - Kobold, S.* AU - Schiller, H. B. AU - Zierler, S.* AU - Gudermann, T.* AU - Wahl-Schott, C.* AU - Bracher, F.* AU - Yildirim, A.Ö. AU - Biel, M.* AU - Grimm, C.* C1 - 64059 C2 - 51815 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Lung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice. JO - Nat. Commun. VL - 13 IS - 1 PB - Nature Portfolio PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - Many individual genetic risk loci have been associated with multiple common human diseases. However, the molecular basis of this pleiotropy often remains unclear. We present an integrative approach to reveal the molecular mechanism underlying the PROCR locus, associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism (VTE) risk. We identify PROCR-p.Ser219Gly as the likely causal variant at the locus and protein C as a causal factor. Using genetic analyses, human recall-by-genotype and in vitro experimentation, we demonstrate that PROCR-219Gly increases plasma levels of (activated) protein C through endothelial protein C receptor (EPCR) ectodomain shedding in endothelial cells, attenuating leukocyte-endothelial cell adhesion and vascular inflammation. We also associate PROCR-219Gly with an increased pro-thrombotic state via coagulation factor VII, a ligand of EPCR. Our study, which links PROCR-219Gly to CAD through anti-inflammatory mechanisms and to VTE through pro-thrombotic mechanisms, provides a framework to reveal the mechanisms underlying similar cross-phenotype associations. AU - Stacey, D.* AU - Chen, L.* AU - Stanczyk, P.J.* AU - Howson, J.M.M.* AU - Mason, A.M.* AU - Burgess, S.* AU - MacDonald, S.* AU - Langdown, J.* AU - McKinney, H.* AU - Downes, K.* AU - Farahi, N.* AU - Peters, J.E.* AU - Basu, S.* AU - Pankow, J.S.* AU - Tang, W.* AU - Pankratz, N.* AU - Sabater-Lleal, M.* AU - de Vries, P.S.* AU - Smith, N.L.* AU - CHARGE Hemostasis Working Group (Peters, A.) AU - Gelinas, A.D.* AU - Schneider, D.J.* AU - Janjic, N.* AU - Samani, N.J.* AU - Ye, S.* AU - Summers, C.* AU - Chilvers, E.R.* AU - Paul, D.S.* C1 - 65057 C2 - 52018 TI - Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AU - Stacey, D.* AU - Chen, L.* AU - Stanczyk, P.J.* AU - Howson, J.M.M.* AU - Mason, A.M.* AU - Burgess, S.* AU - MacDonald, S.* AU - Langdown, J.* AU - McKinney, H.* AU - Downes, K.* AU - Farahi, N.* AU - Peters, J.E.* AU - Basu, S.* AU - Pankow, J.S.* AU - Tang, W.* AU - Pankratz, N.* AU - Sabater-Lleal, M.* AU - de Vries, P.S.* AU - Smith, N.L.* AU - CHARGE Hemostasis Working Group (Peters, A.) AU - Gelinas, A.D.* AU - Schneider, D.J.* AU - Janjic, N.* AU - Samani, N.J.* AU - Ye, S.* AU - Summers, C.* AU - Chilvers, E.R.* AU - Danesh, J.* AU - Paul, D.S.* C1 - 67026 C2 - 53420 TI - Publisher Correction: Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - Quantitative dynamic models are widely used to study cellular signal processing. A critical step in modelling is the estimation of unknown model parameters from experimental data. As model sizes and datasets are steadily growing, established parameter optimization approaches for mechanistic models become computationally extremely challenging. Mini-batch optimization methods, as employed in deep learning, have better scaling properties. In this work, we adapt, apply, and benchmark mini-batch optimization for ordinary differential equation (ODE) models, thereby establishing a direct link between dynamic modelling and machine learning. On our main application example, a large-scale model of cancer signaling, we benchmark mini-batch optimization against established methods, achieving better optimization results and reducing computation by more than an order of magnitude. We expect that our work will serve as a first step towards mini-batch optimization tailored to ODE models and enable modelling of even larger and more complex systems than what is currently possible. AU - Stapor, P. AU - Schmiester, L. AU - Wierling, C.* AU - Merkt, S.* AU - Pathirana, D.* AU - Lange, B.M.H.* AU - Weindl, D. AU - Hasenauer, J. C1 - 63989 C2 - 51789 TI - Mini-batch optimization enables training of ODE models on large-scale datasets. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - Optoacoustics (OA) is overwhelmingly implemented in the Time Domain (TD) to achieve high signal-to-noise ratios by maximizing the excitation light energy transient. Implementations in the Frequency Domain (FD) have been proposed, but suffer from low signal-to-noise ratios and have not offered competitive advantages over time domain methods to reach high dissemination. It is therefore commonly believed that TD is the optimal way to perform optoacoustics. Here we introduce an optoacoustic concept based on pulse train illumination and frequency domain multiplexing and theoretically demonstrate the superior merits of the approach compared to the time domain. Then, using recent advances in laser diode illumination, we launch Frequency Wavelength Multiplexing Optoacoustic Tomography (FWMOT), at multiple wavelengths, and experimentally showcase how FWMOT optimizes the signal-to-noise ratios of spectral measurements over time-domain methods in phantoms and in vivo. We further find that FWMOT offers the fastest multi-spectral operation ever demonstrated in optoacoustics. AU - Stylogiannis, A. AU - Prade, L. AU - Glasl, S. AU - Mustafa, Q. AU - Zakian Dominguez, C.M. AU - Ntziachristos, V. C1 - 65845 C2 - 52929 TI - Frequency wavelength multiplexed optoacoustic tomography. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - Membrane-less organelles are condensates formed by phase separation whose functions often remain enigmatic. Upon oxidative stress, PML scaffolds Nuclear Bodies (NBs) to regulate senescence or metabolic adaptation. PML NBs recruit many partner proteins, but the actual biochemical mechanism underlying their pleiotropic functions remains elusive. Similarly, PML role in embryonic stem cell (ESC) and retro-element biology is unsettled. Here we demonstrate that PML is essential for oxidative stress-driven partner SUMO2/3 conjugation in mouse ESCs (mESCs) or leukemia, a process often followed by their poly-ubiquitination and degradation. Functionally, PML is required for stress responses in mESCs. Differential proteomics unravel the KAP1 complex as a PML NB-dependent SUMO2-target in arsenic-treated APL mice or mESCs. PML-driven KAP1 sumoylation enables activation of this key epigenetic repressor implicated in retro-element silencing. Accordingly, Pml-/- mESCs re-express transposable elements and display 2-Cell-Like features, the latter enforced by PML-controlled SUMO2-conjugation of DPPA2. Thus, PML orchestrates mESC state by coordinating SUMO2-conjugation of different transcriptional regulators, raising new hypotheses about PML roles in cancer. AU - Tessier, S.* AU - Ferhi, O.* AU - Geoffroy, M.C.* AU - González-Prieto, R.* AU - Canat, A. AU - Quentin, S.* AU - Pla, M.* AU - Niwa-Kawakita, M.* AU - Bercier, P.* AU - Rérolle, D.* AU - Therizols, P.* AU - Fabre, E.* AU - Vertegaal, A.C.O.* AU - de Thé, H.* AU - Lallemand-Breitenbach, V.* C1 - 67016 C2 - 53378 TI - Exploration of nuclear body-enhanced sumoylation reveals that PML represses 2-cell features of embryonic stem cells. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - Under normal conditions, the most significant expansion and differentiation of the adult mammary gland occurs in response to systemic reproductive hormones during pregnancy and lactation to enable milk synthesis and secretion to sustain the offspring. However, human mammary tissue remodelling that takes place during pregnancy and lactation remains poorly understood due to the challenge of acquiring samples. We report here single-cell transcriptomic analysis of 110,744 viable breast cells isolated from human milk or non-lactating breast tissue, isolated from nine and seven donors, respectively. We found that human milk largely contains epithelial cells belonging to the luminal lineage and a repertoire of immune cells. Further transcriptomic analysis of the milk cells identified two distinct secretory cell types that shared similarities with luminal progenitors, but no populations comparable to hormone-responsive cells. Taken together, our data offers a reference map and a window into the cellular dynamics that occur during human lactation and may provide further insights on the interplay between pregnancy, lactation and breast cancer. AU - Twigger, A.-J. AU - Engelbrecht, L.K. AU - Bach, K.* AU - Schultz-Pernice, I. AU - Pensa, S.* AU - Stenning, J.* AU - Petricca, S. AU - Scheel, C. AU - Khaled, W.T.* C1 - 64227 C2 - 51799 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Transcriptional changes in the mammary gland during lactation revealed by single cell sequencing of cells from human milk. JO - Nat. Commun. VL - 13 IS - 1 PB - Nature Portfolio PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - The most common cause of death in the intensive care unit (ICU) is the development of multiorgan dysfunction syndrome (MODS). Besides life-supporting treatments, no cure exists, and its mechanisms are still poorly understood. Catalytic iron is associated with ICU mortality and is known to cause free radical-mediated cellular toxicity. It is thought to induce excessive lipid peroxidation, the main characteristic of an iron-dependent type of cell death conceptualized as ferroptosis. Here we show that the severity of multiorgan dysfunction and the probability of death are indeed associated with plasma catalytic iron and lipid peroxidation. Transgenic approaches underscore the role of ferroptosis in iron-induced multiorgan dysfunction. Blocking lipid peroxidation with our highly soluble ferrostatin-analogue protects mice from injury and death in experimental non-septic multiorgan dysfunction, but not in sepsis-induced multiorgan dysfunction. The limitations of the experimental mice models to mimic the complexity of clinical MODS warrant further preclinical testing. In conclusion, our data suggest ferroptosis targeting as possible treatment option for a stratifiable subset of MODS patients. AU - Van Coillie, S.* AU - Van San, E.* AU - Goetschalckx, I.* AU - Wiernicki, B.* AU - Mukhopadhyay, B.* AU - Tonnus, W.* AU - Choi, S.M.* AU - Roelandt, R.* AU - Dumitrascu, C.* AU - Lamberts, L.E.* AU - Dams, G.* AU - Weyts, W.* AU - Huysentruyt, J.* AU - Hassannia, B.* AU - Ingold, I. AU - Lele, S.* AU - Meyer, E.* AU - Berg, M.* AU - Seurinck, R.* AU - Saeys, Y.* AU - Vermeulen, A.* AU - van Nuijs, A.L.N.* AU - Conrad, M. AU - Linkermann, A.* AU - Rajapurkar, M.* AU - Vandenabeele, P.* AU - Hoste, E.* AU - Augustyns, K.* AU - Vanden Berghe, T.* C1 - 64469 C2 - 51941 TI - Targeting ferroptosis protects against experimental (multi)organ dysfunction and death. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - Silencing of endogenous retroviruses (ERVs) is largely mediated by repressive chromatin modifications H3K9me3 and DNA methylation. On ERVs, these modifications are mainly deposited by the histone methyltransferase Setdb1 and by the maintenance DNA methyltransferase Dnmt1. Knock-out of either Setdb1 or Dnmt1 leads to ERV de-repression in various cell types. However, it is currently not known if H3K9me3 and DNA methylation depend on each other for ERV silencing. Here we show that conditional knock-out of Setdb1 in mouse embryonic endoderm results in ERV de-repression in visceral endoderm (VE) descendants and does not occur in definitive endoderm (DE). Deletion of Setdb1 in VE progenitors results in loss of H3K9me3 and reduced DNA methylation of Intracisternal A-particle (IAP) elements, consistent with up-regulation of this ERV family. In DE, loss of Setdb1 does not affect H3K9me3 nor DNA methylation, suggesting Setdb1-independent pathways for maintaining these modifications. Importantly, Dnmt1 knock-out results in IAP de-repression in both visceral and definitive endoderm cells, while H3K9me3 is unaltered. Thus, our data suggest a dominant role of DNA methylation over H3K9me3 for IAP silencing in endoderm cells. Our findings suggest that Setdb1-meditated H3K9me3 is not sufficient for IAP silencing, but rather critical for maintaining high DNA methylation. AU - Wang, Z.* AU - Fan, R.* AU - Russo, A.* AU - Cernilogar, F.M.* AU - Nuber, A.* AU - Schirge, S. AU - Shcherbakova, I.* AU - Dzhilyanova, I.* AU - Ugur, E.* AU - Anton, T.* AU - Richter, L.* AU - Leonhardt, H.* AU - Lickert, H. AU - Schotta, G.* C1 - 66260 C2 - 52752 TI - Dominant role of DNA methylation over H3K9me3 for IAP silencing in endoderm. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - We performed a multi-ethnic Epigenome Wide Association study on 22,774 individuals to describe the DNA methylation signature of chronic low-grade inflammation as measured by C-Reactive protein (CRP). We find 1,511 independent differentially methylated loci associated with CRP. These CpG sites show correlation structures across chromosomes, and are primarily situated in euchromatin, depleted in CpG islands. These genomic loci are predominantly situated in transcription factor binding sites and genomic enhancer regions. Mendelian randomization analysis suggests altered CpG methylation is a consequence of increased blood CRP levels. Mediation analysis reveals obesity and smoking as important underlying driving factors for changed CpG methylation. Finally, we find that an activated CpG signature significantly increases the risk for cardiometabolic diseases and COPD. AU - Wielscher, M.* AU - Mandaviya, P.R.* AU - Kühnel, B. AU - Joehanes, R.* AU - Mustafa, R.* AU - Robinson, O.* AU - Zhang, Y.* AU - Bodinier, B.* AU - Walton, E.* AU - Mishra, P.P.* AU - Schlosser, P.* AU - Wilson, R. AU - Tsai, P.C.* AU - Palaniswamy, S.* AU - Marioni, R.E.* AU - Fiorito, G.* AU - Cugliari, G.* AU - Karhunen, V.* AU - Ghanbari, M.* AU - Psaty, B.M.* AU - Loh, M.* AU - Bis, J.C.* AU - Lehne, B.* AU - Sotoodehnia, N.* AU - Deary, I.J.* AU - Chadeau-Hyam, M.* AU - Brody, J.A.* AU - Cardona, A.* AU - Selvin, E.* AU - Smith, A.K.* AU - Miller, A.H.* AU - Torres, M.A.* AU - Marouli, E.* AU - Gao, X.* AU - van Meurs, J.B.J.* AU - Graf-Schindler, J. AU - Rathmann, W.* AU - Koenig, W.* AU - Peters, A. AU - Weninger, W.* AU - Farlik, M.* AU - Zhang, T.* AU - Chen, W.* AU - Xia, Y.* AU - Teumer, A.* AU - Nauck, M.* AU - Grabe, H.J.* AU - Doerr, M.* AU - Lehtimäki, T.* AU - Guan, W.* AU - Milani, L.* AU - Tanaka, T.* AU - Fisher, K.* AU - Waite, L.L.* AU - Kasela, S.* AU - Vineis, P.* AU - Verweij, N.* AU - van der Harst, P.* AU - Iacoviello, L.* AU - Sacerdote, C.* AU - Panico, S.* AU - Krogh, V.* AU - Tumino, R.* AU - Tzala, E.* AU - Matullo, G.* AU - Hurme, M.A.* AU - Raitakari, O.T.* AU - Colicino, E.* AU - Baccarelli, A.A.* AU - Kähönen, M.* AU - Herzig, K.H.* AU - Li, S.* AU - Conneely, K.N.* AU - Kooner, J.S.* AU - Köttgen, A.* AU - Heijmans, B.T.* AU - Deloukas, P.* AU - Relton, C.* AU - Ong, K.K.* AU - Bell, J.T.* AU - Boerwinkle, E.* AU - Elliott, P.* AU - Brenner, H.* AU - Beekman, M.* AU - Levy, D.* AU - Waldenberger, M. AU - Chambers, J.C.* AU - Dehghan, A.* AU - Järvelin, M.R.* C1 - 65027 C2 - 52033 TI - DNA methylation signature of chronic low-grade inflammation and its role in cardio-respiratory diseases. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - Current concepts regarding the biology of aging are primarily based on studies aimed at identifying factors regulating lifespan. However, lifespan as a sole proxy measure for aging can be of limited value because it may be restricted by specific pathologies. Here, we employ large-scale phenotyping to analyze hundreds of markers in aging male C57BL/6J mice. For each phenotype, we establish lifetime profiles to determine when age-dependent change is first detectable relative to the young adult baseline. We examine key lifespan regulators (putative anti-aging interventions; PAAIs) for a possible countering of aging. Importantly, unlike most previous studies, we include in our study design young treated groups of animals, subjected to PAAIs prior to the onset of detectable age-dependent phenotypic change. Many PAAI effects influence phenotypes long before the onset of detectable age-dependent change, but, importantly, do not alter the rate of phenotypic change. Hence, these PAAIs have limited effects on aging. AU - Xie, K.* AU - Fuchs, H. AU - Scifo, E.* AU - Liu, D.* AU - Aziz, A.* AU - Aguilar-Pimentel, J.A. AU - Amarie, O.V. AU - Becker, L. AU - da Silva Buttkus, P. AU - Calzada-Wack, J. AU - Cho, Y.-L. AU - Deng, Y.* AU - Edwards, A.C.* AU - Garrett, L. AU - Georgopoulou, C.* AU - Gerlini, R. AU - Hölter, S.M. AU - Klein-Rodewald, T. AU - Kramer, M.* AU - Leuchtenberger, S. AU - Lountzi, D.* AU - Mayer-Kuckuk, P. AU - Nover, L.L.* AU - Oestereicher, M.A. AU - Overkott, C.* AU - Pearson, B.L.* AU - Rathkolb, B. AU - Rozman, J. AU - Russ, J.* AU - Schaaf, K.* AU - Spielmann, N. AU - Sanz-Moreno, A. AU - Stoeger, C. AU - Treise, I. AU - Bano, D.* AU - Busch, D.H.* AU - Graw, J. AU - Klingenspor, M.* AU - Klopstock, T.* AU - Mock, B.A.* AU - Salomoni, P.* AU - Schmidt-Weber, C.B. AU - Weiergräber, M.* AU - Wolf, E.* AU - Wurst, W. AU - Gailus-Durner, V. AU - Breteler, M.M.B.* AU - Hrabě de Angelis, M. AU - Ehninger, D.* C1 - 66661 C2 - 53063 TI - Deep phenotyping and lifetime trajectories reveal limited effects of longevity regulators on the aging process in C57BL/6J mice. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization. AU - Young, W.J.* AU - Lahrouchi, N.* AU - Isaacs, A.* AU - Duong, T.V.* AU - Foco, L.* AU - Ahmed, F.* AU - Brody, J.A.* AU - Salman, R.* AU - Noordam, R.* AU - Benjamins, J.W.* AU - Haessler, J.* AU - Lyytikäinen, L.P.* AU - Repetto, L.* AU - Concas, M.P.* AU - van den Berg, M.E.* AU - Weiss, S.* AU - Baldassari, A.R.* AU - Bartz, T.M.* AU - Cook, J.P.* AU - Evans, D.S.* AU - Freudling, R. AU - Hines, O.* AU - Isaksen, J.L.* AU - Lin, H.* AU - Mei, H.* AU - Moscati, A.* AU - Müller-Nurasyid, M. AU - Nursyifa, C.* AU - Qian, Y.* AU - Richmond, A.* AU - Roselli, C.* AU - Ryan, K.A.* AU - Tarazona-Santos, E.* AU - Thériault, S.* AU - Van Duijvenboden, S.* AU - Warren, H.R.* AU - Yao, J.* AU - Raza, D.* AU - Aeschbacher, S.* AU - Ahlberg, G.* AU - Alonso, A.* AU - Andreasen, L.* AU - Bis, J.C.* AU - Boerwinkle, E.* AU - Campbell, A.* AU - Catamo, E.* AU - Cocca, M.* AU - Cutler, M.J.* AU - Darbar, D.* AU - de Grandi, A.* AU - de Luca, A.* AU - Ding, J.* AU - Ellervik, C.* AU - Ellinor, P.T.* AU - Felix, S.B.* AU - Froguel, P.* AU - Fuchsberger, C.* AU - Gögele, M.* AU - Graff, C.* AU - Graff, M.* AU - Guo, X.* AU - Hansen, T.* AU - Heckbert, S.R.* AU - Huang, P.L.* AU - Huikuri, H.V.* AU - Hutri-Kähönen, N.* AU - Ikram, M.A.* AU - Jackson, R.D.* AU - Junttila, J.* AU - Kavousi, M.* AU - Kors, J.A.* AU - Leal, T.P.* AU - Lemaitre, R.N.* AU - Lin, H.J.* AU - Lind, L.* AU - Linneberg, A.* AU - Liu, S.* AU - Macfarlane, P.W.* AU - Mangino, M.* AU - Mezzavilla, M.* AU - Mishra, P.P.* AU - Mitchell, R.N.* AU - Mononen, N.* AU - Montasser, M.E.* AU - Morrison, A.C.* AU - Nauck, M.* AU - Nauffal, V.* AU - Navarro, P.* AU - Nikus, K.* AU - Paré, G.* AU - Patton, K.K.* AU - Pelliccione, G.* AU - Pittman, A.* AU - Porteous, D.J.* AU - Pramstaller, P.P.* AU - Preuss, M.H.* AU - Raitakari, O.T.* AU - Reiner, A.P.* AU - Ribeiro, A.L.P.* AU - Rice, C.M.* AU - Risch, L.* AU - Schlessinger, D.* AU - Schotten, U.* AU - Schurmann, C.* AU - Shen, X.* AU - Shoemaker, M.B.* AU - Sinagra, G.* AU - Sinner, M.F.* AU - Soliman, E.Z.* AU - Stoll, M.* AU - Strauch, K. AU - Tarasov, K.V.* AU - Taylor, K.D.* AU - Tinker, A.* AU - Trompet, S.* AU - Uitterlinden, A.* AU - Völker, U.* AU - Völzke, H.* AU - Waldenberger, M. AU - Conen, D.* AU - Correa, A.* AU - Cucca, F.* AU - Dörr, M.* AU - Kooperberg, C.* AU - Mook-Kanamori, D.O.* AU - Morris, A.P.* AU - Orini, M.* AU - Padmanabhan, S.* AU - Pattaro, C.* AU - Peters, A. AU - Psaty, B.M.* AU - Rotter, J.I.* AU - Stricker, B.* AU - van der Harst, P.* AU - van Duijn, C.M.* AU - Verweij, N.* AU - Wilson, J.F.* AU - Arking, D.E.* AU - Ramirez, J.* AU - Sotoodehnia, N.* AU - Mifsud, B.* AU - Newton-Cheh, C.* AU - Munroe, P.B.* C1 - 66081 C2 - 52791 TI - Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways. JO - Nat. Commun. VL - 13 IS - 1 PY - 2022 SN - 2041-1723 ER - TY - JOUR AB - Ferroptosis is associated with lipid hydroperoxides generated by the oxidation of polyunsaturated acyl chains. Lipid hydroperoxides are reduced by glutathione peroxidase 4 (GPX4) and GPX4 inhibitors induce ferroptosis. However, the therapeutic potential of triggering ferroptosis in cancer cells with polyunsaturated fatty acids is unknown. Here, we identify conjugated linoleates including α-eleostearic acid (αESA) as ferroptosis inducers. αESA does not alter GPX4 activity but is incorporated into cellular lipids and promotes lipid peroxidation and cell death in diverse cancer cell types. αESA-triggered death is mediated by acyl-CoA synthetase long-chain isoform 1, which promotes αESA incorporation into neutral lipids including triacylglycerols. Interfering with triacylglycerol biosynthesis suppresses ferroptosis triggered by αESA but not by GPX4 inhibition. Oral administration of tung oil, naturally rich in αESA, to mice limits tumor growth and metastasis with transcriptional changes consistent with ferroptosis. Overall, these findings illuminate a potential approach to ferroptosis, complementary to GPX4 inhibition. AU - Beatty, A.* AU - Singh, T.* AU - Tyurina, Y.Y.* AU - Tyurin, V.A.* AU - Samovich, S.* AU - Nicolas, E.* AU - Maslar, K.* AU - Zhou, Y.* AU - Cai, K.Q.* AU - Tan, Y.* AU - Doll, S. AU - Conrad, M. AU - Subramanian, A.* AU - Bayir, H.* AU - Rennefahrt, U.* AU - Peterson, J.R.* C1 - 61853 C2 - 50189 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Ferroptotic cell death triggered by conjugated linolenic acids is mediated by ACSL1. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Research PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - The humoral immune response to SARS-CoV-2 is a benchmark for immunity and detailed analysis is required to understand the manifestation and progression of COVID-19, monitor seroconversion within the general population, and support vaccine development. The majority of currently available commercial serological assays only quantify the SARS-CoV-2 antibody response against individual antigens, limiting our understanding of the immune response. To overcome this, we have developed a multiplex immunoassay (MultiCoV-Ab) including spike and nucleocapsid proteins of SARS-CoV-2 and the endemic human coronaviruses. Compared to three broadly used commercial in vitro diagnostic tests, our MultiCoV-Ab achieves a higher sensitivity and specificity when analyzing a well-characterized sample set of SARS-CoV-2 infected and uninfected individuals. We find a high response against endemic coronaviruses in our sample set, but no consistent cross-reactive IgG response patterns against SARS-CoV-2. Here we show a robust, high-content-enabled, antigen-saving multiplex assay suited to both monitoring vaccination studies and facilitating epidemiologic screenings for humoral immunity towards pandemic and endemic coronaviruses. AU - Becker, M.* AU - Strengert, M.* AU - Junker, D.* AU - Kaiser, P.D.* AU - Kerrinnes, T.* AU - Traenkle, B.* AU - Dinter, H.* AU - Häring, J.* AU - Ghozzi, S.* AU - Zeck, A.* AU - Weise, F.* AU - Peter, A. AU - Hörber, S. AU - Fink, S.* AU - Ruoff, F.* AU - Dulovic, A.* AU - Bakchoul, T.* AU - Baillot, A.* AU - Lohse, S.* AU - Cornberg, M.* AU - Illig, T.* AU - Gottlieb, J.* AU - Smola, S.* AU - Karch, A.* AU - Berger, K.* AU - Rammensee, H.G.* AU - Schenke-Layland, K.* AU - Nelde, A.* AU - Märklin, M.* AU - Heitmann, J.S.* AU - Walz, J.S.* AU - Templin, M.* AU - Joos, T.O.* AU - Rothbauer, U.* AU - Krause, G.* AU - Schneiderhan-Marra, N.* C1 - 61411 C2 - 50235 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Exploring beyond clinical routine SARS-CoV-2 serology using MultiCoV-Ab to evaluate endemic coronavirus cross-reactivity. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Research PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - The co-chaperone p23 is a central part of the Hsp90 machinery. It stabilizes the closed conformation of Hsp90, inhibits its ATPase and is important for client maturation. Yet, how this is achieved has remained enigmatic. Here, we show that a tryptophan residue in the proximal region of the tail decelerates the ATPase by allosterically switching the conformation of the catalytic loop in Hsp90. We further show by NMR spectroscopy that the tail interacts with the Hsp90 client binding site via a conserved helix. This helical motif in the p23 tail also binds to the client protein glucocorticoid receptor (GR) in the free and Hsp90-bound form. In vivo experiments confirm the physiological importance of ATPase modulation and the role of the evolutionary conserved helical motif for GR activation in the cellular context. AU - Biebl, M.M.* AU - Lopez, A. AU - Rehn, A.* AU - Freiburger, L.* AU - Lawatscheck, J.* AU - Blank, B.* AU - Sattler, M. AU - Buchner, J.* C1 - 61339 C2 - 50126 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Structural elements in the flexible tail of the co-chaperone p23 coordinate client binding and progression of the Hsp90 chaperone cycle. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Research PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Epithelial branch elongation is a central developmental process during branching morphogenesis in diverse organs. This fundamental growth process into large arborized epithelial networks is accompanied by structural reorganization of the surrounding extracellular matrix (ECM), well beyond its mechanical linear response regime. Here, we report that epithelial ductal elongation within human mammary organoid branches relies on the non-linear and plastic mechanical response of the surrounding collagen. Specifically, we demonstrate that collective back-and-forth motion of cells within the branches generates tension that is strong enough to induce a plastic reorganization of the surrounding collagen network which results in the formation of mechanically stable collagen cages. Such matrix encasing in turn directs further tension generation, branch outgrowth and plastic deformation of the matrix. The identified mechanical tension equilibrium sets a framework to understand how mechanical cues can direct ductal branch elongation. AU - Buchmann, B.* AU - Engelbrecht, L.K. AU - Fernandez, P.* AU - Hutterer, F.P.* AU - Raich, M.K.* AU - Scheel, C. AU - Bausch, A.R.* C1 - 62033 C2 - 50578 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Mechanical plasticity of collagen directs branch elongation in human mammary gland organoids. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Research PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Osteoarthritis causes debilitating pain and disability, resulting in a considerable socioeconomic burden, yet no drugs are available that prevent disease onset or progression. Here, we develop, validate and use rapid-throughput imaging techniques to identify abnormal joint phenotypes in randomly selected mutant mice generated by the International Knockout Mouse Consortium. We identify 14 genes with functional involvement in osteoarthritis pathogenesis, including the homeobox gene Pitx1, and functionally characterize 6 candidate human osteoarthritis genes in mouse models. We demonstrate sensitivity of the methods by identifying age-related degenerative joint damage in wild-type mice. Finally, we phenotype previously generated mutant mice with an osteoarthritis-associated polymorphism in the Dio2 gene by CRISPR/Cas9 genome editing and demonstrate a protective role in disease onset with public health implications. We hope this expanding resource of mutant mice will accelerate functional gene discovery in osteoarthritis and offer drug discovery opportunities for this common, incapacitating chronic disease. AU - Butterfield, N.C.* AU - Curry, K.F.* AU - Steinberg, J. AU - Dewhurst, H.* AU - Komla-Ebri, D.* AU - Mannan, N.S.* AU - Adoum, A.T.* AU - Leitch, V.D.* AU - Logan, J.G.* AU - Waung, J.A.* AU - Ghirardello, E.* AU - Southam, L. AU - Youlten, S.E.* AU - Wilkinson, J.M.* AU - McAninch, E.A.* AU - Vancollie, V.E.* AU - Kussy, F.* AU - White, J.K.* AU - Lelliott, C.J.* AU - Adams, D.J.* AU - Jacques, R.* AU - Bianco, A.C.* AU - Boyde, A.* AU - Zeggini, E. AU - Croucher, P.I.* AU - Williams, G.R.* AU - Bassett, J.H.D.* C1 - 61075 C2 - 50034 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Accelerating functional gene discovery in osteoarthritis. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Research PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - The original version of this Article contained private information in the Data Availability statement, which was used by reviewers to access Proteomics datasets. This information has now been removed from both the PDF and HTML versions of this article. AU - Butterfield, N.C.* AU - Curry, K.F.* AU - Steinberg, J. AU - Dewhurst, H.* AU - Komla-Ebri, D.* AU - Mannan, N.S.* AU - Adoum, A.T.* AU - Leitch, V.D.* AU - Logan, J.G.* AU - Waung, J.A.* AU - Ghirardello, E.* AU - Southam, L. AU - Youlten, S.E.* AU - Wilkinson, J.M.* AU - McAninch, E.A.* AU - Vancollie, V.E.* AU - Kussy, F.* AU - White, J.K.* AU - Lelliott, C.J.* AU - Adams, D.J.* AU - Jacques, R.* AU - Bianco, A.C.* AU - Boyde, A.* AU - Zeggini, E. AU - Croucher, P.I.* AU - Williams, G.R.* AU - Bassett, J.H.D.* C1 - 62167 C2 - 50547 TI - Publisher Correction: Accelerating functional gene discovery in osteoarthritis (Nature Communications, (2021), 12, 1, (467), 10.1038/s41467-020-20761-5). JO - Nat. Commun. VL - 12 IS - 1 PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Compositional changes of cell types are main drivers of biological processes. Their detection through single-cell experiments is difficult due to the compositionality of the data and low sample sizes. We introduce scCODA ( https://github.com/theislab/scCODA ), a Bayesian model addressing these issues enabling the study of complex cell type effects in disease, and other stimuli. scCODA demonstrated excellent detection performance, while reliably controlling for false discoveries, and identified experimentally verified cell type changes that were missed in original analyses. AU - Büttner, M. AU - Ostner, J. AU - Müller, C.L. AU - Theis, F.J. AU - Schubert, B. C1 - 63628 C2 - 51509 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - scCODA is a Bayesian model for compositional single-cell data analysis. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Portfolio PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - High-throughput sequencing describes multiple alterations in individual tumors, but their functional relevance is often unclear. Clinic-close, individualized molecular model systems are required for functional validation and to identify therapeutic targets of high significance for each patient. Here, we establish a Cre-ERT2-loxP (causes recombination, estrogen receptor mutant T2, locus of X-over P1) based inducible RNAi- (ribonucleic acid interference) mediated gene silencing system in patient-derived xenograft (PDX) models of acute leukemias in vivo. Mimicking anti-cancer therapy in patients, gene inhibition is initiated in mice harboring orthotopic tumors. In fluorochrome guided, competitive in vivo trials, silencing of the apoptosis regulator MCL1 (myeloid cell leukemia sequence 1) correlates to pharmacological MCL1 inhibition in patients´ tumors, demonstrating the ability of the method to detect therapeutic vulnerabilities. The technique identifies a major tumor-maintaining potency of the MLL-AF4 (mixed lineage leukemia, ALL1-fused gene from chromosome 4) fusion, restricted to samples carrying the translocation. DUX4 (double homeobox 4) plays an essential role in patients' leukemias carrying the recently described DUX4-IGH (immunoglobulin heavy chain) translocation, while the downstream mediator DDIT4L (DNA-damage-inducible transcript 4 like) is identified as therapeutic vulnerability. By individualizing functional genomics in established tumors in vivo, our technique decisively complements the value chain of precision oncology. Being broadly applicable to tumors of all kinds, it will considerably reinforce personalizing anti-cancer treatment in the future. AU - Carlet, M. AU - Völse, K. AU - Vergalli, J. AU - Becker, M. AU - Herold, T. AU - Arner, A.* AU - Senft, D. AU - Jurinovic, V. AU - Liu, W.-H. AU - Gao, Y. AU - Dill, V.* AU - Fehse, B.* AU - Baldus, C.D.* AU - Bastian, L.* AU - Lenk, L.* AU - Schewe, D.M.* AU - Bagnoli, J.W.* AU - Vick, B. AU - Schmid, J.P. AU - Wilhelm, A.D.* AU - Marschalek, R.* AU - Jost, P.J.* AU - Miething, C.* AU - Riecken, K.* AU - Schmidt-Supprian, M.* AU - Binder, V.* AU - Jeremias, I. C1 - 63099 C2 - 51128 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - In vivo inducible reverse genetics in patients' tumors to identify individual therapeutic targets. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Portfolio PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - The impact of immune mediators on weight homeostasis remains underdefined. Interrogation of resistance to diet-induced obesity in mice lacking a negative regulator of Toll-like receptor signaling serendipitously uncovered a role for B cell activating factor (BAFF). Here we show that overexpression of BAFF in multiple mouse models associates with protection from weight gain, approximating a log-linear dose response relation to BAFF concentrations. Gene expression analysis of BAFF-stimulated subcutaneous white adipocytes unveils upregulation of lipid metabolism pathways, with BAFF inducing white adipose tissue (WAT) lipolysis. Brown adipose tissue (BAT) from BAFF-overexpressing mice exhibits increased Ucp1 expression and BAFF promotes brown adipocyte respiration and in vivo energy expenditure. A proliferation-inducing ligand (APRIL), a BAFF homolog, similarly modulates WAT and BAT lipid handling. Genetic deletion of both BAFF and APRIL augments diet-induced obesity. Lastly, BAFF/APRIL effects are conserved in human adipocytes and higher BAFF/APRIL levels correlate with greater BMI decrease after bariatric surgery. Together, the BAFF/APRIL axis is a multifaceted immune regulator of weight gain and adipose tissue function. AU - Chan, C.C.* AU - Pfluger, P.T. AU - Trompette, A.* AU - Stankiewicz, T.E.* AU - Allen, J.L.* AU - Moreno-Fernandez, M.E.* AU - Damen, M.S.M.A.* AU - Oates, J.R.* AU - Alarcon, P.C.* AU - Doll, J.R.* AU - Flick, M.J.* AU - Flick, L.M.* AU - Sanchez-Gurmaches, J.* AU - Mukherjee, R.* AU - Karns, R.* AU - Helmrath, M.* AU - Inge, T.H.* AU - Weisberg, S.P.* AU - Pamp, S.J.* AU - Relman, D.A.* AU - Seeley, R.J.* AU - Karp, C.L. AU - Divanovic, S.* C1 - 62094 C2 - 50646 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - A BAFF/APRIL axis regulates obesogenic diet-driven weight gain. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Research PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Biochemical reactions typically depend on the concentrations of the molecules involved, and cell survival therefore critically depends on the concentration of proteins. To maintain constant protein concentrations during cell growth, global mRNA and protein synthesis rates are tightly linked to cell volume. While such regulation is appropriate for most proteins, certain cellular structures do not scale with cell volume. The most striking example of this is the genomic DNA, which doubles during the cell cycle and increases with ploidy, but is independent of cell volume. Here, we show that the amount of histone proteins is coupled to the DNA content, even though mRNA and protein synthesis globally increase with cell volume. As a consequence, and in contrast to the global trend, histone concentrations decrease with cell volume but increase with ploidy. We find that this distinct coordination of histone homeostasis and genome content is already achieved at the transcript level, and is an intrinsic property of histone promoters that does not require direct feedback mechanisms. Mathematical modeling and histone promoter truncations reveal a simple and generalizable mechanism to control the cell volume- and ploidy-dependence of a given gene through the balance of the initiation and elongation rates. AU - Claude, K.-L. AU - Bureik, D. AU - Chatzitheodoridou, D. AU - Adarska, P. AU - Singh, A.* AU - Schmoller, K.M. C1 - 62514 C2 - 50893 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Transcription coordinates histone amounts and genome content. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Portfolio PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - EpiScanpy is a toolkit for the analysis of single-cell epigenomic data, namely single-cell DNA methylation and single-cell ATAC-seq data. To address the modality specific challenges from epigenomics data, epiScanpy quantifies the epigenome using multiple feature space constructions and builds a nearest neighbour graph using epigenomic distance between cells. EpiScanpy makes the many existing scRNA-seq workflows from scanpy available to large-scale single-cell data from other -omics modalities, including methods for common clustering, dimension reduction, cell type identification and trajectory learning techniques, as well as an atlas integration tool for scATAC-seq datasets. The toolkit also features numerous useful downstream functions, such as differential methylation and differential openness calling, mapping epigenomic features of interest to their nearest gene, or constructing gene activity matrices using chromatin openness. We successfully benchmark epiScanpy against other scATAC-seq analysis tools and show its outperformance at discriminating cell types. AU - Danese, A. AU - Richter, M. AU - Chaichoompu, K. AU - Fischer, D.S. AU - Theis, F.J. AU - Colomé-Tatché, M. C1 - 62934 C2 - 51173 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - EpiScanpy: Integrated single-cell epigenomic analysis. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Portfolio PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Carbonaceous meteorites are fragments of asteroids rich in organic material. In the forming solar nebula, parent bodies may have accreted organic materials resulting from the evolution of icy grains observed in dense molecular clouds. The major issues of this scenario are the secondary processes having occurred on asteroids, which may have modified the accreted matter. Here, we explore the evolution of organic analogs of protostellar/protoplanetary disk material once accreted and submitted to aqueous alteration at 150 °C. The evolution of molecular compounds during up to 100 days is monitored by high resolution mass spectrometry. We report significant evolution of the molecular families, with the decreases of H/C and N/C ratios. We find that the post-aqueous products share compositional similarities with the soluble organic matter of the Murchison meteorite. These results give a comprehensive scenario of the possible link between carbonaceous meteorites and ices of dense molecular clouds. AU - Danger, G.* AU - Vinogradoff, V.* AU - Matzka, M. AU - Viennet, J.C.* AU - Remusat, L.* AU - Bernard, S.* AU - Ruf, A.* AU - Le Sergeant d’Hendecourt, L.* AU - Schmitt-Kopplin, P. C1 - 62263 C2 - 50613 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Exploring the link between molecular cloud ices and chondritic organic matter in laboratory. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Research PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - In female mammals, the cessation of ovarian functions is associated with significant metabolic alterations, weight gain, and increased susceptibility to a number of pathologies associated with ageing. The molecular mechanisms triggering these systemic events are unknown because most tissues are responsive to lowered circulating sex steroids. As it has been demonstrated that isoform alpha of the estrogen receptor (ERα) may be activated by both estrogens and amino acids, we test the metabolic effects of a diet enriched in specific amino acids in ovariectomized (OVX) mice. This diet is able to block the OVX-induced weight gain and fat deposition in the liver. The use of liver-specific ERα KO mice demonstrates that the hepatic ERα, through the control of liver lipid metabolism, has a key role in the systemic response to OVX. The study suggests that the liver ERα might be a valuable target for dietary treatments for the post-menopause. AU - Della Torre, S.* AU - Benedusi, V.* AU - Pepe, G.* AU - Meda, C.* AU - Rizzi, N.* AU - Uhlenhaut, N.H. AU - Maggi, A.* C1 - 63627 C2 - 51510 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Dietary essential amino acids restore liver metabolism in ovariectomized mice via hepatic estrogen receptor α. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Portfolio PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - The original version of the Peer Review File associated with this Article was updated shortly after publication to redact unpublished data. AU - Deshpande, D.* AU - Agarwal, N.* AU - Fleming, T. AU - Klose, C.S.N.* AU - Tappe-Theodor, A.* AU - Kuner, R.* AU - Nawroth, P.P. C1 - 61327 C2 - 50154 TI - Publisher Correction: Loss of POMC-mediated antinociception contributes to painful diabetic neuropathy. JO - Nat. Commun. VL - 12 IS - 1 PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Painful neuropathy is a frequent complication in diabetes. Proopiomelanocortin (POMC) is an endogenous opioid precursor peptide, which plays a protective role against pain. Here, we report dysfunctional POMC-mediated antinociception in sensory neurons in diabetes. In streptozotocin-induced diabetic mice the Pomc promoter is repressed due to increased binding of NF-kB p50 subunit, leading to a loss in basal POMC level in peripheral nerves. Decreased POMC levels are also observed in peripheral nervous system tissue from diabetic patients. The antinociceptive pathway mediated by POMC is further impaired due to lysosomal degradation of μ-opioid receptor (MOR). Importantly, the neuropathic phenotype of the diabetic mice is rescued upon viral overexpression of POMC and MOR in the sensory ganglia. This study identifies an antinociceptive mechanism in the sensory ganglia that paves a way for a potential therapy for diabetic neuropathic pain. AU - Deshpande, D.* AU - Agarwal, N.* AU - Fleming, T.* AU - Klose, C.S.N.* AU - Tappe-Theodor, A.* AU - Kuner, R.* AU - Nawroth, P.P. C1 - 61093 C2 - 49680 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Loss of POMC-mediated antinociception contributes to painful diabetic neuropathy. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Research PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - The stomach is inhabited by diverse microbial communities, co-existing in a dynamic balance. Long-term use of drugs such as proton pump inhibitors (PPIs), or bacterial infection such as Helicobacter pylori, cause significant microbial alterations. Yet, studies revealing how the commensal bacteria re-organize, due to these perturbations of the gastric environment, are in early phase and rely principally on linear techniques for multivariate analysis. Here we disclose the importance of complementing linear dimensionality reduction techniques with nonlinear ones to unveil hidden patterns that remain unseen by linear embedding. Then, we prove the advantages to complete multivariate pattern analysis with differential network analysis, to reveal mechanisms of bacterial network re-organizations which emerge from perturbations induced by a medical treatment (PPIs) or an infectious state (H. pylori). Finally, we show how to build bacteria-metabolite multilayer networks that can deepen our understanding of the metabolite pathways significantly associated to the perturbed microbial communities. AU - Durán, C.* AU - Ciucci, S.* AU - Palladini, A. AU - Ijaz, U.Z.* AU - Zippo, A.G.* AU - Sterbini, F.P.* AU - Masucci, L.* AU - Cammarota, G.* AU - Ianiro, G.* AU - Spuul, P.* AU - Schroeder, M.* AU - Grill, S.W.* AU - Parsons, B.N.* AU - Pritchard, D.M.* AU - Posteraro, B.* AU - Sanguinetti, M.C.* AU - Gasbarrini, G.* AU - Gasbarrini, A.* AU - Cannistraci, C.V.* C1 - 61680 C2 - 50389 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Nonlinear machine learning pattern recognition and bacteria-metabolite multilayer network analysis of perturbed gastric microbiome. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Research PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - The in vivo phenotypic profile of T cells reactive to severe acute respiratory syndrome (SARS)-CoV-2 antigens remains poorly understood. Conventional methods to detect antigen-reactive T cells require in vitro antigenic re-stimulation or highly individualized peptide-human leukocyte antigen (pHLA) multimers. Here, we use single-cell RNA sequencing to identify and profile SARS-CoV-2-reactive T cells from Coronavirus Disease 2019 (COVID-19) patients. To do so, we induce transcriptional shifts by antigenic stimulation in vitro and take advantage of natural T cell receptor (TCR) sequences of clonally expanded T cells as barcodes for 'reverse phenotyping'. This allows identification of SARS-CoV-2-reactive TCRs and reveals phenotypic effects introduced by antigen-specific stimulation. We characterize transcriptional signatures of currently and previously activated SARS-CoV-2-reactive T cells, and show correspondence with phenotypes of T cells from the respiratory tract of patients with severe disease in the presence or absence of virus in independent cohorts. Reverse phenotyping is a powerful tool to provide an integrated insight into cellular states of SARS-CoV-2-reactive T cells across tissues and activation states. AU - Fischer, D.S. AU - Ansari, M. AU - Wagner, K.I.* AU - Jarosch, S.* AU - Huang, Y.* AU - Mayr, C. AU - Strunz, M. AU - Lang, N.J. AU - D'Ippolito, E.* AU - Hammel, M.* AU - Mateyka, L.* AU - Weber, S.* AU - Wolff, L.S.* AU - Witter, K.* AU - Fernandez, I.E.* AU - Leuschner, G.* AU - Milger, K.* AU - Frankenberger, M. AU - Nowak, L.* AU - Heinig-Menhard, K.* AU - Koch, I. AU - Stoleriu, M.-G. AU - Hilgendorff, A. AU - Behr, J.* AU - Pichlmair, A.* AU - Schubert, B. AU - Theis, F.J. AU - Busch, D.H. AU - Schiller, H. B. AU - Schober, K.* C1 - 62626 C2 - 49950 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Single-cell RNA sequencing reveals ex vivo signatures of SARS-CoV-2-reactive T cells through 'reverse phenotyping'. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Research PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - The post-translational modification of proteins with ubiquitin (Ub) and Ub-like modifiers (Ubls) represents one of the most important regulators in eukaryotic biology. Polymeric Ub/Ubl chains of distinct topologies control the activity, stability, interaction and localization of almost all cellular proteins and elicit a variety of biological outputs. Our ability to characterize the roles of distinct Ub/Ubl topologies and to identify enzymes and receptors that create, recognize and remove these modifications is however hampered by the difficulty to prepare them. Here we introduce a modular toolbox (Ubl-tools) that allows the stepwise assembly of Ub/Ubl chains in a flexible and user-defined manner facilitated by orthogonal sortase enzymes. We demonstrate the universality and applicability of Ubl-tools by generating distinctly linked Ub/Ubl hybrid chains, and investigate their role in DNA damage repair. Importantly, Ubl-tools guarantees straightforward access to target proteins, site-specifically modified with distinct homo- and heterotypic (including branched) Ub chains, providing a powerful approach for studying the functional impact of these complex modifications on cellular processes. AU - Fottner, M.* AU - Weyh, M.* AU - Gaussmann, S. AU - Schwarz, D.* AU - Sattler, M. AU - Lang, K.* C1 - 63557 C2 - 51441 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - A modular toolbox to generate complex polymeric ubiquitin architectures using orthogonal sortase enzymes. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Portfolio PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Human pre-mRNA introns vary in size from under fifty to over a million nucleotides. We searched for essential factors involved in the splicing of human short introns by screening siRNAs against 154 human nuclear proteins. The splicing activity was assayed with a model HNRNPH1 pre-mRNA containing short 56-nucleotide intron. We identify a known alternative splicing regulator SPF45 (RBM17) as a constitutive splicing factor that is required to splice out this 56-nt intron. Whole-transcriptome sequencing of SPF45-deficient cells reveals that SPF45 is essential in the efficient splicing of many short introns. To initiate the spliceosome assembly on a short intron with the truncated poly-pyrimidine tract, the U2AF-homology motif (UHM) of SPF45 competes out that of U2AF65 (U2AF2) for binding to the UHM-ligand motif (ULM) of the U2 snRNP protein SF3b155 (SF3B1). We propose that splicing in a distinct subset of human short introns depends on SPF45 but not U2AF heterodimer. AU - Fukumura, K.* AU - Yoshimoto, R.* AU - Sperotto, L. AU - Kang, H.-S. AU - Hirose, T.* AU - Inoue, K.* AU - Sattler, M. AU - Mayeda, A.* C1 - 62833 C2 - 51088 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - SPF45/RBM17-dependent, but not U2AF-dependent, splicing in a distinct subset of human short introns. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Portfolio PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - The proper functional interaction between different tissues represents a key component in systemic metabolic control. Indeed, disruption of endocrine inter-tissue communication is a hallmark of severe metabolic dysfunction in obesity and diabetes. Here, we show that the FNDC4-GPR116, liver-white adipose tissue endocrine axis controls glucose homeostasis. We found that the liver primarily controlled the circulating levels of soluble FNDC4 (sFNDC4) and lowering of the hepatokine FNDC4 led to prediabetes in mice. Further, we identified the orphan adhesion GPCR GPR116 as a receptor of sFNDC4 in the white adipose tissue. Upon direct and high affinity binding of sFNDC4 to GPR116, sFNDC4 promoted insulin signaling and insulin-mediated glucose uptake in white adipocytes. Indeed, supplementation with FcsFNDC4 in prediabetic mice improved glucose tolerance and inflammatory markers in a white-adipocyte selective and GPR116-dependent manner. Of note, the sFNDC4-GPR116, liver-adipose tissue axis was dampened in (pre) diabetic human patients. Thus our findings will now allow for harnessing this endocrine circuit for alternative therapeutic strategies in obesity-related pre-diabetes. AU - Georgiadi, A. AU - Lopez Salazar, V. AU - El-Merahbi, R. AU - Karikari, R.A. AU - Ma, X.* AU - Mourao, A. AU - Klepac, K. AU - Bühler, L. AU - Alfaro, A.J. AU - Kaczmarek, I.* AU - Linford, A. AU - Bosma, M.* AU - Shilkova, O.* AU - Ritvos, O.* AU - Nakamura, N.* AU - Hirose, S.* AU - Lassi, M. AU - Teperino, R. AU - Machado, J. AU - Scheideler, M. AU - Dietrich, A.* AU - Geerlof, A. AU - Feuchtinger, A. AU - Blutke, A. AU - Fischer, K. AU - Müller, T.D. AU - Kessler, K.* AU - Schöneberg, T.* AU - Thor, D.* AU - Hornemann, S.* AU - Kruse, M.* AU - Nawroth, P.P. AU - Pivovarova-Ramich, O.* AU - Pfeiffer, A.F.H.* AU - Sattler, M. AU - Blüher, M.* AU - Herzig, S. C1 - 62087 C2 - 50559 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Orphan GPR116 mediates the insulin sensitizing effects of the hepatokine FNDC4 in adipose tissue. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Research PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - p53 regulates several signaling pathways to maintain the metabolic homeostasis of cells and modulates the cellular response to stress. Deficiency or excess of nutrients causes cellular metabolic stress, and we hypothesized that p53 could be linked to glucose maintenance. We show here that upon starvation hepatic p53 is stabilized by O-GlcNAcylation and plays an essential role in the physiological regulation of glucose homeostasis. More specifically, p53 binds to PCK1 promoter and regulates its transcriptional activation, thereby controlling hepatic glucose production. Mice lacking p53 in the liver show a reduced gluconeogenic response during calorie restriction. Glucagon, adrenaline and glucocorticoids augment protein levels of p53, and administration of these hormones to p53 deficient human hepatocytes and to liver-specific p53 deficient mice fails to increase glucose levels. Moreover, insulin decreases p53 levels, and over-expression of p53 impairs insulin sensitivity. Finally, protein levels of p53, as well as genes responsible of O-GlcNAcylation are elevated in the liver of type 2 diabetic patients and positively correlate with glucose and HOMA-IR. Overall these results indicate that the O-GlcNAcylation of p53 plays an unsuspected key role regulating in vivo glucose homeostasis. AU - Gonzalez-Rellan, M.J.* AU - Fondevila, M.F.* AU - Fernandez, U.* AU - Rodriguez, A.* AU - Varela-Rey, M.* AU - Veyrat-Durebex, C.* AU - Seoane, S.* AU - Bernardo, G.* AU - Lopitz-Otsoa, F.* AU - Fernández-Ramos, D.* AU - Bilbao, J.* AU - Iglesias, C.* AU - Novoa, E.* AU - Ameneiro, C.* AU - Senra, A.* AU - Beiroa, D.* AU - Cuñarro, J.* AU - DP Chantada-Vazquez, M.* AU - Garcia-Vence, M.* AU - Bravo, S.B.* AU - Da Silva Lima, N.* AU - Porteiro, B.* AU - Carneiro, C.* AU - Vidal, A.* AU - Tovar, S.* AU - Müller, T.D. AU - Ferno, J.* AU - Guallar, D.* AU - Fidalgo, M.* AU - Sabio, G.* AU - Herzig, S. AU - Yang, W.H.* AU - Cho, J.W.* AU - Martínez-Chantar, M.L.* AU - Perez-Fernandez, R.* AU - López, M.* AU - Dieguez, C.* AU - Mato, J.M.* AU - Millet, O.* AU - Coppari, R.* AU - Woodhoo, A.* AU - Fruhbeck, G.* AU - Nogueiras, R.* C1 - 62846 C2 - 51103 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - O-GlcNAcylated p53 in the liver modulates hepatic glucose production. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Portfolio PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias. AU - Goodrich, J.K.* AU - Singer-Berk, M.* AU - Son, R.* AU - Sveden, A.* AU - Wood, J.* AU - England, E.* AU - Cole, J.B.* AU - Weisburd, B.* AU - Watts, N.* AU - Caulkins, L.* AU - Dornbos, P.* AU - Koesterer, R.* AU - Zappala, Z.* AU - Zhang, H.* AU - Maloney, K.A.* AU - Dahl, A.* AU - Aguilar-Salinas, C.A.* AU - Atzmon, G.* AU - Barajas-Olmos, F.* AU - Barzilai, N.* AU - Blangero, J.* AU - Boerwinkle, E.* AU - Bonnycastle, L.L.* AU - Bottinger, E.B.* AU - Bowden, D.W.* AU - Centeno-Cruz, F.* AU - Chambers, J.C.* AU - Chami, N.* AU - Chan, E.* AU - Chan, J.* AU - Cheng, C.Y.* AU - Cho, Y.S.* AU - Contreras-Cubas, C.* AU - Córdova, E.* AU - Correa, A.* AU - DeFronzo, R.A.* AU - Duggirala, R.* AU - Dupuis, J.* AU - Garay-Sevilla, M.E.* AU - García-Ortiz, H.* AU - Gieger, C. AU - Glaser, B.* AU - González-Villalpando, C.* AU - Gonzalez, M.E.* AU - Grarup, N.* AU - Groop, L.* AU - Gross, M.* AU - Haiman, C.* AU - Han, S.* AU - Hanis, C.L.* AU - Hansen, T.* AU - Heard-Costa, N.L.* AU - Henderson, B.E.* AU - Hernandez, J.M.M.* AU - Hwang, M.Y.* AU - Islas-Andrade, S.* AU - Jørgensen, M.E.* AU - Kang, H.M.* AU - Kim, B.J.* AU - Kim, Y.J.* AU - Koistinen, H.A.* AU - Kooner, J.S.* AU - Kuusisto, J.* AU - Kwak, S.H.* AU - Laakso, M.* AU - Lange, L.* AU - Lee, J.Y.* AU - Lee, J.* AU - Lehman, D.M.* AU - Linneberg, A.* AU - Liu, J.* AU - Loos, R.J.F.* AU - Lyssenko, V.* AU - Ma, R.C.W.* AU - Martínez-Hernández, A.* AU - Meigs, J.B.* AU - Meitinger, T.* AU - Mendoza-Caamal, E.* AU - Mohlke, K.L.* AU - Morris, A.D.* AU - Morrison, A.C.* AU - Ng, M.C.Y.* AU - Nilsson, P.M.* AU - O’Donnell, C.J.* AU - Orozco, L.* AU - Palmer, C.N.A.* AU - Park, K.S.* AU - Post, W.S.* AU - Pedersen, O.* AU - Preuss, M.* AU - Psaty, B.M.* AU - Reiner, A.P.* AU - Revilla-Monsalve, C.* AU - Rich, S.S.* AU - Rotter, J.I.* AU - Saleheen, D.* AU - Schurmann, C.* AU - Sim, X.* AU - Sladek, R.* AU - Small, K.S.* AU - So, W.Y.* AU - Spector, T.D.* AU - Strauch, K. AU - Strom, T.M. AU - Tai, E.S.* AU - Tam, C.H.T.* AU - Teo, Y.Y.* AU - Thameem, F.* AU - Tomlinson, B.* AU - Tracy, R.P.* AU - Tuomi, T.* AU - Tuomilehto, J.* AU - Tusié-Luna, T.* AU - van Dam, R.M.* AU - Vasan, R.S.* AU - Wilson, J.G.* AU - Witte, D.R* AU - Wong, T.-Y.* AU - Burtt, N.P.* AU - Zaitlen, N.* AU - McCarthy, M.I.* AU - Boehnke, M.* AU - Pollin, T.I.* AU - Flannick, J.* AU - Mercader, J.M.* AU - O'Donnell-Luria, A.* AU - Baxter, A.* AU - Florez, J.C* AU - MacArthur, D.G.* AU - Udler, M.S.* C1 - 62267 C2 - 50715 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Research PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Previous genome-wide association studies revealed multiple common variants involved in eczema but the role of rare variants remains to be elucidated. Here, we investigate the role of rare variants in eczema susceptibility. We meta-analyze 21 study populations including 20,016 eczema cases and 380,433 controls. Rare variants are imputed with high accuracy using large population-based reference panels. We identify rare exonic variants in DUSP1, NOTCH4, and SLC9A4 to be associated with eczema. In DUSP1 and NOTCH4 missense variants are predicted to impact conserved functional domains. In addition, five novel common variants at SATB1-AS1/KCNH8, TRIB1/LINC00861, ZBTB1, TBX21/OSBPL7, and CSF2RB are discovered. While genes prioritized based on rare variants are significantly up-regulated in the skin, common variants point to immune cell function. Over 20% of the single nucleotide variant-based heritability is attributable to rare and low-frequency variants. The identified rare/low-frequency variants located in functional protein domains point to promising targets for novel therapeutic approaches to eczema. AU - Grosche, S.* AU - Marenholz, I.* AU - Esparza-Gordillo, J.* AU - Arnau-Soler, A.* AU - Pairo-Castineira, E.* AU - Rüschendorf, F.* AU - Ahluwalia, T.S.* AU - Almqvist, C.* AU - Arnold, A.* AU - Baurecht, H.* AU - Bisgaard, H.* AU - Bønnelykke, K.* AU - Brown, S.J.* AU - Bustamante, M.* AU - Curtin, J.A.* AU - Custovic, A.* AU - Dharmage, S.C.* AU - Esplugues, A.* AU - Falchi, M.* AU - Fernandez-Orth, D.* AU - Ferreira, M.A.R.* AU - Franke, A.* AU - Gerdes, S.* AU - Gieger, C. AU - Hakonarson, H.* AU - Holt, P.G.* AU - Homuth, G.* AU - Hubner, N.* AU - Hysi, P.G.* AU - Jarvelin, M.R.* AU - Karlsson, R.* AU - Koppelman, G.H.* AU - Lau, S.* AU - Lutz, M. AU - Magnusson, P.K.E.* AU - Marks, G.B.* AU - Müller-Nurasyid, M. AU - Nöthen, M.M.* AU - Paternoster, L.* AU - Pennell, C.E.* AU - Peters, A. AU - Rawlik, K.* AU - Robertson, C.F.* AU - Rodriguez, E.* AU - Sebert, S.* AU - Simpson, A.* AU - Sleiman, P.M.A.* AU - Standl, M. AU - Stölzl, D.* AU - Strauch, K. AU - Szwajda, A.* AU - Tenesa, A.* AU - Thompson, P.J.* AU - Ullemar, V.* AU - Visconti, A.* AU - Vonk, J.M.* AU - Wang, C.A.* AU - Weidinger, S.* AU - Wielscher, M.* AU - Worth, C.L.* AU - Xu, C.J.* AU - Lee, Y.A.* C1 - 63576 C2 - 51407 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Portfolio PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Post-transcriptional gene regulation in T cells is dynamic and complex as targeted transcripts respond to various factors. This is evident for the Icos mRNA encoding an essential costimulatory receptor that is regulated by several RNA-binding proteins (RBP), including Roquin-1 and Roquin-2. Here, we identify a core RBPome of 798 mouse and 801 human T cell proteins by utilizing global RNA interactome capture (RNA-IC) and orthogonal organic phase separation (OOPS). The RBPome includes Stat1, Stat4 and Vav1 proteins suggesting unexpected functions for these transcription factors and signal transducers. Based on proximity to Roquin-1, we select ~50 RBPs for testing coregulation of Roquin-1/2 targets by induced expression in wild-type or Roquin-1/2-deficient T cells. Besides Roquin-independent contributions from Rbms1 and Cpeb4 we also show Roquin-1/2-dependent and target-specific coregulation of Icos by Celf1 and Igf2bp3. Connecting the cellular RBPome in a post-transcriptional context, we find contributions from multiple RBPs to the prototypic regulation of mRNA targets by individual trans-acting factors. AU - Hoefig, K.P. AU - Reim, A.* AU - Gallus, C. AU - Wong, E.H.* AU - Behrens, G. AU - Conrad, C.* AU - Xu, M. AU - Kifinger, L.* AU - Ito-Kureha, T.* AU - Defourny, K.A.Y.* AU - Geerlof, A. AU - Mautner, J.M.* AU - Hauck, S.M. AU - Baumjohann, D.* AU - Feederle, R. AU - Mann, M.* AU - Wierer, M.* AU - Glasmacher, E. AU - Heissmeyer, V. C1 - 62935 C2 - 51176 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Defining the RBPome of primary T helper cells to elucidate higher-order Roquin-mediated mRNA regulation. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Portfolio PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Activation of non-shivering thermogenesis is considered a promising approach to lower body weight in obesity. p62 deficiency in adipocytes reduces systemic energy expenditure but its role in sustaining mitochondrial function and thermogenesis remains unresolved. NBR1 shares a remarkable structural similarity with p62 and can interact with p62 through their respective PB1 domains. However, the physiological relevance of NBR1 in metabolism, as compared to that of p62, was not clear. Here we show that whole-body and adipocyte-specific ablation of NBR1 reverts the obesity phenotype induced by p62 deficiency by restoring global energy expenditure and thermogenesis in brown adipose tissue. Impaired adrenergic-induced browning of p62-deficient adipocytes is rescued by NBR1 inactivation, unveiling a negative role of NBR1 in thermogenesis under conditions of p62 loss. We demonstrate that upon p62 inactivation, NBR1 represses the activity of PPARγ, establishing an unexplored p62/NBR1-mediated paradigm in adipocyte thermogenesis that is critical for the control of obesity. AU - Huang, J.* AU - Linares, J.F.* AU - Duran, A.* AU - Xia, W.* AU - Saltiel, A.R.* AU - Müller, T.D. AU - Diaz-Meco, M.T.* AU - Moscat, J.* C1 - 62101 C2 - 50620 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - NBR1 is a critical step in the repression of thermogenesis of p62-deficient adipocytes through PPARγ. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Research PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Influenza during pregnancy can affect the health of offspring in later life, among which neurocognitive disorders are among the best described. Here, we investigate whether maternal influenza infection has adverse effects on immune responses in offspring. We establish a two-hit mouse model to study the effect of maternal influenza A virus infection (first hit) on vulnerability of offspring to heterologous infections (second hit) in later life. Offspring born to influenza A virus infected mothers are stunted in growth and more vulnerable to heterologous infections (influenza B virus and MRSA) than those born to PBS- or poly(I:C)-treated mothers. Enhanced vulnerability to infection in neonates is associated with reduced haematopoetic development and immune responses. In particular, alveolar macrophages of offspring exposed to maternal influenza have reduced capacity to clear second hit pathogens. This impaired pathogen clearance is partially reversed by adoptive transfer of alveolar macrophages from healthy offspring born to uninfected dams. These findings suggest that maternal influenza infection may impair immune ontogeny and increase susceptibility to early life infections of offspring. AU - Jacobsen, H.* AU - Walendy-Gnirß, K.* AU - Tekin-Bubenheim, N.* AU - Kouassi, N.M.* AU - Ben-Batalla, I.* AU - Berenbrok, N.* AU - Wolff, M.* AU - dos Reis, V.P.* AU - Zickler, M.* AU - Scholl, L.* AU - Gries, A.* AU - Jania, H.* AU - Kloetgen, A.* AU - Düsedau, A.* AU - Pilnitz-Stolze, G.* AU - Jeridi, A. AU - Yildirim, A.Ö. AU - Fuchs, H. AU - Gailus-Durner, V. AU - Stoeger, C. AU - Hrabě de Angelis, M. AU - Manuylova, T.* AU - Klingel, K.* AU - Culley, F.J.* AU - Behrends, J.* AU - Loges, S.* AU - Schneider, B.* AU - Krauss-Etschmann, S.* AU - Openshaw, P.J.M.* AU - Gabriel, G.* C1 - 62832 C2 - 51087 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Offspring born to influenza A virus infected pregnant mice have increased susceptibility to viral and bacterial infections in early life. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Portfolio PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Here we examine the association between DNA methylation in circulating leukocytes and blood lipids in a multi-ethnic sample of 16,265 subjects. We identify 148, 35, and 4 novel associations among Europeans, African Americans, and Hispanics, respectively, and an additional 186 novel associations through a trans-ethnic meta-analysis. We observe a high concordance in the direction of effects across racial/ethnic groups, a high correlation of effect sizes between high-density lipoprotein and triglycerides, a modest overlap of associations with epigenome-wide association studies of other cardio-metabolic traits, and a largely non-overlap with lipid loci identified to date through genome-wide association studies. Thirty CpGs reached significance in at least 2 racial/ethnic groups including 7 that showed association with the expression of an annotated gene. CpGs annotated to CPT1A showed evidence of being influenced by triglycerides levels. DNA methylation levels of circulating leukocytes show robust and consistent association with blood lipid levels across multiple racial/ethnic groups. AU - Jhun, M.A.* AU - Mendelson, M.* AU - Wilson, R. AU - Gondalia, R.* AU - Joehanes, R.* AU - Salfati, E.L.* AU - Zhao, X.* AU - Braun, K.V.E.* AU - Do, A.N.* AU - Hedman, A.K.* AU - Zhang, T.* AU - Carnero-Montoro, E.* AU - Shen, J.* AU - Bartz, T.M.* AU - Brody, J.A.* AU - Montasser, M.E.* AU - O’Connell, J.R.* AU - Yao, C.* AU - Xia, R.* AU - Boerwinkle, E.* AU - Grove, M.* AU - Guan, W.* AU - Pfeiffer, L. AU - Singmann, P. AU - Müller-Nurasyid, M. AU - Meitinger, T. AU - Gieger, C. AU - Peters, A. AU - Zhao, W.* AU - Ware, E.B.* AU - Smith, J.A.* AU - Dhana, K.* AU - van Meurs, J.* AU - Uitterlinden, A.* AU - Ikram, M.A.* AU - Ghanbari, M.* AU - Zhi, D.* AU - Gustafsson, S.* AU - Lind, L.* AU - Li, S.* AU - Sun, D.* AU - Spector, T.D.* AU - Chen, Y.D.I.* AU - Damcott, C.* AU - Shuldiner, A.R.* AU - Absher, D.M.* AU - Horvath, S.* AU - Tsao, P.S.* AU - Kardia, S.* AU - Psaty, B.M.* AU - Sotoodehnia, N.* AU - Bell, J.T.* AU - Ingelsson, E.* AU - Chen, W.* AU - Dehghan, A.* AU - Arnett, D.K.* AU - Waldenberger, M. AU - Hou, L.* AU - Whitsel, E.A.* AU - Baccarelli, A.* AU - Levy, D.* AU - Fornage, M.* AU - Irvin, M.R.* AU - Assimes, T.L.* C1 - 62392 C2 - 50702 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Research PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - The original version of this Article contained an error in the spelling of the author Min-A Jhun which was incorrectly given as Mina-A Jhun. This has now been corrected in both the PDF and HTML versions of the Article. AU - Jhun, M.A.* AU - Mendelson, M.* AU - Wilson, R. AU - Gondalia, R.* AU - Joehanes, R.* AU - Salfati, E.L.* AU - Zhao, X.* AU - Braun, K.V.E.* AU - Do, A.N.* AU - Hedman, A.K.* AU - Zhang, T.* AU - Carnero-Montoro, E.* AU - Shen, J.* AU - Bartz, T.M.* AU - Brody, J.A.* AU - Montasser, M.E.* AU - O'Connell, J.R.* AU - Yao, C.* AU - Xia, R.* AU - Boerwinkle, E.* AU - Grove, M.* AU - Guan, W.* AU - Pfeiffer, L. AU - Singmann, P. AU - Müller-Nurasyid, M. AU - Meitinger, T. AU - Gieger, C. AU - Peters, A. AU - Zhao, W.* AU - Ware, E.B.* AU - Smith, J.A.* AU - Dhana, K.* AU - van Meurs, J.* AU - Uitterlinden, A.* AU - Ikram, M.A.* AU - Ghanbari, M.* AU - Zhi, D.* AU - Gustafsson, S.* AU - Lind, L.* AU - Li, S.* AU - Sun, D.* AU - Spector, T.D.* AU - Chen, Y.I.* AU - Damcott, C.* AU - Shuldiner, A.R.* AU - Absher, D.M.* AU - Horvath, S.* AU - Tsao, P.S.* AU - Kardia, S.* AU - Psaty, B.M.* AU - Sotoodehnia, N.* AU - Bell, J.T.* AU - Ingelsson, E.* AU - Chen, W.* AU - Dehghan, A.* AU - Arnett, D.K.* AU - Waldenberger, M. AU - Hou, L.* AU - Whitsel, E.A.* AU - Baccarelli, A.* AU - Levy, D.* AU - Fornage, M.* AU - Irvin, M.R.* AU - Assimes, T.L.* C1 - 62530 C2 - 50824 TI - Publisher Correction: A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids. JO - Nat. Commun. VL - 12 IS - 1 PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Coffee and tea are extensively consumed beverages worldwide which have received considerable attention regarding health. Intake of these beverages is consistently linked to, among others, reduced risk of diabetes and liver diseases; however, the mechanisms of action remain elusive. Epigenetics is suggested as a mechanism mediating the effects of dietary and lifestyle factors on disease onset. Here we report the results from epigenome-wide association studies (EWAS) on coffee and tea consumption in 15,789 participants of European and African-American ancestries from 15 cohorts. EWAS meta-analysis of coffee consumption reveals 11 CpGs surpassing the epigenome-wide significance threshold (P-value <1.1×10-7), which annotated to the AHRR, F2RL3, FLJ43663, HDAC4, GFI1 and PHGDH genes. Among them, cg14476101 is significantly associated with expression of the PHGDH and risk of fatty liver disease. Knockdown of PHGDH expression in liver cells shows a correlation with expression levels of genes associated with circulating lipids, suggesting a role of PHGDH in hepatic-lipid metabolism. EWAS meta-analysis on tea consumption reveals no significant association, only two CpGs annotated to CACNA1A and PRDM16 genes show suggestive association (P-value <5.0×10-6). These findings indicate that coffee-associated changes in DNA methylation levels may explain the mechanism of action of coffee consumption in conferring risk of diseases. AU - Karabegović, I.* AU - Portilla-Fernandez, E.* AU - Li, Y.* AU - Ma, J.* AU - Maas, S.C.E.* AU - Sun, D.* AU - Hu, E.A.* AU - Kühnel, B. AU - Zhang, Y.* AU - Ambatipudi, S.* AU - Fiorito, G.* AU - Huang, J.* AU - Castillo-Fernandez, J.E.* AU - Wiggins, K.L.* AU - de Klein, N.* AU - Grioni, S.* AU - Swenson, B.R.* AU - Polidoro, S.* AU - Treur, J.L.* AU - Cuenin, C.* AU - Tsai, P.C.* AU - Costeira, R.* AU - Chajes, V.* AU - Braun, K.* AU - Verweij, N.* AU - Kretschmer, A. AU - Franke, L.* AU - van Meurs, J.B.J.* AU - Uitterlinden, A.G.* AU - de Knegt, R.J.* AU - Ikram, M.A.* AU - Dehghan, A.* AU - Peters, A. AU - Schöttker, B.* AU - Gharib, S.A.* AU - Sotoodehnia, N.* AU - Bell, J.T.* AU - Elliott, P.* AU - Vineis, P.* AU - Relton, C.* AU - Herceg, Z.* AU - Brenner, H.* AU - Waldenberger, M. AU - Rebholz, C.M.* AU - Voortman, T.* AU - Pan, Q.* AU - Fornage, M.* AU - Levy, D.* AU - Kayser, M.* AU - Ghanbari, M.* C1 - 62021 C2 - 50594 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Epigenome-wide association meta-analysis of DNA methylation with coffee and tea consumption. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Research PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - The original version of the Peer Review File associated with this Article was updated after publication to redact two figures in the interest of confidentiality. AU - Keipert, S. AU - Lutter, D. AU - Schroeder, B.O.* AU - Brandt, D. AU - Ståhlman, M.* AU - Schwarzmayr, T. AU - Graf, E. AU - Fuchs, H. AU - Hrabě de Angelis, M. AU - Tschöp, M.H. AU - Rozman, J. AU - Jastroch, M. C1 - 61624 C2 - 50232 TI - Author Correction: Endogenous FGF21-signaling controls paradoxical obesity resistance of UCP1-deficient mice (Nature Communications, (2020), 11, 1, (624), 10.1038/s41467-019-14069-2). JO - Nat. Commun. VL - 12 IS - 1 PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Acute myeloid leukemia (AML) remains incurable, largely due to its resistance to conventional treatments. Here, we find that increased abundance of the ubiquitin ligase RNF5 contributes to AML development and survival. High RNF5 expression in AML patient specimens correlates with poor prognosis. RNF5 inhibition decreases AML cell growth in culture, in patient-derived xenograft (PDX) samples and in vivo, and delays development of MLL-AF9–driven leukemogenesis in mice, prolonging their survival. RNF5 inhibition causes transcriptional changes that overlap with those seen upon histone deacetylase (HDAC)1 inhibition. RNF5 induces the formation of K29 ubiquitin chains on the histone-binding protein RBBP4, promoting its recruitment to and subsequent epigenetic regulation of genes involved in AML maintenance. Correspondingly, RNF5 or RBBP4 knockdown enhances AML cell sensitivity to HDAC inhibitors. Notably, low expression of both RNF5 and HDAC coincides with a favorable prognosis. Our studies identify an ERAD-independent role for RNF5, demonstrating that its control of RBBP4 constitutes an epigenetic pathway that drives AML, and highlight RNF5/RBBP4 as markers useful to stratify patients for treatment with HDAC inhibitors. AU - Khateb, A.* AU - Deshpande, A.* AU - Feng, Y.* AU - Finlay, D.* AU - Lee, J.S.* AU - Lazar, I.* AU - Fabre, B.* AU - Li, Y.* AU - Fujita, Y.* AU - Zhang, T.* AU - Yin, J.* AU - Pass, I.* AU - Livneh, I.* AU - Jeremias, I. AU - Burian, C.* AU - Mason, J.R.* AU - Almog, R.* AU - Horesh, N.* AU - Ofran, Y.* AU - Brown, K.* AU - Vuori, K.* AU - Jackson, M.* AU - Ruppin, E.* AU - Deshpande, A.J.* AU - Ronai, Z.A.* C1 - 63020 C2 - 51216 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - The ubiquitin ligase RNF5 determines acute myeloid leukemia growth and susceptibility to histone deacetylase inhibitors. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Portfolio PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Growing evidence supports that pharmacological application of growth differentiation factor 15 (GDF15) suppresses appetite but also promotes sickness-like behaviors in rodents via GDNF family receptor α-like (GFRAL)-dependent mechanisms. Conversely, the endogenous regulation of GDF15 and its physiological effects on energy homeostasis and behavior remain elusive. Here we show, in four independent human studies that prolonged endurance exercise increases circulating GDF15 to levels otherwise only observed in pathophysiological conditions. This exercise-induced increase can be recapitulated in mice and is accompanied by increased Gdf15 expression in the liver, skeletal muscle, and heart muscle. However, whereas pharmacological GDF15 inhibits appetite and suppresses voluntary running activity via GFRAL, the physiological induction of GDF15 by exercise does not. In summary, exercise-induced circulating GDF15 correlates with the duration of endurance exercise. Yet, higher GDF15 levels after exercise are not sufficient to evoke canonical pharmacological GDF15 effects on appetite or responsible for diminishing exercise motivation. AU - Klein, A.B.* AU - Nicolaisen, T.S.* AU - Ørtenblad, N.* AU - Gejl, K.D.* AU - Jensen, R.* AU - Fritzen, A.M.* AU - Larsen, E.L.* AU - Karstoft, K.* AU - Poulsen, H.E.* AU - Morville, T.* AU - Sahl, R.E.* AU - Helge, J.W.* AU - Lund, J.* AU - Falk, S.* AU - Lyngbæk, M.* AU - Ellingsgaard, H.* AU - Pedersen, B.K.* AU - Lu, W.* AU - Finan, B.* AU - Jørgensen, S.B.* AU - Seeley, R.J.* AU - Kleinert, M. AU - Kiens, B.* AU - Richter, E.A.* AU - Clemmensen, C.* C1 - 61504 C2 - 50321 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Pharmacological but not physiological GDF15 suppresses feeding and the motivation to exercise. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Research PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - With the availability of cellular-resolution connectivity maps, connectomes, from the mammalian nervous system, it is in question how informative such massive connectomic data can be for the distinction of local circuit models in the mammalian cerebral cortex. Here, we investigated whether cellular-resolution connectomic data can in principle allow model discrimination for local circuit modules in layer 4 of mouse primary somatosensory cortex. We used approximate Bayesian model selection based on a set of simple connectome statistics to compute the posterior probability over proposed models given a to-be-measured connectome. We find that the distinction of the investigated local cortical models is faithfully possible based on purely structural connectomic data with an accuracy of more than 90%, and that such distinction is stable against substantial errors in the connectome measurement. Furthermore, mapping a fraction of only 10% of the local connectome is sufficient for connectome-based model distinction under realistic experimental constraints. Together, these results show for a concrete local circuit example that connectomic data allows model selection in the cerebral cortex and define the experimental strategy for obtaining such connectomic data. AU - Klinger, E. AU - Motta, A.* AU - Marr, C. AU - Theis, F.J. AU - Helmstaedter, M.* C1 - 62026 C2 - 50575 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Cellular connectomes as arbiters of local circuit models in the cerebral cortex. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Research PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - The original version of this Article contained an error in Fig. 2, in which panels a and b were inadvertently swapped. This has now been corrected in the PDF and HTML versions of the Article. AU - Lagou, V.* AU - Mägi, R.* AU - Hottenga, J.J.* AU - Grallert, H. AU - Perry, J.R.B.* AU - Bouatia-Naji, N.* AU - Marullo, L.* AU - Rybin, D.* AU - Jansen, R.* AU - Min, J.L.* AU - Dimas, A.S.* AU - Ulrich, A.* AU - Zudina, L.* AU - Gådin, J.R.* AU - Jiang, L.* AU - Faggian, A.* AU - Bonnefond, A.* AU - Fadista, J.* AU - Stathopoulou, M.G.* AU - Isaacs, A.* AU - Willems, S.M.* AU - Navarro, P.* AU - Tanaka, T.* AU - Jackson, A.U.* AU - Montasser, M.E.* AU - O'Connell, J.R.* AU - Bielak, L.F.* AU - Webster, R.J.* AU - Saxena, R.* AU - Stafford, J.M.* AU - Pourcain, B.S.* AU - Timpson, N.J.* AU - Salo, P.* AU - Shin, S.Y.* AU - Amin, N.* AU - Smith, A.V.* AU - Li, G.* AU - Verweij, N.* AU - Goel, A.* AU - Ford, I.* AU - Johnson, P.C.D.* AU - Johnson, T.* AU - Kapur, K.* AU - Thorleifsson, G.* AU - Strawbridge, R.J.* AU - Rasmussen-Torvik, L.J.* AU - Esko, T.* AU - Mihailov, E.* AU - Fall, T.* AU - Fraser, R.M.* AU - Mahajan, A.* AU - Kanoni, S.* AU - Giedraitis, V.* AU - Kleber, M.E.* AU - Silbernagel, G.* AU - Meyer, J. AU - Müller-Nurasyid, M. AU - Ganna, A.* AU - Sarin, A.P.* AU - Yengo, L.* AU - Shungin, D.* AU - Luan, J.* AU - Horikoshi, M.* AU - An, P.* AU - Sanna, S.* AU - Boettcher, Y.* AU - Rayner, N.W.* AU - Nolte, I.M.* AU - Zemunik, T.* AU - Iperen, E.V.* AU - Kovacs, P.* AU - Hastie, N.D.* AU - Wild, S.H.* AU - McLachlan, S.* AU - Campbell, S.* AU - Polasek, O.* AU - Carlson, O.* AU - Egan, J.* AU - Kiess, W.* AU - Willemsen, G.* AU - Kuusisto, J.* AU - Laakso, M.* AU - Dimitriou, M.* AU - Hicks, A.A.* AU - Rauramaa, R.* AU - Bandinelli, S.* AU - Thorand, B. AU - Liu, Y.* AU - Miljkovic, I.* AU - Lind, L.* AU - Doney, A.* AU - Perola, M.* AU - Hingorani, A.* AU - Kivimaki, M.* AU - Kumari, M.* AU - Bennett, A.J.* AU - Groves, C.J.* AU - Herder, C. AU - Koistinen, H.A.* AU - Kinnunen, L.* AU - Faire, U.* AU - Bakker, S.J.L.* AU - Uusitupa, M.* AU - Palmer, C.N.A.* AU - Jukema, J.W.* AU - Sattar, N.* AU - Pouta, A.* AU - Snieder, H.* AU - Boerwinkle, E.* AU - Pankow, J.S.* AU - Magnusson, P.K.* AU - Krus, U.* AU - Scapoli, C.* AU - de Geus, E.J.C.N.* AU - Blüher, M.* AU - Wolffenbuttel, B.H.R.* AU - Province, M.A.* AU - Abecasis, G.R.* AU - Meigs, J.B.* AU - Hovingh, G.K.* AU - Lindström, J.* AU - Wilson, J.F.* AU - Wright, A.F.* AU - Dedoussis, G.V.* AU - Bornstein, S.R.* AU - Schwarz, P.E. AU - Tönjes, A.* AU - Winkelmann, B.R.* AU - Boehm, B.O.* AU - März, W.* AU - Metspalu, A.* AU - Price, J.F.* AU - Deloukas, P.* AU - Körner, A.* AU - Lakka, T.A.* AU - Keinanen-Kiukaanniemi, S.M.* AU - Saaristo, T.E.* AU - Bergman, R.N.* AU - Tuomilehto, J.* AU - Wareham, N.J.* AU - Langenberg, C.* AU - Männistö, S.* AU - Franks, P.W.* AU - Hayward, C.* AU - Vitart, V.* AU - Kaprio, J.* AU - Visvikis-Siest, S.* AU - Balkau, B.* AU - Altshuler, D.* AU - Rudan, I.* AU - Stumvoll, M.* AU - Campbell, H.* AU - van Duijn, C.M.* AU - Gieger, C. AU - Illig, T. AU - Ferrucci, L.* AU - Pedersen, N.L.* AU - Pramstaller, P.P.* AU - Boehnke, M.* AU - Frayling, T.M.* AU - Shuldiner, A.R.* AU - Peyser, P.A.* AU - Kardia, S.L.R.* AU - Palmer, L.J.* AU - Penninx, B.W.* AU - Meneton, P.* AU - Harris, T.B.* AU - Navis, G.* AU - Harst, P.V.* AU - Smith, G.D.* AU - Forouhi, N.G.* AU - Loos, R.J.F.* AU - Salomaa, V.* AU - Soranzo, N.* AU - Boomsma, D.I.* AU - Groop, L.* AU - Tuomi, T.* AU - Hofman, A.* AU - Munroe, P.B.* AU - Gudnason, V.* AU - Siscovick, D.S.* AU - Watkins, H.* AU - Lecoeur, C.* AU - Vollenweider, P.* AU - Franco-Cereceda, A.* AU - Eriksson, P.* AU - Jarvelin, M.R.* AU - Stefansson, K.* AU - Hamsten, A.* AU - Nicholson, G.* AU - Karpe, F.* AU - Dermitzakis, E.T.* AU - Lindgren, C.M.* AU - McCarthy, M.I.* AU - Froguel, P.* AU - Kaakinen, M.A.* AU - Lyssenko, V.* AU - Watanabe, R.M.* AU - Ingelsson, E.* AU - Florez, J.C.* AU - Dupuis, J.* AU - Barroso, I.* AU - Morris, A.P.* AU - Prokopenko, I.* C1 - 61326 C2 - 50199 TI - Publisher Correction: Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability. JO - Nat. Commun. VL - 12 IS - 1 PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes. AU - Lagou, V.* AU - Mägi, R.* AU - Hottenga, J.J.* AU - Grallert, H. AU - Perry, J.R.B.* AU - Bouatia-Naji, N.* AU - Marullo, L.* AU - Rybin, D.* AU - Jansen, R.* AU - Min, J.L.* AU - Dimas, A.S.* AU - Ulrich, A.* AU - Zudina, L.* AU - Gådin, J.R.* AU - Jiang, L.* AU - Faggian, A.* AU - Bonnefond, A.* AU - Fadista, J.* AU - Stathopoulou, M.G.* AU - Isaacs, A.* AU - Willems, S.M.* AU - Navarro, P.* AU - Tanaka, T.* AU - Jackson, A.U.* AU - Montasser, M.E.* AU - O'Connell, J.R.* AU - Bielak, L.F.* AU - Webster, R.J.* AU - Saxena, R.* AU - Stafford, J.M.* AU - Pourcain, B.S.* AU - Timpson, N.J.* AU - Salo, P.* AU - Shin, S.Y.* AU - Amin, N.* AU - Smith, A.V.* AU - Li, G.* AU - Verweij, N.* AU - Goel, A.* AU - Ford, I.* AU - Johnson, P.C.D.* AU - Johnson, T.* AU - Kapur, K.* AU - Thorleifsson, G.* AU - Strawbridge, R.J.* AU - Rasmussen-Torvik, L.J.* AU - Esko, T.* AU - Mihailov, E.* AU - Fall, T.* AU - Fraser, R.M.* AU - Mahajan, A.* AU - Kanoni, S.* AU - Giedraitis, V.* AU - Kleber, M.E.* AU - Silbernagel, G.* AU - Meyer, J. AU - Müller-Nurasyid, M. AU - Ganna, A.* AU - Sarin, A.P.* AU - Yengo, L.* AU - Shungin, D.* AU - Luan, J.* AU - Horikoshi, M.* AU - An, P.* AU - Sanna, S.* AU - Boettcher, Y.* AU - Rayner, N.W.* AU - Nolte, I.M.* AU - Zemunik, T.* AU - Iperen, E.V.* AU - Kovacs, P.* AU - Hastie, N.D.* AU - Wild, S.H.* AU - McLachlan, S.* AU - Campbell, S.* AU - Polasek, O.* AU - Carlson, O.* AU - Egan, J.* AU - Kiess, W.* AU - Willemsen, G.* AU - Kuusisto, J.* AU - Laakso, M.* AU - Dimitriou, M.* AU - Hicks, A.A.* AU - Rauramaa, R.* AU - Bandinelli, S.* AU - Thorand, B. AU - Liu, Y.* AU - Miljkovic, I.* AU - Lind, L.* AU - Doney, A.* AU - Perola, M.* AU - Hingorani, A.* AU - Kivimaki, M.* AU - Kumari, M.* AU - Bennett, A.J.* AU - Groves, C.J.* AU - Herder, C. AU - Koistinen, H.A.* AU - Kinnunen, L.* AU - Faire, U.* AU - Bakker, S.J.L.* AU - Uusitupa, M.* AU - Palmer, C.N.A.* AU - Jukema, J.W.* AU - Sattar, N.* AU - Pouta, A.* AU - Snieder, H.* AU - Boerwinkle, E.* AU - Pankow, J.S.* AU - Magnusson, P.K.* AU - Krus, U.* AU - Scapoli, C.* AU - de Geus, E.J.C.N.* AU - Blüher, M.* AU - Wolffenbuttel, B.H.R.* AU - Province, M.A.* AU - Abecasis, G.R.* AU - Meigs, J.B.* AU - Hovingh, G.K.* AU - Lindström, J.* AU - Wilson, J.F.* AU - Wright, A.F.* AU - Dedoussis, G.V.* AU - Bornstein, S.R.* AU - Schwarz, P.E. AU - Tönjes, A.* AU - Winkelmann, B.R.* AU - Boehm, B.O.* AU - März, W.* AU - Metspalu, A.* AU - Price, J.F.* AU - Deloukas, P.* AU - Körner, A.* AU - Lakka, T.A.* AU - Keinanen-Kiukaanniemi, S.M.* AU - Saaristo, T.E.* AU - Bergman, R.N.* AU - Tuomilehto, J.* AU - Wareham, N.J.* AU - Langenberg, C.* AU - Männistö, S.* AU - Franks, P.W.* AU - Hayward, C.* AU - Vitart, V.* AU - Kaprio, J.* AU - Visvikis-Siest, S.* AU - Balkau, B.* AU - Altshuler, D.* AU - Rudan, I.* AU - Stumvoll, M.* AU - Campbell, H.* AU - van Duijn, C.M.* AU - Gieger, C. AU - Illig, T. AU - Ferrucci, L.* AU - Pedersen, N.L.* AU - Pramstaller, P.P.* AU - Boehnke, M.* AU - Frayling, T.M.* AU - Shuldiner, A.R.* AU - Peyser, P.A.* AU - Kardia, S.L.R.* AU - Palmer, L.J.* AU - Penninx, B.W.* AU - Meneton, P.* AU - Harris, T.B.* AU - Navis, G.* AU - Harst, P.V.* AU - Smith, G.D.* AU - Forouhi, N.G.* AU - Loos, R.J.F.* AU - Salomaa, V.* AU - Soranzo, N.* AU - Boomsma, D.I.* AU - Groop, L.* AU - Tuomi, T.* AU - Hofman, A.* AU - Munroe, P.B.* AU - Gudnason, V.* AU - Siscovick, D.S.* AU - Watkins, H.* AU - Lecoeur, C.* AU - Vollenweider, P.* AU - Franco-Cereceda, A.* AU - Eriksson, P.* AU - Jarvelin, M.R.* AU - Stefansson, K.* AU - Hamsten, A.* AU - Nicholson, G.* AU - Karpe, F.* AU - Dermitzakis, E.T.* AU - Lindgren, C.M.* AU - McCarthy, M.I.* AU - Froguel, P.* AU - Kaakinen, M.A.* AU - Lyssenko, V.* AU - Watanabe, R.M.* AU - Ingelsson, E.* AU - Florez, J.C.* AU - Dupuis, J.* AU - Barroso, I.* AU - Morris, A.P.* AU - Prokopenko, I.* C1 - 60949 C2 - 50000 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Research PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Follicular B (FoB) and marginal zone B (MZB) cells are functionally and spatially distinct mature B cell populations in the spleen, originating from a Notch2-dependent fate decision after splenic influx of immature transitional B cells. In the B cell follicle, a Notch2-signal is provided by DLL-1-expressing fibroblasts. However, it is unclear whether FoB cells, which are in close contact with these DLL-1 expressing fibroblasts, can also differentiate to MZB cells if they receive a Notch2-signal. Here, we show induced Notch2IC-expression in FoB cells re-programs mature FoB cells into bona fide MZB cells as is evident from the surface phenotype, localization, immunological function and transcriptome of these cells. Furthermore, the lineage conversion from FoB to MZB cells occurs in immunocompetent wildtype mice. These findings demonstrate plasticity between mature FoB and MZB cells that can be driven by a singular signaling event, the activation of Notch2. AU - Lechner, M. AU - Engleitner, T.* AU - Babushku, T. AU - Schmidt-Supprian, M.* AU - Rad, R.* AU - Strobl, L.J. AU - Zimber-Strobl, U. C1 - 61408 C2 - 50142 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Notch2-mediated plasticity between marginal zone and follicular B cells. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Research PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we perform a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identify a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 × 10-8; KMT5B). We also identify a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N = 1287) at 6p21.32 (rs3916765; P = 1.51 × 10-10; HLA). Our results inform on AML etiology and identify putative functional genes operating in histone methylation (KMT5B) and immune function (HLA). AU - Lin, W.Y.* AU - Fordham, S.E.* AU - Hungate, E.* AU - Sunter, N.J.* AU - Elstob, C.* AU - Xu, Y.* AU - Park, C.* AU - Quante, A.S. AU - Strauch, K. AU - Gieger, C.* AU - Skol, A.* AU - Rahman, T.* AU - Sucheston-Campbell, L.* AU - Wang, J.* AU - Hahn, T.* AU - Clay-Gilmour, A.I.* AU - Jones, G.L.* AU - Marr, H.J.* AU - Jackson, G.H.* AU - Menne, T.* AU - Collin, M.* AU - Ivey, A.* AU - Hills, R.K.* AU - Burnett, A.K.* AU - Russell, N.H.* AU - Fitzgibbon, J.* AU - Larson, R.A.* AU - Le Beau, M.M.* AU - Stock, W.* AU - Heidenreich, O.* AU - Alharbi, A.* AU - Allsup, D.J.* AU - Houlston, R.S.* AU - Norden, J.* AU - Dickinson, A.M.* AU - Douglas, E.* AU - Lendrem, C.* AU - Daly, A.K.* AU - Palm, L.* AU - Piechocki, K.* AU - Jeffries, S.* AU - Bornhäuser, M.* AU - Röllig, C.* AU - Altmann, H.* AU - Ruhnke, L.* AU - Kunadt, D.* AU - Wagenführ, L.* AU - Cordell, H.J.* AU - Darlay, R.* AU - Andersen, M.K.* AU - Fontana, M.C.* AU - Martinelli, G.* AU - Marconi, G.* AU - Sanz, M.A.* AU - Cervera, J.* AU - Gómez-Seguí, I.* AU - Cluzeau, T.* AU - Moreilhon, C.* AU - Raynaud, S.* AU - Sill, H.* AU - Voso, M.T.* AU - Lo-Coco, F.* AU - Dombret, H.* AU - Cheok, M.* AU - Preudhomme, C.* AU - Gale, R.E.* AU - Linch, D.* AU - Gaal-Wesinger, J.* AU - Masszi, A.* AU - Nowak, D.* AU - Hofmann, W.K.* AU - Gilkes, A.* AU - Porkka, K.* AU - Milosevic Feenstra, J.D.* AU - Kralovics, R.* AU - Grimwade, D.* AU - Meggendorfer, M.* AU - Haferlach, T.* AU - Krizsán, S.* AU - Bödör, C.* AU - Stölzel, F.* AU - Onel, K.* AU - Allan, J.M.* C1 - 63433 C2 - 51432 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Genome-wide association study identifies susceptibility loci for acute myeloid leukemia. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Portfolio PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - The size and shape of peptide ions in the gas phase are an under-explored dimension for mass spectrometry-based proteomics. To investigate the nature and utility of the peptide collisional cross section (CCS) space, we measure more than a million data points from whole-proteome digests of five organisms with trapped ion mobility spectrometry (TIMS) and parallel accumulation-serial fragmentation (PASEF). The scale and precision (CV < 1%) of our data is sufficient to train a deep recurrent neural network that accurately predicts CCS values solely based on the peptide sequence. Cross section predictions for the synthetic ProteomeTools peptides validate the model within a 1.4% median relative error (R > 0.99). Hydrophobicity, proportion of prolines and position of histidines are main determinants of the cross sections in addition to sequence-specific interactions. CCS values can now be predicted for any peptide and organism, forming a basis for advanced proteomics workflows that make full use of the additional information. AU - Meier, F.* AU - Köhler, N. AU - Brunner, A.D.* AU - Wanka, J.-M.H. AU - Voytik, E.* AU - Strauss, M.T.* AU - Theis, F.J. AU - Mann, M.* C1 - 61407 C2 - 49890 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Deep learning the collisional cross sections of the peptide universe from a million experimental values. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Research PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Aberrant splicing is a major cause of rare diseases.  However, its prediction from genome sequence alone remains in most cases inconclusive. Recently, RNA sequencing has proven to be an effective complementary avenue to detect aberrant splicing. Here, we develop FRASER, an algorithm to detect aberrant splicing from RNA sequencing data. Unlike existing methods, FRASER captures not only alternative splicing but also intron retention events. This typically doubles the number of detected aberrant events and identified a pathogenic intron retention in MCOLN1 causing mucolipidosis. FRASER automatically controls for latent confounders, which are widespread and affect sensitivity substantially. Moreover, FRASER is based on a count distribution and multiple testing correction, thus reducing the number of calls by two orders of magnitude over commonly applied z score cutoffs, with a minor loss of sensitivity. Applying FRASER to rare disease diagnostics is demonstrated by reprioritizing a pathogenic aberrant exon truncation in TAZ from a published dataset. FRASER is easy to use and freely available. AU - Mertes, C.* AU - Scheller, I.F. AU - Yépez, V.A.* AU - Çelik, M.H.* AU - Liang, Y.* AU - Kremer, L.S. AU - Gusic, M. AU - Prokisch, H. AU - Gagneur, J. C1 - 61062 C2 - 49689 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Detection of aberrant splicing events in RNA-seq data using FRASER. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Research PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Hsp26 is a small heat shock protein (sHsp) from S. cerevisiae. Its chaperone activity is activated by oligomer dissociation at heat shock temperatures. Hsp26 contains 9 phosphorylation sites in different structural elements. Our analysis of phospho-mimetic mutations shows that phosphorylation activates Hsp26 at permissive temperatures. The cryo-EM structure of the Hsp26 40mer revealed contacts between the conserved core domain of Hsp26 and the so-called thermosensor domain in the N-terminal part of the protein, which are targeted by phosphorylation. Furthermore, several phosphorylation sites in the C-terminal extension, which link subunits within the oligomer, are sensitive to the introduction of negative charges. In all cases, the intrinsic inhibition of chaperone activity is relieved and the N-terminal domain becomes accessible for substrate protein binding. The weakening of domain interactions within and between subunits by phosphorylation to activate the chaperone activity in response to proteotoxic stresses independent of heat stress could be a general regulation principle of sHsps. AU - Mühlhofer, M.* AU - Peters, C.* AU - Kriehuber, T.* AU - Kreuzeder, M.* AU - Kazman, P.* AU - Rodina, N. AU - Reif, B. AU - Haslbeck, M.* AU - Weinkauf, S.* AU - Buchner, J.* C1 - 63561 C2 - 51494 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Phosphorylation activates the yeast small heat shock protein Hsp26 by weakening domain contacts in the oligomer ensemble. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Portfolio PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Transcriptionally mature and immature β-cells co-exist within the adult islet. How such diversity contributes to insulin release remains poorly understood. Here we show that subtle differences in β-cell maturity, defined using PDX1 and MAFA expression, contribute to islet operation. Functional mapping of rodent and human islets containing proportionally more PDX1HIGH and MAFAHIGH β-cells reveals defects in metabolism, ionic fluxes and insulin secretion. At the transcriptomic level, the presence of increased numbers of PDX1HIGH and MAFAHIGH β-cells leads to dysregulation of gene pathways involved in metabolic processes. Using a chemogenetic disruption strategy, differences in PDX1 and MAFA expression are shown to depend on islet Ca2+ signaling patterns. During metabolic stress, islet function can be restored by redressing the balance between PDX1 and MAFA levels across the β-cell population. Thus, preserving heterogeneity in PDX1 and MAFA expression, and more widely in β-cell maturity, might be important for the maintenance of islet function. AU - Nasteska, D.* AU - Fine, N.H.F.* AU - Ashford, F.B.* AU - Cuozzo, F.* AU - Viloria, K.* AU - Smith, G.* AU - Dahir, A.* AU - Dawson, P.W.J.* AU - Lai, Y.C.* AU - Bastidas-Ponce, A. AU - Bakhti, M. AU - Rutter, G.A.* AU - Fiancette, R.* AU - Nano, R.* AU - Piemonti, L.* AU - Lickert, H. AU - Zhou, Q.* AU - Akerman, I.* AU - Hodson, D.J.* C1 - 61196 C2 - 49927 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - PDX1LOW MAFALOW β-cells contribute to islet function and insulin release. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Portfolio PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - The original version of this Article contained an error in ref. 45, which was incorrectly given with the wrong author name as: Dzeja, P. et al. Mice deficient in the respiratory chain gene Cox6a2 are protected against high-fat diet-induced obesity and insulin resistance. PLoS ONE 8, e56719 (2013). The correct form of ref. 45 is: Quintens, R. et al. Mice deficient in the respiratory chain gene Cox6a2 are protected against high-fat diet-induced obesity and insulin resistance. PLoS ONE 8, e56719 (2013). This has been corrected in the PDF and HTML versions of the Article. AU - Nasteska, D.* AU - Fine, N.H.F.* AU - Ashford, F.B.* AU - Cuozzo, F.* AU - Viloria, K.* AU - Smith, G.* AU - Dahir, A.* AU - Dawson, P.W.J.* AU - Lai, Y.C.* AU - Bastidas-Ponce, A. AU - Bakhti, M. AU - Rutter, G.A.* AU - Fiancette, R.* AU - Nano, R.* AU - Piemonti, L.* AU - Lickert, H. AU - Zhou, Q.* AU - Akerman, I.* AU - Hodson, D.J.* C1 - 62655 C2 - 50926 TI - Author Correction: PDX1LOW MAFALOW β-cells contribute to islet function and insulin release. JO - Nat. Commun. VL - 12 IS - 1 PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - To ensure dosage compensation between the sexes, one randomly chosen X chromosome is silenced in each female cell in the process of X-chromosome inactivation (XCI). XCI is initiated during early development through upregulation of the long non-coding RNA Xist, which mediates chromosome-wide gene silencing. Cell differentiation, Xist upregulation and gene silencing are thought to be coupled at multiple levels to ensure inactivation of exactly one out of two X chromosomes. Here we perform an integrated analysis of all three processes through allele-specific single-cell RNA-sequencing. Specifically, we assess the onset of random XCI in differentiating mouse embryonic stem cells, and develop dedicated analysis approaches. By exploiting the inter-cellular heterogeneity of XCI onset, we identify putative Xist regulators. Moreover, we show that transient Xist upregulation from both X chromosomes results in biallelic gene silencing right before transitioning to the monoallelic state, confirming a prediction of the stochastic model of XCI. Finally, we show that genetic variation modulates the XCI process at multiple levels, providing a potential explanation for the long-known X-controlling element (Xce) effect, which leads to preferential inactivation of a specific X chromosome in inter-strain crosses. We thus draw a detailed picture of the different levels of regulation that govern the initiation of XCI. The experimental and computational strategies we have developed here will allow us to profile random XCI in more physiological contexts, including primary human cells in vivo. AU - Pacini, G.* AU - Dunkel, I.* AU - Mages, N.* AU - Mutzel, V.* AU - Timmermann, B.* AU - Marsico, A. AU - Schulz, E.G.* C1 - 62351 C2 - 50706 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Integrated analysis of Xist upregulation and X-chromosome inactivation with single-cell and single-allele resolution. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Research PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Conventional dendritic cells (cDC) are key activators of naive T cells, and can be targeted in adults to induce adaptive immunity, but in early life are considered under-developed or functionally immature. Here we show that, in early life, when the immune system develops, cDC2 exhibit a dual hematopoietic origin and, like other myeloid and lymphoid cells, develop in waves. Developmentally distinct cDC2 in early life, despite being distinguishable by fate mapping, are transcriptionally and functionally similar. cDC2 in early and adult life, however, are exposed to distinct cytokine environments that shape their transcriptional profile and alter their ability to sense pathogens, secrete cytokines and polarize T cells. We further show that cDC2 in early life, despite being distinct from cDC2 in adult life, are functionally competent and can induce T cell responses. Our results thus highlight the potential of harnessing cDC2 for boosting immunity in early life. AU - Papaioannou, N.E.* AU - Salei, N.* AU - Rambichler, S.* AU - Ravi, K.* AU - Popovic, J.* AU - Küntzel, V.* AU - Lehmann, C.H.K.* AU - Fiancette, R.* AU - Salvermoser, J.* AU - Gajdasik, D.W.* AU - Mettler, R.* AU - Messerer, D.* AU - Carrelha, J.* AU - Ohnmacht, C. AU - Haller, D.* AU - Stumm, R.* AU - Straub, T.* AU - Jacobsen, S.E.W.* AU - Schulz, C.* AU - Withers, D.R.* AU - Schotta, G.* AU - Dudziak, D.* AU - Schraml, B.U.* C1 - 61083 C2 - 49686 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Environmental signals rather than layered ontogeny imprint the function of type 2 conventional dendritic cells in young and adult mice. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Research PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - The original version of this Article cited “Mehra, M. R., Desai, S. S., Kuy, S., Henry, T. D. & Patel, A. N. Cardiovascular disease, drug therapy, and mortality in Covid-19. N. Engl. J. Med. 382, e102 (2020)” as Ref. 20. The cited paper was retracted; accordingly, Ref. 20 has been replaced with "Grasselli G et al. Risk factors associated with mortality among patients with COVID-19 in intensive care units in Lombardy, Italy. JAMA Intern. Med. 180, 1345–1355 (2020)”. This has been corrected in the PDF and HTML versions of the article. AU - Pietzner, M.* AU - Wheeler, E.* AU - Carrasco-Zanini, J.* AU - Raffler, J. AU - Kerrison, N.D.* AU - Oerton, E.* AU - Auyeung, V.P.W.* AU - Luan, J.* AU - Finan, C.* AU - Casas, J.P.* AU - Ostroff, R.* AU - Williams, S.A.* AU - Kastenmüller, G. AU - Ralser, M.* AU - Gamazon, E.R.* AU - Wareham, N.J.* AU - Hingorani, A.D.* AU - Langenberg, C.* C1 - 61185 C2 - 50093 TI - Author Correction: Genetic architecture of host proteins involved in SARS-CoV-2 infection. JO - Nat. Commun. VL - 12 IS - 1 PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Despite the increasing global burden of neurological disorders, there is a lack of effective diagnostic and therapeutic biomarkers. Proteins are often dysregulated in disease and have a strong genetic component. Here, we carry out a protein quantitative trait locus analysis of 184 neurologically-relevant proteins, using whole genome sequencing data from two isolated population-based cohorts (N = 2893). In doing so, we elucidate the genetic landscape of the circulating proteome and its connection to neurological disorders. We detect 214 independently-associated variants for 107 proteins, the majority of which (76%) are cis-acting, including 114 variants that have not been previously identified. Using two-sample Mendelian randomisation, we identify causal associations between serum CD33 and Alzheimer's disease, GPNMB and Parkinson's disease, and MSR1 and schizophrenia, describing their clinical potential and highlighting drug repurposing opportunities. AU - Png, G. AU - Barysenska, A. AU - Repetto, L.* AU - Navarro, P.* AU - Shen, X.* AU - Pietzner, M.* AU - Wheeler, E.* AU - Wareham, N.J.* AU - Langenberg, C.* AU - Tsafantakis, E.* AU - Karaleftheri, M.* AU - Dedoussis, G.* AU - Mälarstig, A.* AU - Wilson, J.F.* AU - Gilly, A. AU - Zeggini, E. C1 - 63728 C2 - 51499 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Mapping the serum proteome to neurological diseases using whole genome sequencing. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Portfolio PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Hyperplastic expansion of white adipose tissue (WAT) relies in part on the proliferation of adipocyte precursor cells residing in the stromal vascular cell fraction (SVF) of WAT. This study reveals a circadian clock- and feeding-induced diurnal pattern of cell proliferation in the SVF of visceral and subcutaneous WAT in vivo, with higher proliferation of visceral adipocyte progenitor cells subsequent to feeding in lean mice. Fasting or loss of rhythmic feeding eliminates this diurnal proliferation, while high fat feeding or genetic disruption of the molecular circadian clock modifies the temporal expression of proliferation genes and impinges on diurnal SVF proliferation in eWAT. Surprisingly, high fat diet reversal, sufficient to reverse elevated SVF proliferation in eWAT, was insufficient in restoring diurnal patterns of SVF proliferation, suggesting that high fat diet induces a sustained disruption of the adipose circadian clock. In conclusion, the circadian clock and feeding simultaneously impart dynamic, regulatory control of adipocyte progenitor proliferation, which may be a critical determinant of adipose tissue expansion and health over time. AU - Ribas Latre, A. AU - Santos, R.B.* AU - Fekry, B.* AU - Tamim, Y.M.* AU - Shivshankar, S.* AU - Mohamed, A.M.T.* AU - Baumgartner, C.* AU - Kwok, C.* AU - Gebhardt, C. AU - Rivera, A.* AU - Gao, Z.* AU - Sun, K.* AU - Heiker, J.T. AU - Snyder, B.E.* AU - Kolonin, M.G.* AU - Eckel-Mahan, K.L.* C1 - 62251 C2 - 50717 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Cellular and physiological circadian mechanisms drive diurnal cell proliferation and expansion of white adipose tissue. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Research PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - The original version of this Article contained an error in Ref. 72, which was incorrectly given with the wrong author names as: Mendez-Ferrer, S., Lucas, D., Battista, M. & Frenette, P. S. Age-associated telomere attrition in adipocyte progenitors predisposes to metabolic disease. Nat. Metab. 2, 1482–1497 (2020). The correct form of Ref. 72 is: Gao, Z. et al. Age-associated telomere attrition in adipocyte progenitors predisposes to metabolic disease. Nat. Metab. 2, 1482–1497 (2020). This has been corrected in the PDF and HTML versions of the Article. AU - Ribas Latre, A. AU - Santos, R.B.* AU - Fekry, B.* AU - Tamim, Y.M.* AU - Shivshankar, S.* AU - Mohamed, A.M.T.* AU - Baumgartner, C.* AU - Kwok, C.* AU - Gebhardt, C. AU - Rivera, A.* AU - Gao, Z.* AU - Sun, K.* AU - Heiker, J.T. AU - Snyder, B.E.* AU - Kolonin, M.G.* AU - Eckel-Mahan, K.L.* C1 - 62654 C2 - 50927 TI - Publisher Correction: Cellular and physiological circadian mechanisms drive diurnal cell proliferation and expansion of white adipose tissue. JO - Nat. Commun. VL - 12 IS - 1 PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Single-cell RNA-seq reveals the role of pathogenic cell populations in development and progression of chronic diseases. In order to expand our knowledge on cellular heterogeneity, we have developed a single-nucleus RNA-seq2 method tailored for the comprehensive analysis of the nuclear transcriptome from frozen tissues, allowing the dissection of all cell types present in the liver, regardless of cell size or cellular fragility. We use this approach to characterize the transcriptional profile of individual hepatocytes with different levels of ploidy, and have discovered that ploidy states are associated with different metabolic potential, and gene expression in tetraploid mononucleated hepatocytes is conditioned by their position within the hepatic lobule. Our work reveals a remarkable crosstalk between gene dosage and spatial distribution of hepatocytes. AU - Richter, M. AU - Deligiannis, I.K. AU - Yin, K. AU - Danese, A. AU - Lleshi, E.* AU - Coupland, P.* AU - Vallejos, C.A.* AU - Matchett, K.P.* AU - Henderson, N.C.* AU - Colomé-Tatché, M. AU - Martinez Jimenez, C.P. C1 - 62588 C2 - 50827 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Single-nucleus RNA-seq2 reveals functional crosstalk between liver zonation and ploidy. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Research PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Mitochondria are the powerhouse of eukaryotic cells. They possess their own gene expression machineries where highly divergent and specialized ribosomes, named hereafter mitoribosomes, translate the few essential messenger RNAs still encoded by mitochondrial genomes. Here, we present a biochemical and structural characterization of the mitoribosome in the model green alga Chlamydomonas reinhardtii, as well as a functional study of some of its specific components. Single particle cryo-electron microscopy resolves how the Chlamydomonas mitoribosome is assembled from 13 rRNA fragments encoded by separate non-contiguous gene pieces. Additional proteins, mainly OPR, PPR and mTERF helical repeat proteins, are found in Chlamydomonas mitoribosome, revealing the structure of an OPR protein in complex with its RNA binding partner. Targeted amiRNA silencing indicates that these ribosomal proteins are required for mitoribosome integrity. Finally, we use cryo-electron tomography to show that Chlamydomonas mitoribosomes are attached to the inner mitochondrial membrane via two contact points mediated by Chlamydomonas-specific proteins. Our study expands our understanding of mitoribosome diversity and the various strategies these specialized molecular machines adopt for membrane tethering. AU - Salinas-Giegé, T.* AU - Englmeier, R.* AU - Meichel, H.* AU - Soufari, H.* AU - Kühn, L.* AU - Pfeffer, S.* AU - Förster, F.* AU - Engel, B.D. AU - Giegé, P.* AU - Drouard, L.* AU - Hashem, Y.* AU - Waltz, F. C1 - 63790 C2 - 51612 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - How to build a ribosome from RNA fragments in Chlamydomonas mitochondria. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Portfolio PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Chronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. To extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated glomerular filtration rate (n = 33,605) and urinary albumin-to-creatinine ratio (n = 15,068) and detected 69 and seven CpG sites where DNA methylation was associated with the respective trait. The majority of these findings showed directionally consistent associations with the respective clinical outcomes chronic kidney disease and moderately increased albuminuria. Associations of DNA methylation with kidney function, such as CpGs at JAZF1, PELI1 and CHD2 were validated in kidney tissue. Methylation at PHRF1, LDB2, CSRNP1 and IRF5 indicated causal effects on kidney function. Enrichment analyses revealed pathways related to hemostasis and blood cell migration for estimated glomerular filtration rate, and immune cell activation and response for urinary albumin-to-creatinineratio-associated CpGs. AU - Schlosser, P.* AU - Tin, A.* AU - Matias-Garcia, P.R. AU - Thio, C.H.L.* AU - Joehanes, R.* AU - Liu, H.* AU - Weihs, A.* AU - Yu, Z.* AU - Hoppmann, A.* AU - Grundner-Culemann, F.* AU - Min, J.L.* AU - Adeyemo, A.A.* AU - Agyemang, C.* AU - Ärnlöv, J.* AU - Aziz, N.A.* AU - Baccarelli, A.* AU - Bochud, M.* AU - Brenner, H.* AU - Breteler, M.M.B.* AU - Carmeli, C.* AU - Chaker, L.* AU - Chambers, J.C.* AU - Cole, S.A.* AU - Coresh, J.* AU - Corre, T.* AU - Correa, A.* AU - Cox, S.R.* AU - de Klein, N.* AU - Delgado, G.E.* AU - Domingo-Relloso, A.* AU - Eckardt, K.U.* AU - Ekici, A.B.* AU - Endlich, K.* AU - Evans, K.L.* AU - Floyd, J.S.* AU - Fornage, M.* AU - Franke, L.* AU - Fraszczyk, E.* AU - Gao, X.* AU - Ghanbari, M.* AU - Ghasemi, S.* AU - Gieger, C. AU - Greenland, P.* AU - Grove, M.L.* AU - Harris, S.E.* AU - Hemani, G.* AU - Henneman, P.* AU - Herder, C.* AU - Horvath, S.* AU - Hou, L.* AU - Hurme, M.A.* AU - Hwang, S.J.* AU - Jarvelin, M.R.* AU - Kardia, S.L.R.* AU - Kasela, S.* AU - Kleber, M.E.* AU - Koenig, W.* AU - Kooner, J.S.* AU - Kramer, H.* AU - Kronenberg, F.* AU - Kühnel, B. AU - Lehtimäki, T.* AU - Lind, L.* AU - Liu, D.* AU - Liu, Y.* AU - Lloyd-Jones, D.M.* AU - Lohman, K.* AU - Lorkowski, S.* AU - Lu, A.T.* AU - Marioni, R.E.* AU - März, W.* AU - McCartney, D.L.* AU - Meeks, K.A.C.* AU - Milani, L.* AU - Mishra, P.P.* AU - Nauck, M.* AU - Navas-Acien, A.* AU - Nowak, C.* AU - Peters, A. AU - Prokisch, H. AU - Psaty, B.M.* AU - Raitakari, O.T.* AU - Ratliff, S.M.* AU - Reiner, A.P.* AU - Rosas, S.E.* AU - Schöttker, B.* AU - Schwartz, J.* AU - Sedaghat, S.* AU - Smith, J.A.* AU - Sotoodehnia, N.* AU - Stocker, H.R.* AU - Stringhini, S.* AU - Sundström, J.* AU - Swenson, B.R.* AU - Tellez-Plaza, M.* AU - van Meurs, J.B.J.* AU - van Vliet-Ostaptchouk, J.V.* AU - Venema, A.* AU - Verweij, N.* AU - Walker, R.M.* AU - Wielscher, M.* AU - Winkelmann, J. AU - Wolffenbuttel, B.H.R.* AU - Zhao, W.* AU - Zheng, Y.* AU - Estonian Biobank Research Team* AU - Genetics of DNA Methylation Consortium* AU - Loh, M.* AU - Snieder, H.* AU - Levy, D.* AU - Waldenberger, M. AU - Susztak, K.* AU - Köttgen, A.* AU - Teumer, A.* C1 - 63789 C2 - 51716 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Meta-analyses identify DNA methylation associated with kidney function and damage. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Portfolio PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Single cell RNA-seq has revolutionized transcriptomics by providing cell type resolution for differential gene expression and expression quantitative trait loci (eQTL) analyses. However, efficient power analysis methods for single cell data and inter-individual comparisons are lacking. Here, we present scPower; a statistical framework for the design and power analysis of multi-sample single cell transcriptomic experiments. We modelled the relationship between sample size, the number of cells per individual, sequencing depth, and the power of detecting differentially expressed genes within cell types. We systematically evaluated these optimal parameter combinations for several single cell profiling platforms, and generated broad recommendations. In general, shallow sequencing of high numbers of cells leads to higher overall power than deep sequencing of fewer cells. The model, including priors, is implemented as an R package and is accessible as a web tool. scPower is a highly customizable tool that experimentalists can use to quickly compare a multitude of experimental designs and optimize for a limited budget. AU - Schmid, K. AU - Höllbacher, B. AU - Cruceanu, C.* AU - Böttcher, A. AU - Lickert, H. AU - Binder, E.B.* AU - Theis, F.J. AU - Heinig, M. C1 - 63558 C2 - 51442 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - scPower accelerates and optimizes the design of multi-sample single cell transcriptomic studies. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Portfolio PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - There is conflicting evidence on the influence of weather on COVID-19 transmission. Our aim is to estimate weather-dependent signatures in the early phase of the pandemic, while controlling for socio-economic factors and non-pharmaceutical interventions. We identify a modest non-linear association between mean temperature and the effective reproduction number (Re) in 409 cities in 26 countries, with a decrease of 0.087 (95% CI: 0.025; 0.148) for a 10 °C increase. Early interventions have a greater effect on Re with a decrease of 0.285 (95% CI 0.223; 0.347) for a 5th - 95th percentile increase in the government response index. The variation in the effective reproduction number explained by government interventions is 6 times greater than for mean temperature. We find little evidence of meteorological conditions having influenced the early stages of local epidemics and conclude that population behaviour and government interventions are more important drivers of transmission. AU - Sera, F.* AU - Armstrong, B.* AU - Abbott, S.* AU - Meakin, S.* AU - O’Reilly, K.* AU - von Borries, R.* AU - Schneider, R.* AU - Royé, D.* AU - Hashizume, M.* AU - Pascal, M.* AU - Tobias, A.* AU - Vicedo-Cabrera, A.M.* AU - MCC Collaborative Research Network (Dallavalle, M.) AU - MCC Collaborative Research Network (Schneider, A.E.) AU - Gasparrini, A.* AU - Lowe, R.* C1 - 63385 C2 - 51308 TI - A cross-sectional analysis of meteorological factors and SARS-CoV-2 transmission in 409 cities across 26 countries. JO - Nat. Commun. VL - 12 IS - 1 PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Metabolic diseases are associated with an increased risk of severe COVID-19 and conversely, new-onset hyperglycemia and complications of preexisting diabetes have been observed in COVID-19 patients. Here, we performed a comprehensive analysis of pancreatic autopsy tissue from COVID-19 patients using immunofluorescence, immunohistochemistry, RNA scope and electron microscopy and detected SARS-CoV-2 viral infiltration of beta-cells in all patients. Using SARS-CoV-2 pseudoviruses, we confirmed that isolated human islet cells are permissive to infection. In eleven COVID-19 patients, we examined the expression of ACE2, TMPRSS and other receptors and factors, such as DPP4, HMBG1 and NRP1, that might facilitate virus entry. Whereas 70% of the COVID-19 patients expressed ACE2 in the vasculature, only 30% displayed ACE2-expression in beta-cells. Even in the absence of manifest new-onset diabetes, necroptotic cell death, immune cell infiltration and SARS-CoV-2 viral infection of pancreatic beta-cells may contribute to varying degrees of metabolic dysregulation in patients with COVID-19. AU - Steenblock, C.* AU - Richter, S.* AU - Berger, I.* AU - Barovic, M. AU - Schmid, J.* AU - Schubert, U.* AU - Jarzebska, N.* AU - von Mässenhausen, A.* AU - Linkermann, A.* AU - Schürmann, A. AU - Pablik, J.* AU - Dienemann, T.* AU - Evert, K.* AU - Rodionov, R.N.* AU - Semenova, N.Y.* AU - Zinserling, V.A.* AU - Gainetdinov, R.R.* AU - Baretton, G.* AU - Lindemann, D.* AU - Solimena, M. AU - Ludwig, B. AU - Bornstein, S.R.* C1 - 62262 C2 - 50714 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Viral infiltration of pancreatic islets in patients with COVID-19. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Research PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Osteoarthritis causes pain and functional disability for over 500 million people worldwide. To develop disease-stratifying tools and modifying therapies, we need a better understanding of the molecular basis of the disease in relevant tissue and cell types. Here, we study primary cartilage and synovium from 115 patients with osteoarthritis to construct a deep molecular signature map of the disease. By integrating genetics with transcriptomics and proteomics, we discover molecular trait loci in each tissue type and omics level, identify likely effector genes for osteoarthritis-associated genetic signals and highlight high-value targets for drug development and repurposing. These findings provide insights into disease aetiopathology, and offer translational opportunities in response to the global clinical challenge of osteoarthritis. AU - Steinberg, J. AU - Southam, L. AU - Roumeliotis, T.I.* AU - Clark, M.J.* AU - Jayasuriya, R.L.* AU - Swift, D.* AU - Shah, K.M.* AU - Butterfield, N.C.* AU - Brooks, R.A.* AU - McCaskie, A.W.* AU - Bassett, J.H.D.* AU - Williams, G.R.* AU - Choudhary, J.S.* AU - Wilkinson, J.M.* AU - Zeggini, E. C1 - 61469 C2 - 50276 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - A molecular quantitative trait locus map for osteoarthritis. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Research PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Adipose tissue expansion, as seen in obesity, is often metabolically detrimental causing insulin resistance and the metabolic syndrome. However, white adipose tissue expansion at early ages is essential to establish a functional metabolism. To understand the differences between adolescent and adult adipose tissue expansion, we studied the cellular composition of the stromal vascular fraction of subcutaneous adipose tissue of two and eight weeks old mice using single cell RNA sequencing. We identified a subset of adolescent preadipocytes expressing the mature white adipocyte marker Asc-1 that showed a low ability to differentiate into beige adipocytes compared to Asc-1 negative cells in vitro. Loss of Asc-1 in subcutaneous preadipocytes resulted in spontaneous differentiation of beige adipocytes in vitro and in vivo. Mechanistically, this was mediated by a function of the amino acid transporter ASC-1 specifically in proliferating preadipocytes involving the intracellular accumulation of the ASC-1 cargo D-serine. AU - Suwandhi, L. AU - Altun, I. AU - Karlina, R. AU - Miok, V. AU - Wiedemann, T. AU - Fischer, D.S. AU - Walzthoeni, T. AU - Lindner, C. AU - Böttcher, A. AU - Heinzmann, S.S. AU - Israel, A. AU - Khalil, A. AU - Braun, A.* AU - Pramme-Steinwachs, I. AU - Burtscher, I. AU - Schmitt-Kopplin, P. AU - Heinig, M. AU - Elsner, M.* AU - Lickert, H. AU - Theis, F.J. AU - Ussar, S. C1 - 61550 C2 - 50339 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Asc-1 regulates white versus beige adipocyte fate in a subcutaneous stromal cell population. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Research PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Antibodies bind antigens via flexible loops called complementarity-determining regions (CDRs). These are usually 6-20 residues long. However, some bovine antibodies have ultra-long CDRs comprising more than 50 residues organized in a stalk and a disulfide-rich knob. The design features of this structural unit and its influence on antibody stability remained enigmatic. Here, we show that the stalk length is critical for the folding and stability of antibodies with an ultra-long CDR and that the disulfide bonds in the knob do not contribute to stability; they are important for organizing the antigen-binding knob structure. The bovine ultra-long CDR can be integrated into human antibody scaffolds. Furthermore, mini-domains from de novo design can be reformatted as ultra-long CDRs to create unique antibody-based proteins neutralizing SARS-CoV-2 and the Alpha variant of concern with high efficiency. Our findings reveal basic design principles of antibody structure and open new avenues for protein engineering. AU - Svilenov, H.L.* AU - Sacherl, J. AU - Protzer, U. AU - Zacharias, M.* AU - Buchner, J.* C1 - 63566 C2 - 51561 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Mechanistic principles of an ultra-long bovine CDR reveal strategies for antibody design. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Portfolio PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E-7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits. AU - Tin, A.* AU - Schlosser, P.* AU - Matias-Garcia, P.R. AU - Thio, C.H.L.* AU - Joehanes, R.* AU - Liu, H.* AU - Yu, Z.* AU - Weihs, A.* AU - Hoppmann, A.* AU - Grundner-Culemann, F.* AU - Min, J.L.* AU - Kuhns, V.L.H.* AU - Adeyemo, A.A.* AU - Agyemang, C.* AU - Ärnlöv, J.* AU - Aziz, N.A.* AU - Baccarelli, A.* AU - Bochud, M.* AU - Brenner, H.* AU - Bressler, J.* AU - Breteler, M.M.B.* AU - Carmeli, C.* AU - Chaker, L.* AU - Coresh, J.* AU - Corre, T.* AU - Correa, A.* AU - Cox, S.R.* AU - Delgado, G.E.* AU - Eckardt, K.U.* AU - Ekici, A.B.* AU - Endlich, K.* AU - Floyd, J.S.* AU - Fraszczyk, E.* AU - Gao, X.* AU - Gelber, A.C.* AU - Ghanbari, M.* AU - Ghasemi, S.* AU - Gieger, C. AU - Greenland, P.* AU - Grove, M.L.* AU - Harris, S.E.* AU - Hemani, G.* AU - Henneman, P.* AU - Herder, C.* AU - Horvath, S.* AU - Hou, L.* AU - Hurme, M.A.* AU - Hwang, S.J.* AU - Kardia, S.L.R.* AU - Kasela, S.* AU - Kleber, M.E.* AU - Koenig, W.* AU - Kooner, J.S.* AU - Kronenberg, F.* AU - Kühnel, B. AU - Ladd-Acosta, C.* AU - Lehtimäki, T.* AU - Lind, L.* AU - Liu, D.* AU - Lloyd-Jones, D.M.* AU - Lorkowski, S.* AU - Lu, A.T.* AU - Marioni, R.E.* AU - März, W.* AU - McCartney, D.L.* AU - Meeks, K.A.C.* AU - Milani, L.* AU - Mishra, P.P.* AU - Nauck, M.* AU - Nowak, C.* AU - Peters, A. AU - Prokisch, H. AU - Psaty, B.M.* AU - Raitakari, O.T.* AU - Ratliff, S.M.* AU - Reiner, A.P.* AU - Schöttker, B.* AU - Schwartz, J.* AU - Sedaghat, S.* AU - Smith, J.A.* AU - Sotoodehnia, N.* AU - Stocker, H.R.* AU - Stringhini, S.* AU - Sundström, J.* AU - Swenson, B.R.* AU - van Meurs, J.B.J.* AU - van Vliet-Ostaptchouk, J.V.* AU - Venema, A.* AU - Völker, U.* AU - Winkelmann, J. AU - Wolffenbuttel, B.H.R.* AU - Zhao, W.* AU - Zheng, Y.* AU - Estonian Biobank Research Team* AU - Genetics of DNA Methylation Consortium* AU - Loh, M.* AU - Snieder, H.* AU - Waldenberger, M. AU - Levy, D.* AU - Akilesh, S.* AU - Woodward, O.M.* AU - Susztak, K.* AU - Teumer, A.* AU - Köttgen, A.* C1 - 63791 C2 - 51715 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Portfolio PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Acute kidney injury (AKI) is morphologically characterized by a synchronized plasma membrane rupture of cells in a specific section of a nephron, referred to as acute tubular necrosis (ATN). Whereas the involvement of necroptosis is well characterized, genetic evidence supporting the contribution of ferroptosis is lacking. Here, we demonstrate that the loss of ferroptosis suppressor protein 1 (Fsp1) or the targeted manipulation of the active center of the selenoprotein glutathione peroxidase 4 (Gpx4cys/-) sensitize kidneys to tubular ferroptosis, resulting in a unique morphological pattern of tubular necrosis. Given the unmet medical need to clinically inhibit AKI, we generated a combined small molecule inhibitor (Nec-1f) that simultaneously targets receptor interacting protein kinase 1 (RIPK1) and ferroptosis in cell lines, in freshly isolated primary kidney tubules and in mouse models of cardiac transplantation and of AKI and improved survival in models of ischemia-reperfusion injury. Based on genetic and pharmacological evidence, we conclude that GPX4 dysfunction hypersensitizes mice to ATN during AKI. Additionally, we introduce Nec-1f, a solid inhibitor of RIPK1 and weak inhibitor of ferroptosis. AU - Tonnus, W.* AU - Meyer, C.* AU - Steinebach, C.* AU - Belavgeni, A.* AU - von Mässenhausen, A.* AU - Gonzalez, N.Z.* AU - Maremonti, F.* AU - Gembardt, F.* AU - Himmerkus, N.* AU - Latk, M.* AU - Locke, S.* AU - Marschner, J.A.* AU - Li, W.* AU - Short, S.C.* AU - Doll, S. AU - Ingold, I. AU - Proneth, B. AU - Daniel, C.* AU - Kabgani, N.* AU - Kramann, R.* AU - Motika, S.* AU - Hergenrother, P.J.* AU - Bornstein, S.R. AU - Hugo, C.* AU - Becker, J.U.* AU - Amann, K.* AU - Anders, H.J.* AU - Kreisel, D.* AU - Pratt, D.A.* AU - Gütschow, M.* AU - Conrad, M. AU - Linkermann, A.* C1 - 62656 C2 - 50990 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Dysfunction of the key ferroptosis-surveilling systems hypersensitizes mice to tubular necrosis during acute kidney injury. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Research PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - In the original version of this article the Figure Legends in the Supplementary Information were inadvertently omitted. The HTML of the article has been updated to include the correct version of the Supplementary Information. The original version of the article also incorrectly referenced Supplementary Figures 2D and Supplementary Figure 2E, which were cited as Figure 2D and Figure 2E. This has been corrected in both the PDF and HTML versions of the Article. AU - Volta, F. AU - Scerbo, M.J. AU - Seelig, A. AU - Wagner, R. AU - O'Brien, N. AU - Gerst, F. AU - Fritsche, A. AU - Häring, H.-U. AU - Zeigerer, A. AU - Ullrich, S. AU - Gerdes, J.M. C1 - 62762 C2 - 51050 TI - Author Correction: Glucose homeostasis is regulated by pancreatic β-cell cilia via endosomal EphA-processing. JO - Nat. Commun. VL - 12 IS - 1 PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - The largest terrestrial organic carbon pool, carbon in soils, is regulated by an intricate connection between plant carbon inputs, microbial activity, and the soil matrix. This is manifested by how microorganisms, the key players in transforming plant-derived carbon into soil organic carbon, are controlled by the physical arrangement of organic and inorganic soil particles. Here we conduct an incubation of isotopically labelled litter to study effects of soil structure on the fate of litter-derived organic matter. While microbial activity and fungal growth is enhanced in the coarser-textured soil, we show that occlusion of organic matter into aggregates and formation of organo-mineral associations occur concurrently on fresh litter surfaces regardless of soil structure. These two mechanisms-the two most prominent processes contributing to the persistence of organic matter-occur directly at plant-soil interfaces, where surfaces of litter constitute a nucleus in the build-up of soil carbon persistence. We extend the notion of plant litter, i.e., particulate organic matter, from solely an easily available and labile carbon substrate, to a functional component at which persistence of soil carbon is directly determined. AU - Witzgall, K.* AU - Vidal, A.* AU - Schubert, D.I.* AU - Höschen, C.* AU - Schweizer, S.A.* AU - Buegger, F. AU - Pouteau, V.* AU - Chenu, C.* AU - Mueller, C.W.* C1 - 62412 C2 - 50844 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Particulate organic matter as a functional soil component for persistent soil organic carbon. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Research PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - The hepatokine follistatin is elevated in patients with type 2 diabetes (T2D) and promotes hyperglycemia in mice. Here we explore the relationship of plasma follistatin levels with incident T2D and mechanisms involved. Adjusted hazard ratio (HR) per standard deviation (SD) increase in follistatin levels for T2D is 1.24 (CI: 1.04–1.47, p < 0.05) during 19-year follow-up (n = 4060, Sweden); and 1.31 (CI: 1.09–1.58, p < 0.01) during 4-year follow-up (n = 883, Finland). High circulating follistatin associates with adipose tissue insulin resistance and non-alcoholic fatty liver disease (n = 210, Germany). In human adipocytes, follistatin dose-dependently increases free fatty acid release. In genome-wide association study (GWAS), variation in the glucokinase regulatory protein gene (GCKR) associates with plasma follistatin levels (n = 4239, Sweden; n = 885, UK, Italy and Sweden) and GCKR regulates follistatin secretion in hepatocytes in vitro. Our findings suggest that GCKR regulates follistatin secretion and that elevated circulating follistatin associates with an increased risk of T2D by inducing adipose tissue insulin resistance. AU - Wu, C.* AU - Borné, Y.* AU - Gao, R.* AU - López Rodriguez, M.* AU - Roell, W.C.* AU - Wilson, J.M.* AU - Regmi, A.* AU - Luan, C.* AU - Aly, D.M.* AU - Peter, A. AU - Machann, J. AU - Staiger, H. AU - Fritsche, A. AU - Birkenfeld, A.L. AU - Tao, R.* AU - Wagner, R. AU - Canouil, M.* AU - Hong, M.G.* AU - Schwenk, J.M.* AU - Ahlqvist, E.* AU - Kaikkonen, M.U.* AU - Nilsson, P.* AU - Shore, A.C.* AU - Khan, F.* AU - Natali, A.* AU - Melander, O.* AU - Orho-Melander, M.* AU - Nilsson, J.* AU - Häring, H.-U. AU - Renström, E.* AU - Wollheim, C.B.* AU - Engström, G.* AU - Weng, J.* AU - Pearson, E.R.* AU - Franks, P.W.* AU - White, M.F.* AU - Duffin, K.L.* AU - Vaag, A.A.* AU - Laakso, M.* AU - Stefan, N. AU - Groop, L.* AU - De Marinis, Y.* C1 - 63526 C2 - 51438 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Elevated circulating follistatin associates with an increased risk of type 2 diabetes. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Portfolio PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Osteocytes are master regulators of the skeleton. We mapped the transcriptome of osteocytes from different skeletal sites, across age and sexes in mice to reveal genes and molecular programs that control this complex cellular-network. We define an osteocyte transcriptome signature of 1239 genes that distinguishes osteocytes from other cells. 77% have no previously known role in the skeleton and are enriched for genes regulating neuronal network formation, suggesting this programme is important in osteocyte communication. We evaluated 19 skeletal parameters in 733 knockout mouse lines and reveal 26 osteocyte transcriptome signature genes that control bone structure and function. We showed osteocyte transcriptome signature genes are enriched for human orthologs that cause monogenic skeletal disorders (P = 2.4 × 10-22) and are associated with the polygenic diseases osteoporosis (P = 1.8 × 10-13) and osteoarthritis (P = 1.6 × 10-7). Thus, we reveal the molecular landscape that regulates osteocyte network formation and function and establish the importance of osteocytes in human skeletal disease. AU - Youlten, S.E.* AU - Kemp, J.P.* AU - Logan, J.G.* AU - Ghirardello, E.J.* AU - Sergio, C.M.* AU - Dack, M.R.G.* AU - Guilfoyle, S.E.* AU - Leitch, V.D.* AU - Butterfield, N.C.* AU - Komla-Ebri, D.* AU - Chai, R.C.* AU - Corr, A.P.* AU - Smith, J.T.* AU - Mohanty, S.T.* AU - Morris, J.A.* AU - McDonald, M.M.* AU - Quinn, J.M.W.* AU - McGlade, A.R.* AU - Bartonicek, N.* AU - Jansson, M.* AU - Hatzikotoulas, K. AU - Irving, M.D.* AU - Beleza-Meireles, A.* AU - Rivadeneira, F.* AU - Duncan, E.* AU - Richards, J.B.* AU - Adams, D.J.* AU - Lelliott, C.J.* AU - Brink, R.* AU - Phan, T.G.* AU - Eisman, J.A.* AU - Evans, D.M* AU - Zeggini, E. AU - Baldock, P.A.* AU - Bassett, J.H.D.* AU - Williams, G.R.* AU - Croucher, P.I.* C1 - 61934 C2 - 50521 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Osteocyte transcriptome mapping identifies a molecular landscape controlling skeletal homeostasis and susceptibility to skeletal disease. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Research PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Blood circulating proteins are confounded readouts of the biological processes that occur in different tissues and organs. Many proteins have been linked to complex disorders and are also under substantial genetic control. Here, we investigate the associations between over 1000 blood circulating proteins and body mass index (BMI) in three studies including over 4600 participants. We show that BMI is associated with widespread changes in the plasma proteome. We observe 152 replicated protein associations with BMI. 24 proteins also associate with a genome-wide polygenic score (GPS) for BMI. These proteins are involved in lipid metabolism and inflammatory pathways impacting clinically relevant pathways of adiposity. Mendelian randomization suggests a bi-directional causal relationship of BMI with LEPR/LEP, IGFBP1, and WFIKKN2, a protein-to-BMI relationship for AGER, DPT, and CTSA, and a BMI-to-protein relationship for another 21 proteins. Combined with animal model and tissue-specific gene expression data, our findings suggest potential therapeutic targets further elucidating the role of these proteins in obesity associated pathologies. AU - Zaghlool, S.B.* AU - Sharma, S. AU - Molnar, M. AU - Matias-Garcia, P.R. AU - Elhadad, M.A. AU - Waldenberger, M. AU - Peters, A. AU - Rathmann, W.* AU - Graumann, J.* AU - Gieger, C. AU - Grallert, H. AU - Suhre, K.* C1 - 61478 C2 - 49906 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Revealing the role of the human blood plasma proteome in obesity using genetic drivers. JO - Nat. Commun. VL - 12 IS - 1 PB - Nature Research PY - 2021 SN - 2041-1723 ER - TY - JOUR AB - Sex and the APOE epsilon 4 genotype are important risk factors for late-onset Alzheimer's disease. In the current study, the authors investigate how sex and APOE epsilon 4 genotype modify the association between Alzheimer's disease biomarkers and metabolites in serum.Late-onset Alzheimer's disease (AD) can, in part, be considered a metabolic disease. Besides age, female sex and APOE epsilon 4 genotype represent strong risk factors for AD that also give rise to large metabolic differences. We systematically investigated group-specific metabolic alterations by conducting stratified association analyses of 139 serum metabolites in 1,517 individuals from the AD Neuroimaging Initiative with AD biomarkers. We observed substantial sex differences in effects of 15 metabolites with partially overlapping differences for APOE epsilon 4 status groups. Several group-specific metabolic alterations were not observed in unstratified analyses using sex and APOE epsilon 4 as covariates. Combined stratification revealed further subgroup-specific metabolic effects limited to APOE epsilon 4+ females. The observed metabolic alterations suggest that females experience greater impairment of mitochondrial energy production than males. Dissecting metabolic heterogeneity in AD pathogenesis can therefore enable grading the biomedical relevance for specific pathways within specific subgroups, guiding the way to personalized medicine. AU - Arnold, M. AU - Nho, K.* AU - Kueider-Paisley, A.* AU - Massaro, T.* AU - Huynh, K.* AU - Brauner, B. AU - MahmoudianDehkordi, S.* AU - Louie, G.* AU - Moseley, M.A.* AU - Thompson, K.* AU - St John-Williams, L.* AU - Tenenbaum, J.D.* AU - Blach, C.* AU - Chang, R.* AU - Brinton, R.D.* AU - Baillie, R.* AU - Han, X.* AU - Trojanowski, J.Q.* AU - Shaw, L.M.* AU - Martins, R.* AU - Weiner, M.W.* AU - Trushina, E.* AU - Toledo, J.B.* AU - Meikle, P.J.* AU - Bennett, D.A.* AU - Krumsiek, J.* AU - Doraiswamy, P.M.* AU - Saykin, A.J.* AU - Kaddurah-Daouk, R.* AU - Kastenmüller, G. C1 - 58506 C2 - 48369 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Sex and APOE ε4 genotype modify the Alzheimer’s disease serum metabolome. JO - Nat. Commun. VL - 11 IS - 1 PB - Nature Publishing Group PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - Correlation networks are frequently used to statistically extract biological interactions between omics markers. Network edge selection is typically based on the statistical significance of the correlation coefficients. This procedure, however, is not guaranteed to capture biological mechanisms. We here propose an alternative approach for network reconstruction: a cutoff selection algorithm that maximizes the overlap of the inferred network with available prior knowledge. We first evaluate the approach on IgG glycomics data, for which the biochemical pathway is known and well-characterized. Importantly, even in the case of incomplete or incorrect prior knowledge, the optimal network is close to the true optimum. We then demonstrate the generalizability of the approach with applications to untargeted metabolomics and transcriptomics data. For the transcriptomics case, we demonstrate that the optimized network is superior to statistical networks in systematically retrieving interactions that were not included in the biological reference used for optimization. AU - Benedetti, E. AU - Pučić-Baković, M.* AU - Keser, T.* AU - Gerstner, N. AU - Büyüközkan, M. AU - Štambuk, T.* AU - Selman, M.H.J.* AU - Rudan, I.* AU - Polašek, O.* AU - Hayward, C.* AU - Al-Amin, H.* AU - Suhre, K.* AU - Kastenmüller, G. AU - Lauc, G.* AU - Krumsiek, J. C1 - 60310 C2 - 49377 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - A strategy to incorporate prior knowledge into correlation network cutoff selection. JO - Nat. Commun. VL - 11 IS - 1 PB - Nature Research PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - Replication and transcription of genomic DNA requires partial disassembly of nucleosomes to allow progression of polymerases. This presents both an opportunity to remodel the underlying chromatin and a danger of losing epigenetic information. Centromeric transcription is required for stable incorporation of the centromere-specific histone dCENP-A in M/G1 phase, which depends on the eviction of previously deposited H3/H3.3-placeholder nucleosomes. Here we demonstrate that the histone chaperone and transcription elongation factor Spt6 spatially and temporarily coincides with centromeric transcription and prevents the loss of old CENP-A nucleosomes in both Drosophila and human cells. Spt6 binds directly to dCENP-A and dCENP-A mutants carrying phosphomimetic residues alleviate this association. Retention of phosphomimetic dCENP-A mutants is reduced relative to wildtype, while non-phosphorylatable dCENP-A retention is increased and accumulates at the centromere. We conclude that Spt6 acts as a conserved CENP-A maintenance factor that ensures long-term stability of epigenetic centromere identity during transcription-mediated chromatin remodeling. AU - Bobkov, G.O.M.* AU - Huang, A.* AU - van den Berg, S.J.W.* AU - Mitra, S.* AU - Anselm, E.* AU - Lazou, V.* AU - Schunter, S.* AU - Feederle, R. AU - Imhof, A.* AU - Lusser, A.* AU - Jansen, L.E.T.* AU - Heun, P.* C1 - 59393 C2 - 48794 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Spt6 is a maintenance factor for centromeric CENP-A. JO - Nat. Commun. VL - 11 IS - 1 PB - Nature Publishing Group PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - Immune checkpoint blockade (ICB)-based or natural cancer immune responses largely eliminate tumours. Yet, they require additional mechanisms to arrest those cancer cells that are not rejected. Cytokine-induced senescence (CIS) can stably arrest cancer cells, suggesting that interferon-dependent induction of senescence-inducing cell cycle regulators is needed to control those cancer cells that escape from killing. Here we report in two different cancers sensitive to T cell-mediated rejection, that deletion of the senescence-inducing cell cycle regulators p16(Ink4a)/p19(Arf) (Cdkn2a) or p21(Cip1) (Cdkn1a) in the tumour cells abrogates both the natural and the ICB-induced cancer immune control. Also in humans, melanoma metastases that progressed rapidly during ICB have losses of senescence-inducing genes and amplifications of senescence inhibitors. Metastatic cells also resist CIS. Such genetic and functional alterations are infrequent in metastatic melanomas regressing during ICB. Thus, activation of tumour-intrinsic, senescence-inducing cell cycle regulators is required to stably arrest cancer cells that escape from eradication. AU - Brenner, E.* AU - Schörg, B.F.* AU - Ahmetlic, F. AU - Wieder, T.* AU - Hilke, F.J.* AU - Simon, N.* AU - Schroeder, C.* AU - Demidov, G.* AU - Riedel, T.* AU - Fehrenbacher, B.* AU - Schaller, M.* AU - Forschner, A.* AU - Eigentler, T.* AU - Niessner, H.* AU - Sinnberg, T.* AU - Böhm, K.S.* AU - Hömberg, N. AU - Braumüller, H.* AU - Dauch, D.* AU - Zwirner, S.* AU - Zender, L.* AU - Sonanini, D.* AU - Geishauser, A. AU - Bauer, J.* AU - Eichner, M.* AU - Jarick, K.J.* AU - Beilhack, A.* AU - Biskup, S.* AU - Döcker, D.* AU - Schadendorf, D.* AU - Quintanilla-Martinez, L.* AU - Pichler, B.J.* AU - Kneilling, M.* AU - Mocikat, R. AU - Röcken, M.* C1 - 58578 C2 - 48416 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Cancer immune control needs senescence induction by interferon-dependent cell cycle regulator pathways in tumours. JO - Nat. Commun. VL - 11 IS - 1 PB - Nature Publishing Group PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery. AU - Cacheiro, P.* AU - Muñoz-Fuentes, V.* AU - Murray, S.A.* AU - Dickinson, M.E.* AU - Bucan, M.* AU - Nutter, L.M.J.* AU - Peterson, K.A.* AU - Haselimashhadi, H.* AU - Flenniken, A.M.* AU - Morgan, H.* AU - Westerberg, H.* AU - Konopka, T.* AU - Hsu, C.W.* AU - Christiansen, A.V.* AU - Lanza, D.G.* AU - Beaudet, A.L.* AU - Heaney, J.D.* AU - Fuchs, H. AU - Gailus-Durner, V. AU - Sorg, T.* AU - Prochazka, J.* AU - Novosadova, V.* AU - Lelliott, C.J.* AU - Wardle-Jones, H.* AU - Wells, S.* AU - Teboul, L.* AU - Cater, H.* AU - Stewart, M.* AU - Hough, T.* AU - Wurst, W. AU - Sedlacek, R.* AU - Adams, D.J.* AU - Seavitt, J.R.* AU - Tocchini-Valentini, G.* AU - Mammano, F.* AU - Braun, R.E.* AU - McKerlie, C.* AU - Herault, Y.* AU - Hrabě de Angelis, M. AU - Mallon, A.M.* AU - Lloyd, K.C.K.* AU - Brown, S.D.M.* AU - Parkinson, H.* AU - Meehan, T.F.* AU - Smedley, D.* AU - International Mouse Phenotyping Consortium (Marschall, S. AU - Lengger, C. AU - Maier, H. AU - Seisenberger, C. AU - Bürger, A. AU - Kühn, R. AU - Schick, J. AU - Hörlein, A. AU - Oritz, O. AU - Giesert, F. AU - Beig, J.) C1 - 58687 C2 - 48240 TI - Human and mouse essentiality screens as a resource for disease gene discovery. JO - Nat. Commun. VL - 11 IS - 1 PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - Membraneless organelles like stress granules are active liquid-liquid phase-separated droplets that are involved in many intracellular processes. Their active and dynamic behavior is often regulated by ATP-dependent reactions. However, how exactly membraneless organelles control their dynamic composition remains poorly understood. Herein, we present a model for membraneless organelles based on RNA-containing active coacervate droplets regulated by a fuel-driven reaction cycle. These droplets emerge when fuel is present, but decay without. Moreover, we find these droplets can transiently up-concentrate functional RNA which remains in its active folded state inside the droplets. Finally, we show that in their pathway towards decay, these droplets break apart in multiple droplet fragments. Emergence, decay, rapid exchange of building blocks, and functionality are all hallmarks of membrane-less organelles, and we believe that our work could be powerful as a model to study such organelles. AU - Donau, C.* AU - Späth, F.* AU - Sosson, M.* AU - Kriebisch, B.A.K.* AU - Schnitter, F.* AU - Tena-Solsona, M.* AU - Kang, H.-S. AU - Salibi, E.* AU - Sattler, M. AU - Mutschler, H.* AU - Boekhoven, J.* C1 - 60311 C2 - 49378 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Active coacervate droplets as a model for membraneless organelles and protocells. JO - Nat. Commun. VL - 11 IS - 1 PB - Nature Research PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - Regulation of cellular iron homeostasis is crucial as both iron excess and deficiency cause hematological and neurodegenerative diseases. Here we show that mice lacking iron-regulatory protein 2 (Irp2), a regulator of cellular iron homeostasis, develop diabetes. Irp2 post-transcriptionally regulates the iron-uptake protein transferrin receptor 1 (TfR1) and the iron-storage protein ferritin, and dysregulation of these proteins due to Irp2 loss causes functional iron deficiency in beta cells. This impairs Fe-S cluster biosynthesis, reducing the function of Cdkal1, an Fe-S cluster enzyme that catalyzes methylthiolation of t(6)A37 in tRNA(UUU)(Lys) to ms(2)t(6)A37. As a consequence, lysine codons in proinsulin are misread and proinsulin processing is impaired, reducing insulin content and secretion. Iron normalizes ms(2)t(6)A37 and proinsulin lysine incorporation, restoring insulin content and secretion in Irp2(-/-) beta cells. These studies reveal a previously unidentified link between insulin processing and cellular iron deficiency that may have relevance to type 2 diabetes in humans. AU - Ferreira dos Santos, M.C.* AU - Anderson, C.P.* AU - Neschen, S. AU - Zumbrennen-Bullough, K.B.* AU - Romney, S.J.* AU - Kahle-Stephan, M. AU - Rathkolb, B. AU - Gailus-Durner, V. AU - Fuchs, H. AU - Wolf, E.* AU - Rozman, J. AU - Hrabě de Angelis, M. AU - Cai, W.M.* AU - Rajan, M.* AU - Hu, J.* AU - Dedon, P.C.* AU - Leibold, E.A.* C1 - 57854 C2 - 48107 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification. JO - Nat. Commun. VL - 11 IS - 1 PB - Nature Publishing Group PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - Surgical adhesions are bands of scar tissues that abnormally conjoin organ surfaces. Adhesions are a major cause of post-operative and dialysis-related complications, yet their patho-mechanism remains elusive, and prevention agents in clinical trials have thus far failed to achieve efficacy. Here, we uncover the adhesion initiation mechanism by coating beads with human mesothelial cells that normally line organ surfaces, and viewing them under adhesion stimuli. We document expansive membrane protrusions from mesothelia that tether beads with massive accompanying adherence forces. Membrane protrusions precede matrix deposition, and can transmit adhesion stimuli to healthy surfaces. We identify cytoskeletal effectors and calcium signaling as molecular triggers that initiate surgical adhesions. A single, localized dose targeting these early germinal events completely prevented adhesions in a preclinical mouse model, and in human assays. Our findings classifies the adhesion pathology as originating from mesothelial membrane bridges and offer a radically new therapeutic approach to treat adhesions. AU - Fischer, A. AU - Koopmans, T. AU - Ramesh, P. AU - Christ, S. AU - Strunz, M. AU - Wannemacher, J. AU - Aichler, M. AU - Feuchtinger, A. AU - Walch, A.K. AU - Ansari, M. AU - Theis, F.J. AU - Schorpp, K.K. AU - Hadian, K. AU - Neumann, P.A.* AU - Schiller, H. B. AU - Rinkevich, Y. C1 - 59428 C2 - 48801 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Post-surgical adhesions are triggered by calcium-dependent membrane bridges between mesothelial surfaces. JO - Nat. Commun. VL - 11 IS - 1 PB - Nature Publishing Group PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - During beta -adrenergic stimulation of brown adipose tissue (BAT), p38 phosphorylates the activating transcription factor 2 (ATF2) which then translocates to the nucleus to activate the expression of Ucp1 and Pgc-1 alpha. The mechanisms underlying ATF2 target activation are unknown. Here we demonstrate that p62 (Sqstm1) binds to ATF2 to orchestrate activation of the Ucp1 enhancer and Pgc-1 alpha promoter. P62(Delta 69-251) mice show reduced expression of Ucp1 and Pgc-1 alpha with impaired ATF2 genomic binding. Modulation of Ucp1 and Pgc-1 alpha expression through p62 regulation of ATF2 signaling is demonstrated in vitro and in vivo in p62(Delta 69-251) mice, global p62(-/-) and Ucp1-Cre p62(flx/flx) mice. BAT dysfunction resulting from p62 deficiency is manifest after birth and obesity subsequently develops despite normal food intake, intestinal nutrient absorption and locomotor activity. In summary, our data identify p62 as a master regulator of BAT function in that it controls the Ucp1 pathway through regulation of ATF2 genomic binding. Beta-adrenergic stimulation of brown adipose tissue leads to thermogenesis via the activating transcription factor 2 (ATF2) mediated expression of the thermogenic genes Ucp1 and Pgc-1 alpha. Here, the authors show that the scaffold protein p62 regulates brown adipose tissue function through modifying ATF2 genomic binding and subsequent Ucp1 and Pgc-1 alpha induction. AU - Fischer, K. AU - Fenzl, A. AU - Liu, D.* AU - Dyar, K.A. AU - Kleinert, M. AU - Brielmeier, M. AU - Clemmensen, C. AU - Fedl, A. AU - Finan, B. AU - Gessner, A.* AU - Jastroch, M. AU - Huang, J.* AU - Keipert, S. AU - Klingenspor, M.* AU - Brüning, J.C.* AU - Kneilling, M.* AU - Maier, F.C.* AU - Othman, A.E.* AU - Pichler, B.J.* AU - Pramme-Steinwachs, I. AU - Sachs, S. AU - Scheideler, A. AU - Thaiss, W.M.* AU - Uhlenhaut, N.H. AU - Ussar, S. AU - Woods, S.C.* AU - Zorn, J.* AU - Stemmer, K. AU - Collins, S.* AU - Diaz-Meco, M.* AU - Moscat, J.* AU - Tschöp, M.H. AU - Müller, T.D. C1 - 59071 C2 - 48567 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - The scaffold protein p62 regulates adaptive thermogenesis through ATF2 nuclear target activation. JO - Nat. Commun. VL - 11 IS - 1 PB - Nature Publishing Group PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - T-cell bispecific antibodies (TCBs) crosslink tumor and T-cells to induce tumor cell killing. While TCBs are very potent, on-target off-tumor toxicity remains a challenge when selecting targets. Here, we describe a protease-activated anti-folate receptor 1 TCB (Prot-FOLR1-TCB) equipped with an anti-idiotypic anti-CD3 mask connected to the anti-CD3 Fab through a tumor protease-cleavable linker. The potency of this Prot-FOLR1-TCB is recovered following protease-cleavage of the linker releasing the anti-idiotypic anti-CD3 scFv. In vivo, the Prot-FOLR1-TCB mediates antitumor efficacy comparable to the parental FOLR1-TCB whereas a noncleavable control Prot-FOLR1-TCB is inactive. In contrast, killing of bronchial epithelial and renal cortical cells with low FOLR1 expression is prevented compared to the parental FOLR1-TCB. The findings are confirmed for mesothelin as alternative tumor antigen. Thus, masking the anti-CD3 Fab fragment with an anti-idiotypic mask and cleavage of the mask by tumor-specific proteases can be applied to enhance specificity and safety of TCBs. AU - Geiger, M.* AU - Stubenrauch, K.G.* AU - Sam, J.* AU - Richter, W.F.* AU - Jordan, G.* AU - Eckmann, J.* AU - Hage, C.* AU - Nicolini, V.* AU - Freimoser-Grundschober, A.* AU - Ritter, M.* AU - Lauer, M.E.* AU - Stahlberg, H.* AU - Ringler, P.* AU - Patel, J.* AU - Sullivan, E.* AU - Grau-Richards, S.* AU - Endres, S. AU - Kobold, S. AU - Umaña, P.* AU - Brünker, P.* AU - Klein, C.* C1 - 59499 C2 - 48884 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Protease-activation using anti-idiotypic masks enables tumor specificity of a folate receptor 1-T cell bispecific antibody. JO - Nat. Commun. VL - 11 IS - 1 PB - Nature Publishing Group PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - The human proteome is a crucial intermediate between complex diseases and their genetic and environmental components, and an important source of drug development targets and biomarkers. Here, we comprehensively assess the genetic architecture of 257 circulating protein biomarkers of cardiometabolic relevance through high-depth (22.5×) whole-genome sequencing (WGS) in 1328 individuals. We discover 131 independent sequence variant associations (P < 7.45 × 10-11) across the allele frequency spectrum, all of which replicate in an independent cohort (n = 1605, 18.4x WGS). We identify for the first time replicating evidence for rare-variant cis-acting protein quantitative trait loci for five genes, involving both coding and noncoding variation. We construct and validate polygenic scores that explain up to 45% of protein level variation. We find causal links between protein levels and disease risk, identifying high-value biomarkers and drug development targets. AU - Gilly, A. AU - Park, Y.C.* AU - Png, G. AU - Barysenska, A. AU - Fischer, I. AU - Bjørnland, T.* AU - Southam, L. AU - Suveges, D.* AU - Neumeyer, S. AU - Rayner, N.W. AU - Tsafantakis, E.* AU - Karaleftheri, M.* AU - Dedoussis, G.* AU - Zeggini, E. C1 - 60761 C2 - 49537 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Whole-genome sequencing analysis of the cardiometabolic proteome. JO - Nat. Commun. VL - 11 IS - 1 PB - Nature Research PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - Blood pressure (BP) was inconsistently associated with migraine and the mechanisms of BP-lowering medications in migraine prophylaxis are unknown. Leveraging large-scale summary statistics for migraine (Ncases/Ncontrols = 59,674/316,078) and BP (N = 757,601), we find positive genetic correlations of migraine with diastolic BP (DBP, rg = 0.11, P = 3.56 × 10−06) and systolic BP (SBP, rg = 0.06, P = 0.01), but not pulse pressure (PP, rg = −0.01, P = 0.75). Cross-trait meta-analysis reveals 14 shared loci (P ≤ 5 × 10−08), nine of which replicate (P < 0.05) in the UK Biobank. Five shared loci (ITGB5, SMG6, ADRA2B, ANKDD1B, and KIAA0040) are reinforced in gene-level analysis and highlight potential mechanisms involving vascular development, endothelial function and calcium homeostasis. Mendelian randomization reveals stronger instrumental estimates of DBP (OR [95% CI] = 1.20 [1.15–1.25]/10 mmHg; P = 5.57 × 10−25) on migraine than SBP (1.05 [1.03–1.07]/10 mmHg; P = 2.60 × 10−07) and a corresponding opposite effect for PP (0.92 [0.88–0.95]/10 mmHg; P = 3.65 × 10−07). These findings support a critical role of DBP in migraine susceptibility and shared biology underlying BP and migraine. AU - Guo, Y.* AU - Rist, P.M.* AU - Daghlas, I.* AU - Giulianini, F.* AU - Kurth, T.* AU - Chasman, D.I.* AU - International Headache Genetics Consortium (Meitinger, T.) C1 - 59633 C2 - 48938 TI - A genome-wide cross-phenotype meta-analysis of the association of blood pressure with migraine. JO - Nat. Commun. VL - 11 IS - 1 PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - Changes to lipid metabolism are tightly associated with the onset and pathology of Alzheimer’s disease (AD). Lipids are complex molecules comprising many isomeric and isobaric species, necessitating detailed analysis to enable interpretation of biological significance. Our expanded targeted lipidomics platform (569 species across 32 classes) allows for detailed lipid separation and characterisation. In this study we examined peripheral samples of two cohorts (AIBL, n = 1112 and ADNI, n = 800). We are able to identify concordant peripheral signatures associated with prevalent AD arising from lipid pathways including; ether lipids, sphingolipids (notably GM3 gangliosides) and lipid classes previously associated with cardiometabolic disease (phosphatidylethanolamine and triglycerides). We subsequently identified similar lipid signatures in both cohorts with future disease. Lastly, we developed multivariate lipid models that improved classification and prediction. Our results provide a holistic view between the lipidome and AD using a comprehensive approach, providing targets for further mechanistic investigation. AU - Huynh, K.* AU - Lim, W.L.F.* AU - Giles, C.* AU - Jayawardana, K.S.* AU - Salim, A.* AU - Mellett, N.A.* AU - Smith, A.A.T.* AU - Olshansky, G.* AU - Drew, B.G.* AU - Chatterjee, P.* AU - Martins, I.* AU - Laws, S.M.* AU - Bush, A.I.* AU - Rowe, C.C.* AU - Villemagne, V.L.* AU - Ames, D.* AU - Masters, C.L.* AU - Arnold, M. AU - Nho, K.* AU - Saykin, A.J.* AU - Baillie, R.* AU - Han, X.* AU - Kaddurah-Daouk, R.* AU - Meikle, P.J.* C1 - 60529 C2 - 49339 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Concordant peripheral lipidome signatures in two large clinical studies of Alzheimer’s disease. JO - Nat. Commun. VL - 11 IS - 1 PB - Nature Research PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - Interactions between U2AF homology motifs (UHMs) and U2AF ligand motifs (ULMs) play a crucial role in early spliceosome assembly in eukaryotic gene regulation. UHM-ULM interactions mediate heterodimerization of the constitutive splicing factors U2AF65 and U2AF35 and between other splicing factors that regulate spliceosome assembly at the 3′ splice site, where UHM domains of alternative splicing factors, such as SPF45 and PUF60, contribute to alternative splicing regulation. Here, we performed high-throughput screening using fluorescence polarization assays with hit validation by NMR and identified phenothiazines as general inhibitors of UHM-ULM interactions. NMR studies show that these compounds occupy the tryptophan binding pocket of UHM domains. Co-crystal structures of the inhibitors with the PUF60 UHM domain and medicinal chemistry provide structure-activity-relationships and reveal functional groups important for binding. These inhibitors inhibit early spliceosome assembly on pre-mRNA substrates in vitro. Our data show that spliceosome assembly can be inhibited by targeting UHM-ULM interactions by small molecules, thus extending the toolkit of splicing modulators for structural and biochemical studies of the spliceosome and splicing regulation. AU - Jagtap, P.K. AU - Kubelka, T. AU - Soni, K. AU - Will, C.L.* AU - Garg, D. AU - Sippel, C.* AU - Kapp, T.G.* AU - Potukuchi, H.K. AU - Schorpp, K.K. AU - Hadian, K. AU - Kessler, H.* AU - Lührmann, R.* AU - Hausch, F.* AU - Bach, T.* AU - Sattler, M. C1 - 60502 C2 - 49353 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Identification of phenothiazine derivatives as UHM-binding inhibitors of early spliceosome assembly. JO - Nat. Commun. VL - 11 IS - 1 PB - Nature Research PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - Butyrophilin-like (Btnl) genes are emerging as major epithelial determinants of tissueassociated gamma delta T cell compartments. Thus, the development of signature, murine TCR gamma delta(+) intraepithelial lymphocytes (IEL) in gut and skin depends on Btnl family members, Btnl1 and Skint1, respectively. In seeking mechanisms underlying these profound effects, we now show that normal gut and skin gamma delta IEL development additionally requires Btnl6 and Skint2, respectively, and furthermore that different Btnl heteromers can seemingly shape different intestinal gamma delta(+) IEL repertoires. This formal genetic evidence for the importance of Btnl heteromers also applied to the steady-state, since sustained Btnl expression is required to maintain the signature TCR.V gamma 7(+) IEL phenotype, including specific responsiveness to Btnl proteins. In sum, Btnl proteins are required to select and to maintain the phenotypes of tissue-protective gamma delta IEL compartments, with combinatorially diverse heteromers having differential impacts on different IEL subsets. AU - Jandke, A.* AU - Melandri, D.* AU - Monin, L.* AU - Ushakov, D.S.* AU - Laing, A.G.* AU - Vantourout, P.* AU - East, P.* AU - Nitta, T.* AU - Narita, T.* AU - Takayanagi, H.* AU - Feederle, R. AU - Hayday, A.* C1 - 59829 C2 - 49061 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Butyrophilin-like proteins display combinatorial diversity in selecting and maintaining signature intraepithelial γδ T cell compartments. JO - Nat. Commun. VL - 11 IS - 1 PB - Nature Publishing Group PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio=8.82, P=1.18x10(-15)) and replication (adjusted OR=2.93, P=2.22x10(-3)) that is more pronounced in females (adjusted OR=6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR=2.61, P=7.98x10(-22)) and replication datasets (adjusted OR=1.55, P=0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk. In lung cancer, relatively few germline mutations are known to impact risk. Here the authors looked at rare variants in 39,146 individuals and find novel germline mutations associated with risk, as well as implicating ATM and a new candidate gene for lung cancer risk. AU - Ji, X.* AU - Mukherjee, S.* AU - Landi, M.T.* AU - Bosse, Y.* AU - Joubert, P.* AU - Zhu, D.* AU - Gorlov, I.* AU - Xiao, X.* AU - Han, Y.* AU - Gorlova, O.* AU - Hung, R.J.* AU - Brhane, Y.* AU - Carreras-Torres, R.* AU - Christiani, D.C.* AU - Caporaso, N.* AU - Johansson, M.* AU - Liu, G.* AU - Bojesen, S.E.* AU - Le Marchand, L.* AU - Albanes, D.* AU - Bickeböller, H.* AU - Aldrich, M.C.* AU - Bush, W.S.* AU - Tardón, A.* AU - Rennert, G.* AU - Chen, C.* AU - Byun, J.* AU - Dragnev, K.H.* AU - Field, J.K.* AU - Kiemeney, L.F.* AU - Lazarus, P.* AU - Zienolddiny, S.* AU - Lam, S.* AU - Schabath, M.B.* AU - Andrew, A.S.* AU - Bertazzi, P.A.* AU - Pesatori, A.C.* AU - Diao, N.* AU - Su, L.* AU - Song, L.* AU - Zhang, R.* AU - Leighl, N.* AU - Johansen, J.S.* AU - Mellemgaard, A.* AU - Saliba, W.* AU - Haiman, C.* AU - Wilkens, L.* AU - Fernández-Somoano, A.* AU - Fernandez-Tardon, G.* AU - Heijden, E.H.F.M.v.d.* AU - Kim, J.H.* AU - Davies, M.P.A.* AU - Marcus, M.W.* AU - Brunnström, H.* AU - Manjer, J.* AU - Melander, O.* AU - Müller, D.C.* AU - Overvad, K.* AU - Trichopoulou, A.* AU - Tumino, R.* AU - Goodman, G.E.* AU - Cox, A.* AU - Taylor, F.* AU - Woll, P.* AU - Wichmann, H.-E. AU - Muley, T.* AU - Risch, A.* AU - Rosenberger, A.* AU - Grankvist, K.* AU - Shepherd, F.A.* AU - Tsao, M.S.* AU - Arnold, S.M.* AU - Haura, E.B.* AU - Bolca, C.* AU - Holcatova, I.* AU - Janout, V.* AU - Kontic, M.* AU - Lissowska, J.* AU - Mukeria, A.* AU - Ognjanovic, S.* AU - Orlowski, T.M.* AU - Scelo, G.* AU - Swiatkowska, B.* AU - Zaridze, D.* AU - Bakke, P.* AU - Skaug, V.* AU - Butler, L.M.* AU - Offit, K.* AU - Srinivasan, P.* AU - Bandlamudi, C.* AU - Hellmann, M.D.* AU - Solit, D.B.* AU - Robson, M.E.* AU - Rudin, C.M.* AU - Stadler, Z.K.* AU - Taylor, B.S.* AU - Berger, M.F.* AU - Houlston, R.* AU - McLaughlin, J.* C1 - 59142 C2 - 48718 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Protein-altering germline mutations implicate novel genes related to lung cancer development. JO - Nat. Commun. VL - 11 IS - 1 PB - Nature Publishing Group PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - Scars are more severe when the subcutaneous fascia beneath the dermis is injured upon surgical or traumatic wounding. Here, we present a detailed analysis of fascia cell mobilisation by using deep tissue intravital live imaging of acute surgical wounds, fibroblast lineage-specific transgenic mice, and skin-fascia explants (scar-like tissue in a dish – SCAD). We observe that injury triggers a swarming-like collective cell migration of fascia fibroblasts that progressively contracts the skin and form scars. Swarming is exclusive to fascia fibroblasts, and requires the upregulation of N-cadherin. Both swarming and N-cadherin expression are absent from fibroblasts in the upper skin layers and the oral mucosa, tissues that repair wounds with minimal scar. Impeding N-cadherin binding inhibits swarming and skin contraction, and leads to reduced scarring in SCADs and in animals. Fibroblast swarming and N-cadherin thus provide therapeutic avenues to curtail fascia mobilisation and pathological fibrotic responses across a range of medical settings. AU - Jiang, D. AU - Christ, S. AU - Correa-Gallegos, D. AU - Ramesh, P. AU - Kalgudde Gopal, S. AU - Wannemacher, J. AU - Mayr, C. AU - Lupperger, V. AU - Yu, Q. AU - Ye, H. AU - Mück-Häusl, M. AU - Rajendran, V. AU - Wan, L. AU - Liu, J. AU - Mirastschijski, U.* AU - Volz, T.* AU - Marr, C. AU - Schiller, H. B. AU - Rinkevich, Y. C1 - 60505 C2 - 49350 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Injury triggers fascia fibroblast collective cell migration to drive scar formation through N-cadherin. JO - Nat. Commun. VL - 11 IS - 1 PB - Nature Research PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - Brown adipose thermogenesis increases energy expenditure and relies on uncoupling protein 1 (UCP1), however, UCP1 knock-out mice show resistance to diet-induced obesity at room temperature. Here, the authors show that this resistance relies on FGF21-signaling, inducing the browning of white adipose tissue.Uncoupling protein 1 (UCP1) executes thermogenesis in brown adipose tissue, which is a major focus of human obesity research. Although the UCP1-knockout (UCP1 KO) mouse represents the most frequently applied animal model to judge the anti-obesity effects of UCP1, the assessment is confounded by unknown anti-obesity factors causing paradoxical obesity resistance below thermoneutral temperatures. Here we identify the enigmatic factor as endogenous FGF21, which is primarily mediating obesity resistance. The generation of UCP1/FGF21 double-knockout mice (dKO) fully reverses obesity resistance. Within mild differences in energy metabolism, urine metabolomics uncover increased secretion of acyl-carnitines in UCP1 KOs, suggesting metabolic reprogramming. Strikingly, transcriptomics of metabolically important organs reveal enhanced lipid and oxidative metabolism in specifically white adipose tissue that is fully reversed in dKO mice. Collectively, this study characterizes the effects of endogenous FGF21 that acts as master regulator to protect from diet-induced obesity in the absence of UCP1. AU - Keipert, S. AU - Lutter, D. AU - Schroeder, B.O.* AU - Brandt, D. AU - Ståhlman, M.* AU - Schwarzmayr, T. AU - Graf, E. AU - Fuchs, H. AU - Hrabě de Angelis, M. AU - Tschöp, M.H. AU - Rozman, J. AU - Jastroch, M. C1 - 57999 C2 - 48075 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Endogenous FGF21-signaling controls paradoxical obesity resistance of UCP1-deficient mice. JO - Nat. Commun. VL - 11 IS - 1 PB - Nature Publishing Group PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - Posttranslational modification (PTM) of proteins represents an important cellular mechanism for controlling diverse functions such as signalling, localisation or protein-protein interactions. AMPylation (also termed adenylylation) has recently been discovered as a prevalent PTM for regulating protein activity. In human cells AMPylation has been exclusively studied with the FICD protein. Here we investigate the role of AMPylation in human neurogenesis by introducing a cell-permeable propargyl adenosine pronucleotide probe to infiltrate cellular AMPylation pathways and report distinct modifications in intact cancer cell lines, human-derived stem cells, neural progenitor cells (NPCs), neurons and cerebral organoids (COs) via LC-MS/MS as well as imaging methods. A total of 162 AMP modified proteins were identified. FICD-dependent AMPylation remodelling accelerates differentiation of neural progenitor cells into mature neurons in COs, demonstrating a so far unknown trigger of human neurogenesis. AU - Kielkowski, P.* AU - Buchsbaum, I.Y.* AU - Kirsch, V.C.* AU - Bach, N.C.* AU - Drukker, M. AU - Cappello, S.* AU - Sieber, S.A.* C1 - 58740 C2 - 48272 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - FICD activity and AMPylation remodelling modulate human neurogenesis. JO - Nat. Commun. VL - 11 IS - 1 PB - Nature Publishing Group PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - Despite histone H2A variants and acetylation of histones occurring in almost every eukaryotic organism, it has been difficult to establish direct functional links between canonical histones or H2A variant acetylation, deposition of H2A variants and transcription. To disentangle these complex interdependent processes, we devised a highly sensitive strategy for quantifying histone acetylation levels at specific genomic loci. Taking advantage of the unusual genome organization in Trypanosoma brucei, we identified 58 histone modifications enriched at transcription start sites (TSSs). Furthermore, we found TSS-associated H4 and H2A.Z acetylation to be mediated by two different histone acetyltransferases, HAT2 and HAT1, respectively. Whereas depletion of HAT2 decreases H2A.Z deposition and shifts the site of transcription initiation, depletion of HAT1 does not affect H2A.Z deposition but reduces total mRNA levels by 50%. Thus, specifically reducing H4 or H2A.Z acetylation levels enabled us to reveal distinct roles for these modifications in H2A.Z deposition and RNA transcription. Histone modification and deposition are key regulators of transcription. Here, Kraus et al. provide a quantitative histone acetylome for Trypanosoma brucei, identify histone modifications enriched at transcription start sites, and show how H4 and H2A.Z acetylation affect histone deposition and transcription in trypanosomes. AU - Kraus, A.J. AU - Vanselow, J.T.* AU - Lamer, S.* AU - Brink, B.G.* AU - Schlosser, A.* AU - Siegel, T.N.* C1 - 61246 C2 - 49782 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Distinct roles for H4 and H2A.Z acetylation in RNA transcription in African trypanosomes. JO - Nat. Commun. VL - 11 IS - 1 PB - Nature Publishing Group PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - While antigen-primed T cells proliferate at speeds close to the physiologic maximum of mammalian cells, T cell memory is maintained in the absence of antigen by rare cell divisions. The transition between these distinct proliferative programs has been difficult to resolve via population-based analyses. Here, we computationally reconstruct the proliferative history of single CD8(+) T cells upon vaccination and measure the division speed of emerging T cell subsets in vivo. We find that slower cycling central memory precursors, characterized by an elongated G1 phase, segregate early from the bulk of rapidly dividing effector subsets, and further slow-down their cell cycle upon premature removal of antigenic stimuli. In contrast, curtailed availability of inflammatory stimuli selectively restrains effector T cell proliferation due to reduced receptivity for interleukin-2. In line with these findings, persistence of antigenic but not inflammatory stimuli throughout clonal expansion critically determines the later size of the memory compartment. AU - Kretschmer, L.* AU - Flossdorf, M.* AU - Mir, J.* AU - Cho, Y.-L.* AU - Plambeck, M.* AU - Treise, I. AU - Toska, A.* AU - Heinzel, S.* AU - Schiemann, M.* AU - Busch, D.H.* AU - Buchholz, V.R.* C1 - 57778 C2 - 48102 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Differential expansion of T central memory precursor and effector subsets is regulated by division speed. JO - Nat. Commun. VL - 11 IS - 1 PB - Nature Publishing Group PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - The formation and maintenance of subcellular structures and organelles with a well-defined size is a key requirement for cell function, yet our understanding of the underlying size control mechanisms is limited. While budding yeast cell polarization and subsequent assembly of a septin ring at the site of bud formation has been successfully used as a model for biological self-assembly processes, the mechanisms that set the size of the septin ring at the bud neck are unknown. Here, we use live-cell imaging and genetic manipulation of cell volume to show that the septin ring diameter increases with cell volume. This cell-volume-dependence largely accounts for modulations of ring size due to changes in ploidy and genetic manipulation of cell polarization. Our findings suggest that the ring diameter is set through the dynamic interplay of septin recruitment and Cdc42 polarization, establishing it as a model for size homeostasis of self-assembling organelles. Budding yeast cell polarization is known to self-assemble, but it is still not clear what controls the size of the resulting septin ring. Here the authors show that the septin ring diameter is set by cell volume, ensuring that larger cells have larger rings. AU - Kukhtevich, I. AU - Lohrberg, N. AU - Padovani, F. AU - Schneider, R. AU - Schmoller, K.M. C1 - 59355 C2 - 48755 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Cell size sets the diameter of the budding yeast contractile ring. JO - Nat. Commun. VL - 11 IS - 1 PB - Nature Publishing Group PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - Brain insulin action regulates eating behavior and energy fluxes throughout the body. However, numerous people are brain insulin resistant. How brain insulin responsiveness affects long-term weight and body fat composition in humans is still unknown. Here we show that high brain insulin sensitivity before lifestyle intervention associates with a more pronounced reduction in total and visceral fat during the program. High brain insulin sensitivity is also associated with less regain of fat mass during a nine year follow-up. Cross-sectionally, strong insulin responsiveness of the hypothalamus associates with less visceral fat, while subcutaneous fat is unrelated. Our results demonstrate that high brain insulin sensitivity is linked to weight loss during lifestyle intervention and associates with a favorable body fat distribution. Since visceral fat is strongly linked to diabetes, cardiovascular risk and cancer, these findings have implications beyond metabolic diseases and indicate the necessity of strategies to resolve brain insulin resistance. AU - Kullmann, S. AU - Valenta, V. AU - Wagner, R. AU - Tschritter, O.* AU - Machann, J. AU - Häring, H.-U. AU - Fritsche, A. AU - Heni, M. AU - Preissl, H. C1 - 58868 C2 - 48408 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Brain insulin sensitivity is linked to adiposity and body fat distribution. JO - Nat. Commun. VL - 11 IS - 1 PB - Nature Publishing Group PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - The heat shock protein 90 (Hsp90) is a molecular chaperone that employs the free energy of ATP hydrolysis to control the folding and activation of several client proteins in the eukaryotic cell. To elucidate how the local ATPase reaction in the active site couples to the global conformational dynamics of Hsp90, we integrate here large-scale molecular simulations with biophysical experiments. We show that the conformational switching of conserved ion pairs between the N-terminal domain, harbouring the active site, and the middle domain strongly modulates the catalytic barrier of the ATP-hydrolysis reaction by electrostatic forces. Our combined findings provide a mechanistic model for the coupling between catalysis and protein dynamics in Hsp90, and show how long-range coupling effects can modulate enzymatic activity. AU - Mader, S.L.* AU - Lopez, A. AU - Lawatscheck, J.* AU - Luo, Q.* AU - Rutz, D.A.* AU - Gamiz-Hernandez, A.P.* AU - Sattler, M. AU - Buchner, J.* AU - Kaila, V.R.I.* C1 - 58613 C2 - 48537 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Conformational dynamics modulate the catalytic activity of the molecular chaperone Hsp90. JO - Nat. Commun. VL - 11 IS - 1 PB - Nature Publishing Group PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - Gut microbial and metabolite alterations have been linked to the pathogenesis of inflammatory bowel diseases. Here we perform a multi-omics microbiome and metabolite analysis of a longitudinal cohort of Crohn’s disease patients undergoing autologous hematopoietic stem cell transplantation, and investigational therapy that induces drug free remission in a subset of patients. Via comparison of patients who responded and maintained remission, responded but experienced disease relapse and patients who did not respond to therapy, we identify shared functional signatures that correlate with disease activity despite the variability of gut microbiota profiles at taxonomic level. These signatures reflect the disease state when transferred to gnotobiotic mice. Taken together, the integration of microbiome and metabolite profiles from human cohort and mice improves the predictive modelling of disease outcome, and allows the identification of a network of bacteria-metabolite interactions involving sulfur metabolism as a key mechanism linked to disease activity in Crohn’s disease. AU - Metwaly, A.* AU - Dunkel, A.* AU - Waldschmitt, N.* AU - Durai Raj, A.C. AU - Lagkouvardos, I.* AU - Corraliza, A.M.* AU - Mayorgas, A.* AU - Martinez-Medina, M.* AU - Reiter, S.* AU - Schloter, M. AU - Hofmann, T.* AU - Allez, M.* AU - Panes, J.* AU - Salas, A.* AU - Haller, D.* C1 - 59997 C2 - 49159 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Integrated microbiota and metabolite profiles link Crohn’s disease to sulfur metabolism. JO - Nat. Commun. VL - 11 IS - 1 PB - Nature Research PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - Evasion of programmed cell death represents a critical form of oncogene addiction in cancer cells. Understanding the molecular mechanisms underpinning cancer cell survival despite the oncogenic stress could provide a molecular basis for potential therapeutic interventions. Here we explore the role of pro-survival genes in cancer cell integrity during clonal evolution in non-small cell lung cancer (NSCLC). We identify gains of MCL-1 at high frequency in multiple independent NSCLC cohorts, occurring both clonally and subclonally. Clonal loss of functional TP53 is significantly associated with subclonal gains of MCL-1. In mice, tumour progression is delayed upon pharmacologic or genetic inhibition of MCL-1. These findings reveal that MCL-1 gains occur with high frequency in lung adenocarcinoma and can be targeted therapeutically. AU - Munkhbaatar, E.* AU - Dietzen, M.* AU - Agarwal, D.* AU - Anton, M.* AU - Jesinghaus, M.* AU - Boxberg, M.* AU - Pfarr, N.* AU - Bidola, P.* AU - Uhrig, S.* AU - Höckendorf, U.* AU - Meinhardt, A.L.* AU - Wahida, A.* AU - Heid, I.* AU - Braren, R.* AU - Mishra, R.* AU - Warth, A.* AU - Muley, T.* AU - Poh, P.S.P.* AU - Wang, X.* AU - Fröhling, S.* AU - Steiger, K.* AU - Slotta-Huspenina, J.* AU - van Griensven, M.* AU - Pfeiffer, F.* AU - Lange, S.* AU - Rad, R.* AU - Spella, M.* AU - Stathopoulos, G.T. AU - Ruland, J.* AU - Bassermann, F.* AU - Weichert, W.* AU - Strasser, A.* AU - Branca, C.* AU - Heikenwalder, M.* AU - Swanton, C.* AU - McGranahan, N.* AU - Jost, P.J.* C1 - 60047 C2 - 49193 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - MCL-1 gains occur with high frequency in lung adenocarcinoma and can be targeted therapeutically. JO - Nat. Commun. VL - 11 IS - 1 PB - Nature Research PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - Interoceptive feedback transmitted via the vagus nerve plays a vital role in motivation by tuning actions according to physiological needs. Whereas vagus nerve stimulation (VNS) reinforces actions in animals, motivational effects elicited by VNS in humans are still largely elusive. Here, we applied non-invasive transcutaneous auricular VNS (taVNS) on the left or right ear while participants exerted effort to earn rewards using a randomized cross-over design (vs. sham). In line with preclinical studies, acute taVNS enhances invigoration of effort, and stimulation on the left side primarily facilitates invigoration for food rewards. In contrast, we do not find conclusive evidence that acute taVNS affects effort maintenance or wanting ratings. Collectively, our results suggest that taVNS enhances reward-seeking by boosting invigoration, not effort maintenance and that the stimulation side affects generalization beyond food reward. Thus, taVNS may enhance the pursuit of prospective rewards which may pave avenues to treat motivational deficiencies. The vagus nerve transmits signals between the gut and the brain thereby tuning motivated behavior to physiological needs. Here, the authors show that acute non-invasive stimulation of the vagus nerve via the ear enhances the invigoration of effort for rewards. AU - Neuser, M.P.* AU - Teckentrup, V.* AU - Kühnel, A.* AU - Hallschmid, M. AU - Walter, M.* AU - Kroemer, N.B.* C1 - 59696 C2 - 48928 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Vagus nerve stimulation boosts the drive to work for rewards. JO - Nat. Commun. VL - 11 IS - 1 PB - Nature Publishing Group PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N=293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci. AU - Ntalla, I.* AU - Weng, L.C.* AU - Cartwright, J.H.* AU - Hall, A.W.* AU - Sveinbjornsson, G.* AU - Tucker, N.R.* AU - Choi, S.H.* AU - Chaffin, M.D.* AU - Roselli, C.* AU - Barnes, M.R.* AU - Mifsud, B.* AU - Warren, H.R.* AU - Hayward, C.* AU - Marten, J.* AU - Cranley, J.J.* AU - Concas, M.P.* AU - Gasparini, P.* AU - Boutin, T.* AU - Kolcic, I.* AU - Polasek, O.* AU - Rudan, I.* AU - Araujo, N.M.* AU - Lima-Costa, M.F.* AU - Ribeiro, A.L.P.* AU - Souza, R.P.* AU - Tarazona-Santos, E.* AU - Giedraitis, V.* AU - Ingelsson, E.* AU - Mahajan, A.* AU - Morris, A.P.* AU - Del Greco M, F.* AU - Foco, L.* AU - Gögele, M.* AU - Hicks, A.A.* AU - Cook, J.P.* AU - Lind, L.* AU - Lindgren, C.M.* AU - Sundström, J.* AU - Nelson, C.P.* AU - Riaz, M.B.* AU - Samani, N.J.* AU - Sinagra, G.* AU - Ulivi, S.* AU - Kähönen, M.* AU - Mishra, P.P.* AU - Mononen, N.* AU - Nikus, K.* AU - Caulfield, M.J.* AU - Dominiczak, A.* AU - Padmanabhan, S.* AU - Montasser, M.E.* AU - O'Connell, J.R.* AU - Ryan, K.* AU - Shuldiner, A.R.* AU - Aeschbacher, S.* AU - Conen, D.* AU - Risch, L.* AU - Thériault, S.* AU - Hutri-Kähönen, N.* AU - Lehtimäki, T.* AU - Lyytikäinen, L.P.* AU - Raitakari, O.T.* AU - Barnes, C.L.K.* AU - Campbell, H.* AU - Joshi, P.K.* AU - Wilson, J.F.* AU - Isaacs, A.* AU - Kors, J.A.* AU - van Duijn, C.M.* AU - Huang, P.L.* AU - Gudnason, V.* AU - Harris, T.B.* AU - Launer, L.J.* AU - Smith, A.V.* AU - Bottinger, E.P.* AU - Loos, R.J.F.* AU - Nadkarni, G.N.* AU - Preuss, M.H.* AU - Correa, A.* AU - Mei, H.* AU - Wilson, J.* AU - Meitinger, T. AU - Müller-Nurasyid, M. AU - Peters, A. AU - Waldenberger, M. AU - Mangino, M.* AU - Spector, T.D.* AU - Rienstra, M.* AU - van de Vegte, Y.J.* AU - van der Harst, P.* AU - Verweij, N.* AU - Kääb, S.* AU - Schramm, K. AU - Sinner, M.F.* AU - Strauch, K. AU - Cutler, M.J.* AU - Fatkin, D.* AU - London, B.* AU - Olesen, M.* AU - Roden, D.M.* AU - Benjamin Shoemaker, M.* AU - Gustav Smith, J.* AU - Biggs, M.L.* AU - Bis, J.C.* AU - Brody, J.A.* AU - Psaty, B.M.* AU - Rice, K.* AU - Sotoodehnia, N.* AU - de Grandi, A.* AU - Fuchsberger, C.* AU - Pattaro, C.* AU - Pramstaller, P.P.* AU - Ford, I.* AU - Wouter Jukema, J.* AU - Macfarlane, P.W.* AU - Trompet, S.* AU - Dörr, M.* AU - Felix, S.B.* AU - Völker, U.* AU - Weiss, S.* AU - Havulinna, A.S.* AU - Jula, A.* AU - Sääksjärvi, K.* AU - Salomaa, V.* AU - Guo, X.* AU - Heckbert, S.R.* AU - Lin, H.J.* AU - Rotter, J.I.* AU - Taylor, K.D.* AU - Yao, J.* AU - de Mutsert, R.* AU - Maan, A.C.* AU - Mook-Kanamori, D.O.* AU - Noordam, R.* AU - Cucca, F.* AU - Ding, J.* AU - Lakatta, E.G.* AU - Qian, Y.* AU - Tarasov, K.V.* AU - Levy, D.* AU - Lin, H.* AU - Newton-Cheh, C.H.* AU - Lunetta, K.L.* AU - Murray, A.D.* AU - Porteous, D.J.* AU - Smith, B.H.* AU - Stricker, B.H.* AU - Uitterlinden, A.* AU - van den Berg, M.E.* AU - Haessler, J.* AU - Jackson, R.D.* AU - Kooperberg, C.* AU - Peters, U.* AU - Reiner, A.P.* AU - Whitsel, E.A.* AU - Alonso, A.* AU - Arking, D.E.* AU - Boerwinkle, E.* AU - Ehret, G.B.* AU - Soliman, E.Z.* AU - Avery, C.L.* AU - Gogarten, S.M.* AU - Kerr, K.F.* AU - Laurie, C.C.* AU - Seyerle, A.A.* AU - Stilp, A.* AU - Assa, S.* AU - Abdullah Said, M.* AU - Yldau van der Ende, M.* AU - Lambiase, P.D.* AU - Orini, M.* AU - Ramirez, J.* AU - Van Duijvenboden, S.* AU - Arnar, D.O.* AU - Gudbjartsson, D.F.* AU - Holm, H.* AU - Sulem, P.* AU - Thorleifsson, G.* AU - Thorolfsdottir, R.B.* AU - Thorsteinsdottir, U.* AU - Benjamin, E.J.* AU - Tinker, A.* AU - Stefansson, K.* AU - Ellinor, P.T.* AU - Jamshidi, Y.* AU - Lubitz, S.A.* AU - Munroe, P.B.* C1 - 59191 C2 - 48661 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction. JO - Nat. Commun. VL - 11 IS - 1 PB - Nature Publishing Group PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - Understanding the genetic architecture of host proteins interacting with SARS-CoV-2 or mediating the maladaptive host response to COVID-19 can help to identify new or repurpose existing drugs targeting those proteins. We present a genetic discovery study of 179 such host proteins among 10,708 individuals using an aptamer-based technique. We identify 220 host DNA sequence variants acting in cis (MAF 0.01-49.9%) and explaining 0.3-70.9% of the variance of 97 of these proteins, including 45 with no previously known protein quantitative trait loci (pQTL) and 38 encoding current drug targets. Systematic characterization of pQTLs across the phenome identified protein-drug-disease links and evidence that putative viral interaction partners such as MARK3 affect immune response. Our results accelerate the evaluation and prioritization of new drug development programmes and repurposing of trials to prevent, treat or reduce adverse outcomes. Rapid sharing and detailed interrogation of results is facilitated through an interactive webserver (https://omicscience.org/apps/covidpgwas/). AU - Pietzner, M.* AU - Wheeler, E.* AU - Carrasco-Zanini, J.* AU - Raffler, J. AU - Kerrison, N.D.* AU - Oerton, E.* AU - Auyeung, V.P.W.* AU - Luan, J.* AU - Finan, C.* AU - Casas, J.P.* AU - Ostroff, R.* AU - Williams, S.A.* AU - Kastenmüller, G. AU - Ralser, M.* AU - Gamazon, E.R.* AU - Wareham, N.J.* AU - Hingorani, A.D.* AU - Langenberg, C.* C1 - 60822 C2 - 49665 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Genetic architecture of host proteins involved in SARS-CoV-2 infection. JO - Nat. Commun. VL - 11 IS - 1 PB - Nature Research PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - Calcium (Ca2+) influx into mitochondria occurs through a Ca2+-selective uniporter channel, which regulates essential cellular processes in eukaryotic organisms. Previous evolutionary analyses of its pore-forming subunits MCU and EMRE, and gatekeeper MICU1, pinpointed an evolutionary paradox: the presence of MCU homologs in fungal species devoid of any other uniporter components and of mt-Ca2+ uptake. Here, we trace the mt-Ca2+ uniporter evolution across 1,156 fully-sequenced eukaryotes and show that animal and fungal MCUs represent two distinct paralogous subfamilies originating from an ancestral duplication. Accordingly, we find EMRE orthologs outside Holoza and uncover the existence of an animal-like uniporter within chytrid fungi, which enables mt-Ca2+ uptake when reconstituted in vivo in the yeast Saccharomyces cerevisiae. Our study represents the most comprehensive phylogenomic analysis of the mt-Ca2+ uptake system and demonstrates that MCU, EMRE, and MICU formed the core of the ancestral opisthokont uniporter, with major implications for comparative structural and functional studies. The mitochondrial calcium uptake system, crucial for cellular processes, evolved in ancient eukaryotes. Here, authors perform a phylogenomic analysis across 1,156 eukaryotes, and show that previously identified animal and fungal genes in this system originated from an ancestral duplication. AU - Pittis, A.A.* AU - Goh, V. AU - Cebrian Serrano, A. AU - Wettmarshausen, J. AU - Perocchi, F. AU - Gabaldón, T.* C1 - 59907 C2 - 49111 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England SP - 4031 TI - Discovery of EMRE in fungi resolves the true evolutionary history of the mitochondrial calcium uniporter. JO - Nat. Commun. VL - 11 IS - 1 PB - Nature Publishing Group PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - Grasses have varying inflorescence shapes; however, little is known about the genetic mechanisms specifying such shapes among tribes. Here, we identify the grass-specific TCP transcription factor COMPOSITUM 1 (COM1) expressing in inflorescence meristematic boundaries of different grasses. COM1 specifies branch-inhibition in barley (Triticeae) versus branch-formation in non-Triticeae grasses. Analyses of cell size, cell walls and transcripts reveal barley COM1 regulates cell growth, thereby affecting cell wall properties and signaling specifically in meristematic boundaries to establish identity of adjacent meristems. COM1 acts upstream of the boundary gene Liguleless1 and confers meristem identity partially independent of the COM2 pathway. Furthermore, COM1 is subject to purifying natural selection, thereby contributing to specification of the spike inflorescence shape. This meristem identity pathway has conceptual implications for both inflorescence evolution and molecular breeding in Triticeae. Grasses have diverse inflorescence morphologies, but the underlying genetic mechanisms are unclear. Here, the authors report a TCP transcription factor COM1 affects cell growth through regulation of cell wall properties and promotes branch formation in non-Triticeae grasses but branch inhibition in barley (Triticeae). AU - Poursarebani, N.* AU - Trautewig, C.* AU - Melzer, M.* AU - Nussbaumer, T. AU - Lundqvist, U.* AU - Rutten, T.* AU - Schmutzer, T.* AU - Brandt, R.* AU - Himmelbach, A.* AU - Altschmied, L.* AU - Koppolu, R.* AU - Youssef, H.M.* AU - Sibout, R.* AU - Dalmais, M.* AU - Bendahmane, A.* AU - Stein, N.* AU - Xin, Z.* AU - Schnurbusch, T.* C1 - 60320 C2 - 49383 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - COMPOSITUM 1 contributes to the architectural simplification of barley inflorescence via meristem identity signals. JO - Nat. Commun. VL - 11 IS - 1 PB - Nature Research PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - An amendment to this paper has been published and can be accessed via a link at the top of the paper. AU - Prorok, P.* AU - Artufel, M.* AU - Aze, A.* AU - Coulombe, P.* AU - Peiffer, I.* AU - Lacroix, L.* AU - Guédin, A.* AU - Mergny, J.L.* AU - Damaschke, J. AU - Schepers, A. AU - Cayrou, C.* AU - Teulade-Fichou, M.P.* AU - Ballester, B.* AU - Méchali, M.* C1 - 59356 C2 - 48759 TI - Author Correction: Involvement of G-quadruplex regions in mammalian replication origin activity (Nature Communications, (2019), 10, 1, (3274), 10.1038/s41467-019-11104-0). JO - Nat. Commun. VL - 11 IS - 1 PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - The culture of live pancreatic tissue slices is a powerful tool for the interrogation of physiology and pathology in an in vitro setting that retains near-intact cytoarchitecture. However, current culture conditions for human pancreatic slices (HPSs) have only been tested for short-term applications, which are not permissive for the long-term, longitudinal study of pancreatic endocrine regeneration. Using a culture system designed to mimic the physiological oxygenation of the pancreas, we demonstrate high viability and preserved endocrine and exocrine function in HPS for at least 10 days after sectioning. This extended lifespan allowed us to dynamically lineage trace and quantify the formation of insulin-producing cells in HPS from both non-diabetic and type 2 diabetic donors. This technology is expected to be of great impact for the conduct of real-time regeneration/developmental studies in the human pancreas. The ability to culture live pancreatic tissue slices for long periods of time would enable longitudinal studies ex vivo. Here the authors culture human and mouse pancreatic slices in a perfluorocarbon-based culture system and show stable endocrine and exocrine function for up to ten days in culture. AU - Qadir, M.M.F.* AU - Álvarez-Cubela, S.* AU - Weitz, J.* AU - Panzer, J.K.* AU - Klein, D.* AU - Moreno-Hernández, Y.* AU - Cechin, S.* AU - Tamayo, A.* AU - Almaça, J.* AU - Hiller, H.* AU - Beery, M.* AU - Kusmartseva, I.* AU - Atkinson, M.* AU - Speier, S. AU - Ricordi, C.* AU - Pugliese, A.* AU - Caicedo, A.* AU - Fraker, C.A.* AU - Pastori, R.L.* AU - Domínguez-Bendala, J.* C1 - 59540 C2 - 48900 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Long-term culture of human pancreatic slices as a model to study real-time islet regeneration. JO - Nat. Commun. VL - 11 IS - 1 PB - Nature Publishing Group PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - An amendment to this paper has been published and can be accessed via a link at the top of the paper. AU - Qadir, M.M.F.* AU - Álvarez-Cubela, S.* AU - Weitz, J.* AU - Panzer, J.K.* AU - Klein, D.* AU - Moreno-Hernández, Y.* AU - Cechin, S.* AU - Tamayo, A.* AU - Almaça, J.* AU - Hiller, H.* AU - Beery, M.* AU - Kusmartseva, I.* AU - Atkinson, M.* AU - Speier, S. AU - Ricordi, C.* AU - Pugliese, A.* AU - Caicedo, A.* AU - Fraker, C.A.* AU - Pastori, R.L.* AU - Domínguez-Bendala, J.* C1 - 59758 C2 - 48941 TI - Erratum: Publisher Correction: Long-term culture of human pancreatic slices as a model to study real-time islet regeneration (Nature communications (2020) 11 1 (3265)). JO - Nat. Commun. VL - 11 IS - 1 PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials. AU - Sargurupremraj, M.* AU - Suzuki, H.* AU - Jian, X.* AU - Sarnowski, C.* AU - Evans, T.E.* AU - Bis, J.C.* AU - Eiriksdottir, G.* AU - Sakaue, S.* AU - Terzikhan, N.* AU - Habes, M.* AU - Zhao, W.* AU - Armstrong, N.J.* AU - Hofer, E.* AU - Yanek, L.R.* AU - Hagenaars, S.P.* AU - Kumar, R.B.* AU - van den Akker, E.B.* AU - McWhirter, R.E.* AU - Trompet, S.* AU - Mishra, A.* AU - Saba, Y.* AU - Satizabal, C.L.* AU - Beaudet, G.* AU - Petit, L.* AU - Tsuchida, A.* AU - Zago, L.* AU - Schilling, S.* AU - Sigurdsson, S.* AU - Gottesman, R.F.* AU - Lewis, C.E.* AU - Aggarwal, N.T.* AU - Lopez, O.L.* AU - Smith, J.A.* AU - Valdés Hernández, M.C.* AU - van der Grond, J.* AU - Wright, M.J.* AU - Knol, M.J.* AU - Dörr, M.* AU - Thomson, R.J.* AU - Bordes, C.* AU - Le Grand, Q.* AU - Duperron, M.G.* AU - Smith, A.V.* AU - Knopman, D.S.* AU - Schreiner, P.J.* AU - Evans, D.A.* AU - Rotter, J.I.* AU - Beiser, A.S.* AU - Maniega, S.M.* AU - Beekman, M.* AU - Trollor, J.* AU - Stott, D.J.* AU - Vernooij, M.W.* AU - Wittfeld, K.* AU - Niessen, W.J.* AU - Soumaré, A.* AU - Boerwinkle, E.* AU - Sidney, S.* AU - Turner, S.T.* AU - Davies, G.* AU - Thalamuthu, A.* AU - Völker, U.* AU - van Buchem, M.A.* AU - Bryan, R.N.* AU - Dupuis, J.* AU - Bastin, M.E.* AU - Ames, D.* AU - Teumer, A.* AU - Amouyel, P.* AU - Kwok, J.B.* AU - Bülow, R.* AU - Deary, I.J.* AU - Schofield, P.R.* AU - Brodaty, H.* AU - Jiang, J.* AU - Tabara, Y.* AU - Setoh, K.* AU - Miyamoto, S.* AU - Yoshida, K.* AU - Nagata, M.* AU - Kamatani, Y.* AU - Matsuda, F.* AU - Psaty, B.M.* AU - Bennett, D.A.* AU - de Jager, P.L.* AU - Mosley, T.H.* AU - Sachdev, P.S.* AU - Schmidt, R.* AU - Warren, H.R.* AU - Evangelou, E.* AU - Trégouët, D.A.* AU - Ikram, M.A.* AU - Wen, W.* AU - Decarli, C.* AU - Srikanth, P.* AU - Jukema, J.W.* AU - Slagboom, E.* AU - Kardia, S.L.R.* AU - Okada, Y.* AU - Mazoyer, B.* AU - Wardlaw, J.M.* AU - Nyquist, P.A.* AU - Mather, K.A.* AU - Grabe, H.J.* AU - Schmidt, H.* AU - van Duijn, C.M.* AU - Gudnason, V.* AU - Longstreth Jr, W.T.* AU - Launer, L.J.* AU - Lathrop, M* AU - Seshadri, S* AU - Tzourio, C.* AU - Adams, H.H.* AU - Matthews, P.M.* AU - Fornage, M.* AU - Debette, S.* AU - International Headache Genomics Consortium (Meitinger, T.) C1 - 60749 C2 - 49546 TI - Cerebral small vessel disease genomics and its implications across the lifespan. JO - Nat. Commun. VL - 11 IS - 1 PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - Whole-body imaging of mice is a key source of information for research. Organ segmentation is a prerequisite for quantitative analysis but is a tedious and error-prone task if done manually. Here, we present a deep learning solution called AIMOS that automatically segments major organs (brain, lungs, heart, liver, kidneys, spleen, bladder, stomach, intestine) and the skeleton in less than a second, orders of magnitude faster than prior algorithms. AIMOS matches or exceeds the segmentation quality of state-of-the-art approaches and of human experts. We exemplify direct applicability for biomedical research for localizing cancer metastases. Furthermore, we show that expert annotations are subject to human error and bias. As a consequence, we show that at least two independently created annotations are needed to assess model performance. Importantly, AIMOS addresses the issue of human bias by identifying the regions where humans are most likely to disagree, and thereby localizes and quantifies this uncertainty for improved downstream analysis. In summary, AIMOS is a powerful open-source tool to increase scalability, reduce bias, and foster reproducibility in many areas of biomedical research. AU - Schoppe, O. AU - Pan, C. AU - Coronel, J.* AU - Mai, H. AU - Rong, Z. AU - Todorov, M.I. AU - Müskes, A.* AU - Navarro, F.* AU - Li, H.* AU - Ertürk, A. AU - Menze, B.H.* C1 - 60504 C2 - 49351 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Deep learning-enabled multi-organ segmentation in whole-body mouse scans. JO - Nat. Commun. VL - 11 IS - 1 PB - Nature Research PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - Optical microscopy improves in resolution and signal-to-noise ratio by correcting for the system's point spread function; a measure of how a point source is resolved, typically determined by imaging nanospheres. Optical-resolution optoacoustic (photoacoustic) microscopy could be similarly corrected, especially to account for the spatially-dependent signal distortions induced by the acoustic detection and the time-resolved and bi-polar nature of optoacoustic signals. Correction algorithms must therefore include the spatial dependence of signals' origins and profiles in time, i.e. the four-dimensional total impulse response (TIR). However, such corrections have been so far impeded by a lack of efficient TIR-characterization methods. We introduce high-quality TIR determination based on spatially-distributed optoacoustic point sources (SOAPs), produced by scanning an optical focus on an axially-translatable 250nm gold layer. Using a spatially-dependent TIR-correction improves the signal-to-noise ratio by >10dB and the axial resolution by similar to 30%. This accomplishment displays a new performance paradigm for optoacoustic microscopy. AU - Seeger, M. AU - Soliman, D. AU - Aguirre Bueno, J. AU - Diot, G. AU - Wierzbowski, J.* AU - Ntziachristos, V. C1 - 59337 C2 - 48747 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Pushing the boundaries of optoacoustic microscopy by total impulse response characterization. JO - Nat. Commun. VL - 11 IS - 1 PB - Nature Publishing Group PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - The cell type specific sequences of transcriptional programs during lung regeneration have remained elusive. Using time-series single cell RNA-seq of the bleomycin lung injury model, we resolved transcriptional dynamics for 28 cell types. Trajectory modeling together with lineage tracing revealed that airway and alveolar stem cells converge on a unique Krt8+transitional stem cell state during alveolar regeneration. These cells have squamous morphology, feature p53 and NFkB activation and display transcriptional features of cellular senescence. The Krt8+ state appears in several independent models of lung injury and persists in human lung fibrosis, creating a distinct cell-cell communication network with mesenchyme and macrophages during repair. We generated a model of gene regulatory programs leading to Krt8+transitional cells and their terminal differentiation to alveolar type-1 cells. We propose that in lung fibrosis, perturbed molecular checkpoints on the way to terminal differentiation can cause aberrant persistence of regenerative intermediate stem cell states. Injury repair is characterized by the generation of transient cell states important for tissue recovery. Here, the authors present a single cell RNA-seq map of recovery from bleomycin lung injury in mice and uncover a Krt8+ transitional stem cell state that precedes the regeneration of AT1 cells and persists in human lung fibrosis. AU - Strunz, M. AU - Simon, L. AU - Ansari, M. AU - Kathiriya, J.J.* AU - Angelidis, I. AU - Mayr, C. AU - Tsidiridis, G. AU - Lange, M. AU - Mattner, L. AU - Yee, M.* AU - Ogar, P. AU - Sengupta, A. AU - Kukhtevich, I. AU - Schneider, R. AU - Zhao, Z.* AU - Voss, C. AU - Stöger, T. AU - Neumann, J.H.L.* AU - Hilgendorff, A. AU - Behr, J. AU - O'Reilly, M.* AU - Lehmann, M. AU - Burgstaller, G. AU - Königshoff, M. AU - Chapman, H.A.* AU - Theis, F.J. AU - Schiller, H. B. C1 - 59695 C2 - 49014 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Alveolar regeneration through a Krt8+transitional stem cell state that persists in human lung fibrosis. JO - Nat. Commun. VL - 11 IS - 1 PB - Nature Publishing Group PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - We investigated the effect of different training scenarios on predicting the (retro)synthesis of chemical compounds using text-like representation of chemical reactions (SMILES) and Natural Language Processing (NLP) neural network Transformer architecture. We showed that data augmentation, which is a powerful method used in image processing, eliminated the effect of data memorization by neural networks and improved their performance for prediction of new sequences. This effect was observed when augmentation was used simultaneously for input and the target data simultaneously. The top-5 accuracy was 84.8% for the prediction of the largest fragment (thus identifying principal transformation for classical retro-synthesis) for the USPTO-50k test dataset, and was achieved by a combination of SMILES augmentation and a beam search algorithm. The same approach provided significantly better results for the prediction of direct reactions from the single-step USPTO-MIT test set. Our model achieved 90.6% top-1 and 96.1% top-5 accuracy for its challenging mixed set and 97% top-5 accuracy for the USPTO-MIT separated set. It also significantly improved results for USPTO-full set single-step retrosynthesis for both top-1 and top-10 accuracies. The appearance frequency of the most abundantly generated SMILES was well correlated with the prediction outcome and can be used as a measure of the quality of reaction prediction. AU - Tetko, I.V. AU - Karpov, P. AU - Van Deursen, R.* AU - Godin, G.* C1 - 60486 C2 - 49478 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - State-of-the-art augmented NLP transformer models for direct and single-step retrosynthesis. JO - Nat. Commun. VL - 11 IS - 1 PB - Nature Research PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - I kappa B kinase 2 (IKK2) is well known for its pivotal role as a mediator of the canonical NF-kappa B pathway, which has important functions in inflammation and immunity, but also in cancer. Here we identify a novel and critical function of IKK2 and its co-factor NEMO in the activation of oncogenic c-Jun N-terminal kinase (JNK) signaling, induced by the latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV). Independent of its kinase activity, the TGF beta -activated kinase 1 (TAK1) mediates LMP1 signaling complex formation, NEMO ubiquitination and subsequent IKK2 activation. The tumor progression locus 2 (TPL2) kinase is induced by LMP1 via IKK2 and transmits JNK activation signals downstream of IKK2. The IKK2-TPL2-JNK axis is specific for LMP1 and differs from TNF alpha, Interleukin-1 and CD40 signaling. This pathway mediates essential LMP1 survival signals in EBV-transformed human B cells and post-transplant lymphoma, and thus qualifies as a target for treatment of EBV-induced cancer. IKK2 is the main mediator of the NF-kappaB pathway. Here, the authors demonstrate that LMP1 sustains the survival of Epstein-Barr virus-transformed human B cells and post-transplant lymphoma through IKK2 that induces JNK signaling through TPL2. AU - Voigt, S. AU - Sterz, K. AU - Giehler, F. AU - Mohr, A.-W. AU - Wilson, J.B.* AU - Moosmann, A. AU - Kieser, A. C1 - 58791 C2 - 48327 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - A central role of IKK2 and TPL2 in JNK activation and viral B-cell transformation. JO - Nat. Commun. VL - 11 IS - 1 PB - Nature Publishing Group PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - DNA methylation and blood circulating proteins have been associated with many complex disorders, but the underlying disease-causing mechanisms often remain unclear. Here, we report an epigenome-wide association study of 1123 proteins from 944 participants of the KORA population study and replication in a multi-ethnic cohort of 344 individuals. We identify 98 CpG-protein associations (pQTMs) at a stringent Bonferroni level of significance. Overlapping associations with transcriptomics, metabolomics, and clinical endpoints suggest implication of processes related to chronic low-grade inflammation, including a network involving methylation of NLRC5, a regulator of the inflammasome, and associated pQTMs implicating key proteins of the immune system, such as CD48, CD163, CXCL10, CXCL11, LAG3, FCGR3B, and B2M. Our study links DNA methylation to disease endpoints via intermediate proteomics phenotypes and identifies correlative networks that may eventually be targeted in a personalized approach of chronic low-grade inflammation. AU - Zaghlool, S.B.* AU - Kühnel, B. AU - Elhadad, M.A. AU - Kader, S.* AU - Halama, A.* AU - Thareja, G.* AU - Engelke, R.* AU - Sarwath, H.* AU - Al-Dous, E.K.* AU - Mohamoud, Y.A.* AU - Meitinger, T. AU - Wilson, R. AU - Strauch, K. AU - Peters, A. AU - Mook-Kanamori, D.O.* AU - Graumann, J.* AU - Malek, J.A.* AU - Gieger, C. AU - Waldenberger, M. AU - Suhre, K.* C1 - 57760 C2 - 48086 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Epigenetics meets proteomics in an epigenome-wide association study with circulating blood plasma protein traits. JO - Nat. Commun. VL - 11 IS - 1 PB - Nature Publishing Group PY - 2020 SN - 2041-1723 ER - TY - JOUR AB - Aging promotes lung function decline and susceptibility to chronic lung diseases, which are the third leading cause of death worldwide. Here, we use single cell transcriptomics and mass spectrometry-based proteomics to quantify changes in cellular activity states across 30 cell types and chart the lung proteome of young and old mice. We show that aging leads to increased transcriptional noise, indicating deregulated epigenetic control. We observe cell type-specific effects of aging, uncovering increased cholesterol biosynthesis in type-2 pneumocytes and lipofibroblasts and altered relative frequency of airway epithelial cells as hallmarks of lung aging. Proteomic profiling reveals extracellular matrix remodeling in old mice, including increased collagen IV and XVI and decreased Fraser syndrome complex proteins and collagen XIV. Computational integration of the aging proteome with the single cell transcriptomes predicts the cellular source of regulated proteins and creates an unbiased reference map of the aging lung. AU - Angelidis, I. AU - Simon, L. AU - Fernandez, I.E. AU - Strunz, M. AU - Mayr, C. AU - Greiffo, F.R. AU - Tsitsiridis, G. AU - Ansari, M. AU - Graf, E. AU - Strom, T.M. AU - Nagendran, M.* AU - Desai, T.* AU - Eickelberg, O.* AU - Mann, M.* AU - Theis, F.J. AU - Schiller, H. B. C1 - 55599 C2 - 46376 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - An atlas of the aging lung mapped by single cell transcriptomics and deep tissue proteomics. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - Master transcription factors have the ability to direct and reverse cellular identities, and consequently their genes must be subject to particular transcriptional control. However, it is unclear which molecular processes are responsible for impeding their activation and safeguarding cellular identities. Here we show that the targeting of dCas9-VP64 to the promoter of the master transcription factor Sox1 results in strong transcript and protein up-regulation in neural progenitor cells (NPCs). This gene activation restores lost neuronal differentiation potential, which substantiates the role of Sox1 as a master transcription factor. However, despite efficient transactivator binding, major proportions of progenitor cells are unresponsive to the transactivating stimulus. By combining the transactivation domain with epigenome editing we find that among a series of euchromatic processes, the removal of DNA methylation (by dCas9-Tet1) has the highest potential to increase the proportion of cells activating foreign master transcription factors and thus breaking down cell identity barriers. AU - Baumann, V.* AU - Wiesbeck, M.* AU - Breunig, C.T.* AU - Braun, J.M.* AU - Köferle, A.* AU - Ninkovic, J. AU - Götz, M. AU - Stricker, S.H. C1 - 56030 C2 - 46788 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Targeted removal of epigenetic barriers during transcriptional reprogramming. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - The original version of this Article contained an error in the spelling of the author Laurence Faivre, which was incorrectly given as Laurence Faive. This has now been corrected in both the PDF and HTML versions of the Article. AU - Blok, L.S.* AU - Rousseau, J.* AU - Twist, J.* AU - Ehresmann, S.* AU - Takaku, M.* AU - Venselaar, H.* AU - Rodan, L.H.* AU - Nowak, C.B.* AU - Douglas, J.* AU - Swoboda, K.J.* AU - Steeves, M.A.* AU - Sahai, I.* AU - Stumpel, C.T.R.M.* AU - Stegmann, A.P.A.* AU - Wheeler, P.* AU - Willing, M.* AU - Fiala, E.* AU - Kochhar, A.* AU - Gibson, W.T.* AU - Cohen, A.S.A.* AU - Agbahovbe, R.* AU - Innes, A.M.* AU - Au, P.Y.B.* AU - Rankin, J.* AU - Anderson, I.J.* AU - Skinner, S.A.* AU - Louie, R.J.* AU - Warren, H.E.* AU - Afenjar, A.* AU - Keren, B.* AU - Nava, C.* AU - Buratti, J.* AU - Isapof, A.* AU - Rodriguez, D.* AU - Lewandowski, R.* AU - Propst, J.* AU - van Essen, T.* AU - Choi, M.* AU - Lee, S.* AU - Chae, J.H.* AU - Price, S.* AU - Schnur, R.E.* AU - Douglas, G.* AU - Wentzensen, I.M.* AU - Zweier, C.* AU - Reis, A.* AU - Bialer, M.G.* AU - Moore, C.* AU - Koopmans, M.* AU - Brilstra, E.H.* AU - Monroe, G.R.* AU - van Gassen, K.L.I.* AU - van Binsbergen, E.* AU - Newbury-Ecob, R.* AU - Bownass, L.* AU - Bader, I.* AU - Mayr, J.A.* AU - Wortmann, S.B. AU - Jakielski, K.J.* AU - Strand, E.A.* AU - Kloth, K.* AU - Bierhals, T.* AU - Roberts, J.D.* AU - Petrovich, R.M.* AU - Machida, S.* AU - Kurumizaka, H.* AU - Lelieveld, S.* AU - Pfundt, R.* AU - Jansen, S.* AU - Deriziotis, P.* AU - Faivre, L.* AU - Thevenon, J.* AU - Assoum, M.* AU - Shriberg, L.* AU - Kleefstra, T.* AU - Brunner, H.G.* AU - Wade, P.A.* AU - Fisher, S.E.* AU - Campeau, P.M.* C1 - 55555 C2 - 46224 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language (vol 9, 4619, 2018). JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - In Drosophila, a complex consisting of Calypso and ASX catalyzes H2A deubiquitination and has been reported to act as part of the Polycomb machinery in transcriptional silencing. The mammalian homologs of these proteins (BAP1 and ASXL1/2/3, respectively), are frequently mutated in various cancer types, yet their precise functions remain unclear. Using an integrative approach based on isogenic cell lines generated with CRISPR/Cas9, we uncover an unanticipated role for BAP1 in gene activation. This function requires the assembly of an enzymatically active BAP1-associated core complex (BAP1. com) containing one of the redundant ASXL proteins. We investigate the mechanism underlying BAP1. com-mediated transcriptional regulation and show that it does not participate in Polycomb-mediated silencing. Instead, our results establish that the function of BAP1. com is to safeguard transcriptionally active genes against silencing by the Polycomb Repressive Complex 1. AU - Campagne, A.* AU - Lee, M.K.* AU - Zielinski, D.* AU - Michaud, A.* AU - Le Corre, S.* AU - Dingli, F.* AU - Chen, H.* AU - Shahidian, L.Z. AU - Vassilev, I.* AU - Servant, N.* AU - Loew, D.* AU - Pasmant, E.* AU - Postel-Vinay, S.* AU - Wassef, M.* AU - Margueron, R.* C1 - 55301 C2 - 46277 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - BAP1 complex promotes transcription by opposing PRC1-mediated H2A ubiquitylation. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - Polyubiquitination promotes proteasomal degradation, or signaling and localization, of targeted proteins. Here we show that the E3 ubiquitin ligase Hectd3 is necessary for pathogenic Th17 cell generation in experimental autoimmune encephalomyelitis (EAE), a mouse model for human multiple sclerosis. Hectd3-deficient mice have lower EAE severity, reduced Th17 program and inefficient Th17 cell differentiation. However, Stat3, but not ROR gamma t, has decreased polyubiquitination, as well as diminished tyrosine-705 activating phosphorylation. Additionally, non-degradative polyubiquitination of Malt1, critical for NF-kappa B activation and Th17 cell function, is reduced. Mechanistically, Hectd3 promotes K27-linked and K29-linked polyubiquitin chains on Malt1, and K27-linked polyubiquitin chains on Stat3. Moreover, Stat3 K180 and Malt1 K648 are targeted by Hectd3 for non-degradative polyubiquitination to mediate robust generation of ROR gamma t+ IL-17A(hi) effector CD4(+) T cells. Thus, our studies delineate a mechanism connecting signaling related polyubiquitination of Malt1 and Stat3, leading to NF-kB activation and ROR gamma t expression, to pathogenic Th17 cell function in EAE. AU - Cho, J.J.* AU - Xu, Z.* AU - Parthasarathy, U.* AU - Drashansky, T.T.* AU - Helm, E.Y.* AU - Zuniga, A.N.* AU - Lorentsen, K.J.* AU - Mansouri, S.* AU - Cho, J.Y.* AU - Edelmann, M.J.* AU - Duong, D.M.* AU - Gehring, T. AU - Seeholzer, T. AU - Krappmann, D. AU - Uddin, M.N.* AU - Califano, D.* AU - Wang, R.L.* AU - Jin, L.* AU - Li, H.* AU - Lv, D.* AU - Zhou, D.* AU - Zhou, L.* AU - Avram, D.* C1 - 55484 C2 - 46360 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Hectd3 promotes pathogenic Th17 lineage through Stat3 activation and Malt1 signaling in neuroinflammation. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F-ROH) for >1.4 million individuals, we show that F-ROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F-ROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F-ROH are confirmed within full-sibling pairs, where the variation in F-ROH is independent of all environmental confounding. AU - Clark, D.W.* AU - Okada, Y.* AU - Moore, K.H.S.* AU - Mason, D.* AU - Pirastu, N.* AU - Gandin, I.* AU - Mattsson, H.* AU - Barnes, C.L.K.* AU - Lin, K.* AU - Zhao, J.H.* AU - Deelen, P.* AU - Rohde, R.* AU - Schurmann, C.* AU - Guo, X.* AU - Giulianini, F.* AU - Zhang, W.* AU - Medina-Gomez, C.* AU - Karlsson, R.* AU - Bao, Y.* AU - Bartz, T.M.* AU - Baumbach, C. AU - Biino, G.* AU - Bixley, M.J.* AU - Brumat, M.* AU - Chai, J.F.* AU - Corre, T.* AU - Cousminer, D.L.* AU - Dekker, A.M.* AU - Eccles, D.A.* AU - van Eijk, K.R.* AU - Fuchsberger, C.* AU - Gao, H.* AU - Germain, M.* AU - Gordon, S.D.* AU - de Haan, H.G.* AU - Harris, S.E.* AU - Hofer, E.* AU - Huerta-Chagoya, A.* AU - Igartua, C.* AU - Jansen, I.E.* AU - Jia, Y.* AU - Kacprowski, T.* AU - Karlsson, T.* AU - Kleber, M.E.* AU - Li, S.A.* AU - Li-Gao, R.* AU - Mahajan, A.* AU - Matsuda, K.* AU - Meidtner, K.* AU - Meng, W.* AU - Montasser, M.E.* AU - van der Most, P.J.* AU - Munz, M.* AU - Nutile, T.* AU - Palviainen, T.* AU - Prasad, G.* AU - Prasad, R.B.* AU - Priyanka, T.D.S.* AU - Rizzi, F.* AU - Salvi, E.* AU - Sapkota, B.R.* AU - Shriner, D.* AU - Skotte, L.* AU - Smart, M.C.* AU - Smith, A.V.* AU - van der Spek, A.* AU - Spracklen, C.N.* AU - Strawbridge, R.J.* AU - Tajuddin, S.M.* AU - Trompet, S.* AU - Turman, C.* AU - Verweij, N.* AU - Viberti, C.* AU - Wang, L.* AU - Warren, H.R.* AU - Wootton, R.E.* AU - Yanek, L.R.* AU - Yao, J.* AU - Yousri, N.A.* AU - Zhao, W.* AU - Adeyemo, A.A.* AU - Afaq, S.* AU - Aguilar-Salinas, C.A.* AU - Akiyama, M.* AU - Albert, M.L.* AU - Allison, M.A.* AU - Alver, M.* AU - Aung, T.* AU - Azizi, F.* AU - Bentley, A.R.* AU - Boeing, H.* AU - Boerwinkle, E.* AU - Borja, J.B.* AU - de Borst, G.J.* AU - Bottinger, E.P.* AU - Broer, L.* AU - Campbell, H.* AU - Chanock, S.* AU - Chee, M.L.* AU - Chen, G.* AU - Chen, Y.I.* AU - Chen, Z.* AU - Chiu, Y.F.* AU - Cocca, M.* AU - Collins, F.S.* AU - Concas, M.P.* AU - Corley, J.* AU - Cugliari, G.* AU - van Dam, R.M.* AU - Damulina, A.* AU - Daneshpour, M.S.* AU - Day, F.R.* AU - Delgado, G.E.* AU - Dhana, K.* AU - Doney, A.S.F.* AU - Dörr, M.* AU - Doumatey, A.P.* AU - Dzimiri, N.* AU - Ebenesersdóttir, S.S.* AU - Elliott, J.* AU - Ewert, R.* AU - Felix, J.F.* AU - Fischer, K.* AU - Freedman, B.I.* AU - Girotto, G.* AU - Goel, A.* AU - Gögele, M.* AU - Goodarzi, M.O.* AU - Graff, M.* AU - Granot-Hershkovitz, E.* AU - Grodstein, F.* AU - Guarrera, S.* AU - Gudbjartsson, D.F.* AU - Guity, K.* AU - Gunnarsson, B.* AU - Guo, Y.* AU - Hagenaars, S.P.* AU - Haiman, C.A.* AU - Halevy, A.* AU - Harris, T.B.* AU - Hedayati, M.* AU - van Heel, D.A.* AU - Hirata, M.* AU - Höfer, I.* AU - Hsiung, C.A.* AU - Huang, J.* AU - Hung, Y.J.* AU - Ikram, M.A.* AU - Jagadeesan, A.* AU - Jousilahti, P.* AU - Kamatani, Y.* AU - Kanai, M.* AU - Kerrison, N.D.* AU - Kessler, T.* AU - Khaw, K.T.* AU - Khor, C.C.* AU - de Kleijn, D.P.V.* AU - Koh, W.P.* AU - Kolcic, I.* AU - Kraft, P.* AU - Krämer, B.K.* AU - Kutalik, Z.* AU - Kuusisto, J.* AU - Langenberg, C.* AU - Launer, L.J.* AU - Lawlor, D.A.* AU - Lee, I.T.* AU - Lee, W.J.* AU - Lerch, M.M.* AU - Li, L.* AU - Liu, J.* AU - Loh, M.* AU - London, S.J.* AU - Loomis, S.J.* AU - Lu, Y.* AU - Luan, J.* AU - Mägi, R.* AU - Manichaikul, A.W.* AU - Manunta, P.* AU - Másson, G.* AU - Matoba, N.* AU - Mei, X.W.* AU - Meisinger, C. AU - Meitinger, T. AU - Mezzavilla, M.* AU - Milani, L.* AU - Millwood, I.Y.* AU - Momozawa, Y.* AU - Moore, A.* AU - Morange, P.E.* AU - Moreno-Macías, H.* AU - Mori, T.A.* AU - Morrison, A.C.* AU - Muka, T.* AU - Murakami, Y.* AU - Murray, A.D.* AU - de Mutsert, R.* AU - Mychaleckyj, J.C.* AU - Nalls, M.A.* AU - Nauck, M.* AU - Neville, M.J.* AU - Nolte, I.M.* AU - Ong, K.K.* AU - Orozco, L.* AU - Padmanabhan, S.* AU - Pálsson, G.* AU - Pankow, J.S.* AU - Pattaro, C.* AU - Pattie, A.* AU - Polasek, O.* AU - Poulter, N.* AU - Pramstaller, P.P.* AU - Quintana-Murci, L.* AU - Räikkönen, K.* AU - Ralhan, S.* AU - Rao, D.C.* AU - van Rheenen, W.* AU - Rich, S.S.* AU - Ridker, P.M.* AU - Rietveld, C.A.* AU - Robino, A.* AU - van Rooij, F.J.A.* AU - Ruggiero, D.* AU - Saba, Y.* AU - Sabanayagam, C.* AU - Sabater-Lleal, M.* AU - Sala, C.F.* AU - Salomaa, V.* AU - Sandow, K.* AU - Schmidt, H.* AU - Scott, L.J.* AU - Scott, W.R.* AU - Sedaghati-Khayat, B.* AU - Sennblad, B.* AU - van Setten, J.* AU - Sever, P.J.* AU - Sheu, W.H.* AU - Shi, Y.* AU - Shrestha, S.* AU - Shukla, S.R.* AU - Sigurdsson, J.K.* AU - Sikka, T.T.* AU - Singh, J.R.* AU - Smith, B.H.* AU - Stancáková, A.* AU - Stanton, A.* AU - Starr, J.M.* AU - Stefansdottir, L.* AU - Straker, L.* AU - Sulem, P.* AU - Sveinbjornsson, G.* AU - Swertz, M.A.* AU - Taylor, A.M.* AU - Taylor, K.D.* AU - Terzikhan, N.* AU - Tham, Y.C.* AU - Thorleifsson, G.* AU - Thorsteinsdottir, U.* AU - Tillander, A.* AU - Tracy, R.P.* AU - Tusié-Luna, T.* AU - Tzoulaki, I.* AU - Vaccargiu, S.* AU - Vangipurapu, J.* AU - Veldink, J.H.* AU - Vitart, V.* AU - Völker, U.* AU - Vuoksimaa, E.* AU - Wakil, S.M.* AU - Waldenberger, M. AU - Wander, G.S.* AU - Wang, Y.X.* AU - Wareham, N.J.* AU - Wild, S.* AU - Yajnik, C.S.* AU - Yuan, J.M.* AU - Zeng, L.* AU - Zhang, L.* AU - Zhou, J.* AU - Amin, N.* AU - Asselbergs, F.W.* AU - Bakker, S.J.L.* AU - Becker, D.M.* AU - Lehne, B.* AU - Bennett, D.A.* AU - van den Berg, L.H.* AU - Berndt, S.I.* AU - Bharadwaj, D.* AU - Bielak, L.F.* AU - Bochud, M.* AU - Boehnke, M.* AU - Bouchard, C.* AU - Bradfield, J.P.* AU - Brody, J.A.* AU - Campbell, A.* AU - Carmi, S.* AU - Caulfield, M.J.* AU - Cesarini, D.* AU - Chandak, G.R.* AU - Cheng, C.Y.* AU - Ciullo, M.* AU - Cornelis, M.* AU - Cusi, D.* AU - Smith, G.D.* AU - Deary, I.J.* AU - Dorajoo, R.* AU - van Duijn, C.M.* AU - Ellinghaus, D.* AU - Erdmann, J.* AU - Evangelou, E.* AU - Evans, M.K.* AU - Faul, J.D.* AU - Feenstra, B.* AU - Feitosa, M.* AU - Foisy, S.* AU - Franke, A.* AU - Friedlander, Y.* AU - Gasparini, P.* AU - Gieger, C. AU - Gonzalez, C.* AU - Goyette, P.* AU - Grant, S.F.A.* AU - Griffiths, L.R.* AU - Groop, L.* AU - Gudnason, V.* AU - Gyllensten, U.* AU - Hakonarson, H.* AU - Hamsten, A.* AU - van der Harst, P.* AU - Heng, C.K.* AU - Hicks, A.A.* AU - Hochner, H.* AU - Huikuri, H.* AU - Hunt, S.C.* AU - Jaddoe, V.W.V.* AU - de Jager, P.L.* AU - Johannesson, M.* AU - Johansson, Å* AU - Jonas, J.B.* AU - Jukema, J.W.* AU - Junttila, J.* AU - Kaprio, J.* AU - Kardia, S.L.R.* AU - Karpe, F.* AU - Kumari, M.* AU - Laakso, M.* AU - van der Laan, S.W.* AU - Lahti, J.* AU - Laudes, M.* AU - Lea, R.A.* AU - Lieb, W.* AU - Lumley, T.* AU - Martin, N.G.* AU - März, W.* AU - Matullo, G.* AU - McCarthy, M.I.* AU - Medland, S.E.* AU - Merriman, T.R.* AU - Metspalu, A.* AU - Meyer, B.F.* AU - Mohlke, K.L.* AU - Montgomery, G.W.* AU - Mook-Kanamori, D.O.* AU - Munroe, P.B.* AU - North, K.E.* AU - Nyholt, D.R.* AU - O'Connell, J.R.* AU - Ober, C.* AU - Oldehinkel, A.J.* AU - Palmas, W.* AU - Palmer, C.* AU - Pasterkamp, G.G.* AU - Patin, E.* AU - Pennell, C.E.* AU - Perusse, L.* AU - Peyser, P.A.* AU - Pirastu, M.* AU - Polderman, T.J.C.* AU - Porteous, D.J.* AU - Posthuma, D.* AU - Psaty, B.M.* AU - Rioux, J.D.* AU - Rivadeneira, F.* AU - Rotimi, C.* AU - Rotter, J.I.* AU - Rudan, I.* AU - den Ruijter, H.M.* AU - Sanghera, D.K.* AU - Sattar, N.* AU - Schmidt, R.* AU - Schulze, M.B.* AU - Schunkert, H.* AU - Scott, R.A.* AU - Shuldiner, A.R.* AU - Sim, X.* AU - Small, N.* AU - Smith, J.A.* AU - Sotoodehnia, N.* AU - Tai, E.S.* AU - Teumer, A.* AU - Timpson, N.J.* AU - Toniolo, D.* AU - Tregouet, D.A.* AU - Tuomi, T.* AU - Vollenweider, P.* AU - Wang, C.A.* AU - Weir, D.R.* AU - Whitfield, J.B.* AU - Wijmenga, C.* AU - Wong, T.Y.* AU - Wright, J.* AU - Yang, J.* AU - Yu, L.* AU - Zemel, B.S.* AU - Zonderman, A.B.* AU - Perola, M.* AU - Magnusson, P.K.E.* AU - Uitterlinden, A.G.* AU - Kooner, J.S.* AU - Chasman, D.I.* AU - Loos, R.J.F.* AU - Franceschini, N.* AU - Franke, L.* AU - Haley, C.S.* AU - Hayward, C.* AU - Walters, R.G.* AU - Perry, J.R.B.* AU - Esko, T.* AU - Helgason, A.* AU - Stefansson, K.* AU - Joshi, P.K.* AU - Kubo, M.* AU - Wilson, J.F.* C1 - 57245 C2 - 47664 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Associations of autozygosity with a broad range of human phenotypes. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike's information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk. AU - Czamara, D.* AU - Eraslan, G. AU - Page, C.M.* AU - Lahti, J.* AU - Lahti-Pulkkinen, M.* AU - Hämäläinen, E.* AU - Kajantie, E.* AU - Laivuori, H.* AU - Villa, P.M.* AU - Reynolds, R.M.* AU - Nystad, W.* AU - Håberg, S.E.* AU - London, S.J.* AU - O'Donnell, K.J.* AU - Garg, E.* AU - Meaney, M.J.* AU - Entringer, S.* AU - Wadhwa, P.D.* AU - Buss, C.* AU - Jones, M.J.* AU - Lin, D.T.S.* AU - MacIsaac, J.L.* AU - Kobor, M.S.* AU - Koen, N.* AU - Zar, H.J.* AU - Koenen, K.C.* AU - Dalvie, S.* AU - Stein, D.J.* AU - Kondofersky, I. AU - Müller, N.S. AU - Theis, F.J. AU - Räikkönen, K.* AU - Binder, E.B.* C1 - 56297 C2 - 46970 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - Predicting longer-term mortality risk requires collection of clinical data, which is often cumbersome. Therefore, we use a well-standardized metabolomics platform to identify metabolic predictors of long-term mortality in the circulation of 44,168 individuals (age at baseline 18-109), of whom 5512 died during follow-up. We apply a stepwise (forward-backward) procedure based on meta-analysis results and identify 14 circulating biomarkers independently associating with all-cause mortality. Overall, these associations are similar in men and women and across different age strata. We subsequently show that the prediction accuracy of 5- and 10-year mortality based on a model containing the identified biomarkers and sex (C-statistic = 0.837 and 0.830, respectively) is better than that of a model containing conventional risk factors for mortality (C-statistic = 0.772 and 0.790, respectively). The use of the identified metabolic profile as a predictor of mortality or surrogate endpoint in clinical studies needs further investigation. AU - Deelen, J.* AU - Kettunen, J.* AU - Fischer, K.* AU - van der Spek, A.* AU - Trompet, S.* AU - Kastenmüller, G. AU - Boyd, A.W.* AU - Zierer, J. AU - van den Akker, E.B.* AU - Amin, N.* AU - Demirkan, A.* AU - Ghanbari, M.* AU - van Heemst, D.* AU - Ikram, M.A.* AU - van Klinken, J.B.* AU - Mooijaart, S.P.* AU - Peters, A. AU - Salomaa, V.* AU - Sattar, N.* AU - Spector, T.D.* AU - Tiemeier, H.* AU - Verhoeven, A.* AU - Waldenberger, M. AU - Würtz, P.* AU - Davey Smith, G.* AU - Metspalu, A.* AU - Perola, M.* AU - Menni, C.* AU - Geleijnse, J.M.* AU - Drenos, F.* AU - Beekman, M.* AU - Jukema, J.W.* AU - van Duijn, C.M.* AU - Slagboom, P.E.* C1 - 56781 C2 - 47292 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - A metabolic profile of all-cause mortality risk identified in an observational study of 44,168 individuals. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - Single-cell RNA sequencing (scRNA-seq) has enabled researchers to study gene expression at a cellular resolution. However, noise due to amplification and dropout may obstruct analyses, so scalable denoising methods for increasingly large but sparse scRNA-seq data are needed. We propose a deep count autoencoder network (DCA) to denoise scRNA-seq datasets. DCA takes the count distribution, overdispersion and sparsity of the data into account using a negative binomial noise model with or without zero-inflation, and nonlinear gene-gene dependencies are captured. Our method scales linearly with the number of cells and can, therefore, be applied to datasets of millions of cells. We demonstrate that DCA denoising improves a diverse set of typical scRNA-seq data analyses using simulated and real datasets. DCA outperforms existing methods for data imputation in quality and speed, enhancing biological discovery. AU - Eraslan, G. AU - Simon, L. AU - Mircea, M. AU - Müller, N.S. AU - Theis, F.J. C1 - 55317 C2 - 46242 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Single-cell RNA-seq denoising using a deep count autoencoder. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - In vitro models incorporating the complexity and function of adult human tissues are highly desired for translational research. Whilst vital slices of human myocardium approach these demands, their rapid degeneration in tissue culture precludes long-term experimentation. Here, we report preservation of structure and performance of human myocardium under conditions of physiological preload, compliance, and continuous excitation. In biomimetic culture, tissue slices prepared from explanted failing human hearts attain a stable state of contractility that can be monitored for up to 4 months or 2000000 beats in vitro. Cultured myocardium undergoes particular alterations in biomechanics, structure, and mRNA expression. The suitability of the model for drug safety evaluation is exemplified by repeated assessment of refractory period that permits sensitive analysis of repolarization impairment induced by the multimodal hERG-inhibitor pentamidine. Biomimetic tissue culture will provide new opportunities to study drug targets, gene functions, and cellular plasticity in adult human myocardium. AU - Fischer, C.* AU - Milting, H.* AU - Fein, E.* AU - Reiser, E.* AU - Lu, K.* AU - Seidel, T.* AU - Schinner, C.* AU - Schwarzmayr, T. AU - Schramm, R.* AU - Tomasi, R.* AU - Husse, B.* AU - Cao-Ehlker, X.* AU - Pohl, U.* AU - Dendorfer, A.* C1 - 55117 C2 - 46327 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Long-term functional and structural preservation of precision-cut human myocardium under continuous electromechanical stimulation in vitro. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - The original version of this Article incorrectly acknowledged Elisabeth Reiser and Rene Schramm as a corresponding author. This has now been corrected in both the PDF and HTML versions of the Article. AU - Fischer, C.* AU - Milting, H.* AU - Fein, E.* AU - Reiser, E.* AU - Lu, K.* AU - Seidel, T.* AU - Schinner, C.* AU - Schwarzmayr, T. AU - Schramm, R.* AU - Tomasi, R.* AU - Husse, B.* AU - Cao-Ehlker, X.* AU - Pohl, U.* AU - Dendorfer, A.* C1 - 55357 C2 - 46328 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Publisher Correction: Long-term functional and structural preservation of precision-cut human myocardium under continuous electromechanical stimulation in vitro. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - Autophagy is an essential cellular process affecting virus infections and other diseases and Beclinl (BECN1) is one of its key regulators. Here, we identified S-phase kinase-associated protein 2 (SKP2) as E3 ligase that executes lysine-48-linked poly-ubiquitination of BECN1, thus promoting its proteasomal degradation. SKP2 activity is regulated by phosphorylation in a hetero-complex involving FKBP51, PHLPP, AKT1, and BECN1. Genetic or pharmacological inhibition of SKP2 decreases BECN1 ubiquitination, decreases BECN1 degradation and enhances autophagic flux. Middle East respiratory syndrome coronavirus (MERS-CoV) multiplication results in reduced BECN1 levels and blocks the fusion of autophagosomes and lysosomes. Inhibitors of SKP2 not only enhance autophagy but also reduce the replication of MERS-CoV up to 28,000-fold. The SKP2-BECN1 link constitutes a promising target for host-directed antiviral drugs and possibly other autophagy-sensitive conditions. AU - Gassen, N.C.* AU - Niemeyer, D.* AU - Corman, V.M.* AU - Martinelli, S.* AU - Gassen, A.* AU - Hafner, K.* AU - Papies, J.* AU - Mösbauer, K.* AU - Zellner, A.* AU - Zannas, A.S.* AU - Herrmann, A. AU - Holsboer, F.* AU - Brack-Werner, R. AU - Boshart, M.* AU - Müller-Myhsok, B.* AU - Drosten, C.* AU - Müller, M.A.* AU - Rein, T.* C1 - 57702 C2 - 47872 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - SKP2 attenuates autophagy through Beclin1-ubiquitination and its inhibition reduces MERS-Coronavirus infection. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - The molecular chaperone Hsp90 is an important regulator of proteostasis. It has remained unclear why S. cerevisiae possesses two Hsp90 isoforms, the constitutively expressed Hsc82 and the stress-inducible Hsp82. Here, we report distinct differences despite a sequence identity of 97%. Consistent with its function under stress conditions, Hsp82 is more stable and refolds more efficiently than Hsc82. The two isoforms also differ in their ATPases and conformational cycles. Hsc82 is more processive and populates closed states to a greater extent. Variations in the N-terminal ATP-binding domain modulate its dynamics and conformational cycle. Despite these differences, the client interactomes are largely identical, but isoform-specific interactors exist both under physiological and heat shock conditions. Taken together, changes mainly in the N-domain create a stress-specific, more resilient protein with a shifted activity profile. Thus, the precise tuning of the Hsp90 isoforms preserves the basic mechanism but adapts it to specific needs. AU - Girstmair, H.* AU - Tippel, F.* AU - Lopez, A. AU - Tych, K.* AU - Stein, F.* AU - Haberkant, P.* AU - Schmid, P.W.N.* AU - Helm, D.* AU - Rief, M.* AU - Sattler, M. AU - Buchner, J.* C1 - 56733 C2 - 47246 TI - The Hsp90 isoforms from S. cerevisiae differ in structure, function and client range. JO - Nat. Commun. VL - 10 IS - 1 PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - Advances in genetic engineering have enabled the use of bacterial outer membrane vesicles (OMVs) to deliver vaccines, drugs and immunotherapy agents, as a strategy to circumvent biocompatibility and large-scale production issues associated with synthetic nanomaterials. We investigate bioengineered OMVs for contrast enhancement in optoacoustic (photoacoustic) imaging. We produce OMVs encapsulating biopolymer-melanin (OMVMel) using a bacterial strain expressing a tyrosinase transgene. Our results show that upon near-infrared light irradiation, OMVMel generates strong optoacoustic signals appropriate for imaging applications. In addition, we show that OMVMel builds up intense heat from the absorbed laser energy and mediates photothermal effects both in vitro and in vivo. Using multispectral optoacoustic tomography, we noninvasively monitor the spatio-temporal, tumour-associated OMVMel distribution in vivo. This work points to the use of bioengineered vesicles as potent alternatives to synthetic particles more commonly employed for optoacoustic imaging, with the potential to enable both image enhancement and photothermal applications. AU - Gujrati, V. AU - Prakash, J. AU - Malekzadeh Najafabadi, J. AU - Stiel, A.-C. AU - Klemm, U. AU - Mettenleiter, G. AU - Aichler, M. AU - Walch, A.K. AU - Ntziachristos, V. C1 - 55638 C2 - 46458 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Bioengineered bacterial vesicles as biological nano-heaters for optoacoustic imaging. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - Diabetes is a global health problem caused primarily by the inability of pancreatic beta-cells to secrete adequate levels of insulin. The molecular mechanisms underlying the progressive failure of beta-cells to respond to glucose in type-2 diabetes remain unresolved. Using a combination of transcriptomics and proteomics, we find significant dysregulation of major metabolic pathways in islets of diabetic beta V59M mice, a non-obese, eulipidaemic diabetes model. Multiple genes/proteins involved in glycolysis/gluconeogenesis are upregulated, whereas those involved in oxidative phosphorylation are downregulated. In isolated islets, glucose-induced increases in NADH and ATP are impaired and both oxidative and glycolytic glucose metabolism are reduced. INS-1 beta-cells cultured chronically at high glucose show similar changes in protein expression and reduced glucose-stimulated oxygen consumption: targeted metabolomics reveals impaired metabolism. These data indicate hyperglycaemia induces metabolic changes in beta-cells that markedly reduce mitochondrial metabolism and ATP synthesis. We propose this underlies the progressive failure of beta-cells in diabetes. AU - Haythorne, E.* AU - Rohm, M. AU - van de Bunt, M.* AU - Brereton, M.F.* AU - Tarasov, A.I.* AU - Blacker, T.S.* AU - Sachse, G.* AU - Silva Dos Santos, M.* AU - Terron Exposito, R.* AU - Davis, S.* AU - Baba, O.* AU - Fischer, R.* AU - Duchen, M.R.* AU - Rorsman, P.* AU - MacRae, J.I.* AU - Ashcroft, F.M.* C1 - 56268 C2 - 46962 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic beta-cells. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - Throughout metazoans, Staufen (Stau) proteins are core factors of mRNA localization particles. They consist of three to four double-stranded RNA binding domains (dsRBDs) and a Cterminal dsRBD-like domain. Mouse Staufen2 (mStau2)-like Drosophila Stau (dmStau) contains four dsRBDs. Existing data suggest that only dsRBDs 3-4 are necessary and sufficient for mRNA binding. Here, we show that dsRBDs 1 and 2 of mStau2 bind RNA with similar affinities and kinetics as dsRBDs 3 and 4. While RNA binding by these tandem domains is transient, all four dsRBDs recognize their target RNAs with high stability. Rescue experiments in Drosophila oocytes demonstrate that mStau2 partially rescues dmStau-dependent mRNA localization. In contrast, a rescue with mStau2 bearing RNA-binding mutations in dsRBD1-2 fails, confirming the physiological relevance of our findings. In summary, our data show that the dsRBDs 1-2 play essential roles in the mRNA recognition and function of Stau-family proteins of different species. AU - Heber, S. AU - Gáspár, I.* AU - Tants, J.-N. AU - Günther, J. AU - Fernandez Moya, S.M.* AU - Janowski, R. AU - Ephrussi, A.* AU - Sattler, M. AU - Niessing, D. C1 - 55728 C2 - 46589 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Staufen2-mediated RNA recognition and localization requires combinatorial action of multiple domains. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - Glucocorticoids (GCs) are effective drugs, but their clinical use is compromised by severe side effects including hyperglycemia, hyperlipidemia and obesity. They bind to the Glucocorticoid Receptor (GR), which acts as a transcription factor. The activation of metabolic genes by GR is thought to underlie these adverse effects. We identify the bHLH factor E47 as a modulator of GR target genes. Using mouse genetics, we find that E47 is required for the regulation of hepatic glucose and lipid metabolism by GR, and that loss of E47 prevents the development of hyperglycemia and hepatic steatosis in response to GCs. Here we show that E47 and GR co-occupy metabolic promoters and enhancers. E47 is needed for the efficient recruitment of GR and coregulators such as Mediator to chromatin. Altogether, our results illustrate how GR and E47 regulate hepatic metabolism, and might provide an entry point for novel therapies with reduced side effects. AU - Hemmer, M.C. AU - Wierer, M.* AU - Schachtrup, K.* AU - Downes, M.* AU - Hübner, N.* AU - Evans, R.M.* AU - Uhlenhaut, N.H. C1 - 55255 C2 - 46245 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - E47 modulates hepatic glucocorticoid action. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis. AU - Jiang, X.* AU - Finucane, H.K.* AU - Schumacher, F.R.* AU - Schmit, S.L.* AU - Tyrer, J.P.* AU - Han, Y.* AU - Michailidou, K.* AU - Lesseur, C.* AU - Kuchenbaecker, K.B.* AU - Dennis, J.* AU - Conti, D.V.* AU - Casey, G.* AU - Gaudet, M.M.* AU - Huyghe, J.R.* AU - Albanes, D.* AU - Aldrich, M.C.* AU - Andrew, A.S.* AU - Andrulis, I.L.* AU - Anton-Culver, H.* AU - Antoniou, A.C.* AU - Antonenkova, N.N.* AU - Arnold, S.M.* AU - Aronson, K.J.* AU - Arun, B.K.* AU - Bandera, E.V.* AU - Barkardottir, R.B.* AU - Barnes, D.R.* AU - Batra, J.* AU - Beckmann, M.W.* AU - Benítez, J.* AU - Benlloch, S.* AU - Berchuck, A.* AU - Berndt, S.I.* AU - Bickeböller, H.* AU - Bien, S.A.* AU - Blomqvist, C.* AU - Boccia, S.* AU - Bogdanova, N.V.* AU - Bojesen, S.E.* AU - Bolla, M.K.* AU - Brauch, H.* AU - Brenner, H.* AU - Brenton, J.D.* AU - Brook, M.N.* AU - Brunet, J.* AU - Brunnström, H.* AU - Buchanan, D.D.* AU - Burwinkel, B.* AU - Butzow, R.* AU - Cadoni, G.* AU - Caldés, T.* AU - Caligo, M.A.* AU - Campbell, I.* AU - Campbell, P.T.* AU - Cancel-Tassin, G.* AU - Cannon-Albright, L.* AU - Campa, D.* AU - Caporaso, N.* AU - Carvalho, A.L.* AU - Chan, A.T.* AU - Chang-Claude, J.* AU - Chanock, S.J.* AU - Chen, C.* AU - Christiani, D.C.* AU - Claes, K.B.M.* AU - Claessens, F.* AU - Clements, J.* AU - Collee, J.M.* AU - Cruz Correa, M.* AU - Couch, F.J.* AU - Cox, A.* AU - Cunningham, J.M.* AU - Cybulski, C.* AU - Czene, K.* AU - Daly, M.B.* AU - deFazio, A.* AU - Devilee, P.* AU - Diez, O.* AU - Gago-Dominguez, M.* AU - Donovan, J.L.* AU - Dörk, T.* AU - Duell, E.J.* AU - Dunning, A.M.* AU - Dwek, M.* AU - Eccles, D.M.* AU - Edlund, C.K.* AU - Velez Edwards, D.R.* AU - Ellberg, C.* AU - Evans, G.* AU - Fasching, P.A.* AU - Ferris, R.L.* AU - Liloglou, T.* AU - Figueiredo, J.C.* AU - Fletcher, O.* AU - Fortner, R.T.* AU - Fostira, F.* AU - Franceschi, S.* AU - Friedman, E.* AU - Gallinger, S.J.* AU - Ganz, P.A.* AU - Garber, J.* AU - García-Sáenz, J.A.* AU - Gayther, S.A.* AU - Giles, G.G.* AU - Godwin, A.K.* AU - Goldberg, M.S.* AU - Goldgar, D.E.* AU - Goode, E.L.* AU - Goodman, M.T.* AU - Goodman, G.* AU - Grankvist, K.* AU - Greene, M.H.* AU - Grönberg, H.* AU - Gronwald, J.* AU - Guénel, P.* AU - Hakansson, N.* AU - Hamann, U.* AU - Hamdy, F.C.* AU - Hamilton, R.J.* AU - Hampe, J.* AU - Haugen, A.* AU - Heitz, F.* AU - Herrero, R.* AU - Hillemanns, P.* AU - Hoffmeister, M.* AU - Høgdall, E.* AU - Hong, Y.-C.* AU - Hopper, J.L.* AU - Houlston, R.* AU - Hulick, P.J.* AU - Hunter, D.J.* AU - Huntsman, D.G.* AU - Idos, G.* AU - Imyanitov, E.N.* AU - Ingles, S.A.* AU - Isaacs, C.* AU - Jakubowska, A.* AU - James, P.* AU - Jenkins, M.A.* AU - Johansson, M.* AU - John, E.M.* AU - Joshi, A.D.* AU - Kaneva, R.* AU - Karlan, B.Y.* AU - Kelemen, L.E.* AU - Kühl, T.* AU - Khaw, K.-T.* AU - Khusnutdinova, E.* AU - Kibel, A.S.* AU - Kiemeney, L.A.* AU - Kim, J.* AU - Kjaer, S.K.* AU - Knight, J.A.* AU - Kogevinas, M* AU - Kote-Jarai, Z.* AU - Koutros, S.* AU - Kristensen, V.N.* AU - Kupryjanczyk, J.* AU - Lacko, M.* AU - Lam, S.* AU - Lambrechts, D.* AU - Landi, M.T.* AU - Lazarus, P.* AU - Le, N.D.* AU - Lee, E.* AU - Lejbkowicz, F.* AU - Lenz, H.-J.* AU - Leslie, G.* AU - Lessel, D.* AU - Lester, J.* AU - Levine, D.A.* AU - Li, L.* AU - Li, C.I.* AU - Lindblom, A.* AU - Lindor, N.M.* AU - Liu, G.* AU - Loupakis, F.* AU - Lubinski, J.* AU - Maehle, L.* AU - Maier, C.* AU - Mannermaa, A.* AU - Le Marchand, L.* AU - Margolin, S.* AU - May, T.* AU - McGuffog, L.* AU - Meindl, A.* AU - Middha, P.* AU - Miller, A.* AU - Milne, R.L.* AU - MacInnis, R.J.* AU - Modugno, F.* AU - Montagna, M.* AU - Moreno, V.* AU - Moysich, K.B.* AU - Mucci, L.* AU - Muir, K.* AU - Mulligan, A.M.* AU - Nathason, K.L.* AU - Neal, D.E.* AU - Ness, A.R.* AU - Neuhausen, S.L.* AU - Nevanlinna, H.* AU - Newcomb, P.A.* AU - Newcomb, L.F.* AU - Nielsen, F.C.* AU - Nikitina-Zake, L.* AU - Nørdestgaard, B.G.* AU - Nussbaum, R.L.* AU - Offit, K.* AU - Olah, E.* AU - Al Olama, A.A.* AU - Olopade, O.I.* AU - Olshan, A.F.* AU - Olsson, H.* AU - Osorio, A.* AU - Pandha, H.* AU - Park, J.Y.* AU - Pashayan, N.* AU - Parsons, M.T.* AU - Pejovic, T.* AU - Penney, K.L.* AU - Peters, W.H.M.* AU - Phelan, C.M.* AU - Phipps, A.I.* AU - Plaseska-Karanfilska, D.* AU - Pring, M.* AU - Prokofyeva, D.* AU - Radice, P.* AU - Stefansson, K.* AU - Ramus, S.J.* AU - Raskin, L.* AU - Rennert, G.* AU - Rennert, H.S.* AU - van Rensburg, E.J.* AU - Riggan, M.J.* AU - Risch, H.A.* AU - Risch, A.* AU - Roobol, M.J.* AU - Rosenstein, B.S.* AU - Rossing, M.A.* AU - De Ruyck, K.* AU - Saloustros, E.* AU - Sandler, D.P.* AU - Sawyer, E.J.* AU - Schabath, M.B.* AU - Schleutker, J.* AU - Schmidt, M.K.* AU - Setiawan, V.W.* AU - Shen, H.* AU - Siegel, E.M.* AU - Sieh, W.* AU - Singer, C.F.* AU - Slattery, M.* AU - Sorensen, K.D.* AU - Southey, M.C.* AU - Spurdle, A.B.* AU - Stanford, J.L.* AU - Stevens, V.L.* AU - Stintzing, S.* AU - Stone, J.* AU - Sundfeldt, K.* AU - Sutphen, R.* AU - Swerdlow, A.J.* AU - Tajara, E.H.* AU - Tangen, C.M.* AU - Tardón, A.* AU - Taylor, J.A.* AU - Teare, M.D.* AU - Teixeira, M.R.* AU - Terry, M.B.* AU - Terry, K.L.* AU - Thibodeau, S.N.* AU - Thomassen, M.* AU - Bjørge, L.* AU - Tischkowitz, M.* AU - Toland, A.E.* AU - Torres, D.* AU - Townsend, P.A.* AU - Travis, R.C.* AU - Tung, N.* AU - Tworoger, S.S.* AU - Ulrich, C.M.* AU - Usmani, N.* AU - Vachon, C.M.* AU - van Nieuwenhuysen, E.* AU - Vega, A.* AU - Aguado-Barrera, M.E.* AU - Wang, Q.* AU - Webb, P.M.* AU - Weinberg, C.R.* AU - Weinstein, S.* AU - Weissler, M.C.* AU - Weitzel, J.N.* AU - West, C.M.L.* AU - White, E.* AU - Whittemore, A.S.* AU - Wichmann, H.-E. AU - Wiklund, F.* AU - Winqvist, R.* AU - Wolk, A.* AU - Woll, P.* AU - Woods, M.* AU - Wu, A.H.* AU - Wu, X.* AU - Yannoukakos, D.* AU - Zheng, W.* AU - Zienolddiny, S.* AU - Ziogas, A.* AU - Zorn, K.K.* AU - Lane, J.M.* AU - Saxena, R.* AU - Thomas, D.* AU - Hung, R.J.* AU - Dierergaarde, B.* AU - McKay, J.* AU - Peters, U.* AU - Hsu, L.* AU - Garcia-Closas, M.* AU - Eeles, R.A.* AU - Chenevix-Trench, G.* AU - Brennan, P.J.* AU - Haiman, C.A.* AU - Simard, J.* AU - Easton, D.E.* AU - Gruber, S.B.* AU - Pharoah, P.D.P.* AU - Price, A.L.* AU - Pasaniuc, B.* AU - Amos, C.I.* AU - Kraft, P.* AU - Lindström, S.* C1 - 55409 C2 - 46286 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Shared heritability and functional enrichment across six solid cancers. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - An amendment to this paper has been published and can be accessed via a link at the top of the paper. AU - Jiang, X.* AU - Finucane, H.K.* AU - Schumacher, F.R.* AU - Schmit, S.L.* AU - Tyrer, J.P.* AU - Han, Y.* AU - Michailidou, K.* AU - Lesseur, C.* AU - Kuchenbaecker, K.B.* AU - Dennis, J.* AU - Conti, D.V.* AU - Casey, G.* AU - Gaudet, M.M.* AU - Huyghe, J.R.* AU - Albanes, D.* AU - Aldrich, M.C.* AU - Andrew, A.S.* AU - Andrulis, I.L.* AU - Anton-Culver, H.* AU - Antoniou, A.C.* AU - Antonenkova, N.N.* AU - Arnold, S.M.* AU - Aronson, K.J.* AU - Arun, B.K.* AU - Bandera, E.V.* AU - Barkardottir, R.B.* AU - Barnes, D.R.* AU - Batra, J.* AU - Beckmann, M.W.* AU - Benítez, J.* AU - Benlloch, S.* AU - Berchuck, A.* AU - Berndt, S.I.* AU - Bickeböller, H.* AU - Bien, S.A.* AU - Blomqvist, C.* AU - Boccia, S.* AU - Bogdanova, N.V.* AU - Bojesen, S.E.* AU - Bolla, M.K.* AU - Brauch, H.* AU - Brenner, H.* AU - Brenton, J.D.* AU - Brook, M.N.* AU - Brunet, J.* AU - Brunnström, H.* AU - Buchanan, D.D.* AU - Burwinkel, B.* AU - Butzow, R.* AU - Cadoni, G.* AU - Caldés, T.* AU - Caligo, M.A.* AU - Campbell, I.* AU - Campbell, P.T.* AU - Cancel-Tassin, G.* AU - Cannon-Albright, L.* AU - Campa, D.* AU - Caporaso, N.* AU - Carvalho, A.L.* AU - Chan, A.T.* AU - Chang-Claude, J.* AU - Chanock, S.J.* AU - Chen, C.* AU - Christiani, D.C.* AU - Claes, K.B.M.* AU - Claessens, F.* AU - Clements, J.* AU - Collée, J.M.* AU - Correa, M.C.* AU - Couch, F.J.* AU - Cox, A.* AU - Cunningham, J.M.* AU - Cybulski, C.* AU - Czene, K.* AU - Daly, M.B.* AU - deFazio, A.* AU - Devilee, P.* AU - Diez, O.* AU - Gago-Dominguez, M.* AU - Donovan, J.L.* AU - Dörk, T.* AU - Duell, E.J.* AU - Dunning, A.M.* AU - Dwek, M.* AU - Eccles, D.M.* AU - Edlund, C.K.* AU - Edwards, D.R.V.* AU - Ellberg, C.* AU - Evans, D.G.* AU - Fasching, P.A.* AU - Ferris, R.L.* AU - Liloglou, T.* AU - Figueiredo, J.C.* AU - Fletcher, O.* AU - Fortner, R.T.* AU - Fostira, F.* AU - Franceschi, S.* AU - Friedman, E.* AU - Gallinger, S.J.* AU - Ganz, P.A.* AU - Garber, J.* AU - García-Sáenz, J.A.* AU - Gayther, S.A.* AU - Giles, G.G.* AU - Godwin, A.K.* AU - Goldberg, M.S.* AU - Goldgar, D.E.* AU - Goode, E.L.* AU - Goodman, M.T.* AU - Goodman, G.* AU - Grankvist, K.* AU - Greene, M.H.* AU - Grönberg, H.* AU - Gronwald, J.* AU - Guénel, P.* AU - Håkansson, N.* AU - Hall, P.* AU - Hamann, U.* AU - Hamdy, F.C.* AU - Hamilton, R.J.* AU - Hampe, J.* AU - Haugen, A.* AU - Heitz, F.* AU - Herrero, R.* AU - Hillemanns, P.* AU - Hoffmeister, M.* AU - Høgdall, E.* AU - Hong, Y.C.* AU - Hopper, J.L.* AU - Houlston, R.* AU - Hulick, P.J.* AU - Hunter, D.J.* AU - Huntsman, D.G.* AU - Idos, G.* AU - Imyanitov, E.N.* AU - Ingles, S.A.* AU - Isaacs, C.* AU - Jakubowska, A.* AU - James, P.* AU - Jenkins, M.A.* AU - Johansson, M.* AU - John, E.M.* AU - Joshi, A.D.* AU - Kaneva, R.* AU - Karlan, B.Y.* AU - Kelemen, L.E.* AU - Kühl, T.* AU - Khaw, K.T.* AU - Khusnutdinova, E.* AU - Kibel, A.S.* AU - Kiemeney, L.A.* AU - Kim, J.* AU - Kjaer, S.K.* AU - Knight, J.A.* AU - Kogevinas, M.* AU - Kote-Jarai, Z.* AU - Koutros, S.* AU - Kristensen, V.N.* AU - Kupryjanczyk, J.* AU - Lacko, M.* AU - Lam, S.* AU - Lambrechts, D.* AU - Landi, M.T.* AU - Lazarus, P.* AU - Le, N.D.* AU - Lee, E.* AU - Lejbkowicz, F.* AU - Lenz, H.J.* AU - Leslie, G.* AU - Lessel, D.* AU - Lester, J.* AU - Levine, D.A.* AU - Li, L.* AU - Li, C.I.* AU - Lindblom, A.* AU - Lindor, N.M.* AU - Liu, G.* AU - Loupakis, F.* AU - Lubiński, J.* AU - Maehle, L.* AU - Maier, C.* AU - Mannermaa, A.* AU - Marchand, L.L.* AU - Margolin, S.* AU - May, T.* AU - McGuffog, L.* AU - Meindl, A.* AU - Middha, P.* AU - Miller, A.* AU - Milne, R.L.* AU - MacInnis, R.J.* AU - Modugno, F.* AU - Montagna, M.* AU - Moreno, V.* AU - Moysich, K.B.* AU - Mucci, L.* AU - Muir, K.* AU - Mulligan, A.M.* AU - Nathanson, K.L.* AU - Neal, D.E.* AU - Ness, A.R.* AU - Neuhausen, S.L.* AU - Nevanlinna, H.* AU - Newcomb, P.A.* AU - Newcomb, L.F.* AU - Nielsen, F.C.* AU - Nikitina-Zake, L.* AU - Nørdestgaard, B.G.* AU - Nussbaum, R.L.* AU - Offit, K.* AU - Olah, E.* AU - Olama, A.A.A.* AU - Olopade, O.I.* AU - Olshan, A.F.* AU - Olsson, H.* AU - Osorio, A.* AU - Pandha, H.* AU - Park, J.Y.* AU - Pashayan, N.* AU - Parsons, M.T.* AU - Pejovic, T.* AU - Penney, K.L.* AU - Peters, W.H.M.* AU - Phelan, C.M.* AU - Phipps, A.I.* AU - Plaseska-Karanfilska, D.* AU - Pring, M.* AU - Prokofyeva, D.* AU - Radice, P.* AU - Stefansson, K.* AU - Ramus, S.J.* AU - Raskin, L.* AU - Rennert, G.* AU - Rennert, H.S.* AU - van Rensburg, E.J.* AU - Riggan, M.J.* AU - Risch, H.A.* AU - Risch, A.* AU - Roobol, M.J.* AU - Rosenstein, B.S.* AU - Rossing, M.A.* AU - De Ruyck, K.* AU - Saloustros, E.* AU - Sandler, D.P.* AU - Sawyer, E.J.* AU - Schabath, M.B.* AU - Schleutker, J.* AU - Schmidt, M.K.* AU - Setiawan, V.W.* AU - Shen, H.* AU - Siegel, E.M.* AU - Sieh, W.* AU - Singer, C.F.* AU - Slattery, M.L.* AU - Sorensen, K.D.* AU - Southey, M.C.* AU - Spurdle, A.B.* AU - Stanford, J.L.* AU - Stevens, V.L.* AU - Stintzing, S.* AU - Stone, J.* AU - Sundfeldt, K.* AU - Sutphen, R.* AU - Swerdlow, A.J.* AU - Tajara, E.H.* AU - Tangen, C.M.* AU - Tardón, A.* AU - Taylor, J.A.* AU - Teare, M.D.* AU - Teixeira, M.R.* AU - Terry, M.B.* AU - Terry, K.L.* AU - Thibodeau, S.N.* AU - Thomassen, M.* AU - Bjørge, L.* AU - Tischkowitz, M.* AU - Toland, A.E.* AU - Torres, D.* AU - Townsend, P.A.* AU - Travis, R.C.* AU - Tung, N.* AU - Tworoger, S.S.* AU - Ulrich, C.M.* AU - Usmani, N.* AU - Vachon, C.M.* AU - van Nieuwenhuysen, E.* AU - Vega, A.* AU - Aguado-Barrera, M.E.* AU - Wang, Q.* AU - Webb, P.M.* AU - Weinberg, C.R.* AU - Weinstein, S.* AU - Weissler, M.C.* AU - Weitzel, J.N.* AU - West, C.M.L.* AU - White, E.* AU - Whittemore, A.S.* AU - Wichmann, H.-E. AU - Wiklund, F.* AU - Winqvist, R.* AU - Wolk, A.* AU - Woll, P.* AU - Woods, M.* AU - Wu, A.H.* AU - Wu, X.* AU - Yannoukakos, D.* AU - Zheng, W.* AU - Zienolddiny, S.* AU - Ziogas, A.* AU - Zorn, K.K.* AU - Lane, J.M.* AU - Saxena, R.* AU - Thomas, D.* AU - Hung, R.J.* AU - Diergaarde, B.* AU - Mckay, J.* AU - Peters, U.* AU - Hsu, L.* AU - García-Closas, M.* AU - Eeles, R.A.* AU - Chenevix-Trench, G.* AU - Brennan, P.J.* AU - Haiman, C.A.* AU - Simard, J.* AU - Easton, D.F.* AU - Gruber, S.B.* AU - Pharoah, P.D.P.* AU - Price, A.L.* AU - Pasaniuc, B.* AU - Amos, C.I.* AU - Kraft, P.* AU - Lindström, S.* C1 - 56961 C2 - 47361 TI - Erratum: Publisher Correction: Shared heritability and functional enrichment across six solid cancers (Nature communications (2019) 10 1 (431)). JO - Nat. Commun. VL - 10 IS - 1 PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - Lung adenocarcinoma (LUAD)-derived Wnts increase cancer cell proliferative/stemness potential, but whether they impact the immune microenvironment is unknown. Here we show that LUAD cells use paracrine Wnt1 signaling to induce immune resistance. In TCGA, Wnt1 correlates strongly with tolerogenic genes. In another LUAD cohort, Wnt1 inversely associates with T cell abundance. Altering Wnt1 expression profoundly affects growth of murine lung adenocarcinomas and this is dependent on conventional dendritic cells (cDCs) and T cells. Mechanistically, Wnt1 leads to transcriptional silencing of CC/CXC chemokines in cDCs, T cell exclusion and cross-tolerance. Wnt-target genes are up-regulated in human intratumoral cDCs and decrease upon silencing Wnt1, accompanied by enhanced T cell cytotoxicity. siWnt1-nanoparticles given as single therapy or part of combinatorial immunotherapies act at both arms of the cancer-immune ecosystem to halt tumor growth. Collectively, our studies show that Wnt1 induces immunologically cold tumors through cDCs and highlight its immunotherapeutic targeting. AU - Kerdidani, D.* AU - Chouvardas, P.* AU - Arjo, A.R.* AU - Giopanou, I.* AU - Ntaliarda, G.* AU - Guo, Y.A.* AU - Tsikitis, M.* AU - Kazamias, G.* AU - Potaris, K.* AU - Stathopoulos, G.T. AU - Zakynthinos, S.* AU - Kalomenidis, I.* AU - Soumelis, V.* AU - Kollias, G.* AU - Tsoumakidou, M.* C1 - 55840 C2 - 46598 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Wnt1 silences chemokine genes in dendritic cells and induces adaptive immune resistance in lung adenocarcinoma. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol- increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels. AU - Kilpeläinen, T.O.* AU - Bentley, A.R.* AU - Noordam, R.* AU - Sung, Y.J.* AU - Schwander, K.* AU - Winkler, T.W.* AU - Jakupović, H.* AU - Chasman, D.I.* AU - Manning, A.* AU - Ntalla, I.* AU - Aschard, H.* AU - Brown, M.R.* AU - de Las Fuentes, L.* AU - Franceschini, N.* AU - Guo, X.* AU - Vojinovic, D.* AU - Aslibekyan, S.* AU - Feitosa, M.F.* AU - Kho, M.* AU - Musani, S.K.* AU - Richard, M.* AU - Wang, H.* AU - Wang, Z.* AU - Bartz, T.M.* AU - Bielak, L.F.* AU - Campbell, A.* AU - Dorajoo, R.* AU - Fisher, V.* AU - Hartwig, F.P.* AU - Horimoto, A.R.V.R.* AU - Li, C.* AU - Lohman, K.K.* AU - Marten, J.* AU - Sim, X.* AU - Smith, A.V.* AU - Tajuddin, S.M.* AU - Alver, M.* AU - Amini, M.* AU - Boissel, M.* AU - Chai, J.F.* AU - Chen, X.* AU - Divers, J.* AU - Evangelou, E.* AU - Gao, C.* AU - Graff, M.* AU - Harris, S.E.* AU - He, M.* AU - Hsu, F.C.* AU - Jackson, A.U.* AU - Zhao, J.H.* AU - Kraja, A.T.* AU - Kühnel, B. AU - Laguzzi, F.* AU - Lyytikäinen, L.P.* AU - Nolte, I.M.* AU - Rauramaa, R.* AU - Riaz, M.* AU - Robino, A.* AU - Rueedi, R.* AU - Stringham, H.M.* AU - Takeuchi, F.* AU - van der Most, P.J.* AU - Varga, T.V.* AU - Verweij, N.* AU - Ware, E.B.* AU - Wen, W.* AU - Li, X.* AU - Yanek, L.R.* AU - Amin, N.* AU - Arnett, D.K.* AU - Boerwinkle, E.* AU - Brumat, M.* AU - Cade, B.* AU - Canouil, M.* AU - Chen, Y.D.I.* AU - Concas, M.P.* AU - Connell, J.* AU - de Mutsert, R.* AU - de Silva, H.J.* AU - de Vries, P.S.* AU - Demirkan, A.* AU - Ding, J.* AU - Eaton, C.B.* AU - Faul, J.D.* AU - Friedlander, Y.* AU - Gabriel, K.P.* AU - Ghanbari, M.* AU - Giulianini, F.* AU - Gu, C.C.* AU - Gu, D.* AU - Harris, T.B.* AU - He, J.* AU - Heikkinen, S.* AU - Heng, C.-K.* AU - Hunt, S.C.* AU - Ikram, M.A.* AU - Jonas, J.B.* AU - Koh, W.-P.* AU - Komulainen, P.* AU - Krieger, J.E.* AU - Kritchevsky, S.B.* AU - Kutalik, Z.* AU - Kuusisto, J.* AU - Langefeld, C.D.* AU - Langenberg, C.* AU - Launer, L.J.* AU - Leander, K.* AU - Lemaitre, R.N.* AU - Lewis, C.E.* AU - Liang, J.* AU - Lifelines Cohort Study* AU - Liu, J.* AU - Mägi, R.* AU - Manichaikul, A.* AU - Meitinger, T. AU - Metspalu, A.* AU - Milaneschi, Y.* AU - Mohlke, K.L.* AU - Mosley, T.H Jr.* AU - Murray, A.D.* AU - Nalls, M.A.* AU - Nang, E.-E. K.* AU - Nelson, C.P.* AU - Nona, S.* AU - Norris, J.M.* AU - Nwuba, C.V.* AU - O’Connell, J.* AU - Palmer, N.D.* AU - Papanicolau, G.J.* AU - Pazoki, R.* AU - Pedersen, N.L.* AU - Peters, A. AU - Peyser, P.A.* AU - Polasek, O.* AU - Porteous, D.J.* AU - Poveda, A.* AU - Raitakari, O.T.* AU - Rich, S.S.* AU - Risch, N.* AU - Robinson, J.G.* AU - Rose, L.M.* AU - Rudan, I.* AU - Schreiner, P.J.* AU - Scott, R.A.* AU - Sidney, S.S.* AU - Sims, M.* AU - Smith, J.A.* AU - Snieder, H.* AU - Sofer, T.* AU - Starr, J.M.* AU - Sternfeld, B.* AU - Strauch, K. AU - Tang, H.* AU - Taylor, K.D.* AU - Tsai, M.Y.* AU - Tuomilehto, J.* AU - Uitterlinden, A.G.* AU - van der Ende, M.Y.* AU - van Heemst, D.* AU - Voortman, T.* AU - Waldenberger, M. AU - Wennberg, P.* AU - Wilson, G.* AU - Xiang, Y.-B.* AU - Yao, J.* AU - Yu, C.* AU - Yuan, J.-M.* AU - Zhao, W.* AU - Zonderman, A.B.* AU - Becker, D.M.* AU - Boehnke, M.* AU - Bowden, D.W* AU - de Faire, U.* AU - Deary, I.J.* AU - Elliott, P.* AU - Esko, T.* AU - Freedman, B.I.* AU - Froguel, P.* AU - Gasparini, P.* AU - Gieger, C. AU - Kato, N.* AU - Laakso, M.* AU - Lakka, T.A.* AU - Lehtimäki, T.* AU - Magnusson, P.K.E.* AU - Oldehinkel, A.J.* AU - Penninx, B.W.J.H.* AU - Samani, N.J.* AU - Shu, X.-O.* AU - van der Harst, P.* AU - van Vliet-Ostaptchouk, J.V.* AU - Vollenweider, P.* AU - Wagenknecht, L.E.* AU - Wang, Y.X.* AU - Wareham, N.J.* AU - Weir, D.R.* AU - Wu, T.* AU - Zheng, W.* AU - Zhu, X.* AU - Evans, M.K.* AU - Franks, P.W.* AU - Gudnason, V.* AU - Hayward, C.* AU - Horta, B.L.* AU - Kelly, T.N.* AU - Liu, Y.* AU - North, K.E.* AU - Pereira, A.C.* AU - Ridker, P.M.* AU - Tai, E.S.* AU - van Dam, R.M.* AU - Fox, E.R.* AU - Kardia, S.L.R.* AU - Liu, C.-T.* AU - Mook-Kanamori, D.O.* AU - Province, M.A.* AU - Redline, S.* AU - van Duijn, C.M.* AU - Rotter, J.I.* AU - Kooperberg, C.* AU - Gauderman, W.J.* AU - Psaty, B.M.* AU - Rice, K.* AU - Munroe, P.B.* AU - Fornage, M.* AU - Cupples, L.A.* AU - Rotimi, C.N.* AU - Morrison, A.C.* AU - Rao, D.C.* AU - Loos, R.J.F.* C1 - 55353 C2 - 46338 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - Advances in precision molecular imaging promise to transform our ability to detect, diagnose and treat disease. Here, we describe the engineering and validation of a new cystine knot peptide (knottin) that selectively recognizes human integrin αvβ6 with single-digit nanomolar affinity. We solve its 3D structure by NMR and x-ray crystallography and validate leads with 3 different radiolabels in pre-clinical models of cancer. We evaluate the lead tracer’s safety, biodistribution and pharmacokinetics in healthy human volunteers, and show its ability to detect multiple cancers (pancreatic, cervical and lung) in patients at two study locations. Additionally, we demonstrate that the knottin PET tracers can also detect fibrotic lung disease in idiopathic pulmonary fibrosis patients. Our results indicate that these cystine knot PET tracers may have potential utility in multiple disease states that are associated with upregulation of integrin αvβ6. AU - Kimura, R.H.* AU - Wang, L.* AU - Shen, B.* AU - Huo, L.* AU - Tummers, W.* AU - Filipp, F.V. AU - Guo, H.H.* AU - Haywood, T.* AU - Abou-Elkacem, L.* AU - Baratto, L.* AU - Habte, F.* AU - Devulapally, R.* AU - Witney, T.H.* AU - Cheng, Y.* AU - Tikole, S. AU - Chakraborti, S.* AU - Nix, J.* AU - Bonagura, C.A.* AU - Hatami, N.* AU - Mooney, J.J.* AU - Desai, T.* AU - Turner, S.* AU - Gaster, R.S.* AU - Otte, A.* AU - Visser, B.C.* AU - Poultsides, G.A.* AU - Norton, J.* AU - Park, W.* AU - Stolowitz, M.* AU - Lau, K.* AU - Yang, E.* AU - Natarajan, A.* AU - Ilovich, O.* AU - Srinivas, S.* AU - Srinivasan, A.* AU - Paulmurugan, R.* AU - Willmann, J.* AU - Chin, F.T.* AU - Cheng, Z.* AU - Iagaru, A.* AU - Li, F.* AU - Gambhir, S.S.* C1 - 57121 C2 - 47546 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Evaluation of integrin αvβ6 cystine knot PET tracers to detect cancer and idiopathic pulmonary fibrosis. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - Most genome-wide association studies are based on samples of European descent. We assess whether the genetic determinants of blood lipids, a major cardiovascular risk factor, are shared across populations. Genetic correlations for lipids between European-ancestry and Asian cohorts are not significantly different from 1. A genetic risk score based on LDL-cholesterol-associated loci has consistent effects on serum levels in samples from the UK, Uganda and Greece (r= 0.23-0.28, p < 1.9 x 10(-14)). Overall, there is evidence of reproducibility for -75% of the major lipid loci from European discovery studies, except triglyceride loci in the Ugandan samples (10% of loci). Individual transferable loci are identified using trans-ethnic colocalization. Ten of fourteen loci not transferable to the Ugandan population have pleiotropic associations with BMI in Europeans; none of the transferable loci do. The non-transferable loci might affect lipids by modifying food intake in environments rich in certain nutrients, which suggests a potential role for gene-environment interactions. AU - Kuchenbaecker, K.* AU - Telkar, N.* AU - Reiker, T.* AU - Walters, R.G.* AU - Lin, K.* AU - Eriksson, A.* AU - Gurdasani, D.* AU - Gilly, A. AU - Southam, L. AU - Tsafantakis, E.* AU - Karaleftheri, M.* AU - Seeley, J.* AU - Kamali, A.* AU - Asiki, G.* AU - Millwood, I.Y.* AU - Holmes, M.* AU - Du, H.* AU - Guo, Y.* AU - Kumari, M.* AU - Dedoussis, G.* AU - Li, L.* AU - Chen, Z.* AU - Sandhu, M.S.* AU - Zeggini, E. C1 - 56969 C2 - 47375 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - The transferability of lipid loci across African, Asian and European cohorts. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - Despite existing reports on differential DNA methylation in type 2 diabetes (T2D) and obesity, our understanding of its functional relevance remains limited. Here we show the effect of differential methylation in the early phases of T2D pathology by a blood-based epigenome-wide association study of 4808 non-diabetic Europeans in the discovery phase and 11,750 individuals in the replication. We identify CpGs in LETM1, RBM20, IRS2, MAN2A2 and the 1q25.3 region associated with fasting insulin, and in FCRL6, SLAMF1, APOBEC3H and the 15q26.1 region with fasting glucose. In silico cross-omics analyses highlight the role of differential methylation in the crosstalk between the adaptive immune system and glucose homeostasis. The differential methylation explains at least 16.9% of the association between obesity and insulin. Our study sheds light on the biological interactions between genetic variants driving differential methylation and gene expression in the early pathogenesis of T2D. AU - Liu, J.* AU - Carnero-Montoro, E.* AU - van Dongen, J.* AU - Lent, S.* AU - Nedeljkovic, I.* AU - Ligthart, S.* AU - Tsai, P.C.* AU - Martin, T.C.* AU - Mandaviya, P.R.* AU - Jansen, R.* AU - Peters, M.J.* AU - Duijts, L.* AU - Jaddoe, V.W.V.* AU - Tiemeier, H.* AU - Felix, J.F.* AU - Willemsen, G.* AU - de Geus, E.J.C.* AU - Chu, A.Y.* AU - Levy, D.* AU - Hwang, S.J.* AU - Bressler, J.* AU - Gondalia, R.* AU - Salfati, E.L.* AU - Herder, C.* AU - Hidalgo, B.A.* AU - Tanaka, T.* AU - Moore, A.Z.* AU - Lemaitre, R.N.* AU - Jhun, M.A.* AU - Smith, J.A.* AU - Sotoodehnia, N.* AU - Bandinelli, S.* AU - Ferrucci, L.* AU - Arnett, D.K.* AU - Grallert, H. AU - Assimes, T.L.* AU - Hou, L.* AU - Baccarelli, A.* AU - Whitsel, E.A.* AU - van Dijk, K.W.* AU - Amin, N.* AU - Uitterlinden, A.G.* AU - Sijbrands, E.J.G.* AU - Franco, O.H.* AU - Dehghan, A.* AU - Spector, T.D.* AU - Dupuis, J.* AU - Hivert, M.F.* AU - Rotter, J.I.* AU - Meigs, J.B.* AU - Pankow, J.S.* AU - van Meurs, J.B.J.* AU - Isaacs, A.* AU - Boomsma, D.I.* AU - Bell, J.T.* AU - Demirkan, A.* AU - van Duijn, C.M.* C1 - 56331 C2 - 46999 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - An integrative cross-omics analysis of DNA methylation sites of glucose and insulin homeostasis. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - The functionality of most secreted proteins depends on their assembly into a defined quaternary structure. Despite this, it remains unclear how cells discriminate unassembled proteins en route to the native state from misfolded ones that need to be degraded. Here we show how chaperones can regulate and control assembly of heterodimeric proteins, using interleukin 23 (IL-23) as a model. We find that the IL-23 α-subunit remains partially unstructured until assembly with its β-subunit occurs and identify a major site of incomplete folding. Incomplete folding is recognized by different chaperones along the secretory pathway, realizing reliable assembly control by sequential checkpoints. Structural optimization of the chaperone recognition site allows it to bypass quality control checkpoints and provides a secretion-competent IL-23α subunit, which can still form functional heterodimeric IL-23. Thus, locally-restricted incomplete folding within single-domain proteins can be used to regulate and control their assembly. AU - Meier, S.* AU - Bohnacker, S. AU - Klose, C.J.* AU - Lopez, A. AU - Choe, C.A.* AU - Schmid, P.W.N.* AU - Bloemeke, N.* AU - Rührnößl, F.* AU - Haslbeck, M.* AU - Esser-von Bieren, J.* AU - Sattler, M. AU - Huang, P.S.* AU - Feige, M.J.* C1 - 56891 C2 - 47416 TI - The molecular basis of chaperone-mediated interleukin 23 assembly control. JO - Nat. Commun. VL - 10 IS - 1 PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca's large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells. AU - Menden, M.P. AU - Wang, D.* AU - Mason, M.J.* AU - Szalai, B.* AU - Bulusu, K.C.* AU - Guan, Y.* AU - Yu, T.* AU - Kang, J.* AU - Jeon, M.* AU - Wolfinger, R.* AU - Nguyen, T.* AU - Zaslavskiy, M.* AU - Jang, I.S.* AU - Ghazoui, Z.* AU - Ahsen, M.E.* AU - Vogel, R.* AU - Neto, E.C.* AU - Norman, T.* AU - Tang, E.K.Y.* AU - Garnett, M.J.* AU - Veroli, G.Y.D.* AU - Fawell, S.* AU - Stolovitzky, G.* AU - Guinney, J.* AU - Dry, J.R.* AU - Saez-Rodriguez, J.* AU - AstraZeneca-Sanger Drug Combination DREAM Consortium (Kurz, C.F.) C1 - 56346 C2 - 47011 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles. AU - Noordam, R.* AU - Bos, M.M.* AU - Wang, H.* AU - Winkler, T.W.* AU - Bentley, A.R.* AU - Kilpeläinen, T.O.* AU - de Vries, P.S.* AU - Sung, Y.J.* AU - Schwander, K.* AU - Cade, B.E.* AU - Manning, A.* AU - Aschard, H.* AU - Brown, M.R.* AU - Chen, H.* AU - Franceschini, N.* AU - Musani, S.K.* AU - Richard, M.* AU - Vojinovic, D.* AU - Aslibekyan, S.* AU - Bartz, T.M.* AU - de Las Fuentes, L.* AU - Feitosa, M.* AU - Horimoto, A.R.* AU - Ilkov, M.* AU - Kho, M.* AU - Kraja, A.* AU - Li, C.* AU - Lim, E.* AU - Liu, Y.* AU - Mook-Kanamori, D.O.* AU - Rankinen, T.* AU - Tajuddin, S.M.* AU - van der Spek, A.* AU - Wang, Z.* AU - Marten, J.* AU - Laville, V.* AU - Alver, M.* AU - Evangelou, E.* AU - Graff, M.E.* AU - He, M.* AU - Kühnel, B. AU - Lyytikäinen, L.P.* AU - Marques-Vidal, P.* AU - Nolte, I.M.* AU - Palmer, N.D.* AU - Rauramaa, R.* AU - Shu, X.O.* AU - Snieder, H.* AU - Weiss, S.* AU - Wen, W.* AU - Yanek, L.R.* AU - Adolfo, C.* AU - Ballantyne, C.* AU - Bielak, L.* AU - Biermasz, N.R.* AU - Boerwinkle, E.* AU - Dimou, N.* AU - Eiriksdottir, G.* AU - Gao, C.* AU - Gharib, S.A.* AU - Gottlieb, D.J.* AU - Haba-Rubio, J.* AU - Harris, T.B.* AU - Heikkinen, S.* AU - Heinzer, R.* AU - Hixson, J.E.* AU - Homuth, G.* AU - Ikram, M.A.* AU - Komulainen, P.* AU - Krieger, J.E.* AU - Lee, J.* AU - Liu, J.* AU - Lohman, K.K.* AU - Luik, A.I.* AU - Mägi, R.* AU - Martin, L.W.* AU - Meitinger, T. AU - Metspalu, A.* AU - Milaneschi, Y.* AU - Nalls, M.A.* AU - O'Connell, J.* AU - Peters, A. AU - Peyser, P.* AU - Raitakari, O.T.* AU - Reiner, A.P.* AU - Rensen, P.C.N.* AU - Rice, T.K.* AU - Rich, S.S.* AU - Roenneberg, T.* AU - Rotter, J.I.* AU - Schreiner, P.J.* AU - Shikany, J.* AU - Sidney, S.S.* AU - Sims, M.* AU - Sitlani, C.M.* AU - Sofer, T.* AU - Strauch, K. AU - Swertz, M.A.* AU - Taylor, K.D.* AU - Uitterlinden, A.G.* AU - van Duijn, C.M.* AU - Völzke, H.* AU - Waldenberger, M. AU - Wallance, R.B.* AU - van Dijk, K.W.* AU - Yu, C.* AU - Zonderman, A.B.* AU - Becker, D.M.* AU - Elliott, P.* AU - Esko, T.* AU - Gieger, C. AU - Grabe, H.J.* AU - Lakka, T.A.* AU - Lehtimäki, T.* AU - North, K.E.* AU - Penninx, B.W.J.H.* AU - Vollenweider, P.* AU - Wagenknecht, L.E.* AU - Wu, T.* AU - Xiang, Y.B.* AU - Zheng, W.* AU - Arnett, D.K.* AU - Bouchard, C.* AU - Evans, M.K.* AU - Gudnason, V.* AU - Kardia, S.* AU - Kelly, T.N.* AU - Kritchevsky, S.B.* AU - Loos, R.J.F.* AU - Pereira, A.C.* AU - Province, M.* AU - Psaty, B.M.* AU - Rotimi, C.* AU - Zhu, X.* AU - Amin, N.* AU - Cupples, L.A.* AU - Fornage, M.* AU - Fox, E.F.* AU - Guo, X.* AU - Gauderman, W.J.* AU - Rice, K.* AU - Kooperberg, C.* AU - Munroe, P.B.* AU - Liu, C.T.* AU - Morrison, A.C.* AU - Rao, D.C.* AU - van Heemst, D.* AU - Redline, S.* C1 - 57329 C2 - 47743 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - The morphology, physiology and immunology, of solid tumors exhibit spatial heterogeneity which complicates our understanding of cancer progression and therapy response. Understanding spatial heterogeneity necessitates high resolution in vivo imaging of anatomical and pathophysiological tumor information. We introduce Rhodobacter as bacterial reporter for multispectral optoacoustic (photoacoustic) tomography (MSOT). We show that endogenous bacteriochlorophyll a in Rhodobacter gives rise to strong optoacoustic signals >800 nm away from interfering endogenous absorbers. Importantly, our results suggest that changes in the spectral signature of Rhodobacter which depend on macrophage activity inside the tumor can be used to reveal heterogeneity of the tumor microenvironment. Employing non-invasive high resolution MSOT in longitudinal studies we show spatiotemporal changes of Rhodobacter spectral profiles in mice bearing 4T1 and CT26.WT tumor models. Accessibility of Rhodobacter to genetic modification and thus to sensory and therapeutic functions suggests potential for a theranostic platform organism. AU - Peters, L.* AU - Weidenfeld, I. AU - Klemm, U. AU - Loeschcke, A.* AU - Weihmann, R.* AU - Jaeger, K.E.* AU - Drepper, T.* AU - Ntziachristos, V. AU - Stiel, A.-C. C1 - 55685 C2 - 46518 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Phototrophic purple bacteria as optoacoustic in vivo reporters of macrophage activity. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - Genome-wide association studies (GWAS) have identified thousands of variants associated with complex traits, but their biological interpretation often remains unclear. Most of these variants overlap with expression QTLs, indicating their potential involvement in regulation of gene expression. Here, we propose a transcriptome-wide summary statistics-based Mendelian Randomization approach (TWMR) that uses multiple SNPs as instruments and multiple gene expression traits as exposures, simultaneously. Applied to 43 human phenotypes, it uncovers 3,913 putatively causal gene-trait associations, 36% of which have no genome-wide significant SNP nearby in previous GWAS. Using independent association summary statistics, we find that the majority of these loci were missed by GWAS due to power issues. Noteworthy among these links is educational attainment-associated BSCL2, known to carry mutations leading to a Mendelian form of encephalopathy. We also find pleiotropic causal effects suggestive of mechanistic connections. TWMR better accounts for pleiotropy and has the potential to identify biological mechanisms underlying complex traits. AU - Porcu, E.* AU - Rüeger, S.* AU - Lepik, K.* AU - eQTLGen Consortium (Müller-Nurasyid, M. AU - Strauch, K. AU - Prokisch, H.) AU - Santoni, F.A.* AU - Reymond, A.* AU - Kutalik, Z.* C1 - 56692 C2 - 47205 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Mendelian randomization integrating GWAS and eQTL data reveals genetic determinants of complex and clinical traits. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - Genome-wide studies of DNA replication origins revealed that origins preferentially associate with an Origin G-rich Repeated Element (OGRE), potentially forming G-quadruplexes (G4). Here, we functionally address their requirements for DNA replication initiation in a series of independent approaches. Deletion of the OGRE/G4 sequence strongly decreased the corresponding origin activity. Conversely, the insertion of an OGRE/G4 element created a new replication origin. This element also promoted replication of episomal EBV vectors lacking the viral origin, but not if the OGRE/G4 sequence was deleted. A potent G4 ligand, PhenDC3, stabilized G4s but did not alter the global origin activity. However, a set of new, G4-associated origins was created, whereas suppressed origins were largely G4-free. In vitro Xenopus laevis replication systems showed that OGRE/G4 sequences are involved in the activation of DNA replication, but not in the pre-replication complex formation. Altogether, these results converge to the functional importance of OGRE/G4 elements in DNA replication initiation. AU - Prorok, P.* AU - Artufel, M.* AU - Aze, A.* AU - Coulombe, P.* AU - Peiffer, I.* AU - Lacroix, L.* AU - Guédin, A.* AU - Mergny, J.L.* AU - Damaschke, J. AU - Schepers, A. AU - Ballester, B.* AU - Méchali, M.* C1 - 56614 C2 - 47182 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Involvement of G-quadruplex regions in mammalian replication origin activity. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - The Polycomb group of proteins is required for the proper orchestration of gene expression due to its role in maintaining transcriptional silencing. It is composed of several chromatin modifying complexes, including Polycomb Repressive Complex 2 (PRC2), which deposits H3K27me2/3. Here, we report the identification of a cofactor of PRC2, EZHIP (EZH1/2 Inhibitory Protein), expressed predominantly in the gonads. EZHIP limits the enzymatic activity of PRC2 and lessens the interaction between the core complex and its accessory subunits, but does not interfere with PRC2 recruitment to chromatin. Deletion of Ezhip in mice leads to a global increase in H3K27me2/3 deposition both during spermatogenesis and at late stages of oocyte maturation. This does not affect the initial number of follicles but is associated with a reduction of follicles in aging. Our results suggest that mature oocytes Ezhip-/- might not be fully functional and indicate that fertility is strongly impaired in Ezhip-/- females. Altogether, our study uncovers EZHIP as a regulator of chromatin landscape in gametes. AU - Ragazzini, R.* AU - Pérez-Palacios, R.* AU - Baymaz, I.H.* AU - Diop, S.* AU - Ancelin, K.* AU - Zielinski, D.* AU - Michaud, A.* AU - Givelet, M.* AU - Borsos, M. AU - Aflaki, S.* AU - Legoix, P.* AU - Jansen, P.W.T.C.* AU - Servant, N.* AU - Torres-Padilla, M.E. AU - Bourc'his, D.* AU - Fouchet, P.* AU - Vermeulen, M.* AU - Margueron, R.* C1 - 56807 C2 - 47296 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - EZHIP constrains Polycomb Repressive Complex 2 activity in germ cells. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - Regulatory T cells (Tregs) have crucial functions in the inhibition of immune responses. Their development and suppressive functions are controlled by the T cell receptor (TCR), but the TCR signaling mechanisms that mediate these effects remain ill-defined. Here we show that CARD11-BCL10-MALT1 (CBM) signaling mediates TCR-induced NF-kappa B activation in Tregs and controls the conversion of resting Tregs to effector Tregs under homeostatic conditions. However, in inflammatory milieus, cytokines can bypass the CBM requirement for this differentiation step. By contrast, CBM signaling, in a MALT1 protease-dependent manner, is essential for mediating the suppressive function of Tregs. In malignant melanoma models, acute genetic blockade of BCL10 signaling selectively in Tregs or pharmacological MALT1 inhibition enhances anti-tumor immune responses. Together, our data uncover a segregation of Treg differentiation and suppressive function at the CBM complex level, and provide a rationale to explore MALT1 inhibitors for cancer immunotherapy. AU - Rosenbaum, M.* AU - Gewies, A. AU - Pechloff, K.* AU - Heuser, C.* AU - Engleitner, T.* AU - Gehring, T. AU - Hartjes, L.* AU - Krebs, S.* AU - Krappmann, D. AU - Kriegsmann, M.* AU - Weichert, W.* AU - Rad, R.* AU - Kurts, C.* AU - Ruland, J.* C1 - 56184 C2 - 46874 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Bcl10-controlled Malt1 paracaspase activity is key for the immune suppressive function of regulatory T cells. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - In type 1 diabetes, the appearance of islet autoantibodies indicates the onset of islet autoimmunity, often many years before clinical symptoms arise. While T cells play a major role in the destruction of pancreatic beta cells, molecular underpinnings promoting aberrant T cell activation remain poorly understood. Here, we show that during islet autoimmunity an miR142-3p/Tet2/Foxp3 axis interferes with the efficient induction of regulatory T (Treg) cells, resulting in impaired Treg stability in mouse and human. Specifically, we demonstrate that miR142-3p is induced in islet autoimmunity and that its inhibition enhances Treg induction and stability, leading to reduced islet autoimmunity in non-obese diabetic mice. Using various cellular and molecular approaches we identify Tet2 as a direct target of miR142-3p, thereby linking high miR142-3p levels to epigenetic remodeling in Tregs. These findings offer a mechanistic model where during islet autoimmunity miR142-3p/Tet2-mediated Treg instability contributes to autoimmune activation and progression. AU - Scherm, M.G. AU - Serr, I. AU - Zahm, A.M.* AU - Schug, J.* AU - Bellusci, S.* AU - Manfredini, R.* AU - Salb, V.K. AU - Gerlach, K.* AU - Weigmann, B.* AU - Ziegler, A.-G. AU - Kaestner, K.H.* AU - Daniel, C. C1 - 57638 C2 - 47846 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - miRNA142-3p targets Tet2 and impairs Treg differentiation and stability in models of type 1 diabetes. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - How multidomain RNA-binding proteins recognize their specific target sequences, based on a combinatorial code, represents a fundamental unsolved question and has not been studied systematically so far. Here we focus on a prototypical multidomain RNA-binding protein, IMP3 (also called IGF2BP3), which contains six RNA-binding domains (RBDs): four KH and two RRM domains. We establish an integrative systematic strategy, combining single-domain-resolved SELEX-seq, motif-spacing analyses, in vivo iCLIP, functional validation assays, and structural biology. This approach identifies the RNA-binding specificity and RNP topology of IMP3, involving all six RBDs and a cluster of up to five distinct and appropriately spaced CA-rich and GGC-core RNA elements, covering a >100 nucleotide-long target RNA region. Our generally applicable approach explains both specificity and flexibility of IMP3-RNA recognition, allows the prediction of IMP3 targets, and provides a paradigm for the function of multivalent interactions with multidomain RNA-binding proteins in gene regulation. AU - Schneider, T.* AU - Hung, L.H.* AU - Aziz, M. AU - Wilmen, A.* AU - Thaum, S.* AU - Wagner, J.* AU - Janowski, R. AU - Müller, S.* AU - Schreiner, S.* AU - Friedhoff, P.* AU - Hüttelmaier, S.* AU - Niessing, D. AU - Sattler, M. AU - Schlundt, A. AU - Bindereif, A.* C1 - 56137 C2 - 46842 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Combinatorial recognition of clustered RNA elements by the multidomain RNA-binding protein IMP3. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - Activation of endoplasmic reticulum (ER) stress/the unfolded protein response (UPR) has been linked to cancer, but the molecular mechanisms are poorly understood and there is a paucity of reagents to translate this for cancer therapy. Here, we report that an IRE1 alpha RNase-specific inhibitor, MKC8866, strongly inhibits prostate cancer (PCa) tumor growth as monotherapy in multiple preclinical models in mice and shows synergistic antitumor effects with current PCa drugs. Interestingly, global transcriptomic analysis reveal that IRE1 alpha-XBP1s pathway activity is required for c-MYC signaling, one of the most highly activated oncogenic pathways in PCa. XBP1s is necessary for optimal c-MYC mRNA and protein expression, establishing, for the first time, a direct link between UPR and oncogene activation. In addition, an XBP1-specific gene expression signature is strongly associated with PCa prognosis. Our data establish IRE1 alpha-XBP1s signaling as a central pathway in PCa and indicate that its targeting may offer novel treatment strategies. AU - Sheng, X.* AU - Nenseth, H.Z.* AU - Qu, S.* AU - Kuzu, O.F.* AU - Frahnow, T. AU - Simon, L. AU - Greene, S.* AU - Zeng, Q.* AU - Fazli, L.* AU - Rennie, P.S.* AU - Mills, I.G.* AU - Danielsen, H.* AU - Theis, F.J. AU - Patterson, J.B.* AU - Jin, Y.* AU - Saatcioglu, F.* C1 - 55329 C2 - 46335 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - IRE1α-XBP1s pathway promotes prostate cancer by activating c-MYC signaling. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - The HTML and PDF versions of this Article were updated after publication to remove images of one individual from Figure 1. AU - Snijders Blok, L.* AU - Rousseau, J.* AU - Twist, J.* AU - Ehresmann, S.* AU - Takaku, M.* AU - Venselaar, H.* AU - Rodan, L.H.* AU - Nowak, C.B.* AU - Douglas, J.* AU - Swoboda, K.J.* AU - Steeves, M.A.* AU - Sahai, I.* AU - Stumpel, C.T.R.M.* AU - Stegmann, A.P.A.* AU - Wheeler, P.* AU - Willing, M.* AU - Fiala, E.* AU - Kochhar, A.* AU - Gibson, W.T.* AU - Cohen, A.S.A.* AU - Agbahovbe, R.* AU - Innes, A.M.* AU - Au, P.Y.B.* AU - Rankin, J.* AU - Anderson, I.J.* AU - Skinner, S.A.* AU - Louie, R.J.* AU - Warren, H.E.* AU - Afenjar, A.* AU - Keren, B.* AU - Nava, C.* AU - Buratti, J.* AU - Isapof, A.* AU - Rodriguez, D.* AU - Lewandowski, R.* AU - Propst, J.* AU - van Essen, T.* AU - Choi, M.* AU - Lee, S.* AU - Chae, J.H.* AU - Price, S.* AU - Schnur, R.E.* AU - Douglas, G.* AU - Wentzensen, I.M.* AU - Zweier, C.* AU - Reis, A.* AU - Bialer, M.G.* AU - Moore, C.* AU - Koopmans, M.* AU - Brilstra, E.H.* AU - Monroe, G.R.* AU - van Gassen, K.L.I.* AU - van Binsbergen, E.* AU - Newbury-Ecob, R.* AU - Bownass, L.* AU - Bader, I.* AU - Mayr, J.A.* AU - Wortmann, S.B. AU - Jakielski, K.J.* AU - Strand, E.A.* AU - Kloth, K.* AU - Bierhals, T.* AU - Roberts, J.D.* AU - Petrovich, R.M.* AU - Machida, S.* AU - Kurumizaka, H.* AU - Lelieveld, S.* AU - Pfundt, R.* AU - Jansen, S.* AU - Deriziotis, P.* AU - Faivre, L.* AU - Thevenon, J.* AU - Assoum, M.* AU - Shriberg, L.* AU - Kleefstra, T.* AU - Brunner, H.G.* AU - Wade, P.A.* AU - Fisher, S.E.* AU - Campeau, P.M.* C1 - 55971 C2 - 46706 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language (vol 9, 4619, 2018). JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - OTULIN (OTU Deubiquitinase With Linear Linkage Specificity) specifically hydrolyzes methionine1 (Met1)-linked ubiquitin chains conjugated by LUBAC (linear ubiquitin chain assembly complex). Here we report on the mass spectrometric identification of the OTULIN interactor SNX27 (sorting nexin 27), an adaptor of the endosomal retromer complex responsible for protein recycling to the cell surface. The C-terminal PDZ-binding motif (PDZbm) in OTULIN associates with the cargo-binding site in the PDZ domain of SNX27. By solving the structure of the OTU domain in complex with the PDZ domain, we demonstrate that a second interface contributes to the selective, high affinity interaction of OTULIN and SNX27. SNX27 does not affect OTULIN catalytic activity, OTULIN-LUBAC binding or Met1-linked ubiquitin chain homeostasis. However, via association, OTULIN antagonizes SNX27-dependent cargo loading, binding of SNX27 to the VPS26A-retromer subunit and endosome-to-plasma membrane trafficking. Thus, we define an additional, non-catalytic function of OTULIN in the regulation of SNX27-retromer assembly and recycling to the cell surface. AU - Stangl, A. AU - Elliott, P.R.* AU - Pinto-Fernandez, A.* AU - Bonham, S.* AU - Harrison, L. AU - Schaub, A. AU - Kutzner, K. AU - Keusekotten, K* AU - Pfluger, P.T. AU - El Oualid, F.* AU - Kessler, B.M.* AU - Komander, D.* AU - Krappmann, D. C1 - 56948 C2 - 47373 TI - Regulation of the endosomal SNX27-retromer by OTULIN. JO - Nat. Commun. VL - 10 IS - 1 PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - Bone area is one measure of bone size that is easily derived from dual-energy X-ray absorptiometry (DXA) scans. In a GWA study of DXA bone area of the hip and lumbar spine (N >= 28,954), we find thirteen independent association signals at twelve loci that replicate in samples of European and East Asian descent (N = 13,608-21,277). Eight DXA area loci associate with osteoarthritis, including rs143384 in GDF5 and a missense variant in COL11A1 (rs3753841). The strongest DXA area association is with rs11614913[T] in the microRNA MIR196A2 gene that associates with lumbar spine area (P = 2.3 x 10(-42), beta = -0.090) and confers risk of hip fracture (P = 1.0 x 10(-8), OR = 1.11). We demonstrate that the risk allele is less efficient in repressing miR-196a-5p target genes. We also show that the DXA area measure contributes to the risk of hip fracture independent of bone density. AU - Styrkarsdottir, U.* AU - Stefansson, O.A.* AU - Gunnarsdottir, K.* AU - Thorleifsson, G.* AU - Lund, S.H.* AU - Stefansdottir, L.* AU - Juliusson, K.* AU - Agustsdottir, A.B.* AU - Zink, F.* AU - Halldorsson, G.H.* AU - Ivarsdottir, E.V.* AU - Benonisdottir, S.* AU - Jonsson, H.* AU - Gylfason, A.* AU - Norland, K.* AU - Trajanoska, K.* AU - Boer, C.G.* AU - Southam, L.* AU - Leung, J.C.S.* AU - Tang, N.L.S.* AU - Kwok, T.C.Y.* AU - Lee, J.S.W.* AU - Ho, S.C.* AU - Byrjalsen, I.* AU - Center, J.R.* AU - Lee, S.H.* AU - Koh, J.M.* AU - Lohmander, L.S.* AU - Ho-Pham, L.T.* AU - Nguyen, T.V.* AU - Eisman, J.A.* AU - Woo, J.* AU - Leung, P.C.* AU - Loughlin, J.* AU - Zeggini, E. AU - Christiansen, C.* AU - Rivadeneira, F.* AU - van Meurs, J.* AU - Uitterlinden, A.G.* AU - Mogensen, B.* AU - Ingvarsson, T.* AU - Sigurdsson, G.* AU - Benediktsson, R.* AU - Sulem, P.* AU - Jonsdottir, I.* AU - Masson, G.* AU - Holm, H.* AU - Norddahl, G.L.* AU - Thorsteinsdottir, U.* AU - Gudbjartsson, D.F.* AU - Stefansson, K.* C1 - 55988 C2 - 46734 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - GWAS of bone size yields twelve loci that also affect height, BMD, osteoarthritis or fractures. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - The original HTML version of this Article was updated shortly after publication to add links to the Peer Review file.In addition, affiliations 16 and 17 incorrectly read 'School of Medicine Sydney, University of Notre Dame Australia, Sydney, WA, 6160, Australia' and 'St Vincent's Clinical School, University of New South Wales Medicine, University of New South Wales, Sydney, NSW, 2052, Australia.' This has now been corrected in both the PDF and HTML versions of the Article. AU - Styrkarsdottir, U.* AU - Stefansson, O.A.* AU - Gunnarsdottir, K.* AU - Thorleifsson, G.* AU - Lund, S.H.* AU - Stefansdottir, L.* AU - Juliusson, K.* AU - Agustsdottir, A.B.* AU - Zink, F.* AU - Halldorsson, G.H.* AU - Ivarsdottir, E.V.* AU - Benonisdottir, S.* AU - Jonsson, H.* AU - Gylfason, A.* AU - Norland, K.* AU - Trajanoska, K.* AU - Boer, C.G.* AU - Southam, L.* AU - Leung, J.C.S.* AU - Tang, N.L.S.* AU - Kwok, T.C.Y.* AU - Lee, J.S.W.* AU - Ho, S.C.* AU - Byrjalsen, I.* AU - Center, J.R.* AU - Lee, S.H.* AU - Koh, J.M.* AU - Lohmander, L.S.* AU - Ho-Pham, L.T.* AU - Nguyen, T.V.* AU - Eisman, J.A.* AU - Woo, J.* AU - Leung, P.C.* AU - Loughlin, J.* AU - Zeggini, E. AU - Christiansen, C.* AU - Rivadeneira, F.* AU - van Meurs, J.* AU - Uitterlinden, A.G.* AU - Mogensen, B.* AU - Ingvarsson, T.* AU - Sigurdsson, G.* AU - Benediktsson, R.* AU - Sulem, P.* AU - Jonsdottir, I.* AU - Masson, G.* AU - Holm, H.* AU - Norddahl, G.L.* AU - Thorsteinsdottir, U.* AU - Gudbjartsson, D.F.* AU - Stefansson, K.* C1 - 56163 C2 - 46864 TI - Erratum: Publisher Correction: GWAS of bone size yields twelve loci that also affect height, BMD, osteoarthritis or fractures (Nature communications (2019) 10 1 (2054)). JO - Nat. Commun. VL - 10 IS - 1 PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - Hyperinflammatory syndromes are life-threatening disorders caused by overzealous immune cell activation and cytokine release, often resulting from defects in negative feedback mechanisms. In the quintessential hyperinflammatory syndrome familial hemophagocytic lymphohistiocytosis (HLH), inborn errors of cytotoxicity result in effector cell accumulation, immune dysregulation and, if untreated, tissue damage and death. Here, we describe a human case with a homozygous nonsense R688* RC3H1 mutation suffering from hyperinflammation, presenting as relapsing HLH. RC3H1 encodes Roquin-1, a posttranscriptional repressor of immuneregulatory proteins such as ICOS, OX40 and TNF. Comparing the R688* variant with the murine M199R variant reveals a phenotypic resemblance, both in immune cell activation, hypercytokinemia and disease development. Mechanistically, R688* Roquin-1 fails to localize to P-bodies and interact with the CCR4-NOT deadenylation complex, impeding mRNA decay and dysregulating cytokine production. The results from this unique case suggest that impaired Roquin-1 function provokes hyperinflammation by a failure to quench immune activation. AU - Tavernier, S.J.* AU - Athanasopoulos, V.* AU - Verloo, P.* AU - Behrens, G. AU - Staal, J.* AU - Bogaert, D.J.* AU - Naesens, L.* AU - De Bruyne, M.* AU - Van Gassen, S.* AU - Parthoens, E.* AU - Ellyard, J.* AU - Cappello, J.* AU - Morris, L.X.* AU - Van Gorp, H.* AU - Van Isterdael, G.* AU - Saeys, Y.* AU - Lamkanfi, M.* AU - Schelstraete, P.* AU - Dehoorne, J.* AU - Bordon, V.* AU - van Coster, R.* AU - Lambrecht, B.N.* AU - Menten, B.* AU - Beyaert, R.* AU - Vinuesa, C.G.* AU - Heissmeyer, V. AU - Dullaers, M.* AU - Haerynck, F.* C1 - 57171 C2 - 47574 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - A human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - The original version of the Supplementary Information associated with this Article included an incorrect Supplementary Information file, in which only the first page of the file was included. The HTML has been updated to include a corrected and complete version of the Supplementary Information file. AU - Tavernier, S.J.* AU - Athanasopoulos, V.* AU - Verloo, P.* AU - Behrens, G. AU - Staal, J.* AU - Bogaert, D.J.* AU - Naesens, L.* AU - De Bruyne, M.* AU - Van Gassen, S.* AU - Parthoens, E.* AU - Ellyard, J.* AU - Cappello, J.* AU - Morris, L.X.* AU - Van Gorp, H.* AU - Van Isterdael, G.* AU - Saeys, Y.* AU - Lamkanfi, M.* AU - Schelstraete, P.* AU - Dehoorne, J.* AU - Bordon, V.* AU - van Coster, R.* AU - Lambrecht, B.N.* AU - Menten, B.* AU - Beyaert, R.* AU - Vinuesa, C.G.* AU - Heissmeyer, V. AU - Dullaers, M.* AU - Haerynck, F.* C1 - 57372 C2 - 47721 TI - Author Correction: A human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation (Nature Communications, (2019), 10, 1, (4779), 10.1038/s41467-019-12704-6). JO - Nat. Commun. VL - 10 IS - 1 PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria. AU - Teumer, A.* AU - Li, Y.* AU - Ghasemi, S.* AU - Prins, B.P.* AU - Wuttke, M.* AU - Hermle, T.* AU - Giri, A.* AU - Sieber, K.B.* AU - Qiu, C.* AU - Kirsten, H.* AU - Tin, A.* AU - Chu, A.Y.* AU - Bansal, N.* AU - Feitosa, M.F.* AU - Wang, L.* AU - Chai, J.F.* AU - Cocca, M.* AU - Fuchsberger, C.* AU - Gorski, M.* AU - Hoppmann, A.* AU - Horn, K.* AU - Li, M.* AU - Marten, J.* AU - Noce, D.* AU - Nutile, T.* AU - Sedaghat, S.* AU - Sveinbjornsson, G.* AU - Tayo, B.O.* AU - van der Most, P.J.* AU - Xu, Y.* AU - Yu, Z.* AU - Gerstner, L.* AU - Ärnlöv, J.* AU - Bakker, S.J.L.* AU - Baptista, D.* AU - Biggs, M.L.* AU - Boerwinkle, E.* AU - Brenner, H.* AU - Burkhardt, R.* AU - Carroll, R.J.* AU - Chee, M.L.* AU - Chen, M.* AU - Cheng, C.Y.* AU - Cook, J.P.* AU - Coresh, J.* AU - Corre, T.* AU - Danesh, J.* AU - de Borst, M.H.* AU - de Grandi, A.* AU - de Mutsert, R.* AU - de Vries, A.P.J.* AU - Degenhardt, F.* AU - Dittrich, K.* AU - Divers, J.* AU - Eckardt, K.U.* AU - Ehret, G.* AU - Endlich, K.* AU - Felix, J.F.* AU - Franco, O.H.* AU - Franke, A.* AU - Freedman, B.I.* AU - Freitag-Wolf, S.* AU - Gansevoort, R.T.* AU - Giedraitis, V.* AU - Gögele, M.* AU - Grundner-Culemann, F.* AU - Gudbjartsson, D.F.* AU - Gudnason, V.* AU - Hamet, P.* AU - Harris, T.B.* AU - Hicks, A.A.* AU - Holm, H.* AU - Foo, V.H.X.* AU - Hwang, S.J.* AU - Ikram, M.A.* AU - Ingelsson, E.* AU - Jaddoe, V.W.V.* AU - Jakobsdottir, J.* AU - Josyula, N.S.* AU - Jung, B.* AU - Kähönen, M.* AU - Khor, C.C.* AU - Kiess, W.* AU - Koenig, W.* AU - Körner, A.* AU - Kovacs, P.* AU - Kramer, H.* AU - Krämer, B.K.* AU - Kronenberg, F.* AU - Lange, L.A.* AU - Langefeld, C.D.* AU - Lee, J.J.* AU - Lehtimäki, T.* AU - Lieb, W.* AU - Lim, S.C.* AU - Lind, L.* AU - Lindgren, C.M.* AU - Liu, J.* AU - Loeffler, M.* AU - Lyytikäinen, L.P.* AU - Mahajan, A.* AU - Maranville, J.C.* AU - Mascalzoni, D.* AU - McMullen, B.* AU - Meisinger, C. AU - Meitinger, T. AU - Miliku, K.* AU - Mook-Kanamori, D.O.* AU - Müller-Nurasyid, M. AU - Mychaleckyj, J.C.* AU - Nauck, M.* AU - Nikus, K.* AU - Ning, B.* AU - Noordam, R.* AU - Connell, J.O.* AU - Olafsson, I.* AU - Palmer, N.D.* AU - Peters, A. AU - Podgornaia, A.I.* AU - Ponte, B.* AU - Poulain, T.* AU - Pramstaller, P.P.* AU - Rabelink, T.J.* AU - Raffield, L.M.* AU - Reilly, D.F.* AU - Rettig, R.* AU - Rheinberger, M.* AU - Rice, K.M.* AU - Rivadeneira, F.* AU - Runz, H.* AU - Ryan, K.A.* AU - Sabanayagam, C.* AU - Saum, K.U.* AU - Schöttker, B.* AU - Shaffer, C.M.* AU - Shi, Y.* AU - Smith, A.V.* AU - Strauch, K. AU - Stumvoll, M.* AU - Sun, B.B.* AU - Szymczak, S.* AU - Tai, E.S.* AU - Tan, N.Y.Q.* AU - Taylor, K.D.* AU - Teren, A.* AU - Tham, Y.C.* AU - Thiery, J.* AU - Thio, C.H.L.* AU - Thomsen, H.* AU - Thorsteinsdottir, U.* AU - Tönjes, A.* AU - Tremblay, J.* AU - Uitterlinden, A.G.* AU - van der Harst, P.* AU - Verweij, N.* AU - Vogelezang, S.* AU - Völker, U.* AU - Waldenberger, M. AU - Wang, C.* AU - Wilson, O.D.* AU - Wong, C.* AU - Wong, T.Y.* AU - Yang, Q.* AU - Yasuda, M.* AU - Akilesh, S.* AU - Bochud, M.* AU - Böger, C.A.* AU - Devuyst, O.* AU - Edwards, T.L.* AU - Ho, K.* AU - Morris, A.P.* AU - Parsa, A.* AU - Pendergrass, S.A.* AU - Psaty, B.M.* AU - Rotter, J.I.* AU - Stefansson, K.* AU - Wilson, J.G.* AU - Susztak, K.* AU - Snieder, H.* AU - Heid, I.M.* AU - Scholz, M.* AU - Butterworth, A.S.* AU - Hung, A.M.* AU - Pattaro, C.* AU - Köttgen, A.* C1 - 56890 C2 - 47414 TI - Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria. JO - Nat. Commun. VL - 10 IS - 1 PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - Diabetes mellitus affects one in eleven adults worldwide. Most suffer from Type 2 Diabetes which features elevated blood glucose levels and an inability to adequately secrete or respond to insulin. Insulin producing beta-cells have primary cilia which are implicated in the regulation of glucose metabolism, insulin signaling and secretion. To better understand how beta-cell cilia affect glucose handling, we ablate cilia from mature beta-cells by deleting key cilia component Ift88. Here we report that glucose homeostasis and insulin secretion deteriorate over 12 weeks post-induction. Cilia/basal body components are required to suppress spontaneous auto-activation of EphA3 and hyper-phosphorylation of EphA receptors inhibits insulin secretion. In beta-cells, loss of cilia/basal body function leads to polarity defects and epithelial-to-mesenchymal transition. Defective insulin secretion from IFT88-depleted human islets and elevated pEPHA3 in islets from diabetic donors both point to a role for cilia/basal body proteins in human glucose homeostasis. AU - Volta, F. AU - Scerbo, M.J. AU - Seelig, A. AU - Wagner, R. AU - O'Brien, N. AU - Gerst, F. AU - Fritsche, A. AU - Häring, H.-U. AU - Zeigerer, A. AU - Ullrich, S. AU - Gerdes, J.M. C1 - 57634 C2 - 47841 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Glucose homeostasis is regulated by pancreatic beta-cell cilia via endosomal EphA-processing. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - Alterations of Ca2+ homeostasis have been implicated in a wide range of neurodegenerative diseases. Ca2+ efflux from the endoplasmic reticulum into the cytoplasm is controlled by binding of inositol 1,4,5-trisphosphate to its receptor. Activated inositol 1,4,5-trisphosphate receptors are then rapidly degraded by the endoplasmic reticulum-associated degradation pathway. Mutations in genes encoding the neuronal isoform of the inositol 1,4,5-trispho-sphate receptor (ITPR1) and genes involved in inositol 1,4,5-trisphosphate receptor degradation (ERLIN1, ERLIN2) are known to cause hereditary spastic paraplegia (HSP) and cerebellar ataxia. We provide evidence that mutations in the ubiquitin E3 ligase gene RNF170, which targets inositol 1,4,5-trisphosphate receptors for degradation, are the likely cause of autosomal recessive HSP in four unrelated families and functionally evaluate the consequences of mutations in patient fibroblasts, mutant SH-SY5Y cells and by gene knockdown in zebrafish. Our findings highlight inositol 1,4,5-trisphosphate signaling as a candidate key pathway for hereditary spastic paraplegias and cerebellar ataxias and thus prioritize this pathway for therapeutic interventions. AU - Wagner, M. AU - Osborn, D.P.S.* AU - Gehweiler, I.* AU - Nagel, M.* AU - Ulmer, U.* AU - Bakhtiari, S.* AU - Amouri, R.* AU - Boostani, R.* AU - Hentati, F.* AU - Hockley, M.M.* AU - Hölbling, B.* AU - Schwarzmayr, T. AU - Karimiani, E.G.* AU - Kernstock, C.* AU - Maroofian, R.* AU - Müller-Felber, W.* AU - Ozkan, E.* AU - Padilla-Lopez, S.* AU - Reich, S.* AU - Reichbauer, J.* AU - Darvish, H.* AU - Shahmohammadibeni, N.* AU - Tafakhori, A.* AU - Vill, K.* AU - Zuchner, S.* AU - Kruer, M.C.* AU - Winkelmann, J. AU - Jamshidi, Y.* AU - Schüle, R.* C1 - 57170 C2 - 47575 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - B-cell lymphoma (BCL) is the most common hematologic malignancy. While sequencing studies gave insights into BCL genetics, identification of non-mutated cancer genes remains challenging. Here, we describe PiggyBac transposon tools and mouse models for recessive screening and show their application to study clonal B-cell lymphomagenesis. In a genome-wide screen, we discover BCL genes related to diverse molecular processes, including signaling, transcriptional regulation, chromatin regulation, or RNA metabolism. Cross-species analyses show the efficiency of the screen to pinpoint human cancer drivers altered by non-genetic mechanisms, including clinically relevant genes dysregulated epigenetically, transcriptionally, or post-transcriptionally in human BCL. We also describe a CRISPR/Cas9-based in vivo platform for BCL functional genomics, and validate discovered genes, such as Rfx7, a transcription factor, and Phip, a chromatin regulator, which suppress lymphomagenesis in mice. Our study gives comprehensive insights into the molecular landscapes of BCL and underlines the power of genome-scale screening to inform biology. AU - Weber, J.* AU - de la Rosa, J.* AU - Grove, C.S.* AU - Schick, M.* AU - Rad, L.* AU - Baranov, O.* AU - Strong, A.* AU - Pfaus, A.* AU - Friedrich, M.J.* AU - Engleitner, T.* AU - Lersch, R.* AU - Öllinger, R.* AU - Grau, M.* AU - Menendez, I.G.* AU - Martella, M.* AU - Kohlhofer, U.* AU - Banerjee, R.* AU - Turchaninova, M.A.* AU - Scherger, A.* AU - Hoffman, G.J.* AU - Hess J. AU - Kuhn, L. AU - Ammon, T.* AU - Kim, J.* AU - Schneider, G.* AU - Unger, K. AU - Zimber-Strobl, U. AU - Heikenwälder, M.* AU - Schmidt-Supprian, M.* AU - Yang, F.* AU - Saur, D.* AU - Liu, P.* AU - Steiger, K.* AU - Chudakov, D.M.* AU - Lenz, G.* AU - Quintanilla-Martinez, L.* AU - Keller, U.* AU - Vassiliou, G.S.* AU - Cadiñanos, J.* AU - Bradley, A.* AU - Rad, R.* C1 - 55787 C2 - 46547 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - PiggyBac transposon tools for recessive screening identify B-cell lymphoma drivers in mice. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - Macrophages are one of the most functionally-diverse cell types with roles in innate immunity, homeostasis and disease making them attractive targets for diagnostics and therapy. Photo- or optoacoustics could provide non-invasive, deep tissue imaging with high resolution and allow to visualize the spatiotemporal distribution of macrophages in vivo. However, present macrophage labels focus on synthetic nanomaterials, frequently limiting their ability to combine both host cell viability and functionality with strong signal generation. Here, we present a homogentisic acid-derived pigment (HDP) for biocompatible intracellular labeling of macrophages with strong optoacoustic contrast efficient enough to resolve single cells against a strong blood background. We study pigment formation during macrophage differentiation and activation, and utilize this labeling method to track migration of pro-inflammatory macrophages in vivo with whole-body imaging. We expand the sparse palette of macrophage labels for in vivo optoacoustic imaging and facilitate research on macrophage functionality and behavior. AU - Weidenfeld, I. AU - Zakian Dominguez, C.M. AU - Duewell, P.* AU - Chmyrov, A. AU - Klemm, U. AU - Aguirre Bueno, J. AU - Ntziachristos, V. AU - Stiel, A.-C. C1 - 57298 C2 - 47673 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Homogentisic acid-derived pigment as a biocompatible label for optoacoustic imaging of macrophages. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - Salicylic acid (SA)-mediated innate immune responses are activated in plants perceiving volatile monoterpenes. Here, we show that monoterpene-associated responses are propagated in feed-forward loops involving the systemic acquired resistance (SAR) signaling components pipecolic acid, glycerol-3-phosphate, and LEGUME LECTIN-LIKE PROTEIN1 (LLP1). In this cascade, LLP1 forms a key regulatory unit in both within-plant and betweenplant propagation of immunity. The data integrate molecular components of SAR into systemic signaling networks that are separate from conventional, SA-associated innate immune mechanisms. These networks are central to plant-to-plant propagation of immunity, potentially raising SAR to the population level. In this process, monoterpenes act as microbe-inducible plant volatiles, which as part of plant-derived volatile blends have the potential to promote the generation of a wave of innate immune signaling within canopies or plant stands. Hence, plant-to-plant propagation of SAR holds significant potential to fortify future durable crop protection strategies following a single volatile trigger. AU - Wenig, M. AU - Ghirardo, A. AU - Sales, J.H. AU - Pabst, E. AU - Breitenbach, H.H. AU - Antritter, F. AU - Weber, B. AU - Lange, B. AU - Lenk, M. AU - Cameron, R.K.* AU - Schnitzler, J.-P. AU - Vlot, A.C. C1 - 56812 C2 - 47257 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Systemic acquired resistance networks amplify airborne defense cues. JO - Nat. Commun. VL - 10 IS - 1 PB - Nature Publishing Group PY - 2019 SN - 2041-1723 ER - TY - JOUR AB - The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology. AU - Abou-Khalil, B.* AU - Auce, P.* AU - Avbersek, A.* AU - Bahlo, M.* AU - Balding, D.J.* AU - Bast, T.* AU - Baum, L.* AU - Becker, A.J.* AU - Becker, F.* AU - Berghuis, B.* AU - Berkovic, S.F.* AU - Boysen, K.E.* AU - Bradfield, J.P.* AU - Brody, L.C.* AU - Buono, R.J.* AU - Campbell, E.* AU - Cascino, G.D.* AU - Catarino, C.B.* AU - Cavalleri, G.L.* AU - Cherny, S.S.* AU - Chinthapalli, K.* AU - Coffey, A.J.* AU - Compston, A.* AU - Coppola, A.* AU - Cossette, P.* AU - Craig, J.J.* AU - de Haan, G.J.* AU - de Jonghe, P.* AU - de Kovel, C.G.F.* AU - Delanty, N.* AU - Depondt, C.* AU - Devinsky, O.* AU - Dlugos, D.J.* AU - Doherty, C.P.* AU - Elger, C.E.* AU - Eriksson, J.G.* AU - Ferraro, T.N.* AU - Feucht, M.* AU - Francis, B.* AU - Franke, A.* AU - French, J.A.* AU - Freytag, S.* AU - Gaus, V.* AU - Geller, E.B.* AU - Gieger, C. AU - Glauser, T.* AU - Glynn, S.* AU - Goldstein, D.B.* AU - Gui, H.* AU - Guo, Y.* AU - Haas, K.F.* AU - Hakonarson, H.* AU - Hallmann, K.* AU - Strauch, K. AU - Zara, F.* AU - Helbig, I.* AU - Hengsbach, C.* AU - Hjalgrim, H.* AU - Iacomino, M.* AU - Ingason, A.* AU - Jamnadas-Khoda, J.* AU - Johnson, M.R.* AU - Kälviäinen, R.* AU - Kantanen, A.M.* AU - Kasperavičiūte, D.* AU - Kasteleijn-Nolst Trenite, D.* AU - Kirsch, H.E.* AU - Knowlton, R.C.* AU - Koeleman, B.P.C.* AU - Krause, R.* AU - Krenn, M.* AU - Kunz, W.S.* AU - Kuzniecky, R.* AU - Kwan, P.* AU - Zimprich, F.* C1 - 54977 C2 - 46003 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies. JO - Nat. Commun. VL - 9 IS - 1 PB - Nature Publishing Group PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - Correction to: Nature Communications (2017) 8:1231. doi:10.1038/s41467-017-01525-0. AU - Benedetti, E. AU - Pučić-Baković, M.* AU - Keser, T.* AU - Wahl, A. AU - Hassinen, A.* AU - Yang, J.Y.* AU - Liu, L.* AU - Trbojević-Akmačić, I.* AU - Razdorov, G.* AU - Štambuk, J.* AU - Klarić, L.* AU - Ugrina, I.* AU - Selman, M.H.J.* AU - Wuhrer, M.* AU - Rudan, I.* AU - Polasek, O.* AU - Hayward, C.* AU - Grallert, H. AU - Strauch, K. AU - Peters, A. AU - Meitinger, T. AU - Gieger, C. AU - Vilaj, M.* AU - Boons, G.J.* AU - Moremen, K.W.* AU - Ovchinnikova, T.* AU - Bovin, N.* AU - Kellokumpu, S.* AU - Theis, F.J. AU - Lauc, G.* AU - Krumsiek, J. C1 - 52975 C2 - 44391 CY - London TI - Erratum: Publisher Correction: Network inference from glycoproteomics data reveals new reactions in the IgG glycosylation pathway (Nature communications (2017) 8 1 (1483)). JO - Nat. Commun. VL - 9 IS - 1 PB - Nature Publishing Group PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - Pharmacological stimulation of brown adipose tissue (BAT) thermogenesis to increase energy expenditure is progressively being pursued as a viable anti-obesity strategy. Here, we report that pharmacological activation of the cold receptor transient receptor potential cation channel subfamily M member 8 (TRPM8) with agonist icilin mimics the metabolic benefits of cold exposure. In diet-induced obese (DIO) mice, treatment with icilin enhances energy expenditure, and decreases body weight, without affecting food intake. To further potentiate the thermogenic action profile of icilin and add complementary anorexigenic mechanisms, we set out to identify pharmacological partners next to icilin. To that end, we specifically targeted nicotinic acetylcholine receptor (nAChR) subtype alpha3beta4 (α3β4), which we had recognized as a potential regulator of energy homeostasis and glucose metabolism. Combinatorial targeting of TRPM8 and nAChR α3β4 by icilin and dimethylphenylpiperazinium (DMPP) orchestrates synergistic anorexic and thermogenic pathways to reverse diet-induced obesity, dyslipidemia, and glucose intolerance in DIO mice. AU - Clemmensen, C. AU - Jall, S. AU - Kleinert, M. AU - Quarta, C. AU - Gruber, T. AU - Reber, J. AU - Sachs, S. AU - Fischer, K. AU - Feuchtinger, A. AU - Karlas, A. AU - Simonds, S.E.* AU - Grandl, G. AU - Loher, D. AU - Sanchez-Quant, E. AU - Keipert, S. AU - Jastroch, M. AU - Hofmann, S.M. AU - Nascimento, E.B.M.* AU - Schrauwen, P.* AU - Ntziachristos, V. AU - Cowley, M.A.* AU - Finan, B. AU - Müller, T.D. AU - Tschöp, M.H. C1 - 54595 C2 - 45703 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Coordinated targeting of cold and nicotinic receptors synergistically improves obesity and type 2 diabetes. JO - Nat. Commun. VL - 9 IS - 1 PB - Nature Publishing Group PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - In the original PDF version of this article, affiliation 1, 'Institute for Diabetes and Obesity, Helmholtz Diabetes Center (HDC), Helmholtz Zentrum Muenchen & German Center for Diabetes Research (DZD), Neuherberg, Germany', was incorrectly given as 'Institute of Diabetes and Regeneration Research, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health (GmbH), Neuherberg, Germany '. This has now been corrected in the PDF version of the article; the HTML version was correct at the time of publication. AU - Clemmensen, C. AU - Jall, S. AU - Kleinert, M. AU - Quarta, C. AU - Gruber, T. AU - Reber, J. AU - Sachs, S. AU - Fischer, K. AU - Feuchtinger, A. AU - Karlas, A. AU - Simonds, S.E.* AU - Grandl, G. AU - Loher, D. AU - Sanchez-Quant, E. AU - Keipert, S. AU - Jastroch, M. AU - Hofmann, S.M. AU - Nascimento, E.B.M.* AU - Schrauwen, P.* AU - Ntziachristos, V. AU - Cowley, M.A.* AU - Finan, B. AU - Müller, T.D. AU - Tschöp, M.H. C1 - 54781 C2 - 45861 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Coordinated targeting of cold and nicotinic receptors synergistically improves obesity and type 2 diabetes (vol 9, 4304, 2018). JO - Nat. Commun. VL - 9 IS - 1 PB - Nature Publishing Group PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - Polymorphism is a key feature of amyloid fibril structures but it remains challenging to explain these variations for a particular sample. Here, we report electron cryomicroscopy-based reconstructions from different fibril morphologies formed by a peptide fragment from an amyloidogenic immunoglobulin light chain. The observed fibril morphologies vary in the number and cross-sectional arrangement of a structurally conserved building block. A comparison with the theoretically possible constellations reveals the experimentally observed spectrum of fibril morphologies to be governed by opposing sets of forces that primarily arise from the beta-sheet twist, as well as peptide-peptide interactions within the fibril cross-section. Our results provide a framework for rationalizing and predicting the structure and polymorphism of cross-beta fibrils, and suggest that a small number of physical parameters control the observed fibril architectures. AU - Close, W.* AU - Neumann, M.* AU - Schmidt, A.* AU - Hora, M. AU - Annamalai, K.* AU - Schmidt, M.* AU - Reif, B. AU - Schmidt, V.* AU - Grigorieff, N.* AU - Fändrich, M.* C1 - 53051 C2 - 44378 CY - London TI - Physical basis of amyloid fibril polymorphism. JO - Nat. Commun. VL - 9 IS - 1 PB - Nature Publishing Group PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - The RNA-binding proteins Roquin-1 and Roquin-2 redundantly control gene expression and cell-fate decisions. Here, we show that Roquin not only interacts with stem-loop structures, but also with a linear sequence element present in about half of its targets. Comprehensive analysis of a minimal response element of the Nfkbid 3'-UTR shows that six stem-loop structures cooperate to exert robust and profound post-transcriptional regulation. Only binding of multiple Roquin proteins to several stem-loops exerts full repression, which redundantly involved deadenylation and decapping, but also translational inhibition. Globally, most Roquin targets are regulated by mRNA decay, whereas a small subset, including the Nfat5 mRNA, with more binding sites in their 3'-UTRs, are also subject to translational inhibition. These findings provide insights into how the robustness and magnitude of Roqu-inmediated regulation is encoded in complex cis-elements. AU - Essig, K.* AU - Kronbeck, N.* AU - Guimaraes, J.C.* AU - Lohs, C. AU - Schlundt, A. AU - Hoffmann, A.L.* AU - Behrens, G.* AU - Brenner, S. AU - Kowalska, J.* AU - Lopez-Rodriguez, C.* AU - Jemielity, J.* AU - Holtmann, H.* AU - Reiche, K.* AU - Hackermüller, J.* AU - Sattler, M. AU - Zavolan, M.* AU - Heissmeyer, V. C1 - 54373 C2 - 45537 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Roquin targets mRNAs in a 3 '-UTR-specific manner by different modes of regulation. JO - Nat. Commun. VL - 9 IS - 1 PB - Nature Publishing Group PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - Trade-offs and synergies in the supply of forest ecosystem services are common but the drivers of these relationships are poorly understood. To guide management that seeks to promote multiple services, we investigated the relationships between 12 stand-level forest attributes, including structure, composition, heterogeneity and plant diversity, plus 4 environmental factors, and proxies for 14 ecosystem services in 150 temperate forest plots. Our results show that forest attributes are the best predictors of most ecosystem services and are also good predictors of several synergies and trade-offs between services. Environmental factors also play an important role, mostly in combination with forest attributes. Our study suggests that managing forests to increase structural heterogeneity, maintain large trees, and canopy gaps would promote the supply of multiple ecosystem services. These results highlight the potential for forest management to encourage multifunctional forests and suggest that a coordinated landscape-scale strategy could help to mitigate trade-offs in human-dominated landscapes. AU - Felipe-Lucia, M.R.* AU - Soliveres, S.* AU - Penone, C.* AU - Manning, P.* AU - van der Plas, F.* AU - Boch, S.* AU - Prati, D.* AU - Ammer, C.* AU - Schall, P.* AU - Gossner, M.M.* AU - Bauhus, J.* AU - Buscot, F.* AU - Blaser, S.* AU - Blüthgen, N.* AU - de Frutos, A.* AU - Ehbrecht, M.* AU - Frank, K.* AU - Goldmann, K.* AU - Hänsel, F.* AU - Jung, K.* AU - Kahl, T.* AU - Nauss, T.* AU - Oelmann, Y.* AU - Pena, R.* AU - Polle, A.* AU - Renner, S.* AU - Schloter, M. AU - Schöning, I.* AU - Schrumpf, M.* AU - Schulze, E.D.* AU - Solly, E.* AU - Sorkau, E.* AU - Stempfhuber, B. AU - Tschapka, M.* AU - Weisser, W.W.* AU - Wubet, T.* AU - Fischer, M.* AU - Allan, E.* C1 - 54767 C2 - 45812 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Multiple forest attributes underpin the supply of multiple ecosystem services. JO - Nat. Commun. VL - 9 IS - 1 PB - Nature Publishing Group PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); although the basis for these associations remains elusive. Here, we analyze MHC genetic variation among 26,044 lung cancer patients and 20,836 controls densely genotyped across the MHC, using the Illumina Illumina OncoArray or Illumina 660W SNP microarray. We impute sequence variation in classical HLA genes, fine-map MHC associations for lung cancer risk with major histologies and compare results between ethnicities. Independent and novel associations within HLA genes are identified in Europeans including amino acids in the HLA-B*0801 peptide binding groove and an independent HLA-DQB1*06 loci group. In Asians, associations are driven by two independent HLA allele sets that both increase risk in HLA-DQB1*0401 and HLA-DRB1*0701; the latter better represented by the amino acid Ala-104. These results implicate several HLA–tumor peptide interactions as the major MHC factor modulating lung cancer susceptibility. AU - Ferreiro-Iglesias, A.* AU - Lesseur, C.* AU - Mckay, J.* AU - Hung, R.J.* AU - Han, Y.* AU - Zong, X.* AU - Christiani, D.C.* AU - Johansson, M.* AU - Xiao, X.* AU - Li, Y.* AU - Qian, D.C.* AU - Ji, X.* AU - Liu, G.* AU - Caporaso, N.* AU - Scelo, G.* AU - Zaridze, D.* AU - Mukeriya, A.* AU - Kontic, M.* AU - Ognjanovic, S.* AU - Lissowska, J.* AU - Szołkowska, M.* AU - Swiatkowska, B.* AU - Janout, V.* AU - Holcatova, I.* AU - Bolca, C.* AU - Savić, M.* AU - Ognjanovic, M.* AU - Bojesen, S.E.* AU - Wu, X.* AU - Albanes, D.* AU - Aldrich, M.C.* AU - Tardón, A.* AU - Fernández-Somoano, A.* AU - Fernandez-Tardon, G.* AU - Le Marchand, L.* AU - Rennert, G.* AU - Chen, C.* AU - Doherty, J.A.* AU - Goodman, G.* AU - Bickeböller, H.* AU - Wichmann, H.-E. AU - Risch, A.* AU - Rosenberger, A.* AU - Shen, H.* AU - Dai, J.* AU - Field, J.K.* AU - Davies, M.J.* AU - Woll, P.* AU - Teare, M.D.* AU - Kiemeney, L.A.* AU - van der Heijden, E.H.F.M.* AU - Yuan, J.M.* AU - Hong, Y.C.* AU - Haugen, A.* AU - Zienolddiny, S.* AU - Lam, S.* AU - Tsao, M.S.* AU - Grankvist, K.* AU - Schabath, M.B.* AU - Andrew, A.S.* AU - Duell, E.* AU - Melander, O.* AU - Brunnström, H.* AU - Lazarus, P.* AU - Arnold, S.J.* AU - Slone, S.* AU - Byun, J.* AU - Kamal, A.K.* AU - Zhu, D.* AU - Landi, M.T.* AU - Amos, C.I.* AU - Brennan, P.* C1 - 54434 C2 - 45571 TI - Fine mapping of MHC region in lung cancer highlights independent susceptibility loci by ethnicity. JO - Nat. Commun. VL - 9 IS - 1 PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - The role of rare variants in complex traits remains uncharted. Here, we conduct deep whole genome sequencing of 1457 individuals from an isolated population, and test for rare variant burdens across six cardiometabolic traits. We identify a role for rare regulatory variation, which has hitherto been missed. We find evidence of rare variant burdens that are independent of established common variant signals (ADIPOQ and adiponectin, P = 4.2 x 10(-8); APOC3 and triglyceride levels, P = 1.5 x 10(-26)), and identify replicating evidence for a burden associated with triglyceride levels in FAM189B (P = 2.2 x 10(-8)), indicating a role for this gene in lipid metabolism. AU - Gilly, A.* AU - Suveges, D.* AU - Kuchenbaecker, K.B.* AU - Pollard, M.* AU - Southam, L.* AU - Hatzikotoulas, K. AU - Farmaki, A.-E.* AU - Bjornland, T.* AU - Waples, R.* AU - Appel, E.V.R.* AU - Casalone, E.* AU - Melloni, G.* AU - Kilian, B.* AU - Rayner, N.W.* AU - Ntalla, I.* AU - Kundu, K.* AU - Walter, K.* AU - Danesh, J.* AU - Butterworth, A.S.* AU - Barroso, I.* AU - Tsafantakis, E.* AU - Dedoussis, G.* AU - Moltke, I.* AU - Zeggini, E. C1 - 54738 C2 - 45824 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Cohort-wide deep whole genome sequencing and the allelic architecture of complex traits. JO - Nat. Commun. VL - 9 IS - 1 PB - Nature Publishing Group PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - The original version of this Article contained an error in Fig. 2. In panel a, the two legend items "rare" and "common" were inadvertently swapped. This has been corrected in both the PDF and HTML versions of the Article. AU - Gilly, A.* AU - Suveges, D.* AU - Kuchenbaecker, K.B.* AU - Pollard, M.* AU - Southam, L.* AU - Hatzikotoulas, K. AU - Farmaki, A.-E.* AU - Bjornland, T.* AU - Waples, R.* AU - Appel, E.V.R.* AU - Casalone, E.* AU - Melloni, G.* AU - Kilian, B.* AU - Rayner, N.W.* AU - Ntalla, I.* AU - Kundu, K.* AU - Walter, K.* AU - Danesh, J.* AU - Butterworth, A.S.* AU - Barroso, I.* AU - Tsafantakis, E.* AU - Dedoussis, G.* AU - Moltke, I.* AU - Zeggini, E. C1 - 55060 C2 - 46048 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Cohort-wide deep whole genome sequencing and the allelic architecture of complex traits. JO - Nat. Commun. VL - 9 IS - 1 PB - Nature Publishing Group PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - The northern white rhinoceros (NWR, Ceratotherium simum cottoni) is the most endangered mammal in the world with only two females surviving. Here we adapt existing assisted reproduction techniques (ART) to fertilize Southern White Rhinoceros (SWR) oocytes with NWR spermatozoa. We show that rhinoceros oocytes can be repeatedly recovered from live SWR females by transrectal ovum pick-up, matured, fertilized by intracytoplasmic sperm injection and developed to the blastocyst stage in vitro. Next, we generate hybrid rhinoceros embryos in vitro using gametes of NWR and SWR. We also establish embryonic stem cell lines from the SWR blastocysts. Blastocysts are cryopreserved for later embryo transfer. Our results indicate that ART could be a viable strategy to rescue genes from the iconic, almost extinct, northern white rhinoceros and may also have broader impact if applied with similar success to other endangered large mammalian species. AU - Hildebrandt, T.B.* AU - Hermes, R.* AU - Colleoni, S.* AU - Diecke, S.* AU - Holtze, S.* AU - Renfree, M.B.* AU - Stejskal, J.* AU - Hayashi, K.* AU - Drukker, M. AU - Loi, P.* AU - Göritz, F.* AU - Lazzari, G.* AU - Galli, C.* C1 - 53875 C2 - 45050 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Embryos and embryonic stem cells from the white rhinoceros. JO - Nat. Commun. VL - 9 IS - 1 PB - Nature Publishing Group PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - The human gut microbiome has been associated with many health factors but variability between studies limits exploration of effects between them. Gut microbiota profiles are available for >2700 members of the deeply phenotyped TwinsUK cohort, providing a uniform platform for such comparisons. Here, we present gut microbiota association analyses for 38 common diseases and 51 medications within the cohort. We describe several novel associations, highlight associations common across multiple diseases, and determine which diseases and medications have the greatest association with the gut microbiota. These results provide a reference for future studies of the gut microbiome and its role in human health. AU - Jackson, M.A.* AU - Verdi, S.* AU - Maxan, M.E.* AU - Shin, C.M.* AU - Zierer, J. AU - Bowyer, R.C.E.* AU - Martin, T.* AU - Williams, F.M.K.* AU - Menni, C.* AU - Bell, J.T.* AU - Spector, T.D.* AU - Steves, C.J.* C1 - 53964 C2 - 45159 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Gut microbiota associations with common diseases and prescription medications in a population-based cohort. JO - Nat. Commun. VL - 9 IS - 1 PB - Nature Publishing Group PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer. AU - Ji, X.* AU - Bossé, Y.* AU - Landi, M.T.* AU - Gui, J.* AU - Xiao, X.* AU - Qian, D.C.* AU - Joubert, P.* AU - Lamontagne, M.* AU - Li, Y.* AU - Gorlov, I.* AU - de Biasi, M.* AU - Han, Y.* AU - Gorlova, O.* AU - Hung, R.J.* AU - Wu, X.* AU - Mckay, J.* AU - Zong, X.* AU - Carreras-Torres, R.* AU - Christiani, D.C.* AU - Caporaso, N.* AU - Johansson, M.* AU - Liu, G.* AU - Bojesen, S.E.* AU - Le Marchand, L.* AU - Albanes, D.* AU - Bickeböller, H.* AU - Aldrich, M.C.* AU - Bush, W.S.* AU - Tardón, A.* AU - Rennert, G.* AU - Chen, C.* AU - Teare, M.D.* AU - Field, J.K.* AU - Kiemeney, L.A.* AU - Lazarus, P.* AU - Haugen, A.* AU - Lam, S.* AU - Schabath, M.B.* AU - Andrew, A.S.* AU - Shen, H.* AU - Hong, Y.C.* AU - Yuan, J.M.* AU - Bertazzi, P.A.* AU - Pesatori, A.C.* AU - Ye, Y.* AU - Diao, N.* AU - Su, L.* AU - Zhang, R.* AU - Brhane, Y.* AU - Leighl, N.* AU - Johansen, J.S.* AU - Mellemgaard, A.* AU - Saliba, W.* AU - Haiman, C.* AU - Wilkens, L.* AU - Fernández-Somoano, A.* AU - Fernandez-Tardon, G.* AU - van der Heijden, E.H.F.M.* AU - Kim, J.H.* AU - Dai, J.C.* AU - Hu, Z.* AU - Davies, M.P.A.* AU - Marcus, M.W.* AU - Brunnström, H.* AU - Manjer, J.* AU - Melander, O.* AU - Müller, D.C.* AU - Overvad, K.* AU - Trichopoulou, A.* AU - Tumino, R.* AU - Doherty, J.A.* AU - Goodman, G.E.* AU - Cox, A.* AU - Taylor, F.* AU - Woll, P.* AU - Brüske, I. AU - Manz, J. AU - Muley, T.* AU - Risch, A.* AU - Rosenberger, A.* AU - Grankvist, K.* AU - Shepherd, F.A.* AU - Tsao, M.S.* AU - Arnold, S.M.* AU - Haura, E.B.* AU - Bolca, C.* AU - Holcatova, I.* AU - Janout, V.* AU - Kontic, M.* AU - Lissowska, J.* AU - Mukeria, A.* AU - Ognjanovic, S.* AU - Orlowski, T.M.* AU - Scelo, G.* AU - Swiatkowska, B.* AU - Zaridze, D.* AU - Bakke, P.* AU - Skaug, V.* AU - Zienolddiny, S.* AU - Duell, E.J.* AU - Butler, L.M.* AU - Koh, W.P.* AU - Gao, Y.T.* AU - Houlston, R.* AU - McLaughlin, J.* AU - Stevens, V.L.* AU - Nickle, D.C.* AU - Obeidat, M.* AU - Timens, W.* AU - Zhu, B.M.* AU - Song, L.* AU - Artigas, M.S.* AU - Tobin, M.D.* AU - Wain, L.V.* AU - Gu, F.* AU - Byun, J.* AU - Kamal, A.K.* AU - Zhu, D.* AU - Tyndale, R.F.* AU - Wei, W.Q.* AU - Chanock, S.* AU - Brennan, P.* AU - Amos, C.I.* C1 - 54135 C2 - 45310 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk. JO - Nat. Commun. VL - 9 IS - 1 PB - Nature Publishing Group PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10 -9 at rs8018720 in SEC23A, and P = 1.9×10 -14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels. AU - Jiang, X.* AU - O'Reilly, P.F.* AU - Aschard, H.* AU - Hsu, Y.H.* AU - Richards, J.B.* AU - Dupuis, J.* AU - Ingelsson, E.* AU - Karasik, D.* AU - Pilz, S.* AU - Berry, D.* AU - Kestenbaum, B.* AU - Zheng, J.* AU - Luan, J.* AU - Sofianopoulou, E.* AU - Streeten, E.A.* AU - Albanes, D.* AU - Lutsey, P.L.* AU - Yao, L.* AU - Tang, W.* AU - Econs, M.J.* AU - Wallaschofski, H.* AU - Voelzke, H.* AU - Zhou, A.* AU - Power, C.* AU - McCarthy, M.I.* AU - Michos, E.D.* AU - Boerwinkle, E.* AU - Weinstein, S.J.* AU - Freedman, N.D.* AU - Huang, W.* AU - van Schoor, N.M.* AU - van der Velde, N.* AU - de Groot, L.C.P.G.M.* AU - Enneman, A.W.* AU - Cupples, L.A.* AU - Booth, S.L.* AU - Vasan, R.S.* AU - Liu, C.* AU - Zhou, Y.* AU - Ripatti, S.* AU - Ohlsson, C.* AU - Vandenput, L.* AU - Lorentzon, M.* AU - Eriksson, J.G.* AU - Shea, M.K.* AU - Houston, D.K.* AU - Kritchevsky, S.B.* AU - Liu, Y.* AU - Lohman, K.K.* AU - Ferrucci, L.* AU - Peacock, M.* AU - Gieger, C. AU - Beekman, M.* AU - Slagboom, E.* AU - Deelen, J.* AU - van Heemst, D.* AU - Kleber, M.E.* AU - Maerz, W.* AU - de Boer, I.H.* AU - Wood, A.C.* AU - Rotter, J.I.* AU - Rich, S.S.* AU - Robinson-Cohen, C.* AU - den Heijer, M.* AU - Jarvelin, M.R.* AU - Cavadino, A.* AU - Joshi, P.K.* AU - Wilson, J.F.* AU - Hayward, C.* AU - Lind, L.* AU - Michaelsson, K.* AU - Trompet, S.* AU - Zillikens, M.C.* AU - Uitterlinden, A.G.* AU - Rivadeneira, F.* AU - Broer, L.* AU - Zgaga, L.* AU - Campbell, H.* AU - Theodoratou, E.* AU - Farrington, S.M.* AU - Timofeeva, M.* AU - Dunlop, M.G.* AU - Valdes, A.M.* AU - Tikkanen, E.* AU - Lehtimäki, T.* AU - Lyytikainen, L.* AU - Kähönen, M.* AU - Raitakari, O.T.* AU - Mikkilä, V.* AU - Ikram, M.A.* AU - Sattar, N.* AU - Jukema, J.W.* AU - Wareham, N.J.* AU - Langenberg, C.* AU - Forouhi, N.G.* AU - Gundersen, T.E.* AU - Khaw, K.* AU - Butterworth, A.S.* AU - Danesh, J.* AU - Spector, T.* AU - Wang, T.J.* AU - Hyppönen, E.* AU - Kraft, P.* AU - Kiel, D.P.* C1 - 52846 C2 - 44307 CY - London TI - Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels. JO - Nat. Commun. VL - 9 IS - 1 PB - Nature Publishing Group PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - Interactions between the gut microbial ecosystem and host lipid homeostasis are highly relevant to host physiology and metabolic diseases. We present a comprehensive multiomics view of the effect of intestinal microbial colonization on hepatic lipid metabolism, integrating transcriptomic, proteomic, phosphoproteomic, and lipidomic analyses of liver and plasma samples from germfree and specific pathogen-free mice. Microbes induce monounsaturated fatty acid generation by stearoyl-CoA desaturase 1 and polyunsaturated fatty acid elongation by fatty acid elongase 5, leading to significant alterations in glycerophospholipid acyl-chain profiles. A composite classification score calculated from the observed alterations in fatty acid profiles in germfree mice clearly differentiates antibiotic-treated mice from untreated controls with high sensitivity. Mechanistic investigations reveal that acetate originating from gut microbial degradation of dietary fiber serves as precursor for hepatic synthesis of C16 and C18 fatty acids and their related glycerophospholipid species that are also released into the circulation. AU - Kindt, A. AU - Liebisch, G.* AU - Clavel, T.* AU - Haller, D.* AU - Hörmannsperger, G.* AU - Yoon, H.* AU - Kolmeder, D.* AU - Sigruener, A.* AU - Krautbauer, S.* AU - Seeliger, C.* AU - Ganzha, A.* AU - Schweizer, S.* AU - Morisset, R.* AU - Strowig, T.* AU - Daniel, H.* AU - Helm, D.* AU - Küster, B.* AU - Krumsiek, J. AU - Ecker, J.R.* C1 - 54376 C2 - 45525 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - The gut microbiota promotes hepatic fatty acid desaturation and elongation in mice. JO - Nat. Commun. VL - 9 IS - 1 PB - Nature Publishing Group PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - Post-transcriptional mechanisms play a predominant role in the control of microRNA (miRNA) production. Recognition of the terminal loop of precursor miRNAs by RNA-binding proteins (RBPs) influences their processing; however, the mechanistic basis for how levels of individual or subsets of miRNAs are regulated is mostly unexplored. We previously showed that hnRNP A1, an RBP implicated in many aspects of RNA processing, acts as an auxiliary factor that promotes the Microprocessor-mediated processing of pri-mir-18a. Here, by using an integrative structural biology approach, we show that hnRNP A1 forms a 1:1 complex with pri-mir-18a where both RNA recognition motifs (RRMs) bind to cognate RNA sequence motifs in the terminal loop of pri-mir-18a. Terminal loop binding induces an allosteric destabilization of base-pairing in the pri-mir-18a stem that promotes its downstream processing. Our results highlight terminal loop RNA recognition by RBPs as a potential general principle of miRNA biogenesis and regulation. AU - Kooshapur, H. AU - Choudhury, N.R.* AU - Simon, B.* AU - Mühlbauer, M.* AU - Jussupow, A.* AU - Fernandez, N.* AU - Jones, A. AU - Dallmann, A. AU - Gabel, F.* AU - Camilloni, C.* AU - Michlewski, G.* AU - Caceres, J.F.* AU - Sattler, M. C1 - 53912 C2 - 45151 TI - Structural basis for terminal loop recognition and stimulation of pri-miRNA-18a processing by hnRNP A1. JO - Nat. Commun. VL - 9 IS - 1 PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - Human adenovirus (HAdV) E1B-55K is a multifunctional regulator of productive viral replication and oncogenic transformation in nonpermissive mammalian cells. These functions depend on E1B-55K's posttranslational modification with the SUMO protein and its binding to HAdV E4orf6. Both early viral proteins recruit specific host factors to form an E3 ubiquitin ligase complex that targets antiviral host substrates for proteasomal degradation. Recently, we reported that the PML-NB associated factor Daxx represses efficient HAdV productive infection and is proteasomally degraded via a SUMO-E1B-55K-dependent, E4orf6-independent pathway, the details of which remained to be established. RNF4, a cellular SUMO-targeted ubiquitin ligase (STUbL), induces ubiquitinylation of specific SUMOy lated proteins and plays an essential role during DNA repair. Here, we show that E1B-55K recruits RNF4 to the insoluble nuclear matrix fraction of the infected cell to support RNF4/Daxx association, promoting Daxx PTM and thus inhibiting this antiviral factor. Removing RNF4 from infected cells using RNA interference resulted in blocking the proper establishment of viral replication centers and significantly diminished viral gene expression. These results provide a model for how HAdV antagonize the antiviral host responses by exploiting the functional capacity of cellular STUbLs. Thus, RNF4 and its STUbL function represent a positive factor during lytic infection and a novel candidate for future therapeutic antiviral intervention strategies.IMPORTANCE Daxx is a PML-NB-associated transcription factor that was recently shown to repress efficient HAdV productive infection. To counteract this antiviral measurement during infection, Daxx is degraded via a novel pathway including viral E1B-55K and host proteasomes. This virus-mediated degradation is independent of the classical HAdV E3 ubiquitin ligase complex, which is essential during viral infection to target other host antiviral substrates. To maintain a productive viral life cycle, HAdV E1B-55K early viral protein inhibits the chromatin-remodeling factor Daxx in a SUMO-dependent manner. In addition, viral E1B-55K protein recruits the STUbL RNF4 and sequesters it into the insoluble fraction of the infected cell. E1B-55K promotes complex formation between RNF4-and E1B-55K-targeted Daxx protein, supporting Daxx posttranslational modification prior to functional inhibition. Hence, RNF4 represents a novel host factor that is beneficial for HAdV gene expression by supporting Daxx counteraction. In this regard, RNF4 and other STUbL proteins might represent novel targets for therapeutic intervention. AU - Kular, L.* AU - Liu, Y.* AU - Ruhrmann, S.* AU - Zheleznyakova, G.* AU - Marabita, F.* AU - Gomez-Cabrero, D.* AU - James, T.* AU - Ewing, E.* AU - Lindén, M.* AU - Górnikiewicz, B.* AU - Aeinehband, S.* AU - Stridh, P.* AU - Link, J.* AU - Andlauer, T.F.M.* AU - Gasperi, C.* AU - Wiendl, H.* AU - Zipp, F.* AU - Gold, R.* AU - Tackenberg, B.* AU - Weber, F.* AU - Hemmer, B.* AU - Strauch, K. AU - Heilmann-Heimbach, S.* AU - Rawal, R.* AU - Schminke, U.* AU - Schmidt, C.O.* AU - Kacprowski, T.* AU - Franke, A.* AU - Laudes, M.* AU - Dilthey, A.T.* AU - Celius, E.G.* AU - Søndergaard, H.B.* AU - Tegnér, J.* AU - Harbo, H.F.* AU - Oturai, A.B.* AU - Olafsson, S.* AU - Eggertsson, H.P.* AU - Halldorsson, B.V.* AU - Hjaltason, H.* AU - Olafsson, E.* AU - Jonsdottir, I.* AU - Stefansson, K.* AU - Olsson, T.* AU - Piehl, F.* AU - Ekström, T.J.* AU - Kockum, I.* AU - Feinberg, A.P.* AU - Jagodic, M.* C1 - 53684 C2 - 44938 CY - 1752 N St Nw, Washington, Dc 20036-2904 Usa TI - DNA methylation as a mediator of HLA-DRB1(star)15:01 and a protective variant in multiple sclerosis. JO - Nat. Commun. VL - 9 IS - 1 PB - Amer Soc Microbiology PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - Dynamic polarisation of tumour cells is essential for metastasis. While the role of polarisation during dedifferentiation and migration is well established, polarisation of metastasising tumour cells during phases of detachment has not been investigated. Here we identify and characterise a type of polarisation maintained by single cells in liquid phase termed single-cell (sc) polarity and investigate its role during metastasis. We demonstrate that sc polarity is an inherent feature of cells from different tumour entities that is observed in circulating tumour cells in patients. Functionally, we propose that the sc pole is directly involved in early attachment, thereby affecting adhesion, transmigration and metastasis. In vivo, the metastatic capacity of cell lines correlates with the extent of sc polarisation. By manipulating sc polarity regulators and by generic depolarisation, we show that sc polarity prior to migration affects transmigration and metastasis in vitro and in vivo. AU - Lorentzen, A.R. AU - Becker, P.F. AU - Kosla, J. AU - Saini, M.* AU - Weidele, K.* AU - Ronchi, P.* AU - Klein, C.* AU - Wolf, M.J.* AU - Geist, F.* AU - Seubert, B. AU - Ringelhan, M. AU - Mihic-Probst, D.* AU - Esser, K. AU - Roblek, M.* AU - Kuehne, F. AU - Bianco, G. AU - O'Connor, T. AU - Müller, Q.* AU - Schuck, K.* AU - Lange, S.* AU - Hartmann, D.* AU - Spaich, S.* AU - Groß, O.* AU - Utikal, J.* AU - Haferkamp, S.* AU - Sprick, M.R.* AU - Damle-Vartak, A.* AU - Hapfelmeier, A.* AU - Hüser, N.* AU - Protzer, U. AU - Trumpp, A.* AU - Saur, D.* AU - Vartak, N.* AU - Klein, C.A.* AU - Polzer, B.* AU - Borsig, L.* AU - Heikenwälder, M. C1 - 53080 C2 - 44470 CY - London TI - Single cell polarity in liquid phase facilitates tumour metastasis. JO - Nat. Commun. VL - 9 IS - 1 PB - Nature Publishing Group PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - X-chromosome inactivation (XCI), i.e., the inactivation of one of the female X chromosomes, restores equal expression of X-chromosomal genes between females and males. However, similar to 10% of genes show variable degrees of escape from XCI between females, although little is known about the causes of variable XCI. Using a discovery data-set of 1867 females and 1398 males and a replication sample of 3351 females, we show that genetic variation at three autosomal loci is associated with female-specific changes in X-chromosome methylation. Through cis-eQTL expression analysis, we map these loci to the genes SMCHD1/METTL4, TRIM6/HBG2, and ZSCAN9. Low-expression alleles of the loci are predominantly associated with mild hypomethylation of CpG islands near genes known to variably escape XCI, implicating the autosomal genes in variable XCI. Together, these results suggest a genetic basis for variable escape from XCI and highlight the potential of a population genomics approach to identify genes involved in XCI. AU - Luijk, R.* AU - Wu, H.* AU - Ward-Caviness, C.K. AU - Hannon, E.* AU - Carnero-Montoro, E.* AU - Min, J.L.* AU - Mandaviya, P.R.* AU - Müller-Nurasyid, M. AU - Mei, H.* AU - van der Maarel, S.M.* AU - BIOS Consortium* AU - Relton, C.* AU - Mill, J.* AU - Waldenberger, M. AU - Bell, J.T.* AU - Jansen, R.* AU - Zhernakova, A.* AU - Franke, L.* AU - 't Hoen, P.A.C.* AU - Boomsma, D.I.* AU - van Duijn, C.M.* AU - Van Greevenbroek, M.M.J.* AU - Veldink, J.H.* AU - Wijmenga, C.* AU - van Meurs, J.B.* AU - Daxinger, L.* AU - Slagboom, P.E.* AU - van Zwet, E.W.* AU - Heijmans, B.T.* C1 - 54320 C2 - 45464 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Autosomal genetic variation is associated with DNA methylation in regions variably escaping X-chromosome inactivation. JO - Nat. Commun. VL - 9 IS - 1 PB - Nature Publishing Group PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - Ewing sarcoma (EWS) is a pediatric cancer characterized by the EWSR1-FLI1 fusion. We performed a genome-wide association study of 733 EWS cases and 1346 unaffected individuals of European ancestry. Our study replicates previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1, and identifies new loci at 6p25.1, 20p11.22 and 20p11.23. Effect estimates exhibit odds ratios in excess of 1.7, which is high for cancer GWAS, and striking in light of the rarity of EWS cases in familial cancer syndromes. Expression quantitative trait locus (eQTL) analyses identify candidate genes at 6p25.1 (RREB1) and 20p11.23 (KIZ). The 20p11.22 locus is near NKX2-2, a highly overexpressed gene in EWS. Interestingly, most loci reside near GGAA repeat sequences and may disrupt binding of the EWSR1-FLI1 fusion protein. The high locus to case discovery ratio from 733 EWS cases suggests a genetic architecture in which moderate risk SNPs constitute a significant fraction of risk. AU - Machiela, M.J.* AU - Grünewald, T.G.P.* AU - Surdez, D.* AU - Reynaud, S.* AU - Mirabeau, O.* AU - Karlins, E.* AU - Rubio, R.A.* AU - Zaidi, S.* AU - Grossetete-Lalami, S.* AU - Ballet, S.* AU - Lapouble, E.* AU - Laurence, V.* AU - Michon, J.* AU - Pierron, G.* AU - Kovar, H.* AU - Gaspar, N.* AU - Kontny, U.* AU - González-Neira, A.* AU - Picci, P.* AU - Alonso, J.* AU - Patino-Garcia, A.* AU - Corradini, N.* AU - Bérard, P.M.* AU - Freedman, N.D.* AU - Rothman, N.* AU - Dagnall, C.L.* AU - Burdett, L.* AU - Jones, K.* AU - Manning, M.* AU - Wyatt, K.* AU - Zhou, W.* AU - Yeager, M.* AU - Cox, D.G.* AU - Hoover, R.N.* AU - Khan, J.C.* AU - Armstrong, G.T.* AU - Leisenring, W.M.* AU - Bhatia, S.* AU - Robison, L.L.* AU - Kulozik, A.E.* AU - Kriebel, J. AU - Meitinger, T. AU - Metzler, M.* AU - Hartmann, W.* AU - Strauch, K. AU - Kirchner, T.* AU - Dirksen, U.* AU - Morton, L.M.* AU - Mirabello, L.* AU - Tucker, M.A.* AU - Tirode, F.* AU - Chanock, S.J.* AU - Delattre, O.* C1 - 54162 C2 - 45332 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility. JO - Nat. Commun. VL - 9 IS - 1 PB - Nature Publishing Group PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - Interaction proteomics studies have provided fundamental insights into multimeric biomolecular assemblies and cell-scale molecular networks. Significant recent developments in mass spectrometry-based interaction proteomics have been fueled by rapid advances in label-free, isotopic, and isobaric quantitation workflows. Here, we report a quantitative protein-DNA and protein-nucleosome binding assay that uses affinity purifications from nuclear extracts coupled with isobaric chemical labeling and mass spectrometry to quantify apparent binding affinities proteome-wide. We use this assay with a variety of DNA and nucleosome baits to quantify apparent binding affinities of monomeric and multimeric transcription factors and chromatin remodeling complexes. AU - Makowski, M.M.* AU - Grawe, C.* AU - Foster, B. AU - Nguyen, N.V.* AU - Bartke, T. AU - Vermeulen, M.* C1 - 53819 C2 - 45061 CY - 233 Spring St, New York, Ny 10013 Usa TI - Global profiling of protein-DNA and protein-nucleosome binding affinities using quantitative mass spectrometry. JO - Nat. Commun. VL - 9 IS - 1 PB - Springer PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - The Wnt signalling pathway, one of the core de-regulated pathways in chronic lymphocytic leukaemia (CLL), is activated in only a subset of patients through somatic mutations. Here we describe alternative, microenvironment-dependent mechanisms of Wnt activation in malignant B cells. We show that tumour cells specifically induce Notch2 activity in mesenchymal stromal cells (MSCs) required for the transcription of the complement factor C1q. MSC-derived C1q in turn inhibits Gsk3-β mediated degradation of β-catenin in CLL cells. Additionally, stromal Notch2 activity regulates N-cadherin expression in CLL cells, which interacts with and further stabilises β-catenin. Together, these stroma Notch2-dependent mechanisms induce strong activation of canonical Wnt signalling in CLL cells. Pharmacological inhibition of the Wnt pathway impairs microenvironment-mediated survival of tumour cells. Similarly, inhibition of Notch signalling diminishes survival of stroma-protected CLL cells in vitro and disease engraftment in vivo. Notch2 activation in the microenvironment is a pre-requisite for the activation of canonical Wnt signalling in tumour cells. AU - Mangolini, M.* AU - Götte, F.* AU - Moore, A.* AU - Ammon, T.* AU - Oelsner, M.* AU - Lutzny-Geier, G.* AU - Klein-Hitpass, L.* AU - Williamson, J.C.* AU - Lehner, P.J.* AU - Dürig, J.* AU - Möllmann, M.* AU - Rásó-Barnett, L.* AU - Hughes, K.* AU - Santoro, A.* AU - Méndez-Ferrer, S.* AU - Oostendorp, R.A.J.* AU - Zimber-Strobl, U. AU - Peschel, C.* AU - Hodson, D.J.* AU - Schmidt-Supprian, M.* AU - Ringshausen, I.* C1 - 54435 C2 - 45572 TI - Notch2 controls non-autonomous Wnt-signalling in chronic lymphocytic leukaemia. JO - Nat. Commun. VL - 9 IS - 1 PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - Malignant pleural effusion (MPE) is a frequent metastatic manifestation of human cancers. While we previously identified KRAS mutations as molecular culprits of MPE formation, the underlying mechanism remained unknown. Here, we determine that non-canonical IKK alpha-RelB pathway activation of KRAS-mutant tumor cells mediates MPE development and this is fueled by host-provided interleukin IL-1 beta. Indeed, IKK alpha is required for the MPE-competence of KRAS-mutant tumor cells by activating non-canonical NF-kappa B signaling. IL-1 beta fuels addiction of mutant KRAS to IKK alpha resulting in increased CXCL1 secretion that fosters MPE-associated inflammation. Importantly, IL-1 beta-mediated NF-kappa B induction in KRAS-mutant tumor cells, as well as their resulting MPE-competence, can only be blocked by co-inhibition of both KRAS and IKK alpha, a strategy that overcomes drug resistance to individual treatments. Hence we show that mutant KRAS facilitates IKK alpha-mediated responsiveness of tumor cells to host IL-1 beta, thereby establishing a host-to-tumor signaling circuit that culminates in inflammatory MPE development and drug resistance. AU - Marazioti, A.* AU - Lilis, I.* AU - Vreka, M. AU - Apostolopoulou, H.* AU - Kalogeropoulou, A.* AU - Giopanou, I.* AU - Giotopoulou, G.A.* AU - Krontira, A.C.* AU - Iliopoulou, M.* AU - Kanellakis, N.I.* AU - Agalioti, T.* AU - Giannou, A.D.* AU - Jones-Paris, C.* AU - Iwakura, Y.* AU - Kardamakis, D.* AU - Blackwell, T.S.* AU - Taraviras, S.* AU - Spella, M.* AU - Stathopoulos, G.T. C1 - 53055 C2 - 44380 CY - London TI - Myeloid-derived interleukin-1β drives oncogenic KRAS-NF-κΒ addiction in malignant pleural effusion. JO - Nat. Commun. VL - 9 IS - 1 PB - Nature Publishing Group PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - Human adenovirus (HAdV) E1B-55K is a multifunctional regulator of productive viral replication and oncogenic transformation in nonpermissive mammalian cells. These functions depend on E1B-55K's posttranslational modification with the SUMO protein and its binding to HAdV E4orf6. Both early viral proteins recruit specific host factors to form an E3 ubiquitin ligase complex that targets antiviral host substrates for proteasomal degradation. Recently, we reported that the PML-NB associated factor Daxx represses efficient HAdV productive infection and is proteasomally degraded via a SUMO-E1B-55K-dependent, E4orf6-independent pathway, the details of which remained to be established. RNF4, a cellular SUMO-targeted ubiquitin ligase (STUbL), induces ubiquitinylation of specific SUMOy lated proteins and plays an essential role during DNA repair. Here, we show that E1B-55K recruits RNF4 to the insoluble nuclear matrix fraction of the infected cell to support RNF4/Daxx association, promoting Daxx PTM and thus inhibiting this antiviral factor. Removing RNF4 from infected cells using RNA interference resulted in blocking the proper establishment of viral replication centers and significantly diminished viral gene expression. These results provide a model for how HAdV antagonize the antiviral host responses by exploiting the functional capacity of cellular STUbLs. Thus, RNF4 and its STUbL function represent a positive factor during lytic infection and a novel candidate for future therapeutic antiviral intervention strategies.IMPORTANCE Daxx is a PML-NB-associated transcription factor that was recently shown to repress efficient HAdV productive infection. To counteract this antiviral measurement during infection, Daxx is degraded via a novel pathway including viral E1B-55K and host proteasomes. This virus-mediated degradation is independent of the classical HAdV E3 ubiquitin ligase complex, which is essential during viral infection to target other host antiviral substrates. To maintain a productive viral life cycle, HAdV E1B-55K early viral protein inhibits the chromatin-remodeling factor Daxx in a SUMO-dependent manner. In addition, viral E1B-55K protein recruits the STUbL RNF4 and sequesters it into the insoluble fraction of the infected cell. E1B-55K promotes complex formation between RNF4-and E1B-55K-targeted Daxx protein, supporting Daxx posttranslational modification prior to functional inhibition. Hence, RNF4 represents a novel host factor that is beneficial for HAdV gene expression by supporting Daxx counteraction. In this regard, RNF4 and other STUbL proteins might represent novel targets for therapeutic intervention. AU - Momozawa, Y.* AU - Dmitrieva, J.* AU - Théâtre, E.* AU - Deffontaine, V.* AU - Rahmouni, S.* AU - Charloteaux, B.* AU - Crins, F.* AU - Docampo, E.* AU - Elansary, M.* AU - Gori, A.S.* AU - Lecut, C.* AU - Mariman, R.* AU - Mni, M.* AU - Oury, C.* AU - Altukhov, I.* AU - Alexeev, D.* AU - Aulchenko, Y.* AU - Amininejad, L.* AU - Bouma, G.* AU - Hoentjen, F.* AU - Löwenberg, M.* AU - Oldenburg, B.* AU - Pierik, M.J.* AU - Vander Meulen-De Jong, A.E.* AU - Van Der Woude, C.J.* AU - Visschedijk, M.C.* AU - Lathrop, M* AU - Hugot, J.P.* AU - Weersma, R.K.* AU - de Vos, M.* AU - Franchimont, D.* AU - Vermeire, S.* AU - Kubo, M.* AU - Louis, E.* AU - Georges, M.* AU - Abraham, C.* AU - Achkar, J.P.* AU - Ahmad, T.* AU - Ananthakrishnan, A.N.* AU - Andersen, V.* AU - Anderson, C.A.* AU - Andrews, J.M.* AU - Annese, V.* AU - Aumais, G.* AU - Baidoo, L.* AU - Baldassano, R.N.* AU - Bampton, P.A.* AU - Barclay, M.* AU - Barrett, J.C.* AU - Bayless, T.M.* AU - Bethge, J.* AU - Bitton, A.* AU - Boucher, G.* AU - Brand, S.* AU - Brandt, B.* AU - Brant, S.R.* AU - Büning, C.* AU - Chew, A.* AU - Cho, J.H.* AU - Cleynen, I.* AU - Cohain, A.* AU - Croft, A.* AU - Daly, M.J.* AU - D'Amato, M.* AU - Danese, S.* AU - de Jong, D.* AU - Denapiene, G.* AU - Denson, L.A.* AU - Devaney, K.L.* AU - Dewit, O.* AU - D'Inca, R.* AU - Dubinsky, M.* AU - Duerr, R.H.* AU - Edwards, C.* AU - Ellinghaus, D.* AU - Essers, J.* AU - Ferguson, L.R.* AU - Festen, E.A.* AU - Fleshner, P.* AU - Florin, T.* AU - Franke, A.* AU - Fransen, K.* AU - Gearry, R.* AU - International IBD Genetics Consortium (IIBDGC) (Gieger, C.) C1 - 53728 C2 - 44962 CY - 1752 N St Nw, Washington, Dc 20036-2904 Usa TI - IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes. JO - Nat. Commun. VL - 9 IS - 1 PB - Amer Soc Microbiology PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - The thioredoxin-1 (Trx1) system is an important contributor to cellular redox balance and is a sensor of energy and glucose metabolism. Here we show critical c-Myc-dependent activation of the Trx1 system during thymocyte and peripheral T-cell proliferation, but repression during T-cell quiescence. Deletion of thioredoxin reductase-1 (Txnrd1) prevents expansion the CD4-CD8-thymocyte population, whereas Txnrd1 deletion in CD4+CD8+thymocytes does not affect further maturation and peripheral homeostasis of αβT cells. However, Txnrd1 is critical for expansion of the activated T-cell population during viral and parasite infection. Metabolomics show that TrxR1 is essential for the last step of nucleotide biosynthesis by donating reducing equivalents to ribonucleotide reductase. Impaired availability of 2′-deoxyribonucleotides induces the DNA damage response and cell cycle arrest of Txnrd1-deficient T cells. These results uncover a pivotal function of the Trx1 system in metabolic reprogramming of thymic and peripheral T cells and provide a rationale for targeting Txnrd1 in T-cell leukemia. AU - Muri, J.* AU - Heer, S.* AU - Matsushita, M.* AU - Pohlmeier, L.* AU - Tortola, L.* AU - Fuhrer, T.* AU - Conrad, M. AU - Zamboni, N.* AU - Kisielow, J.* AU - Kopf, M.* C1 - 53509 C2 - 44702 TI - The thioredoxin-1 system is essential for fueling DNA synthesis during T-cell metabolic reprogramming and proliferation. JO - Nat. Commun. VL - 9 IS - 1 PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - An impediment to a mechanistic understanding of how some species sense the geomagnetic field ("magnetoreception") is the lack of vertebrate genetic models that exhibit well-characterized magnetoreceptive behavior and are amenable to whole-brain analysis. We investigated the genetic model organisms zebrafish and medaka, whose young stages are transparent and optically accessible. In an unfamiliar environment, adult fish orient according to the directional change of a magnetic field even in darkness. To enable experiments also in juveniles, we applied slowly oscillating magnetic fields, aimed at generating conflicting sensory inputs during exploratory behavior. Medaka (but not zebrafish) increase their locomotor activity in this assay. Complementary brain activity mapping reveals neuronal activation in the lateral hindbrain during magnetic stimulation. These comparative data support magnetoreception in teleosts, provide evidence for a light-independent mechanism, and demonstrate the usefulness of zebrafish and medaka as genetic vertebrate models for studying the biophysical and neuronal mechanisms underlying magnetoreception. AU - Myklatun, A. AU - Lauri, A. AU - Eder, S.H.K.* AU - Cappetta, M. AU - Shcherbakov, D.* AU - Wurst, W. AU - Winklhofer, M.* AU - Westmeyer, G.G. C1 - 53047 C2 - 44334 CY - London TI - Zebrafish and medaka offer insights into the neurobehavioral correlates of vertebrate magnetoreception. JO - Nat. Commun. VL - 9 IS - 1 PB - Nature Publishing Group PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - In the original version of this Article, Oryzias latipes was incorrectly spelt Oryzias lapites in the main text and in Fig. 1. These errors have been corrected in both the PDF and HTML versions of the Article. AU - Myklatun, A. AU - Lauri, A. AU - Eder, S.H.K.* AU - Cappetta, M.* AU - Shcherbakov, D.* AU - Wurst, W. AU - Winklhofer, M.* AU - Westmeyer, G.G. C1 - 53966 C2 - 45157 TI - Author Correction: Zebrafish and medaka offer insights into the neurobehavioral correlates of vertebrate magnetoreception (Nature Communications DOI: 10.1038/s41467-018-03090-6). JO - Nat. Commun. VL - 9 IS - 1 PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - This Article contains an error in Figure 2. In panel a, the second lane of the western blot should have been labelled 'siNT'. A correct version of Figure 2a appears in the Author Correction associated with this Article; the error has not been fixed in the original Article. AU - Neelakantan, D.* AU - Zhou, H.* AU - Oliphant, M.U.J.* AU - Zhang, X.* AU - Simon, L. AU - Henke, D.M.* AU - Shaw, C.A.* AU - Wu, M.F.* AU - Hilsenbeck, S.G.* AU - White, L.D.* AU - Lewis, M.T.* AU - Ford, H.L.* C1 - 54721 C2 - 45809 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - EMT cells increase breast cancer metastasis via paracrine GLI activation in neighbouring tumour cells (vol 8, 15773, 2017). JO - Nat. Commun. VL - 9 IS - 1 PB - Nature Publishing Group PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - Understanding the difference in genetic regulation of gene expression between brain and blood is important for discovering genes for brain-related traits and disorders. Here, we estimate the correlation of genetic effects at the top-associated cis-expression or -DNA methylation (DNAm) quantitative trait loci (cis-eQTLs or cis-mQTLs) between brain and blood (rb). Using publicly available data, we find that genetic effects at the top cis-eQTLs or mQTLs are highly correlated between independent brain and blood samples (r b = 0.70 for cis-eQTLs and r ^ b = 0.78 for cis-mQTLs). Using meta-analyzed brain cis-eQTL/mQTL data (n = 526 to 1194), we identify 61 genes and 167 DNAm sites associated with four brain-related phenotypes, most of which are a subset of the discoveries (97 genes and 295 DNAm sites) using data from blood with larger sample sizes (n = 1980 to 14,115). Our results demonstrate the gain of power in gene discovery for brain-related phenotypes using blood cis-eQTL/mQTL data with large sample sizes. AU - Qi, T.* AU - Wu, Y.* AU - Zeng, J.* AU - Zhang, F.* AU - Xue, A.* AU - Jiang, L.* AU - Zhu, Z.* AU - Kemper, K.* AU - Yengo, L.* AU - Zheng, Z.* AU - eQTLGen Consortium* AU - Marioni, R.E.* AU - Montgomery, G.W.* AU - Deary, I.J.* AU - Wray, N.R.* AU - Visscher, P.M.* AU - McRae, A.F.* AU - Yang, J.* AU - eQTLGen Consortium (Müller-Nurasyid, M. AU - Prokisch, H. AU - Schramm, K.) C1 - 53667 C2 - 44812 TI - Identifying gene targets for brain-related traits using transcriptomic and methylomic data from blood. JO - Nat. Commun. VL - 9 IS - 1 PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - p53 is a well-known tumor suppressor that has emerged as an important player in energy balance. However, its metabolic role in the hypothalamus remains unknown. Herein, we show that mice lacking p53 in agouti-related peptide (AgRP), but not proopiomelanocortin (POMC) or steroidogenic factor-1 (SF1) neurons, are more prone to develop diet-induced obesity and show reduced brown adipose tissue (BAT) thermogenic activity. AgRP-specific ablation of p53 resulted in increased hypothalamic c-Jun N-terminal kinase (JNK) activity before the mice developed obesity, and central inhibition of JNK reversed the obese phenotype of these mice. The overexpression of p53 in the ARC or specifically in AgRP neurons of obese mice decreased body weight and stimulated BAT thermogenesis, resulting in body weight loss. Finally, p53 in AgRP neurons regulates the ghrelin-induced food intake and body weight. Overall, our findings provide evidence that p53 in AgRP neurons is required for normal adaptations against diet-induced obesity. AU - Quiñones, M.* AU - Al-Massadi, O.* AU - Folgueira, C.* AU - Bremser, S.* AU - Gallego, R.* AU - Torres-Leal, L.* AU - Haddad-Tóvolli, R.* AU - García-Cáceres, C. AU - Hernandez-Bautista, R.* AU - Lam, B.Y.H.* AU - Beiroa, D.* AU - Sanchez-Rebordelo, E.* AU - Senra, A.* AU - Malagon, J.A.* AU - Valerio, P.* AU - Fondevila, M.F.* AU - Fernø, J.* AU - Malagon, M.M.* AU - Contreras, R. AU - Pfluger, P.T. AU - Brüning, J.C.* AU - Yeo, G.* AU - Tschöp, M.H. AU - Diéguez, C.* AU - López, M.* AU - Claret, M.* AU - Kloppenburg, P.* AU - Sabio, G.* AU - Nogueiras, R.* C1 - 54186 C2 - 45338 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - p53 in AgRP neurons is required for protection against diet-induced obesity via JNK1. JO - Nat. Commun. VL - 9 IS - 1 PB - Nature Publishing Group PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - The ubiquitously expressed RNA-binding proteins Roquin-1 and Roquin-2 are essential for appropriate immune cell function and postnatal survival of mice. Roquin proteins repress target mRNAs by recognizing secondary structures in their 3'-UTRs and by inducing mRNA decay. However, it is unknown if other cellular proteins contribute to target control. To identify cofactors of Roquin, we used RNA interference to screen similar to 1500 genes involved in RNA-binding or mRNA degradation, and identified NUFIP2 as a cofactor of Roquin-induced mRNA decay. NUFIP2 binds directly and with high affinity to Roquin, which stabilizes NUFIP2 in cells. Post-transcriptional repression of human ICOS by endogenous Roquin proteins requires two neighboring non-canonical stem-loops in the ICOS 3'-UTR. This unconventional cis-element as well as another tandem loop known to confer Roquin-mediated regulation of the Ox40 3'-UTR, are bound cooperatively by Roquin and NUFIP2. NUFIP2 therefore emerges as a cofactor that contributes to mRNA target recognition by Roquin. AU - Rehage, N. AU - Davydova, E.-O. AU - Conrad, C.* AU - Behrens, G.* AU - Maiser, A.* AU - Stehklein, J.E. AU - Brenner, S. AU - Klein, J.* AU - Jeridi, A. AU - Hoffmann, A.L.* AU - Lee, E.* AU - Dianzani, U.* AU - Willemsen, R.* AU - Feederle, R. AU - Reiche, K.* AU - Hackermüller, J.* AU - Leonhardt, H.* AU - Sharma, S.* AU - Niessing, D. AU - Heissmeyer, V. C1 - 52759 C2 - 44289 CY - London TI - Binding of NUFIP2 to Roquin promotes recognition and regulation of ICOS mRNA. JO - Nat. Commun. VL - 9 IS - 1 PB - Nature Publishing Group PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - Metabolic diseases are a worldwide problem but the underlying genetic factors and their relevance to metabolic disease remain incompletely understood. Genome-wide research is needed to characterize so-far unannotated mammalian metabolic genes. Here, we generate and analyze metabolic phenotypic data of 2016 knockout mouse strains under the aegis of the International Mouse Phenotyping Consortium (IMPC) and find 974 gene knockouts with strong metabolic phenotypes. 429 of those had no previous link to metabolism and 51 genes remain functionally completely unannotated. We compared human orthologues of these uncharacterized genes in five GWAS consortia and indeed 23 candidate genes are associated with metabolic disease. We further identify common regulatory elements in promoters of candidate genes. As each regulatory element is composed of several transcription factor binding sites, our data reveal an extensive metabolic phenotype-associated network of co-regulated genes. Our systematic mouse phenotype analysis thus paves the way for full functional annotation of the genome. AU - Rozman, J. AU - Rathkolb, B. AU - Oestereicher, M.A. AU - Schütt, C. AU - Ravindranath, A.C. AU - Leuchtenberger, S. AU - Sharma, S. AU - Kistler, M. AU - Willershäuser, M.* AU - Brommage, R. AU - Meehan, T.F.* AU - Mason, J.* AU - Haselimashhadi, H.* AU - Hough, T.* AU - Mallon, A.-M.* AU - Wells, S.* AU - Santos, L.* AU - Lelliott, C.J.* AU - White, J.K.* AU - Sorg, T.* AU - Champy, M.-F.* AU - Bower, L.R.* AU - Reynolds, C.L.* AU - Flenniken, A.M.* AU - Murray, S.A.* AU - Nutter, L.M.J.* AU - Svenson, K.L.* AU - West, D.* AU - Tocchini-Valentini, G.P.* AU - Beaudet, A.L.* AU - Bosch, F.* AU - Braun, R.B.* AU - Dobbie, M.S.* AU - Gao, X.* AU - Herault, Y.* AU - Moshiri, A.* AU - Moore, B.A.* AU - Kent Lloyd, K.C.* AU - McKerlie, C.* AU - Masuya, H.* AU - Tanaka, N.* AU - Flicek, P.* AU - Parkinson, H.E.* AU - Sedlacek, R.* AU - Seong, J.K.* AU - Wang, C.-K.L.* AU - Moore, M.* AU - Brown, S.D.* AU - Tschöp, M.H. AU - Wurst, W. AU - Klingenspor, M.* AU - Wolf, E.* AU - Beckers, J. AU - Machicao, F.* AU - Peter, A. AU - Staiger, H. AU - Häring, H.-U. AU - Grallert, H. AU - Campillos, M. AU - Maier, H. AU - Fuchs, H. AU - Gailus-Durner, V. AU - Werner, T.* AU - Hrabě de Angelis, M. AU - IMPC Consortium (Eickelberg, O.) AU - IMPC Consortium (Yildirim, A.Ö.) C1 - 52757 C2 - 44329 CY - London TI - Identification of genetic elements in metabolism by high-throughput mouse phenotyping.   JO - Nat. Commun. VL - 9 IS - 1 PB - Nature Publishing Group PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - Heat shock protein 90 (Hsp90) is a dimeric molecular chaperone that undergoes large conformational changes during its functional cycle. It has been established that conformational switch points exist in the N-terminal (Hsp90-N) and C-terminal (Hsp90-C) domains of Hsp90, however information for switch points in the large middle-domain (Hsp90-M) is scarce. Here we report on a tryptophan residue in Hsp90-M as a new type of switch point. Our study shows that this conserved tryptophan senses the interaction of Hsp90 with a stringent client protein and transfers this information via a cation-π interaction with a neighboring lysine. Mutations at this position hamper the communication between domains and the ability of a client protein to affect the Hsp90 cycle. The residue thus allows Hsp90 to transmit information on the binding of a client from Hsp90-M to Hsp90-N which is important for progression of the conformational cycle and the efficient processing of client proteins. AU - Rutz, D.A.* AU - Luo, Q.* AU - Freiburger, L. AU - Madl, T. AU - Kaila, V.R.I.* AU - Sattler, M. AU - Buchner, J.* C1 - 53893 C2 - 45123 TI - A switch point in the molecular chaperone Hsp90 responding to client interaction. JO - Nat. Commun. VL - 9 IS - 1 PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - The CARD11-BCL10-MALT1 (CBM) complex triggers the adaptive immune response in lymphocytes and lymphoma cells. CARD11/CARMA1 acts as a molecular seed inducing BCL10 filaments, but the integration of MALT1 and the assembly of a functional CBM complex has remained elusive. Using cryo-EM we solved the helical structure of the BCL10-MALT1 filament. The structural model of the filament core solved at 4.9 angstrom resolution identified the interface between the N-terminal MALT1 DD and the BCL10 caspase recruitment domain. The C-terminal MALT1 Ig and paracaspase domains protrude from this core to orchestrate binding of mediators and substrates at the filament periphery. Mutagenesis studies support the importance of the identified BCL10-MALT1 interface for CBM complex assembly, MALT1 protease activation and NF-kappa B signaling in Jurkat and primary CD4 T-cells. Collectively, we present a model for the assembly and architecture of the CBM signaling complex and how it functions as a signaling hub in T-lymphocytes. AU - Schlauderer, F.* AU - Seeholzer, T. AU - Desfosses, A.* AU - Gehring, T. AU - Strauss, M.* AU - Hopfner, K.P.* AU - Gutsche, I.* AU - Krappmann, D. AU - Lammens, K.* C1 - 54449 C2 - 45600 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Molecular architecture and regulation of BCL10-MALT1 filaments. JO - Nat. Commun. VL - 9 IS - 1 PB - Nature Publishing Group PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - Testing for association between a set of genetic markers and a phenotype is a fundamental task in genetic studies. Standard approaches for heritability and set testing strongly rely on parametric models that make specific assumptions regarding phenotypic variability. Here, we show that resulting p-values may be inflated by up to 15 orders of magnitude, in a heritability study of methylation measurements, and in a heritability and expression quantitative trait loci analysis of gene expression profiles. We propose FEATHER, a method for fast permutation-based testing of marker sets and of heritability, which properly controls for false-positive results. FEATHER eliminated 47% of methylation sites found to be heritable by the parametric test, suggesting a substantial inflation of false-positive findings by alternative methods. Our approach can rapidly identify heritable phenotypes out of millions of phenotypes acquired via high-throughput technologies, does not suffer from model misspecification and is highly efficient. AU - Schweiger, R.* AU - Fisher, E.* AU - Weissbrod, O.* AU - Rahmani, E.* AU - Müller-Nurasyid, M. AU - Kunze, S. AU - Gieger, C. AU - Waldenberger, M. AU - Rosset, S.* AU - Halperin, E.* C1 - 54818 C2 - 45851 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Detecting heritable phenotypes without a model using fast permutation testing for heritability and set-tests. JO - Nat. Commun. VL - 9 IS - 1 PB - Nature Publishing Group PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - Since modern foods are unnaturally enriched in single metabolites, it is important to understand which metabolites are sensed by the human body and which are not. We previously showed that the fatty acid stearic acid (C18:0) signals via a dedicated pathway to regulate mitofusin activity and thereby mitochondrial morphology and function in cell culture. Whether this pathway is poised to sense changes in dietary intake of C18:0 in humans is not known. We show here that C18:0 ingestion rapidly and robustly causes mitochondrial fusion in people within 3 h after ingestion. C18:0 intake also causes a drop in circulating long-chain acylcarnitines, suggesting increased fatty acid beta-oxidation in vivo. This work thereby identifies C18:0 as a dietary metabolite that is sensed by our bodies to control our mitochondria. This could explain part of the epidemiological differences between C16:0 and C18:0, whereby C16:0 increases cardiovascular and cancer risk whereas C18:0 decreases both. AU - Senyilmaz-Tiebe, D.* AU - Pfaff, D.H.* AU - Virtue, S.* AU - Schwarz, K.V.* AU - Fleming, T. AU - Altamura, S.* AU - Muckenthaler, M.U.* AU - Okun, J.G.* AU - Vidal-Puig, A.* AU - Nawroth, P.P. AU - Teleman, A.A.* C1 - 54148 C2 - 45326 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Dietary stearic acid regulates mitochondria in vivo in humans. JO - Nat. Commun. VL - 9 PB - Nature Publishing Group PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - We genetically controlled compartmentalization in eukaryotic cells by heterologous expression of bacterial encapsulin shell and cargo proteins to engineer enclosed enzymatic reactions and size-constrained metal biomineralization. The shell protein (EncA) from Myxococcus xanthus auto-assembles into nanocompartments inside mammalian cells to which sets of native (EncB,C,D) and engineered cargo proteins self-target enabling localized bimolecular fluorescence and enzyme complementation. Encapsulation of the enzyme tyrosinase leads to the confinement of toxic melanin production for robust detection via multispectral optoacoustic tomography (MSOT). Co-expression of ferritin-like native cargo (EncB,C) results in efficient iron sequestration producing substantial contrast by magnetic resonance imaging (MRI) and allowing for magnetic cell sorting. The monodisperse, spherical, and iron-loading nanoshells are also excellent genetically encoded reporters for electron microscopy (EM). In general, eukaryotically expressed encapsulins enable cellular engineering of spatially confined multicomponent processes with versatile applications in multiscale molecular imaging, as well as intriguing implications for metabolic engineering and cellular therapy. AU - Sigmund, F. AU - Massner, C. AU - Erdmann, P.* AU - Stelzl, A. AU - Rolbieski, H. AU - Desai, M.* AU - Bricault, S.* AU - Wörner, T.P.* AU - Snijder, J.* AU - Geerlof, A. AU - Fuchs, H. AU - Hrabě de Angelis, M. AU - Heck, A.J.R.* AU - Jasanoff, A.* AU - Ntziachristos, V. AU - Plitzko, J.* AU - Westmeyer, G.G. C1 - 53551 C2 - 44631 TI - Bacterial encapsulins as orthogonal compartments for mammalian cell engineering. JO - Nat. Commun. VL - 9 IS - 1 PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - Chromatin remodeling is of crucial importance during brain development. Pathogenic alterations of several chromatin remodeling ATPases have been implicated in neurodevelopmental disorders. We describe an index case with a de novo missense mutation in CHD3, identified during whole genome sequencing of a cohort of children with rare speech disorders. To gain a comprehensive view of features associated with disruption of this gene, we use a genotype-driven approach, collecting and characterizing 35 individuals with de novo CHD3 mutations and overlapping phenotypes. Most mutations cluster within the ATPase/helicase domain of the encoded protein. Modeling their impact on the three-dimensional structure demonstrates disturbance of critical binding and interaction motifs. Experimental assays with six of the identified mutations show that a subset directly affects ATPase activity, and all but one yield alterations in chromatin remodeling. We implicate de novo CHD3 mutations in a syndrome characterized by intellectual disability, macrocephaly, and impaired speech and language. AU - Snijders Blok, L.* AU - Rousseau, J.* AU - Twist, J.* AU - Ehresmann, S.* AU - Takaku, M.* AU - Venselaar, H.* AU - Rodan, L.H.* AU - Nowak, C.B.* AU - Douglas, J.* AU - Swoboda, K.J.* AU - Steeves, M.A.* AU - Sahai, I.* AU - Stumpel, C.T.R.M.* AU - Stegmann, A.P.A.* AU - Wheeler, P.* AU - Willing, M.C.* AU - Fiala, E.* AU - Kochhar, A.* AU - Gibson, W.T.* AU - Cohen, A.S.A.* AU - Agbahovbe, R.* AU - Innes, A.M.* AU - Au, P.Y.B.* AU - Rankin, J.* AU - Anderson, I.J.* AU - Skinner, S.A.* AU - Louie, R.J.* AU - Warren, H.E.* AU - Afenjar, A.* AU - Keren, B.* AU - Nava, C.* AU - Buratti, J.* AU - Isapof, A.* AU - Rodriguez, D.* AU - Lewandowski, R.* AU - Propst, J.* AU - van Essen, T.* AU - Choi, M.* AU - Lee, S.* AU - Chae, J.H.* AU - Price, S.* AU - Schnur, R.E.* AU - Douglas, G.* AU - Wentzensen, I.M.* AU - Zweier, C.* AU - Reis, A.* AU - Bialer, M.G.* AU - Moore, C.* AU - Koopmans, M.* AU - Brilstra, E.H.* AU - Monroe, G.R.* AU - van Gassen, K.L.I.* AU - van Binsbergen, E.* AU - Newbury-Ecob, R.* AU - Bownass, L.* AU - Bader, I.* AU - Mayr, J.A.* AU - Wortmann, S.B. AU - Jakielski, K.J.* AU - Strand, E.A.* AU - Kloth, K.* AU - Bierhals, T.* AU - Roberts, J.D.* AU - Petrovich, R.M.* AU - Machida, S.* AU - Kurumizaka, H.* AU - Lelieveld, S.* AU - Pfundt, R.* AU - Jansen, S.* AU - Deriziotis, P.* AU - Faive, L.* AU - Thevenon, J.* AU - Assoum, M.* AU - Shriberg, L.* AU - Kleefstra, T.* AU - Brunner, H.G.* AU - Wade, P.A.* AU - Fisher, S.E.* AU - Campeau, P.M.* C1 - 54755 C2 - 45832 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language. JO - Nat. Commun. VL - 9 IS - 1 PB - Nature Publishing Group PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - Molecular regulation of cell fate decisions underlies health and disease. To identify molecules that are active or regulated during a decision, and not before or after, the decision time point is crucial. However, cell fate markers are usually delayed and the time of decision therefore unknown. Fortunately, dividing cells induce temporal correlations in their progeny, which allow for retrospective inference of the decision time point. We present a computational method to infer decision time points from correlated marker signals in genealogies and apply it to differentiating hematopoietic stem cells. We find that myeloid lineage decisions happen generations before lineage marker onsets. Inferred decision time points are in agreement with data from colony assay experiments. The levels of the myeloid transcription factor PU.1 do not change during, but long after the predicted lineage decision event, indicating that the PU.1/GATA1 toggle switch paradigm cannot explain the initiation of early myeloid lineage choice. AU - Strasser, M. AU - Hoppe, P.S.* AU - Loeffler, D.* AU - Kokkaliaris, K.D.* AU - Schroeder, T.* AU - Theis, F.J. AU - Marr, C. C1 - 53931 C2 - 45099 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Lineage marker synchrony in hematopoietic genealogies refutes the PU.1/GATA1 toggle switch paradigm. JO - Nat. Commun. VL - 9 IS - 1 PB - Nature Publishing Group PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets. AU - Teumer, A.* AU - Chaker, L.* AU - Groeneweg, S.* AU - Li, Y.* AU - Di Munno, C.* AU - Barbieri, C.* AU - Schultheiss, U.T.* AU - Traglia, M.* AU - Ahluwalia, T.S.* AU - Akiyama, M.* AU - Appel, E.V.R.* AU - Arking, D.E.* AU - Arnold, A.* AU - Astrup, A.* AU - Beekman, M.* AU - Beilby, J.P.* AU - Bekaert, S.* AU - Boerwinkle, E.* AU - Brown, S.J.* AU - De Buyzere, M.* AU - Campbell, P.J.* AU - Ceresini, G.* AU - Cerqueira, C.* AU - Cucca, F.* AU - Deary, I.J.* AU - Deelen, J.* AU - Eckardt, K.U.* AU - Ekici, A.B.* AU - Eriksson, J.G.* AU - Ferrrucci, L.* AU - Fiers, T.* AU - Fiorillo, E.* AU - Ford, I.* AU - Fox, C.S.* AU - Fuchsberger, C.* AU - Galesloot, T.E.* AU - Gieger, C. AU - Gögele, M.* AU - de Grandi, A.* AU - Grarup, N.* AU - Greiser, K.H.* AU - Haljas, K.* AU - Hansen, T.* AU - Harris, S.E.* AU - van Heemst, D.* AU - den Heijer, M.* AU - Hicks, A.A.* AU - den Hollander, W.* AU - Homuth, G.* AU - Hui, J.* AU - Ikram, M.A.* AU - Ittermann, T.* AU - Jensen, R.A.* AU - Jing, J.* AU - Jukema, J.W.* AU - Kajantie, E.* AU - Kamatani, Y.* AU - Kasbohm, E.* AU - Kaufman, J.M.* AU - Kiemeney, L.A.* AU - Kloppenburg, M.* AU - Kronenberg, F.* AU - Kubo, M.* AU - Lahti, J.* AU - Lapauw, B.* AU - Li, S.* AU - Liewald, D.C.M.* AU - Lim, E.M.* AU - Linneberg, A.* AU - Marina, M.* AU - Mascalzoni, D.* AU - Matsuda, K.* AU - Medenwald, D.* AU - Meisinger, C. AU - Meulenbelt, I.* AU - de Meyer, T.* AU - Meyer zu Schwabedissen, H.E.* AU - Mikolajczyk, R.* AU - Moed, M.* AU - Netea-Maier, R.T.* AU - Nolte, I.M.* AU - Okada, Y.* AU - Pala, M.* AU - Pattaro, C.* AU - Pedersen, O.* AU - Petersmann, A.* AU - Porcu, E.* AU - Postmus, I.* AU - Pramstaller, P.P.* AU - Psaty, B.M.* AU - Ramos, Y.F.M.* AU - Rawal, R. AU - Redmond, P.* AU - Richards, J.B.* AU - Rietzschel, E.R.* AU - Rivadeneira, F.* AU - Roef, G.L.* AU - Rotter, J.I.* AU - Sala, C.F.* AU - Schlessinger, D.* AU - Selvin, E.* AU - Slagboom, P.E.* AU - Soranzo, N.* AU - Sørensen, T.I.A.* AU - Spector, T.D.* AU - Starr, J.M.* AU - Stott, D.J.* AU - Taes, Y.E.* AU - Taliun, D.* AU - Tanaka, T.* AU - Thuesen, B.* AU - Tiller, D.* AU - Toniolo, D.* AU - Uitterlinden, A.G.* AU - Visser, W.E.* AU - Walsh, J.P.* AU - Wilson, S.G.* AU - Wolffenbuttel, B.H.R.* AU - Yang, Q.* AU - Zheng, H.F.* AU - Cappola, A.* AU - Peeters, R.P.* AU - Naitza, S.* AU - Völzke, H.* AU - Sanna, S.* AU - Köttgen, A.* AU - Visser, T.J.* AU - Medici, M.* C1 - 54602 C2 - 45707 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation. JO - Nat. Commun. VL - 9 IS - 1 PB - Nature Publishing Group PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - We recently identified the splicing kinase gene SRPK1 as a genetic vulnerability of acute myeloid leukemia (AML). Here, we show that genetic or pharmacological inhibition of SRPK1 leads to cell cycle arrest, leukemic cell differentiation and prolonged survival of mice transplanted with MLL-rearranged AML. RNA-seq analysis demonstrates that SRPK1 inhibition leads to altered isoform levels of many genes including several with established roles in leukemogenesis such as MYB, BRD4 and MED24. We focus on BRD4 as its main isoforms have distinct molecular properties and find that SRPK1 inhibition produces a significant switch from the short to the long isoform at the mRNA and protein levels. This was associated with BRD4 eviction from genomic loci involved in leukemogenesis including BCL2 and MYC. We go on to show that this switch mediates at least part of the anti-leukemic effects of SRPK1 inhibition. Our findings reveal that SRPK1 represents a plausible new therapeutic target against AML. AU - Tzelepis, K.* AU - De Braekeleer, E.* AU - Aspris, D.* AU - Barbieri, I.* AU - Vijayabaskar, M.S.* AU - Liu, W.-H. AU - Gozdecka, M.* AU - Metzakopian, E.* AU - Toop, H.D.* AU - Dudek, M.* AU - Robson, S.C.* AU - Hermida-Prado, F.* AU - Yang, Y.H.* AU - Babaei-Jadidi, R.* AU - Garyfallos, D.A.* AU - Ponstingl, H.* AU - Dias, J.M.L.* AU - Gallipoli, P.* AU - Seiler, M.* AU - Buonamici, S.* AU - Vick, B. AU - Bannister, A.J.* AU - Rad, R.* AU - Prinjha, R.K.* AU - Marioni, J.C.* AU - Huntly, B.* AU - Batson, J.* AU - Morris, J.C.* AU - Pina, C.* AU - Bradley, A.* AU - Jeremias, I. AU - Bates, D.O.* AU - Yusa, K.* AU - Kouzarides, T.* AU - Vassiliou, G.S.* C1 - 55087 C2 - 46031 TI - SRPK1 maintains acute myeloid leukemia through effects on isoform usage of epigenetic regulators including BRD4. JO - Nat. Commun. VL - 9 IS - 1 PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development. AU - van Setten, J.* AU - Brody, J.A.* AU - Jamshidi, Y.* AU - Swenson, B.R.* AU - Butler, A.M.* AU - Campbell, H.* AU - del Greco, F.M.* AU - Evans, D.S.* AU - Gibson, Q.* AU - Gudbjartsson, D.F.* AU - Kerr, K.F.* AU - Krijthe, B.P.* AU - Lyytikäinen, L.-P.* AU - Müller, C.* AU - Müller-Nurasyid, M. AU - Nolte, I.M.* AU - Padmanabhan, S.* AU - Ritchie, M.D.* AU - Robino, A.* AU - Smith, A.V.* AU - Steri, M.* AU - Tanaka, T.* AU - Teumer, A.* AU - Trompet, S.* AU - Ulivi, S.* AU - Verweij, N.* AU - Yin, X.* AU - Arnar, D.O.* AU - Asselbergs, F.W.* AU - Bader, J.S.* AU - Barnard, J.* AU - Bis, J.C.* AU - Blankenberg, S.* AU - Boerwinkle, E.* AU - Bradford, Y.* AU - Buckley, B.M.* AU - Chung, M.K.* AU - Crawford, D.C.* AU - den Hoed, M.* AU - Denny, J.C.* AU - Dominiczak, A.F.* AU - Ehret, G.B.* AU - Eijgelsheim, M.* AU - Ellinor, P.T.* AU - Felix, S.B.* AU - Franco, O.H.* AU - Franke, L.* AU - Harris, T.B.* AU - Holm, H.* AU - Ilaria, G.* AU - Iorio, A.* AU - Kähönen, M.* AU - Kolcic, I.* AU - Kors, J.A.* AU - Lakatta, E.G.* AU - Launer, L.J.* AU - Lin, H.* AU - Lin, H.J.* AU - Loos, R.J.F.* AU - Lubitz, S.A.* AU - Macfarlane, P.W.* AU - Magnani, J.W.* AU - Leach, I.M.* AU - Meitinger, T. AU - Mitchell, B.D.* AU - Münzel, T.* AU - Papanicolau, G.J.* AU - Peters, A. AU - Pfeufer, A.* AU - Pramstaller, P.P.* AU - Raitakari, O.T.* AU - Rotter, J.I.* AU - Rudan, I.* AU - Samani, N.J.* AU - Schlessinger, D.* AU - Silva Aldana, C.T.* AU - Sinner, M.F.* AU - Smith, J.D.* AU - Snieder, H.* AU - Soliman, E.Z.* AU - Spector, T.D.* AU - Stott, D.J.* AU - Strauch, K. AU - Tarasov, K.V.* AU - Thorsteinsdottir, U.* AU - Uitterlinden, A.G.* AU - van Wagoner, D.R.* AU - Völker, U.* AU - Völzke, H.* AU - Waldenberger, M. AU - Jan Westra, H.* AU - Wild, P.S.* AU - Zeller, T.* AU - Alonso, A.* AU - Avery, C.L.* AU - Bandinelli, S.* AU - Benjamin, E.J.* AU - Cucca, F.* AU - Dörr, M.* AU - Ferrucci, L.* AU - Gasparini, P.* AU - Gudnason, V.* AU - Hayward, C.* AU - Heckbert, S.R.* AU - Hicks, A.A.* AU - Jukema, J.W.* AU - Kääb, S.* AU - Lehtimäki, T.* AU - Liu, Y.* AU - Munroe, P.B.* AU - Parsa, A.* AU - Polasek, O.* AU - Psaty, B.M.* AU - Roden, D.M.* AU - Schnabel, R.B.* AU - Sinagra, G.* AU - Stefansson, K.* AU - Stricker, B.H.* AU - van der Harst, P.* AU - van Duijn, C.M.* AU - Wilson, J.F.* AU - Gharib, S.A.* AU - de Bakker, P.I.W.* AU - Isaacs, A.* AU - Arking, D.E.* AU - Sotoodehnia, N.* C1 - 54029 C2 - 45205 TI - PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity. JO - Nat. Commun. VL - 9 IS - 1 PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - A parasitic lifestyle, where plants procure some or all of their nutrients from other living plants, has evolved independently in many dicotyledonous plant families and is a major threat for agriculture globally. Nevertheless, no genome sequence of a parasitic plant has been reported to date. Here we describe the genome sequence of the parasitic field dodder, Cuscuta campestris. The genome contains signatures of a fairly recent whole-genome duplication and lacks genes for pathways superfluous to a parasitic lifestyle. Specifically, genes needed for high photosynthetic activity are lost, explaining the low photosynthesis rates displayed by the parasite. Moreover, several genes involved in nutrient uptake processes from the soil are lost. On the other hand, evidence for horizontal gene transfer by way of genomic DNA integration from the parasite’s hosts is found. We conclude that the parasitic lifestyle has left characteristic footprints in the C. campestris genome. AU - Vogel, A.* AU - Schwacke, R.* AU - Denton, A.K.* AU - Usadel, B.* AU - Hollmann, J.* AU - Fischer, K.* AU - Bolger, A.* AU - Schmidt, M.H.H.* AU - Bolger, M.E.* AU - Gundlach, H. AU - Mayer, K.F.X. AU - Weiss-Schneeweiss, H.* AU - Temsch, E.M.* AU - Krause, K.* C1 - 53734 C2 - 44988 CY - Po Box 211, 1000 Ae Amsterdam, Netherlands TI - Footprints of parasitism in the genome of the parasitic flowering plant Cuscuta campestris. JO - Nat. Commun. VL - 9 IS - 1 PB - Elsevier Science Bv PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - Genetic, epigenetic, and environmental factors contribute to the multifactorial disorder progressive supranuclear palsy (PSP). Here, we study epigenetic changes by genome-wide analysis of DNA from postmortem tissue of forebrains of patients and controls and detect significant (P < 0.05) methylation differences at 717 CpG sites in PSP vs. controls. Four-hundred fifty-one of these sites are associated with protein-coding genes. While differential methylation only affects a few sites in most genes, DLX1 is hypermethylated at multiple sites. Expression of an antisense transcript of DLX1, DLX1AS, is reduced in PSP brains. The amount of DLX1 protein is increased in gray matter of PSP forebrains. Pathway analysis suggests that DLX1 influences MAPT-encoded Tau protein. In a cell system, overexpression of DLX1 results in downregulation of MAPT while overexpression of DLX1AS causes upregulation of MAPT. Our observations suggest that altered DLX1 methylation and expression contribute to pathogenesis of PSP by influencing MAPT. AU - Weber, A.* AU - Schwarz, S.C.* AU - Tost, J.* AU - Trümbach, D. AU - Winter, P.* AU - Busato, F.* AU - Tacik, P.* AU - Windhorst, A.C.* AU - Fagny, M.* AU - Arzberger, T.* AU - McLean, C.* AU - van Swieten, J.C.* AU - Schwarz, J.* AU - Vogt Weisenhorn, D.M. AU - Wurst, W. AU - Adhikary, T.* AU - Dickson, D.W.* AU - Höglinger, G.U.* AU - Müller, U.* C1 - 54020 C2 - 45209 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Epigenome-wide DNA methylation profiling in Progressive Supranuclear Palsy reveals major changes at DLX1. JO - Nat. Commun. VL - 9 IS - 1 PB - Nature Publishing Group PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - Type 2 diabetes (T2D) is a very common disease in humans. Here we conduct a meta-analysis of genome-wide association studies (GWAS) with ~16 million genetic variants in 62,892 T2D cases and 596,424 controls of European ancestry. We identify 139 common and 4 rare variants associated with T2D, 42 of which (39 common and 3 rare variants) are independent of the known variants. Integration of the gene expression data from blood (n = 14,115 and 2765) with the GWAS results identifies 33 putative functional genes for T2D, 3 of which were targeted by approved drugs. A further integration of DNA methylation (n = 1980) and epigenomic annotation data highlight 3 genes (CAMK1D, TP53INP1, and ATP5G1) with plausible regulatory mechanisms, whereby a genetic variant exerts an effect on T2D through epigenetic regulation of gene expression. Our study uncovers additional loci, proposes putative genetic regulatory mechanisms for T2D, and provides evidence of purifying selection for T2D-associated variants. AU - Xue, A.* AU - Wu, Y.* AU - Zhu, Z.* AU - Zhang, F.* AU - Kemper, K.E.* AU - Zheng, Z.* AU - Yengo, L.* AU - Lloyd-Jones, L.R.* AU - Sidorenko, J.* AU - eQTLGen Consortium* AU - Agbessi, M.* AU - Ahsan, H.* AU - Alves, I.* AU - Andiappan, A.K.* AU - Awadalla, P.* AU - Battle, A.* AU - Beutner, F.* AU - Bonder, M.J.* AU - Boomsma, D.* AU - Christiansen, M.W.* AU - Claringbould, A.* AU - Deelen, P.* AU - Esko, T.* AU - Favé, M.J.* AU - Franke, L.* AU - Frayling, T.* AU - Gharib, S.A.* AU - Gibson, G.* AU - Hemani, G.* AU - Jansen, R.* AU - Kähönen, M.* AU - Kalnapenkis, A.* AU - Kasela, S.* AU - Kettunen, J.* AU - Kim, Y.* AU - Kirsten, H.* AU - Kovacs, P.* AU - Krohn, K.* AU - Kronberg-Guzman, J.* AU - Kukushkina, V.* AU - Kutalik, Z.* AU - Lee, B.* AU - Lehtimäki, T.* AU - Loeffler, M.* AU - Marigorta, U.M.* AU - Metspalu, A.* AU - Milani, L.* AU - eQTLGen Consortium (Müller-Nurasyid, M. AU - Prokisch, H. AU - Schramm, K.) AU - Nauck, M.* AU - Nivard, M.* AU - Penninx, B.* AU - Perola, M.* AU - Pervjakova, N.* AU - Pierce, B.F.* AU - Powell, J.* AU - Psaty, B.* AU - Raitakari, O.* AU - Ring, S.* AU - Ripatti, S.* AU - Rotzschke, O.* AU - Ruëger, S.* AU - Saha, A.* AU - Scholz, M.* AU - Seppälä, I.* AU - Stumvoll, M.* AU - Sullivan, P.F.* AU - Teumer, A.* AU - Thiery, J.* AU - Tong, L.* AU - Tönjes, A.* AU - van Dongen, J.* AU - van Meurs, J.B.* AU - Verlouw, J.* AU - Völker, U.* AU - Võsa, U.* AU - Yaghootkar, H.* AU - Zeng, B.* AU - McRae, A.F.* AU - Visscher, P.M.* AU - Zeng, J.* AU - Yang, J.* C1 - 54086 C2 - 45303 TI - Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes. JO - Nat. Commun. VL - 9 IS - 1 PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - Identifying genetic variants associated with circulating protein concentrations (protein quantitative trait loci; pQTLs) and integrating them with variants from genome-wide association studies (GWAS) may illuminate the proteome’s causal role in disease and bridge a knowledge gap regarding SNP-disease associations. We provide the results of GWAS of 71 high-value cardiovascular disease proteins in 6861 Framingham Heart Study participants and independent external replication. We report the mapping of over 16,000 pQTL variants and their functional relevance. We provide an integrated plasma protein-QTL database. Thirteen proteins harbor pQTL variants that match coronary disease-risk variants from GWAS or test causal for coronary disease by Mendelian randomization. Eight of these proteins predict new-onset cardiovascular disease events in Framingham participants. We demonstrate that identifying pQTLs, integrating them with GWAS results, employing Mendelian randomization, and prospectively testing protein-trait associations holds potential for elucidating causal genes, proteins, and pathways for cardiovascular disease and may identify targets for its prevention and treatment. AU - Yao, C.* AU - Chen, G.* AU - Song, C.* AU - Keefe, J.* AU - Mendelson, M.* AU - Huan, T.* AU - Sun, B.B.* AU - Laser, A. AU - Maranville, J.C.* AU - Wu, H.* AU - Ho, J.E.* AU - Courchesne, P.* AU - Lyass, A.* AU - Larson, M.G.* AU - Gieger, C. AU - Graumann, J.* AU - Johnson, A.D.* AU - Danesh, J.* AU - Runz, H.* AU - Hwang, S.-J.* AU - Liu, C.* AU - Butterworth, A.S.* AU - Suhre, K.* AU - Levy, D.* C1 - 54172 C2 - 45379 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Genome-wide mapping of plasma protein QTLs identifies putatively causal genes and pathways for cardiovascular disease. JO - Nat. Commun. VL - 9 IS - 1 PB - Nature Publishing Group PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - In the originally published version of this Article, financial support was not fully acknowledged. The sentence “KS was supported by the ‘Biomedical Research Program’ funds at Weill Cornell Medicine in Qatar, a program funded by the Qatar Foundation” has been added to the acknowledgement section in both the PDF and HTML versions of the Article. AU - Yao, C.* AU - Chen, G.* AU - Song, C.* AU - Keefe, J.* AU - Mendelson, M.* AU - Huan, T.* AU - Sun, B.B.* AU - Laser, A. AU - Maranville, J.C.* AU - Wu, H.* AU - Ho, J.E.* AU - Courchesne, P.* AU - Lyass, A.* AU - Larson, M.G.* AU - Gieger, C. AU - Graumann, J.* AU - Johnson, A.D.* AU - Danesh, J.* AU - Runz, H.* AU - Hwang, S.J.* AU - Liu, C.* AU - Butterworth, A.S.* AU - Suhre, K.* AU - Levy, D.* C1 - 54387 C2 - 45523 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England TI - Genome-wide mapping of plasma protein QTLs identifies putatively causal genes and pathways for cardiovascular disease (vol 9, 3268, 2018). JO - Nat. Commun. VL - 9 IS - 1 PB - Nature Publishing Group PY - 2018 SN - 2041-1723 ER - TY - JOUR AB - The co-chaperone FKBP5 is a stress-responsive protein-regulating stress reactivity, and its genetic variants are associated with T2D related traits and other stress-related disorders. Here we show that FKBP51 plays a role in energy and glucose homeostasis. Fkbp5 knockout (51KO) mice are protected from high-fat diet-induced weight gain, show improved glucose tolerance and increased insulin signaling in skeletal muscle. Chronic treatment with a novel FKBP51 antagonist, SAFit2, recapitulates the effects of FKBP51 deletion on both body weight regulation and glucose tolerance. Using shorter SAFit2 treatment, we show that glucose tolerance improvement precedes the reduction in body weight. Mechanistically, we identify a novel association between FKBP51 and AS160, a substrate of AKT2 that is involved in glucose uptake. FKBP51 antagonism increases the phosphorylation of AS160, increases glucose transporter 4 expression at the plasma membrane, and ultimately enhances glucose uptake in skeletal myotubes. We propose FKBP51 as a mediator between stress and T2D development, and potential target for therapeutic approaches. AU - Balsevich, G.* AU - Häusl, A.S.* AU - Meyer, C.W. AU - Karamihalev, S.* AU - Feng, X.* AU - Pöhlmann, M.L.* AU - Dournes, C.* AU - Uribe-Marino, A.* AU - Santarelli, S.* AU - Labermaier, C.* AU - Hafner, K.* AU - Mao, T.* AU - Breitsamer, M.* AU - Theodoropoulou, M.* AU - Namendorf, C.* AU - Uhr, M.* AU - Paez-Pereda, M.* AU - Winter, G.* AU - Hausch, F.* AU - Chen, A.* AU - Tschöp, M.H. AU - Rein, T.* AU - Gassen, N.C.* AU - Schmidt, M.V.* C1 - 52403 C2 - 43948 CY - London TI - Stress-responsive FKBP51 regulates AKT2-AS160 signaling and metabolic function. JO - Nat. Commun. VL - 8 IS - 1 PB - Nature Publishing Group PY - 2017 SN - 2041-1723 ER - TY - JOUR AB - The recent identification of progenitor populations that contribute to the developing heart in a distinct spatial and temporal manner has fundamentally improved our understanding of cardiac development. However, the mechanisms that direct atrial versus ventricular specification remain largely unknown. Here we report the identification of a progenitor population that gives rise primarily to cardiovascular cells of the ventricles and only to few atrial cells (<5%) of the differentiated heart. These progenitors are specified during gastrulation, when they transiently express Foxa2, a gene not previously implicated in cardiac development. Importantly, Foxa2+ cells contribute to previously identified progenitor populations in a defined pattern and ratio. Lastly, we describe an analogous Foxa2+ population during differentiation of embryonic stem cells. Together, these findings provide insight into the developmental origin of ventricular and atrial cells, and may lead to the establishment of new strategies for generating chamber-specific cell types from pluripotent stem cells. AU - Bardot, E.* AU - Calderon, D.* AU - Santoriello, F.* AU - Han, S.* AU - Cheung, K.* AU - Jadhav, B.* AU - Burtscher, I. AU - Artap, S.* AU - Jain, R.K.* AU - Epstein, J.A.* AU - Lickert, H. AU - Gouon-Evans, V.* AU - Sharp, A.J.* AU - Dubois, N.C.* C1 - 50554 C2 - 42522 CY - London TI - Foxa2 identifies a cardiac progenitor population with ventricular differentiation potential. JO - Nat. Commun. VL - 8 PB - Nature Publishing Group PY - 2017 SN - 2041-1723 ER - TY - JOUR AB - Immune homeostasis in intestinal tissues depends on the generation of regulatory T (Treg) cells. CD103(+) dendritic cells (DCs) acquire microbiota-derived material from the gut lumen for transport to draining lymph nodes and generation of receptor-related orphan γt(+) (RORγt(+)) Helios(-)-induced Treg (iTreg) cells. Here we show CD40-signalling as a microbe-independent signal that can induce migration of CD103(+) DCs from the lamina propria (LP) to the mesenteric lymph nodes. Transgenic mice with constitutive CD11c-specific CD40-signalling have reduced numbers of CD103(+) DCs in LP and a low frequency of RORγt(+)Helios(-) iTreg cells, exacerbated inflammatory Th1/Th17 responses, high titres of microbiota-specific immunoglobulins, dysbiosis and fatal colitis, but no pathology is detected in other tissues. Our data demonstrate a CD40-dependent mechanism capable of abrogating iTreg cell induction by DCs, and suggest that the CD40L/CD40-signalling axis might be able to intervene in the generation of new iTreg cells in order to counter-regulate immune suppression to enhance immunity. AU - Barthels, C.* AU - Ogrinc, A.* AU - Steyer, V.* AU - Meier, S.* AU - Simon, F.* AU - Wimmer, M. AU - Blutke, A.* AU - Straub, T.* AU - Zimber-Strobl, U. AU - Lutgens, E.* AU - Marconi, P.* AU - Ohnmacht, C. AU - Garzetti, D.* AU - Stecher, B.* AU - Brocker, T.* C1 - 50682 C2 - 42830 CY - London TI - CD40-signalling abrogates induction of RORγt+ Treg cells by intestinal CD103+ DCs and causes fatal colitis. JO - Nat. Commun. VL - 8 PB - Nature Publishing Group PY - 2017 SN - 2041-1723 ER - TY - JOUR AB - Immunoglobulin G (IgG) is a major effector molecule of the human immune response, and aberrations in IgG glycosylation are linked to various diseases. However, the molecular mechanisms underlying protein glycosylation are still poorly understood. We present a data-driven approach to infer reactions in the IgG glycosylation pathway using large-scale mass-spectrometry measurements. Gaussian graphical models are used to construct association networks from four cohorts. We find that glycan pairs with high partial correlations represent enzymatic reactions in the known glycosylation pathway, and then predict new biochemical reactions using a rule-based approach. Validation is performed using data from a GWAS and results from three in vitro experiments. We show that one predicted reaction is enzymatically feasible and that one rejected reaction does not occur in vitro. Moreover, in contrast to previous knowledge, enzymes involved in our predictions colocalize in the Golgi of two cell lines, further confirming the in silico predictions. AU - Benedetti, E. AU - Pučić-Baković, M.* AU - Keser, T.* AU - Wahl, A. AU - Hassinen, A.* AU - Yang, J.Y.* AU - Liu, L.* AU - Trbojević-Akmačić, I.* AU - Razdorov, G.* AU - Štambuk, J.* AU - Klarić, L.* AU - Ugrina, I.* AU - Selman, M.H.J.* AU - Wuhrer, M.* AU - Rudan, I.* AU - Polasek, O.* AU - Hayward, C.* AU - Grallert, H. AU - Strauch, K. AU - Peters, A. AU - Meitinger, T. AU - Gieger, C. AU - Vilaj, M.* AU - Boons, G.J.* AU - Moremen, K.W.* AU - Ovchinnikova, T.* AU - Bovin, N.* AU - Kellokumpu, S.* AU - Theis, F.J. AU - Lauc, G.* AU - Krumsiek, J. C1 - 52335 C2 - 43915 CY - London TI - Network inference from glycoproteomics data reveals new reactions in the IgG glycosylation pathway. JO - Nat. Commun. VL - 8 IS - 1 PB - Nature Publishing Group PY - 2017 SN - 2041-1723 ER - TY - JOUR AB - Sleep is essential for health. Slow wave sleep (SWS), the deepest sleep stage hallmarked by electroencephalographic slow oscillations (SOs), appears of particular relevance here. SWS is associated with a unique endocrine milieu comprising minimum cortisol and high aldosterone, growth hormone (GH), and prolactin levels, thereby presumably fostering efficient adaptive immune responses. Yet, whether SWS causes these changes is unclear. Here we enhance SOs in men by auditory closed-loop stimulation, i.e., by delivering tones in synchrony with endogenous SOs. Stimulation intensifies the hormonal milieu characterizing SWS (mainly by further reducing cortisol and increasing aldosterone levels) and reduces T and B cell counts, likely reflecting a redistribution of these cells to lymphoid tissues. GH remains unchanged. In conclusion, closed-loop stimulation of SOs is an easy-to-use tool for probing SWS functions, and might also bear the potential to ameliorate conditions like depression and aging, where disturbed sleep coalesces with specific hormonal and immunological dysregulations. AU - Besedovsky, L.* AU - Ngo, H.V.* AU - Dimitrov, S.* AU - Gassenmaier, C.* AU - Lehmann, R. AU - Born, J. C1 - 52574 C2 - 44051 CY - London TI - Auditory closed-loop stimulation of EEG slow oscillations strengthens sleep and signs of its immune-supportive function. JO - Nat. Commun. VL - 8 PB - Nature Publishing Group PY - 2017 SN - 2041-1723 ER - TY - JOUR AB - Upon binding to the extracellular matrix protein, fibronectin, αV-class and α5β1 integrins trigger the recruitment of large protein assemblies and strengthen cell adhesion. Both integrin classes have been functionally specified, however their specific roles in immediate phases of cell attachment remain uncharacterized. Here, we quantify the adhesion of αV-class and/or α5β1 integrins expressing fibroblasts initiating attachment to fibronectin (≤120 s) by single-cell force spectroscopy. Our data reveals that αV-class integrins outcompete α5β1 integrins. Once engaged, αV-class integrins signal to α5β1 integrins to establish additional adhesion sites to fibronectin, away from those formed by αV-class integrins. This crosstalk, which strengthens cell adhesion, induces α5β1 integrin clustering by RhoA/ROCK/myosin-II and Arp2/3-mediated signalling, whereas overall cell adhesion depends on formins. The dual role of both fibronectin-binding integrin classes commencing with an initial competition followed by a cooperative crosstalk appears to be a basic cellular mechanism in assembling focal adhesions to the extracellular matrix. AU - Bharadwaj, M.* AU - Strohmeyer, N.* AU - Colo, G.P.* AU - Helenius, J.* AU - Beerenwinkel, N.* AU - Schiller, H. B. AU - Fässler, R.* AU - Müller, D.J.* C1 - 50443 C2 - 41219 CY - London TI - αv-class integrins exert dual roles on α5β1 integrins to strengthen adhesion to fibronectin. JO - Nat. Commun. VL - 8 PB - Nature Publishing Group PY - 2017 SN - 2041-1723 ER - TY - JOUR AB - The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function. AU - Bowl, M.R.* AU - Simon, M.M.* AU - Ingham, N.J.* AU - Greenaway, S.* AU - Santos, L.* AU - Cater, H.* AU - Taylor, S.* AU - Mason, J.* AU - Kurbatova, N.* AU - Pearson, S.* AU - Bower, L.R.* AU - Clary, D.* AU - Meziane, H.* AU - Reilly, P.* AU - Minowa, O.* AU - Kelsey, L.* AU - Tocchini-Valentini, G.P.* AU - Gao, X.* AU - Bradley, A.* AU - Skarnes, W.C.* AU - Moore, M.* AU - Beaudet, A.L.* AU - Justice, M.J.* AU - Seavitt, J.R.* AU - Dickinson, M.E.* AU - Wurst, W. AU - Hrabě de Angelis, M. AU - Herault, Y.* AU - Wakana, S.* AU - Nutter, L.M.J.* AU - Flenniken, A.M.* AU - McKerlie, C.* AU - Murray, S.A.* AU - Svenson, K.L.* AU - Braun, R.E.* AU - West, D.B.* AU - Llyod, K.C.K.* AU - Adams, D.J.* AU - White, J.* AU - Karp, N.* AU - Flicek, P.* AU - Smedley, D.* AU - Meehan, T.F.* AU - Parkinson, H.E.* AU - Teboul, L.* AU - Wells, S.* AU - Steel, K.P.* AU - Mallon, A.M.* AU - Brown, S.D.* AU - International Mouse Phenotyping Consortium (Beig, J. AU - Bürger, A. AU - Giesert, F. AU - Graw, J. AU - Kühn, R. AU - Oritz, O. AU - Schick, J. AU - Seisenberger, C. AU - Amarie, O.V. AU - Garrett, L. AU - Hölter, S.M. AU - Zimprich, A. AU - Aguilar-Pimentel, J.A. AU - Beckers, J. AU - Brommage, R. AU - Calzada-Wack, J. AU - Fuchs, H. AU - Gailus-Durner, V. AU - Lengger, C. AU - Leuchtenberger, S. AU - Maier, H. AU - Marschall, S. AU - Moreth, K. AU - Neff, F. AU - Östereicher, M.A. AU - Rozman, J. AU - Steinkamp, R. AU - Stoeger, C. AU - Treise, I. AU - Stöger, T. AU - Yildirim, A.Ö. AU - Becker, L. AU - Rathkolb, B. AU - Eickelberg, O. AU - Schmidt-Weber, C.B.) C1 - 52089 C2 - 43704 CY - London TI - A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction. JO - Nat. Commun. VL - 8 IS - 1 PB - Nature Publishing Group PY - 2017 SN - 2041-1723 ER - TY - JOUR AB - Hepatitis B virus (HBV) is a major global health concern, and the development of curative therapeutics is urgently needed. Such efforts are impeded by the lack of a physiologically relevant, pre-clinical animal model of HBV infection. Here, we report that expression of the HBV entry receptor, human sodium-taurocholate cotransporting polypeptide (hNTCP), on macaque primary hepatocytes facilitates HBV infection in vitro, where all replicative intermediates including covalently closed circular DNA (cccDNA) are present. Furthermore, viral vector-mediated expression of hNTCP on hepatocytes in vivo renders rhesus macaques permissive to HBV infection. These in vivo macaque HBV infections are characterized by longitudinal HBV DNA in serum, and detection of HBV DNA, RNA, and HBV core antigen (HBcAg) in hepatocytes. Together, these results show that expressing hNTCP on macaque hepatocytes renders them susceptible to HBV infection, thereby establishing a physiologically relevant model of HBV infection to study immune clearance and test therapeutic and curative approaches. AU - Burwitz, B.J.* AU - Wettengel, J.M. AU - Mück-Häusl, M. AU - Ringelhan, M. AU - Ko, C. AU - Festag, M.M. AU - Hammond, K.B.* AU - Northrup, M.* AU - Bimber, B.N.* AU - Jacob, T.* AU - Reed, J.S.* AU - Norris, R.* AU - Park, B.* AU - Moller-Tank, S.* AU - Esser, K. AU - Greene, J.M.* AU - Wu, H.L.* AU - Abdulhaqq, S.* AU - Webb, G.* AU - Sutton, W.F.* AU - Klug, A.* AU - Swanson, T.* AU - Legasse, A.W.* AU - Vu, T.Q.* AU - Asokan, A.* AU - Haigwood, N.L.* AU - Protzer, U. AU - Sacha, J.B.* C1 - 52593 C2 - 44101 CY - London TI - Hepatocytic expression of human sodium-taurocholate cotransporting polypeptide enables hepatitis B virus infection of macaques. JO - Nat. Commun. VL - 8 IS - 1 PB - Nature Publishing Group PY - 2017 SN - 2041-1723 ER - TY - JOUR AB - Natural pH regulatory mechanisms can be overruled during several pathologies such as cancer, inflammation and ischaemia, leading to local pH changes in the human body. Here we demonstrate that (13)C-labelled zymonic acid (ZA) can be used as hyperpolarized magnetic resonance pH imaging sensor. ZA is synthesized from [1-(13)C]pyruvic acid and its (13)C resonance frequencies shift up to 3.0 p.p.m. per pH unit in the physiological pH range. The long lifetime of the hyperpolarized signal enhancement enables monitoring of pH, independent of concentration, temperature, ionic strength and protein concentration. We show in vivo pH maps within rat kidneys and subcutaneously inoculated tumours derived from a mammary adenocarcinoma cell line and characterize ZA as non-toxic compound predominantly present in the extracellular space. We suggest that ZA represents a reliable and non-invasive extracellular imaging sensor to localize and quantify pH, with the potential to improve understanding, diagnosis and therapy of diseases characterized by aberrant acid-base balance. AU - Düwel, S.* AU - Hundshammer, C.* AU - Gersch, M.* AU - Feuerecker, B.* AU - Steiger, K.* AU - Buck, A. AU - Walch, A.K. AU - Haase, A.* AU - Glaser, S.J.* AU - Schwaiger, M.* AU - Schilling, F.* C1 - 51105 C2 - 43091 TI - Imaging of pH in vivo using hyperpolarized 13C-labelled zymonic acid. JO - Nat. Commun. VL - 8 PY - 2017 SN - 2041-1723 ER - TY - JOUR AB - The transport of peroxisomal membrane proteins (PMPs) requires the soluble PEX19 protein as chaperone and import receptor. Recognition of cargo PMPs by the C-terminal domain (CTD) of PEX19 is required for peroxisome biogenesis in vivo. Farnesylation at a C-terminal CaaX motif in PEX19 enhances the PMP interaction, but the underlying molecular mechanisms are unknown. Here, we report the NMR-derived structure of the farnesylated human PEX19 CTD, which reveals that the farnesyl moiety is buried in an internal hydrophobic cavity. This induces substantial conformational changes that allosterically reshape the PEX19 surface to form two hydrophobic pockets for the recognition of conserved aromatic/aliphatic side chains in PMPs. Mutations of PEX19 residues that either mediate farnesyl contacts or are directly involved in PMP recognition abolish cargo binding and cannot complement a Delta PEX19 phenotype in human Zellweger patient fibroblasts. Our results demonstrate an allosteric mechanism for the modulation of protein function by farnesylation. AU - Emmanouilidis, L. AU - Schütz, U. AU - Tripsianes, K.* AU - Madl, T. AU - Radke, J.* AU - Rucktaeschel, R.* AU - Wilmanns, M.* AU - Schliebs, W.* AU - Erdmann, R.* AU - Sattler, M. C1 - 50762 C2 - 42838 CY - London TI - Allosteric modulation of peroxisomal membrane protein recognition by farnesylation of the peroxisomal import receptor PEX19. JO - Nat. Commun. VL - 8 PB - Nature Publishing Group PY - 2017 SN - 2041-1723 ER - TY - JOUR AB - We show that deep convolutional neural networks combined with nonlinear dimension reduction enable reconstructing biological processes based on raw image data. We demonstrate this by reconstructing the cell cycle of Jurkat cells and disease progression in diabetic retinopathy. In further analysis of Jurkat cells, we detect and separate a subpopulation of dead cells in an unsupervised manner and, in classifying discrete cell cycle stages, we reach a sixfold reduction in error rate compared to a recent approach based on boosting on image features. In contrast to previous methods, deep learning based predictions are fast enough for on-the-fly analysis in an imaging flow cytometer.The interpretation of information-rich, high-throughput single-cell data is a challenge requiring sophisticated computational tools. Here the authors demonstrate a deep convolutional neural network that can classify cell cycle status on-the-fly. AU - Eulenberg, P. AU - Köhler, N. AU - Blasi, T. AU - Filby, A.* AU - Carpenter, A.E.* AU - Rees, P.* AU - Theis, F.J. AU - Wolf, F.A. C1 - 51837 C2 - 43508 CY - London TI - Reconstructing cell cycle and disease progression using deep learning. JO - Nat. Commun. VL - 8 IS - 1 PB - Nature Publishing Group PY - 2017 SN - 2041-1723 ER - TY - JOUR AB - Genome wide association studies (GWAS) have mapped multiple independent cancer susceptibility loci to chr5p15.33. Here, we show that fine-mapping of pancreatic and testicular cancer GWAS within one of these loci (Region 2 in CLPTM1L) focuses the signal to nine highly correlated SNPs. Of these, rs36115365-C associated with increased pancreatic and testicular but decreased lung cancer and melanoma risk, and exhibited preferred protein-binding and enhanced regulatory activity. Transcriptional gene silencing of this regulatory element repressed TERT expression in an allele-specific manner. Proteomic analysis identifies allele-preferred binding of Zinc finger protein 148 (ZNF148) to rs36115365-C, further supported by binding of purified recombinant ZNF148. Knockdown of ZNF148 results in reduced TERT expression, telomerase activity and telomere length. Our results indicate that the association with chr5p15.33-Region 2 may be explained by rs36115365, a variant influencing TERT expression via ZNF148 in a manner consistent with elevated TERT in carriers of the C allele. AU - Fang, J.C.* AU - Jia, J.* AU - Makowski, M.* AU - Xu, M.* AU - Wang, Z.* AU - Zhang, T.* AU - Hoskins, J.W.* AU - Choi, J.H.* AU - Han, Y.* AU - Zhang, M.* AU - Thomas, J.A.* AU - Kovacs, M.* AU - Collins, I.* AU - Dzyadyk, M.* AU - Thompson, A.* AU - O'Neill, M.* AU - Das, S.* AU - Lan, Q.* AU - Köster, R.* AU - Stolzenberg-Solomon, R.S.* AU - Kraft, P.* AU - Wolpin, B.M.* AU - Jansen, P.W.T.C.* AU - Olson, S.H.* AU - McGlynn, K.A.* AU - Kanetsky, P.A.* AU - Chatterjee, N.* AU - Barrett, J.H.* AU - Dunning, A.M.* AU - Taylor, J.C.* AU - Newton-Bishop, J.A.* AU - Bishop, D.T.* AU - Andresson, T.* AU - Petersen, G.M.* AU - Amos, C.I.* AU - Iles, M.M.* AU - Nathanson, K.L.* AU - Landi, M.T.* AU - TRICL Consortium (Wichmann, H.-E.) AU - Brown, K.M.* AU - Amundadottir, L.T.* C1 - 51298 C2 - 42884 TI - Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148. JO - Nat. Commun. VL - 8 PY - 2017 SN - 2041-1723 ER - TY - JOUR AB - The liver integrates multiple metabolic pathways to warrant systemic energy homeostasis. An excessive lipogenic flux due to chronic dietary stimulation contributes to the development of hepatic steatosis, dyslipidemia and hyperglycemia. Here we show that the oxidoreductase retinol saturase (RetSat) is involved in the development of fatty liver. Hepatic RetSat expression correlates with steatosis and serum triglycerides (TGs) in humans. Liver-specific depletion of RetSat in dietary obese mice lowers hepatic and circulating TGs and normalizes hyperglycemia. Mechanistically, RetSat depletion reduces the activity of carbohydrate response element binding protein (ChREBP), a cellular hexose-phosphate sensor and inducer of lipogenesis. Defects upon RetSat depletion are rescued by ectopic expression of ChREBP but not by its putative enzymatic product 13,14-dihydroretinol, suggesting that RetSat affects hepatic glucose sensing independent of retinol conversion. Thus, RetSat is a critical regulator of liver metabolism functioning upstream of ChREBP. Pharmacological inhibition of liver RetSat may represent a therapeutic approach for steatosis. AU - Heidenreich, S.* AU - Witte, N.* AU - Weber, P.* AU - Goehring, I.* AU - Tolkachov, A.* AU - von Loeffelholz, C.* AU - Doecke, S.* AU - Bauer, M.* AU - Stockmann, M.* AU - Pfeiffer, A.F.H.* AU - Birkenfeld, A.L. AU - Pietzke, M.* AU - Kempa, S.* AU - Muenzner, M.* AU - Schupp, M.* C1 - 51868 C2 - 43539 CY - London TI - Retinol saturase coordinates liver metabolism by regulating ChREBP activity. JO - Nat. Commun. VL - 8 PB - Nature Publishing Group PY - 2017 SN - 2041-1723 ER - TY - JOUR AB - Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution. AU - Justice, A.E.* AU - Winkler, T.W.* AU - Feitosa, M.F.* AU - Graff, M.* AU - Fisher, V.A.* AU - Young, K.L.* AU - Barata, L.* AU - Deng, X.* AU - Czajkowski, J.* AU - Hadley, D.* AU - Ngwa, J.S.* AU - Ahluwalia, T.S.* AU - Chu, A.Y.* AU - Heard-Costa, N.L.* AU - Lim, E.* AU - Perez, J.I.A.* AU - Eicher, J.D.* AU - Kutalik, Z.* AU - Xue, L.* AU - Mahajan, A.* AU - Renström, F.* AU - Wu, J.* AU - Qi, Q.* AU - Ahmad, S.* AU - Alfred, T.* AU - Amin, N.* AU - Bielak, L.F.* AU - Bonnefond, A.* AU - Bragg, J.N.* AU - Cadby, G.* AU - Chittani, M.* AU - Coggeshall, S.* AU - Corre, T.* AU - Direk, N.* AU - Eriksson, J.* AU - Fischer, K.* AU - Gorski, M.* AU - Harder, M.N.* AU - Horikoshi, M.* AU - Huang, T.* AU - Huffman, J.E.* AU - Jackson, A.U.* AU - Justesen, J.M.* AU - Kanoni, S.* AU - Kinnunen, L.* AU - Kleber, M.E.* AU - Komulainen, P.* AU - Kumari, M.* AU - Lim, U.* AU - Luan, J.* AU - Lyytikäinen, L.-P.* AU - Mangino, M.* AU - Manichaikul, A.* AU - Marten, J.* AU - Middelberg, R.P.S.* AU - Müller-Nurasyid, M. AU - Navarro, P.* AU - Perusse, L.* AU - Pervjakova, N.* AU - Sarti, C.* AU - Smith, A.V.* AU - Smith, J.A.* AU - Stancáková, A.* AU - Strawbridge, R.J.* AU - Stringham, H.M.* AU - Sung, Y.J.* AU - Tanaka, T.* AU - Teumer, A.* AU - Trompet, S.* AU - van der Laan, S.W.* AU - van der Most, P.J.* AU - van Vliet-Ostaptchouk, J.V.* AU - Vedantam, S.L.* AU - Verweij, N.* AU - Vink, J.M.* AU - Vitart, V.* AU - Wu, Y.* AU - Yengo, L.* AU - Zhang, W.* AU - Zhao, J.H.* AU - Zimmermann, M.E.* AU - Zubair, N.* AU - Abecasis, G.R.* AU - Adair, L.S.* AU - Afaq, S.* AU - Afzal, U.* AU - Bakker, S.J.L.* AU - Bartz, T.M.* AU - Beilby, J.* AU - Bergman, R.N.* AU - Bergmann, S.* AU - Biffar, R.* AU - Blangero, J.* AU - Boerwinkle, E.* AU - Bonnycastle, L.L.* AU - Bottinger, E.P.* AU - Braga, D.* AU - Buckley, B.M.* AU - Buyske, S.* AU - Campbell, H.* AU - Chambers, J.C.* AU - Collins, F.S.* AU - Curran, J.E.* AU - de Borst, G.J.* AU - de Craen, A.J.M.* AU - de Geus, E.J.C.* AU - Dedoussis, G.* AU - Delgado, G.E.* AU - den Ruijter, H.M.* AU - Eiriksdottir, G.* AU - Eriksson, A.L.* AU - Esko, T.* AU - Faul, J.D.* AU - Ford, I.* AU - Forrester, T.* AU - Gertow, K.* AU - Gigante, B.* AU - Glorioso, N.* AU - Gong, J.* AU - Grallert, H. AU - Grammer, T.B.* AU - Grarup, N.* AU - Haitjema, S.* AU - Hallmans, G.* AU - Hamsten, A.* AU - Hansen, T.* AU - Harris, T.B.* AU - Hartman, C.A.* AU - Hassinen, M.* AU - Hastie, N.D.* AU - Heath, A.C.* AU - Hernandez, D.* AU - Hindorff, L.* AU - Hocking, L.J.* AU - Hollensted, M.* AU - Holmen, O.L.* AU - Homuth, G.* AU - Hottenga, J.J.* AU - Huang, J.* AU - Hung, J.* AU - Hutri-Kähönen, N.* AU - Ingelsson, E.* AU - James, A.L.* AU - Jansson, J.* AU - Jarvelin, M.R.* AU - Jhun, M.A.* AU - Jorgensen, M.E.* AU - Juonala, M.* AU - Kähönen, M.* AU - Karlsson, M.* AU - Koistinen, H.A.* AU - Kolcic, I.* AU - Kolovou, G.* AU - Kooperberg, C.* AU - Krämer, B.K.* AU - Kuusisto, J.* AU - Kvaloy, K.* AU - Lakka, T.A.* AU - Langenberg, C.* AU - Launer, L.J.* AU - Leander, K.* AU - Lee, N.R.* AU - Lind, L.* AU - Lindgren, C.M.* AU - Linneberg, A.* AU - Lobbens, S.* AU - Loh, M.* AU - Lorentzon, M.* AU - Luben, R.* AU - Lubke, G.* AU - Ludolph-Donislawski, A. AU - Lupoli, S.* AU - Madden, P.A.F.* AU - Mannikko, R.* AU - Marques-Vidal, P.* AU - Martin, N.G.* AU - McKenzie, C.A.* AU - McKnight, B.* AU - Mellström, D.* AU - Menni, C.* AU - Montgomery, G.W.* AU - Musk, A.W.* AU - Narisu, N.* AU - Nauck, M.* AU - Nolte, I.M.* AU - Oldehinkel, A.J.* AU - Olden, M.* AU - Ong, K.K.* AU - Padmanabhan, S.* AU - Peyser, P.A.* AU - Pisinger, C.* AU - Porteous, D.J.* AU - Raitakari, O.T.* AU - Rankinen, T.* AU - Rao, D.C.* AU - Rasmussen-Torvik, L.J.* AU - Rawal, R. AU - Rice, T.* AU - Ridker, P.M.* AU - Rose, L.M.* AU - Bien, S.A.* AU - Rudan, I.* AU - Sanna, S.* AU - Sarzynski, M.A.* AU - Sattar, N.* AU - Savonen, K.* AU - Schlessinger, D.* AU - Scholtens, S.* AU - Schurmann, C.* AU - Scott, R.A.* AU - Sennblad, B.* AU - Siemelink, M.A.* AU - Silbernagel, G.* AU - Slagboom, P.E.* AU - Snieder, H.* AU - Staessen, J.A.* AU - Stott, D.J.* AU - Swertz, M.A.* AU - Swift, A.J.* AU - Taylor, K.D.* AU - Tayo, B.O.* AU - Thorand, B. AU - Thuillier, D.* AU - Tuomilehto, J.* AU - Uitterlinden, A.G.* AU - Vandenput, L.* AU - Vohl, M.C.* AU - Völzke, H.* AU - Vonk, J.M.* AU - Waeber, G.* AU - Waldenberger, M. AU - Westendorp, R.G.J.* AU - Wild, S.* AU - Willemsen, G.* AU - Wolffenbuttel, B.H.R.* AU - Wong, A.* AU - Wright, A.F.* AU - Zhao, W.* AU - Zillikens, M.C.* AU - Baldassarre, D.* AU - Balkau, B.* AU - Bandinelli, S.* AU - Böger, C.A.* AU - Boomsma, D.I.* AU - Bouchard, C.* AU - Bruinenberg, M.* AU - Chasman, D.I.* AU - Chen, Y.I.* AU - Chines, P.S.* AU - Cooper, R.S.* AU - Cucca, F.* AU - Cusi, D.* AU - de Faire, U.* AU - Ferrucci, L.* AU - Franks, P.W.* AU - Froguel, P.* AU - Gordon-Larsen, P.* AU - Grabe, H.J.* AU - Gudnason, V.* AU - Haiman, C.A.* AU - Hayward, C.* AU - Hveem, K.* AU - Johnson, A.D.* AU - Jukema, W.* AU - Kardia, S.L.R.* AU - Kivimaki, M.* AU - Kooner, J.S.* AU - Kuh, D.* AU - Laakso, M.* AU - Lehtimäki, T.* AU - Le Marchand, L.* AU - Marz, W.* AU - McCarthy, M.I.* AU - Metspalu, A.* AU - Morris, A.P.* AU - Ohlsson, C.* AU - Palmer, L.J.* AU - Pasterkamp, G.* AU - Pedersen, O.* AU - Peters, A. AU - Peters, U.* AU - Polasek, O.* AU - Psaty, B.M.* AU - Qi, L.* AU - Rauramaa, R.* AU - Smith, B.H.* AU - Sörensen, T.I.A.* AU - Strauch, K. AU - Tiemeier, H.* AU - Tremoli, E.* AU - van der Harst, P.* AU - Vestergaard, H.* AU - Vollenweider, P.* AU - Wareham, N.J.* AU - Weir, D.R.* AU - Whitfield, J.B.* AU - Wilson, J.F.* AU - Tyrrell, J.* AU - Frayling, T.M.* AU - Barroso, I.* AU - Boehnke, M.* AU - Deloukas, P.* AU - Fox, C.S.* AU - Hirschhorn, J.N.* AU - Hunter, D.J.* AU - Spector, T.D.* AU - Strachan, D.P.* AU - van Duijn, C.M.* AU - Heid, I.M. AU - Mohlke, K.L.* AU - Marchini, J.* AU - Loos, R.J.F.* AU - Kilpeläinen, T.O.* AU - Liu, C.* AU - Borecki, I.B.* AU - North, K.E.* AU - Cupples, L.A.* C1 - 51135 C2 - 42702 CY - London TI - Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits. JO - Nat. Commun. VL - 8 PB - Nature Publishing Group PY - 2017 SN - 2041-1723 ER - TY - JOUR AB - The role of sex in biomedical studies has often been overlooked, despite evidence of sexually dimorphic effects in some biological studies. Here, we used high-throughput phenotype data from 14,250 wildtype and 40,192 mutant mice (representing 2,186 knockout lines), analysed for up to 234 traits, and found a large proportion of mammalian traits both in wildtype and mutants are influenced by sex. This result has implications for interpreting disease phenotypes in animal models and humans. AU - Karp, N.A.* AU - Mason, J.* AU - Beaudet, A.L.* AU - Benjamini, Y.* AU - Bower, L.* AU - Braun, R.E.* AU - Brown, S.D.M.* AU - Chesler, E.J.* AU - Dickinson, M.E.* AU - Flenniken, A.M.* AU - Fuchs, H. AU - Hrabě de Angelis, M. AU - Gao, X.* AU - Guo, S.* AU - Greenaway, S.* AU - Heller, R.* AU - Herault, Y.* AU - Justice, M.J.* AU - Kurbatova, N.* AU - Lelliott, C.J.* AU - Lloyd, K.C.K.* AU - Mallon, A.M.* AU - Mank, J.E.* AU - Masuya, H.* AU - McKerlie, C.* AU - Meehan, T.F.* AU - Mott, R.F.* AU - Murray, S.A.* AU - Parkinson, H.* AU - Ramirez-Solis, R.* AU - Santos, L.* AU - Seavitt, J.R.* AU - Smedley, D.* AU - Sorg, T.* AU - Speak, A.O.* AU - Steel, K.P.* AU - Svenson, K.L.* AU - Wakana, S.* AU - West, D.* AU - Wells, S.* AU - Westerberg, H.* AU - Yaacoby, S.* AU - White, J.K.* AU - International Mouse Phenotyping Consortium (Aguilar-Pimentel, J.A. AU - Treise, I. AU - Moreth, K. AU - Stöger, T. AU - Amarie, O.V. AU - Neff, C. AU - Wurst, W. AU - Calzada-Wack, J. AU - Marschall, S. AU - Brommage, R. AU - Steinkamp, R. AU - Lengger, C. AU - Östereicher, M.A. AU - Maier, H. AU - Stoeger, C. AU - Leuchtenberger, S. AU - Yildirim, A.Ö. AU - Garrett, L. AU - Hölter, S.M. AU - Zimprich, A. AU - Seisenberger, C. AU - Bürger, A. AU - Graw, J. AU - Eickelberg, O. AU - Schmidt-Weber, C.B. AU - Gailus-Durner, V. AU - Beckers, J. AU - Rathkolb, B. AU - Rozman, J.) AU - Becker, L. C1 - 51404 C2 - 43201 CY - London TI - Prevalence of sexual dimorphism in mammalian phenotypic traits. JO - Nat. Commun. VL - 8 PB - Nature Publishing Group PY - 2017 SN - 2041-1723 ER - TY - JOUR AB - Across a variety of Mendelian disorders, ∼50-75% of patients do not receive a genetic diagnosis by exome sequencing indicating disease-causing variants in non-coding regions. Although genome sequencing in principle reveals all genetic variants, their sizeable number and poorer annotation make prioritization challenging. Here, we demonstrate the power of transcriptome sequencing to molecularly diagnose 10% (5 of 48) of mitochondriopathy patients and identify candidate genes for the remainder. We find a median of one aberrantly expressed gene, five aberrant splicing events and six mono-allelically expressed rare variants in patient-derived fibroblasts and establish disease-causing roles for each kind. Private exons often arise from cryptic splice sites providing an important clue for variant prioritization. One such event is found in the complex I assembly factor TIMMDC1 establishing a novel disease-associated gene. In conclusion, our study expands the diagnostic tools for detecting non-exonic variants and provides examples of intronic loss-of-function variants with pathological relevance. AU - Kremer, L.S. AU - Bader, D.M.* AU - Mertes, C.* AU - Kopajtich, R. AU - Pichler, G.* AU - Iuso, A. AU - Haack, T.B. AU - Graf, E. AU - Schwarzmayr, T. AU - Terrile, C. AU - Konarikova, E. AU - Repp, B. AU - Kastenmüller, G. AU - Adamski, J. AU - Lichtner, P. AU - Leonhardt, C.* AU - Funalot, B.* AU - Donati, A.* AU - Tiranti, V.* AU - Lombes, A.* AU - Jardel, C.* AU - Gläser, D.* AU - Taylor, R.W.* AU - Ghezzi, D.* AU - Mayr, J.A.* AU - Rötig, A.* AU - Freisinger, P.* AU - Distelmaier, F.* AU - Strom, T.M. AU - Meitinger, T. AU - Gagneur, J.* AU - Prokisch, H. C1 - 51293 C2 - 43155 CY - London TI - Genetic diagnosis of Mendelian disorders via RNA sequencing. JO - Nat. Commun. VL - 8 PB - Nature Publishing Group PY - 2017 SN - 2041-1723 ER - TY - JOUR AB - There are few examples of robust associations between rare copy number variants (CNVs) and complex continuous human traits. Here we present a large-scale CNV association meta-analysis on anthropometric traits in up to 191,161 adult samples from 26 cohorts. The study reveals five CNV associations at 1q21.1, 3q29, 7q11.23, 11p14.2, and 18q21.32 and confirms two known loci at 16p11.2 and 22q11.21, implicating at least one anthropometric trait. The discovered CNVs are recurrent and rare (0.01-0.2%), with large effects on height ( > 2.4 cm), weight ( > 5 kg), and body mass index (BMI) ( > 3.5 kg/m 2 ). Burden analysis shows a 0.41 cm decrease in height, a 0.003 increase in waist-to-hip ratio and increase in BMI by 0.14 kg/m 2 for each Mb of total deletion burden (P = 2.5 × 10 -10 , 6.0 × 10 -5 , and 2.9 × 10 -3 ). Our study provides evidence that the same genes (e.g., MC4R, FIBIN, and FMO5) harbor both common and rare variants affecting body size and that anthropometric traits share genetic loci with developmental and psychiatric disorders. AU - Macé, A.* AU - Tuke, M.A.* AU - Deelen, P.* AU - Kristiansson, K.* AU - Mattsson, H.* AU - Nõukas, M.* AU - Sapkota, Y.* AU - Schick, U.M.* AU - Porcu, E.* AU - Rüeger, S.* AU - McDaid, A.F.* AU - Porteous, D.J.* AU - Winkler, T.W.* AU - Salvi, E.* AU - Shrine, N.* AU - Liu, X.* AU - Ang, W.Q.* AU - Zhang, W.* AU - Feitosa, M.F.* AU - Venturini, C.* AU - van der Most, P.J.* AU - Rosengren, A.* AU - Wood, A.R.* AU - Beaumont, R.N.* AU - Jones, S.E.* AU - Ruth, K.S.* AU - Yaghootkar, H.* AU - Tyrrell, J.* AU - Havulinna, A.S.* AU - Boers, H.* AU - Mägi, R.* AU - Kriebel, J. AU - Müller-Nurasyid, M. AU - Perola, M.* AU - Nieminen, M.S.* AU - Lokki, M.L.* AU - Kähönen, M.* AU - Viikari, J.S.* AU - Geller, F.* AU - Lahti, J.* AU - Palotie, A.* AU - Koponen, P.* AU - Lundqvist, A.* AU - Meitinger, T. AU - Kutalik, Z.* AU - Afaq, S.* AU - Wojczynski, M.K.* AU - Lenzini, P.* AU - Nolte, I.M.* AU - Sparsø, T.* AU - Schupf, N.* AU - Christensen, K.* AU - Perls, T.T.* AU - Newman, A.B.* AU - Werge, T.* AU - Snieder, H.* AU - Spector, T.D.* AU - Chambers, J.C.* AU - Koskinen, S.* AU - Melbye, M.* AU - Raitakari, O.T.* AU - Lehtimäki, T.* AU - Tobin, M.D.* AU - Wain, L.V.* AU - Sinisalo, J.* AU - Peters, A. C1 - 52107 C2 - 43761 CY - London TI - CNV-association meta-analysis in 191,161 European adults reveals new loci associated with anthropometric traits. JO - Nat. Commun. VL - 8 IS - 1 PB - Nature Publishing Group PY - 2017 SN - 2041-1723 ER - TY - JOUR AB - We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P=1 × 10-4) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10-7). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies. AU - McLaughlin, R.L.* AU - Schijven, D.* AU - van Rheenen, W.* AU - van Eijk, K.R.* AU - O'Brien, M.* AU - Kahn, R.S.* AU - Ophoff, R.A.* AU - Goris, A.* AU - Bradley, D.G.* AU - Al-Chalabi, A.* AU - van den Berg, L.H.* AU - Luykx, J.J.* AU - Hardiman, O.* AU - Veldink, J.H.* AU - Shatunov, A.* AU - Dekker, A.M.* AU - Diekstra, F.P.* AU - Pulit, S.L.* AU - Van Der Spek, R.A.A.* AU - Van Doormaal, P.T.C.* AU - Sproviero, W.* AU - Jones, A.R.* AU - Nicholson, G.A.* AU - Rowe, D.B.* AU - Pamphlett, R.* AU - Kiernan, M.C.* AU - Bauer, D.* AU - Kahlke, T.* AU - Williams, K.* AU - Eftimov, F.* AU - Fogh, I.* AU - Ticozzi, N.* AU - Lin, K.* AU - Millecamps, S.* AU - Salachas, F.* AU - Meininger, V.* AU - Carvalho, M.D.* AU - Pinto, S.* AU - Mora, J.S.* AU - Rojas-Garcyá, R.* AU - Polak, M.* AU - Chandran, S.* AU - Colville, S.* AU - Swingler, R.* AU - Morrison, K.E.* AU - Shaw, P.J.* AU - Hardy, J.* AU - Orrell, R.W.* AU - Pittman, A.* AU - Sidle, K.* AU - Fratta, P.* AU - Malaspina, A.* AU - Petri, S.* AU - Abdulla, S.* AU - Drepper, C.* AU - Sendtner, M.* AU - Meyer, T.* AU - Wiedau-Pazos, M.* AU - Lomen-Hoerth, C.* AU - Deerlin, V.M.V.* AU - Trojanowski, J.Q.* AU - Elman, L.* AU - McCluskey, L.* AU - Basak, N.A.* AU - Project MinE GWAS Consortium (Meitinger, T.) AU - Project MinE GWAS Consortium (Lichtner, P.) AU - Project MinE GWAS Consortium (Blagojevic-Radivojkov, M.) AU - Andres, C.R.* AU - Maurel, C.* AU - Bensimon, G.* AU - Landwehrmeyer, B.* AU - Brice, A.* AU - Payan, C.A.M.* AU - Saker-Delye, S.* AU - Dürr, A.* AU - Wood, N.* AU - Tittmann, L.* AU - Lieb, W.* AU - Franke, A.* AU - Rietschel, M.* AU - Cichon, S.* C1 - 50837 C2 - 42916 TI - Genetic correlation between amyotrophic lateral sclerosis and schizophrenia. JO - Nat. Commun. VL - 8 PY - 2017 SN - 2041-1723 ER - TY - JOUR AB - Recent fate-mapping studies concluded that EMT is not required for metastasis of carcinomas. Here we challenge this conclusion by showing that these studies failed to account for possible crosstalk between EMT and non-EMT cells that promotes dissemination of non-EMT cells. In breast cancer models, EMT cells induce increased metastasis of weakly metastatic, non-EMT tumour cells in a paracrine manner, in part by non-cell autonomous activation of the GLI transcription factor. Treatment with GANT61, a GLI1/2 inhibitor, but not with IPI 926, a Smoothened inhibitor, blocks this effect and inhibits growth in PDX models. In human breast tumours, the EMT-transcription factors strongly correlate with activated Hedgehog/GLI signalling but not with the Hh ligands. Our findings indicate that EMT contributes to metastasis via non-cell autonomous effects that activate the Hh pathway. Although all Hh inhibitors may act against tumours with canonical Hh/GLI signalling, only GLI inhibitors would act against non-canonical EMT-induced GLI activation. AU - Neelakantan, D.* AU - Zhou, H.* AU - Oliphant, M.U.J.* AU - Zhang, X.* AU - Simon, L. AU - Henke, D.M.* AU - Shaw, C.A.* AU - Wu, M.F.* AU - Hilsenbeck, S.G.* AU - White, L.D.* AU - Lewis, M.T.* AU - Ford, H.L.* C1 - 51289 C2 - 43156 CY - London TI - EMT cells increase breast cancer metastasis via paracrine GLI activation in neighbouring tumour cells. JO - Nat. Commun. VL - 8 PB - Nature Publishing Group PY - 2017 SN - 2041-1723 ER - TY - JOUR AB - Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74 AU - Nolte, I.M.* AU - Munoz, M.L.* AU - Tragante, V.* AU - Amare, A.T.* AU - Jansen, R.* AU - Vaez, A.* AU - von der Heyde, B.* AU - Avery, C.L.* AU - Bis, J.C.* AU - Dierckx, B.* AU - van Dongen, J.* AU - Gogarten, S.M.* AU - Goyette, P.* AU - Hernesniemi, J.* AU - Huikari, V.* AU - Hwang, S.J.* AU - Jaju, D.* AU - Kerr, K.F.* AU - Kluttig, A.* AU - Krijthe, B.P.* AU - Kumar, J.* AU - van der Laan, S.W.* AU - Lyytikäinen, L.-P.* AU - Maihofer, A.X.* AU - Minassian, A.* AU - van der Most, P.J.* AU - Müller-Nurasyid, M. AU - Nivard, M.* AU - Salvi, E.* AU - Stewart, J.D.* AU - Thayer, J.F.* AU - Verweij, N.* AU - Wong, A.* AU - Zabaneh, D.* AU - Zafarmand, M.H.* AU - Abdellaoui, A.* AU - Albarwani, S.* AU - Albert, C.M.* AU - Alonso, A.* AU - Ashar, F.* AU - Auvinen, J.* AU - Axelsson, T.* AU - Baker, D.G.* AU - de Bakker, P.I.W.* AU - Barcella, M.* AU - Bayoumi, R.* AU - Bieringa, R.J.* AU - Boomsma, D.* AU - Boucher, G.* AU - Britton, A.R.* AU - Christophersen, I.* AU - Dietrich, A.* AU - Ehret, G.B.* AU - Ellinor, P.T.* AU - Eskola, M.* AU - Felix, J.F.* AU - Floras, J.S.* AU - Franco, O.H.* AU - Friberg, P.* AU - Gademan, M.G.J.* AU - Geyer, M.A.* AU - Giedraitis, V.* AU - Hartman, C.A.* AU - Hemerich, D.* AU - Hofman, A.* AU - Hottenga, J.J.* AU - Huikuri, H.* AU - Hutri-Kähönen, N.* AU - Jouven, X.* AU - Junttila, J.* AU - Juonala, M.* AU - Kiviniemi, A.M.* AU - Kors, J.A.* AU - Kumari, M.* AU - Kuznetsova, T.* AU - Laurie, C.C.* AU - Lefrandt, J.D.* AU - Li, Y.* AU - Liao, D.* AU - Limacher, M.C.* AU - Lin, H.J.* AU - Lindgren, C.M.* AU - Lubitz, S.A.* AU - Mahajan, A.* AU - McKnight, B.* AU - Zu Schwabedissen, H.M.* AU - Milaneschi, Y.* AU - Mononen, N.* AU - Morris, A.P.* AU - Nalls, M.A.* AU - Navis, G.* AU - Neijts, M.* AU - Nikus, K.* AU - North, K.E.* AU - O'Connor, D.T.* AU - Ormel, J.* AU - Perz, S. AU - Peters, A. AU - Psaty, B.M.* AU - Raitakari, O.T.* AU - Risbrough, V.B.* AU - Sinner, M.F.* AU - Siscovick, D.* AU - Smit, J.H.* AU - Smith, N.L.* AU - Soliman, E.Z.* AU - Sotoodehnia, N.* AU - Staessen, J.A.* AU - Stein, P.K.* AU - Stilp, A.M.* AU - Stolarz-Skrzypek, K.* AU - Strauch, K. AU - Sundström, J.* AU - Swenne, C.A.* AU - Syvänen, A.C.* AU - Tardif, J.-C.* AU - Taylor, K.D.* AU - Teumer, A.* AU - Thornton, T.A.* AU - Tinker, L.E.* AU - Uitterlinden, A.G.* AU - van Setten, J.* AU - Voss, A.* AU - Waldenberger, M. AU - Wilhelmsen, K.C.* AU - Willemsen, G.* AU - Wong, Q.* AU - Zhang, Z.M.* AU - Zonderman, A.B.* AU - Cusi, D.* AU - Evans, M.K.* AU - Greiser, H.K.* AU - van der Harst, P.* AU - Hassan, M.* AU - Ingelsson, E.* AU - Järvelin, M.R.* AU - Kääb, S.* AU - Kähönen, M.* AU - Kivimaki, M.* AU - Kooperberg, C.* AU - Kuh, D.* AU - Lehtimäki, T.* AU - Lind, L.* AU - Nievergelt, C.M.* AU - O'Donnell, C.J.* AU - Oldehinkel, A.J.* AU - Penninx, B.* AU - Reiner, A.P.* AU - Riese, H.* AU - van Roon, A.M.* AU - Rioux, J.D.* AU - Rotter, J.I.* AU - Sofer, T.* AU - Stricker, B.H.* AU - Tiemeier, H.* AU - Vrijkotte, T.G.M.* AU - Asselbergs, F.W.* AU - Brundel, B.J.J.M.* AU - Heckbert, S.R.* AU - Whitsel, E.A.* AU - den Hoed, M.* AU - Snieder, H.* AU - de Geus, E.J.C.* C1 - 51351 C2 - 43007 CY - London TI - Genetic loci associated with heart rate variability and their effects on cardiac disease risk. JO - Nat. Commun. VL - 8 PB - Nature Publishing Group PY - 2017 SN - 2041-1723 ER - TY - JOUR AB - Although lysyl oxidase-like 1 (LOXL1) is known as the principal genetic risk factor for pseudoexfoliation (PEX) syndrome, a major cause of glaucoma and cardiovascular complications, no functional variants have been identified to date. Here, we conduct a genome-wide association scan on 771 German PEX patients and 1,350 controls, followed by independent testing of associated variants in Italian and Japanese data sets. We focus on a 3.5-kb four-component polymorphic locus positioned spanning introns 1 and 2 of LOXL1 with enhancer-like chromatin features. We find that the rs11638944:C>G transversion exerts a cis-acting effect on the expression levels of LOXL1, mediated by differential binding of the transcription factor RXRα (retinoid X receptor alpha) and by modulating alternative splicing of LOXL1, eventually leading to reduced levels of LOXL1 mRNA in cells and tissues of risk allele carriers. These findings uncover a functional mechanism by which common noncoding variants influence LOXL1 expression. AU - Pasutto, F.* AU - Zenkel, M.* AU - Hoja, U.* AU - Berner, D.* AU - Uebe, S.* AU - Ferrazzi, F.* AU - Schödel, J.* AU - Liravi, P.* AU - Ozaki, M.* AU - Paoli, D.* AU - Frezzotti, P.* AU - Mizoguchi, T.* AU - Nakano, S.* AU - Kubota, T.* AU - Manabe, S.* AU - Salvi, E.* AU - Manunta, P.* AU - Cusi, D.* AU - Gieger, C. AU - Wichmann, H.-E. AU - Aung, T.* AU - Khor, C.C.* AU - Kruse, F.E.* AU - Reis, A.* AU - Schlötzer-Schrehardt, U.* C1 - 51177 C2 - 42873 CY - London TI - Pseudoexfoliation syndrome-associated genetic variants affect transcription factor binding and alternative splicing of LOXL1. JO - Nat. Commun. VL - 8 PB - Nature Publishing Group PY - 2017 SN - 2041-1723 ER - TY - JOUR AB - Quantitative analysis of bioimaging data is often skewed by both shading in space and background variation in time. We introduce BaSiC, an image correction method based on low-rank and sparse decomposition which solves both issues. In comparison to existing shading correction tools, BaSiC achieves high-accuracy with significantly fewer input images, works for diverse imaging conditions and is robust against artefacts. Moreover, it can correct temporal drift in time-lapse microscopy data and thus improve continuous single-cell quantification. BaSiC requires no manual parameter setting and is available as a Fiji/ImageJ plugin. AU - Peng, T. AU - Thorn, K.* AU - Schroeder, T.* AU - Wang, L.* AU - Theis, F.J. AU - Marr, C. AU - Navab, N.* C1 - 51277 C2 - 43160 CY - London TI - A BaSiC tool for background and shading correction of optical microscopy images. JO - Nat. Commun. VL - 8 PB - Nature Publishing Group PY - 2017 SN - 2041-1723 ER - TY - JOUR AB - Bcl-3 is an atypical NF-κB family member that regulates NF-κB-dependent gene expression in effector T cells, but a cell-intrinsic function in regulatory T (Treg) cells and colitis is not clear. Here we show that Bcl-3 expression levels in colonic T cells correlate with disease manifestation in patients with inflammatory bowel disease. Mice with T-cell-specific overexpression of Bcl-3 develop severe colitis that can be attributed to defective Treg cell development and function, leading to the infiltration of immune cells such as pro-inflammatory γδT cells, but not αβ T cells. In Treg cells, Bcl-3 associates directly with NF-κB p50 to inhibit DNA binding of p50/p50 and p50/p65 NF-κB dimers, thereby regulating NF-κB-mediated gene expression. This study thus reveals intrinsic functions of Bcl-3 in Treg cells, identifies Bcl-3 as a potential prognostic marker for colitis and illustrates the mechanism by which Bcl-3 regulates NF-κB activity in Tregs to prevent colitis. AU - Reißig, S.* AU - Tang, Y.* AU - Nikolaev, A.* AU - Gerlach, K.* AU - Wolf, C. AU - Davari, K. AU - Gallus, C. AU - Masri, J.* AU - Mufazalov, I.A.* AU - Neurath, M.F.* AU - Wunderlich, F.T.* AU - Schattenberg, J.M.* AU - Galle, P.R.* AU - Weigmann, B.* AU - Waisman, A.* AU - Glasmacher, E. AU - Hövelmeyer, N.* C1 - 51015 C2 - 43056 CY - London TI - Elevated levels of Bcl-3 inhibits Treg development and function resulting in spontaneous colitis. JO - Nat. Commun. VL - 8 PB - Nature Publishing Group PY - 2017 SN - 2041-1723 ER - TY - JOUR AB - Human T-cell function is dependent on T-cell antigen receptor (TCR) and co-signalling as evidenced by immunodeficiencies affecting TCR-dependent signalling pathways. Here, we show four human patients with EBV + disseminated smooth muscle tumours that carry two homozygous loss-of-function mutations in the CARMIL2 (RLTPR) gene encoding the capping protein regulator and myosin 1 linker 2. These patients lack regulatory T cells without evidence of organ-specific autoimmunity, and have defective CD28 co-signalling associated with impaired T-cell activation, differentiation and function, as well as perturbed cytoskeletal organization associated with T-cell polarity and migration disorders. Human CARMIL2-deficiency is therefore an autosomal recessive primary immunodeficiency disorder associated with defective CD28-mediated TCR co-signalling and impaired cytoskeletal dynamics. AU - Schober, T.* AU - Magg, T.* AU - Laschinger, M.* AU - Rohlfs, M.* AU - Linhares, N.D.* AU - Puchalka, J.* AU - Weisser, T.* AU - Fehlner, K.* AU - Mautner, J. AU - Walz, C.* AU - Hussein, K.* AU - Jaeger, G.* AU - Kammer, B.* AU - Schmid, I.* AU - Bahia, M.* AU - Pena, S.D.J.* AU - Behrends, U. AU - Belohradsky, B.H.* AU - Klein, C.* AU - Hauck, F.* C1 - 50433 C2 - 40685 CY - London TI - A human immunodeficiency syndrome caused by mutations in CARMIL2. JO - Nat. Commun. VL - 8 PB - Nature Publishing Group PY - 2017 SN - 2041-1723 ER - TY - JOUR AB - Infections with Epstein-Barr virus (EBV) are associated with cancer development, and EBV lytic replication (the process that generates virus progeny) is a strong risk factor for some cancer types. Here we report that EBV infection of B-lymphocytes (in vitro and in a mouse model) leads to an increased rate of centrosome amplification, associated with chromosomal instability. This effect can be reproduced with virus-like particles devoid of EBV DNA, but not with defective virus-like particles that cannot infect host cells. Viral protein BNRF1 induces centrosome amplification, and BNRF1-deficient viruses largely lose this property. These findings identify a new mechanism by which EBV particles can induce chromosomal instability without establishing a chronic infection, thereby conferring a risk for development of tumours that do not necessarily carry the viral genome. AU - Shumilov, A.* AU - Tsai, M.H.* AU - Schlosser, Y.T.* AU - Kratz, A.S.* AU - Bernhardt, K.* AU - Fink, S.* AU - Mizani, T.* AU - Lin, X.* AU - Jauch, A.* AU - Mautner, J. AU - Kopp-Schneider, A.* AU - Feederle, R. AU - Hoffmann, I.* AU - Delecluse, H.J.* C1 - 50527 C2 - 42351 CY - London TI - Epstein-Barr virus particles induce centrosome amplification and chromosomal instability. JO - Nat. Commun. VL - 8 PB - Nature Publishing Group PY - 2017 SN - 2041-1723 ER - TY - JOUR AB - The proliferative and functional heterogeneity among seemingly uniform cells is a universal phenomenon. Identifying the underlying factors requires single-cell analysis of function and proliferation. Here we show that the pancreatic beta-cells in zebrafish exhibit different growth-promoting and functional properties, which in part reflect differences in the time elapsed since birth of the cells. Calcium imaging shows that the beta-cells in the embryonic islet become functional during early zebrafish development. At later stages, younger beta-cells join the islet following differentiation from post-embryonic progenitors. Notably, the older and younger beta-cells occupy different regions within the islet, which generates topological asymmetries in glucose responsiveness and proliferation. Specifically, the older beta-cells exhibit robust glucose responsiveness, whereas younger beta-cells are more proliferative but less functional. As the islet approaches its mature state, heterogeneity diminishes and beta-cells synchronize function and proliferation. Our work illustrates a dynamic model of heterogeneity based on evolving proliferative and functional beta-cell states. AU - Singh, S.P.* AU - Janjuha, S. AU - Hartmann, T.* AU - Kayisoglu, O.* AU - Konantz, J.* AU - Birke, S.* AU - Murawala, P.* AU - Alfar, E.A.* AU - Murata, K.* AU - Eugster, A.* AU - Tsuji, N.* AU - Morrissey, E.R.* AU - Brand, M.* AU - Ninov, N. C1 - 52078 C2 - 43713 CY - London TI - Different developmental histories of beta-cells generate functional and proliferative heterogeneity during islet growth. JO - Nat. Commun. VL - 8 PB - Nature Publishing Group PY - 2017 SN - 2041-1723 ER - TY - JOUR AB - Genome-wide association studies (GWAS) with intermediate phenotypes, like changes in metabolite and protein levels, provide functional evidence to map disease associations and translate them into clinical applications. However, although hundreds of genetic variants have been associated with complex disorders, the underlying molecular pathways often remain elusive. Associations with intermediate traits are key in establishing functional links between GWAS-identified risk-variants and disease end points. Here we describe a GWAS using a highly multiplexed aptamer-based affinity proteomics platform. We quantify 539 associations between protein levels and gene variants (pQTLs) in a German cohort and replicate over half of them in an Arab and Asian cohort. Fifty-five of the replicated pQTLs are located in trans. Our associations overlap with 57 genetic risk loci for 42 unique disease end points. We integrate this information into a genome-proteome network and provide an interactive web-tool for interrogations. Our results provide a basis for novel approaches to pharmaceutical and diagnostic applications. AU - Suhre, K.* AU - Arnold, M. AU - Bhagwat, A.M.* AU - Cotton, R.J.* AU - Engelke, R.* AU - Raffler, J. AU - Sarwath, H.* AU - Thareja, G.* AU - Wahl, A. AU - DeLisle, R.K.* AU - Gold, L.* AU - Pezer, M.* AU - Lauc, G.* AU - El-Din Selim, M.A.* AU - Mook-Kanamori, D.O.* AU - Al-Dous, E.K.* AU - Mohamoud, Y.A.* AU - Malek, J.A.* AU - Strauch, K. AU - Grallert, H. AU - Peters, A. AU - Kastenmüller, G. AU - Gieger, C. AU - Graumann, J.* C1 - 50633 C2 - 42470 CY - London TI - Connecting genetic risk to disease end points through the human blood plasma proteome. JO - Nat. Commun. VL - 8 PB - Nature Publishing Group PY - 2017 SN - 2041-1723 ER - TY - JOUR AB - Basalts are recognized as one of the major habitats on Earth, harboring diverse and active microbial populations. Inconsistently, this living component is rarely considered in engineering operations carried out in these environments. This includes carbon capture and storage (CCS) technologies that seek to offset anthropogenic CO2 emissions into the atmosphere by burying this greenhouse gas in the subsurface. Here, we show that deep ecosystems respond quickly to field operations associated with CO2 injections based on a microbiological survey of a basaltic CCS site. Acidic CO2-charged groundwater results in a marked decrease (by ~ 2.5-4) in microbial richness despite observable blooms of lithoautotrophic iron-oxidizing Betaproteobacteria and degraders of aromatic compounds, which hence impact the aquifer redox state and the carbon fate. Host-basalt dissolution releases nutrients and energy sources, which sustain the growth of autotrophic and heterotrophic species whose activities may have consequences on mineral storage. AU - Trias, R.* AU - Ménez, B.* AU - le Campion, P.* AU - Zivanovic, Y.* AU - Lecourt, L.* AU - Lecoeuvre, A.* AU - Schmitt-Kopplin, P. AU - Uhl, J. AU - Gislason, S.R.* AU - Alfreðsson, H.A.* AU - Mesfin, K.G.* AU - Snæbjörnsdóttir, S.* AU - Aradóttir, E.S.* AU - Gunnarsson, I.* AU - Matter, J.M.* AU - Stute, M.* AU - Oelkers, E.H.* AU - Gérard, E.* C1 - 52169 C2 - 43786 CY - London TI - High reactivity of deep biota under anthropogenic CO² injection into basalt. JO - Nat. Commun. VL - 8 IS - 1 PB - Nature Publishing Group PY - 2017 SN - 2041-1723 ER - TY - JOUR AB - Dietary restriction regimes extend lifespan in various animal models. Here we show that longevity in male C57BL/6J mice subjected to every-other-day feeding is associated with a delayed onset of neoplastic disease that naturally limits lifespan in these animals. We compare more than 200 phenotypes in over 20 tissues in aged animals fed with a lifelong every-other-day feeding or ad libitum access to food diet to determine whether molecular, cellular, physiological and histopathological aging features develop more slowly in every-other-day feeding mice than in controls. We also analyze the effects of every-other-day feeding on young mice on shorter-term every-other-day feeding or ad libitum to account for possible aging-independent restriction effects. Our large-scale analysis reveals overall only limited evidence for a retardation of the aging rate in every-other-day feeding mice. The data indicate that every-other-day feeding-induced longevity is sufficiently explained by delays in life-limiting neoplastic disorders and is not associated with a more general slowing of the aging process in mice.Dietary restriction can extend the life of various model organisms. Here, Xie et al. show that intermittent periods of fasting achieved through every-other-day feeding protect mice against neoplastic disease but do not broadly delay organismal aging in animals. AU - Xie, K.* AU - Neff, F. AU - Markert, A.* AU - Rozman, J. AU - Aguilar-Pimentel, A. AU - Amarie, O.V. AU - Becker, L. AU - Brommage, R. AU - Garrett, L. AU - Henzel, K.S.* AU - Hölter, S.M. AU - Janik, D. AU - Lehmann, I.* AU - Moreth, K. AU - Pearson, B.L.* AU - Rácz, I. AU - Rathkolb, B. AU - Ryan, D.P.* AU - Schröder, S.* AU - Treise, I.* AU - Bekeredjian, R.* AU - Busch, D.H.* AU - Graw, J. AU - Ehninger, G.* AU - Klingenspor, M.* AU - Klopstock, T.* AU - Ollert, M.* AU - Sandholzer, M. AU - Schmidt-Weber, C.B. AU - Weiergräber, M.* AU - Wolf, E.* AU - Wurst, W. AU - Zimmer, A.* AU - Gailus-Durner, V. AU - Fuchs, H. AU - Hrabě de Angelis, M. AU - Ehninger, D.* C1 - 51652 C2 - 43329 TI - Every-other-day feeding extends lifespan but fails to delay many symptoms of aging in mice. JO - Nat. Commun. VL - 8 IS - 1 PY - 2017 SN - 2041-1723 ER - TY - JOUR AB - Consuming a calorically dense diet stimulates microglial reactivity in the mediobasal hypothalamus (MBH) in association with decreased number of appetite-curbing pro-opiomelanocortin (POMC) neurons; whether the reduction in POMC neuronal function is secondary to the microglial activation is unclear. Here we show that in hypercaloric diet-induced obese mice, persistently activated microglia in the MBH hypersecrete TNFα that in turn stimulate mitochondrial ATP production in POMC neurons, promoting mitochondrial fusion in their neurites, and increasing POMC neuronal firing rates and excitability. Specific disruption of the gene expressions of TNFα downstream signals TNFSF11A or NDUFAB1 in the MBH of diet-induced obese mice reverses mitochondrial elongation and reduces obesity. These data imply that in a hypercaloric environment, persistent elevation of microglial reactivity and consequent TNFα secretion induces mitochondrial stress in POMC neurons that contributes to the development of obesity. AU - Yi, C.-X. AU - Walter, M.C. AU - Gao, Y. AU - Pitra, S.* AU - Legutko, B. AU - Kälin, S. AU - Layritz, C. AU - García-Cáceres, C. AU - Bielohuby, M.* AU - Bidlingmaier, M.* AU - Woods, S.C.* AU - Ghanem, A.* AU - Conzelmann, K.K.* AU - Stern, J.E.* AU - Jastroch, M. AU - Tschöp, M.H. C1 - 51102 C2 - 42745 TI - TNFα drives mitochondrial stress in POMC neurons in obesity. JO - Nat. Commun. VL - 8 PY - 2017 SN - 2041-1723 ER - TY - JOUR AB - DNA methylation (DNAm) has been revealed to play a role in various diseases. Here we performed epigenome-wide screening and validation to identify mortality-related DNAm signatures in a general population-based cohort with up to 14 years follow-up. In the discovery panel in a case-cohort approach, 11,063 CpGs reach genome-wide significance (FDR<0.05). 58 CpGs, mapping to 38 well-known disease-related genes and 14 intergenic regions, are confirmed in a validation panel. A mortality risk score based on ten selected CpGs exhibits strong association with all-cause mortality, showing hazard ratios (95% CI) of 2.16 (1.10-4.24), 3.42 (1.81-6.46) and 7.36 (3.69-14.68), respectively, for participants with scores of 1, 2-5 and 5+ compared with a score of 0. These associations are confirmed in an independent cohort and are independent from the 'epigenetic clock'. In conclusion, DNAm of multiple disease-related genes are strongly linked to mortality outcomes. The DNAm-based risk score might be informative for risk assessment and stratification. AU - Zhang, Y.* AU - Wilson, R. AU - Heiss, J.* AU - Breitling, L.P.* AU - Saum, K.U.* AU - Schoettker, B.* AU - Holleczek, B.* AU - Waldenberger, M. AU - Peters, A. AU - Brenner, H.* C1 - 50759 C2 - 42567 CY - London TI - DNA methylation signatures in peripheral blood strongly predict all-cause mortality. JO - Nat. Commun. VL - 8 PB - Nature Publishing Group PY - 2017 SN - 2041-1723 ER - TY - JOUR AB - Marine chromophoric dissolved organic matter (CDOM) and its related fluorescent components (FDOM), which are widely distributed but highly photobleached in the surface ocean, are critical in regulating light attenuation in the ocean. However, the origins of marine FDOM are still under investigation. Here we show that cultured picocyanobacteria, Synechococcus and Prochlorococcus, release FDOM that closely match the typical fluorescent signals found in oceanic environments. Picocyanobacterial FDOM also shows comparable apparent fluorescent quantum yields and undergoes similar photo-degradation behaviour when compared with deep-ocean FDOM, further strengthening the similarity between them. Ultrahigh-resolution mass spectrometry (MS) and nuclear magnetic resonance spectroscopy reveal abundant nitrogen-containing compounds in Synechococcus DOM, which may originate from degradation products of the fluorescent phycobilin pigments. Given the importance of picocyanobacteria in the global carbon cycle, our results indicate that picocyanobacteria are likely to be important sources of marine autochthonous FDOM, which may accumulate in the deep ocean. AU - Zhao, Z.* AU - Gonsior, M.* AU - Luek, J.* AU - Timko, S.A.* AU - Ianiri, H.* AU - Hertkorn, N. AU - Schmitt-Kopplin, P. AU - Fang, X.* AU - Zeng, Q.* AU - Jiao, N.* AU - Chen, F.* C1 - 51143 C2 - 43048 CY - London TI - Picocyanobacteria and deep-ocean fluorescent dissolved organic matter share similar optical properties. JO - Nat. Commun. VL - 8 PB - Nature Publishing Group PY - 2017 SN - 2041-1723 ER - TY - JOUR AB - Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 × 10(-8)) or suggestively genome wide (p < 2.3 × 10(-6)). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.Lean body mass is a highly heritable trait and is associated with various health conditions. Here, Kiel and colleagues perform a meta-analysis of genome-wide association studies for whole body lean body mass and find five novel genetic loci to be significantly associated. AU - Zillikens, M.C.* AU - Demissie, S.* AU - Hsu, Y.H.* AU - Yerges-Armstrong, L.M.* AU - Chou, W.C.* AU - Stolk, L.* AU - Livshits, G.* AU - Broer, L.* AU - Johnson, T.* AU - Koller, D.L.* AU - Kutalik, Z.* AU - Luan, J.* AU - Malkin, I.* AU - Ried, J.S. AU - Smith, A.V.* AU - Thorleifsson, G.* AU - Vandenput, L.* AU - Hua Zhao, J.* AU - Zhang, W.* AU - Aghdassi, A.* AU - Åkesson, K.* AU - Amin, N.* AU - Baier, L.J.* AU - Barroso, I.* AU - Bennett, D.A.* AU - Bertram, L.* AU - Biffar, R.* AU - Bochud, M.* AU - Boehnke, M.* AU - Borecki, I.B.* AU - Buchman, A.S.* AU - Byberg, L.* AU - Campbell, H.* AU - Campos Obanda, N.* AU - Cauley, J.A.* AU - Cawthon, P.M.* AU - Cederberg, H.* AU - Chen, Z.* AU - Cho, N.H.* AU - Jin Choi, H.* AU - Claussnitzer, M.* AU - Collins, F.C.* AU - Cummings, S.R.* AU - de Jager, P.L.* AU - Demuth, I.* AU - Dhonukshe-Rutten, R.A.M.* AU - Diatchenko, L.* AU - Eiriksdottir, G.* AU - Enneman, A.W.* AU - Erdos, M.R.* AU - Eriksson, J.G.* AU - Eriksson, J.* AU - Estrada, K.* AU - Evans, D.S.* AU - Feitosa, M.F.* AU - Fu, M.* AU - Garcia, M.* AU - Gieger, C. AU - Girke, T.* AU - Glazer, N.L.* AU - Grallert, H. AU - Grewal, J.* AU - Han, B.G.* AU - Hanson, R.L.* AU - Hayward, C.* AU - Hofman, A.* AU - Hoffman, E.P.* AU - Homuth, G.* AU - Hsueh, W.C.* AU - Hubal, M.J.* AU - Hubbard, A.* AU - Huffman, K.M.* AU - Husted, L.B.* AU - Illig, T. AU - Ingelsson, E.* AU - Ittermann, T.* AU - Jansson, J.O.* AU - Jordan, J.M.* AU - Jula, A.* AU - Karlsson, M.* AU - Khaw, K.T.* AU - Kilpeläinen, T.O.* AU - Klopp, N. AU - Kloth, J.S.L.* AU - Koistinen, H.A.* AU - Kraus, W.E.* AU - Kritchevsky, S.B.* AU - Kuulasmaa, T.* AU - Kuusisto, J.* AU - Laakso, M.* AU - Lahti, J.* AU - Lang, T.* AU - Langdahl, B.L.* AU - Launer, L.J.* AU - Lee, J.Y.* AU - Lerch, M.M.* AU - Lewis, J.R.* AU - Lind, L.* AU - Lindgren, C.* AU - Liu, Y.* AU - Liu, T.* AU - Ljunggren, O.* AU - Lorentzon, M.* AU - Luben, R.N.* AU - Maixner, W.* AU - McGuigan, F.E.* AU - Medina-Gomez, C.* AU - Meitinger, T. AU - Melhus, H.* AU - Mellström, D.* AU - Melov, S.* AU - Michaëlsson, K.* AU - Mitchell, B.D.* AU - Morris, A.P.* AU - Mosekilde, L.* AU - Newman, A.* AU - Nielson, C.M.* AU - O'Connell, J.R.* AU - Oostra, B.A.* AU - Orwoll, E.S.* AU - Palotie, A.* AU - Parker, S.C.* AU - Peacock, M.* AU - Perola, M.* AU - Peters, A. AU - Polasek, O.* AU - Prince, R.L.* AU - Räikkönen, K.* AU - Ralston, S.H.* AU - Ripatti, S.* AU - Robbins, J.A.* AU - Rotter, J.I.* AU - Rudan, I.* AU - Salomaa, V.* AU - Satterfield, S.* AU - Schadt, E.E.* AU - Schipf, S.* AU - Scott, L.J.* AU - Sehmi, J.* AU - Shen, J.* AU - Soo Shin, C.* AU - Sigurdsson, G.* AU - Smith, S.* AU - Soranzo, N.* AU - Stancáková, A.* AU - Steinhagen-Thiessen, E.* AU - Streeten, E.A.* AU - Styrkarsdottir, U.* AU - Swart, K.M.A.* AU - Tan, S.T.* AU - Tarnopolsky, M.A.* AU - Thompson, P.J.* AU - Thomson, C.A.* AU - Thorsteinsdottir, U.* AU - Tikkanen, E.* AU - Tranah, G.J.* AU - Tuomilehto, J.* AU - van Schoor, N.M.* AU - Verma, A.* AU - Vollenweider, P.* AU - Völzke, H.* AU - Wactawski-Wende, J.* AU - Walker, M.* AU - Weedon, M.N.* AU - Welch, R.* AU - Wichmann, H.-E. AU - Widen, E.* AU - Williams, F.M.K.* AU - Wilson, J.F.* AU - Wright, N.C.* AU - Xie, W.* AU - Yu, L.* AU - Zhou, Y.* AU - Chambers, J.C.* AU - Döring, A. AU - van Duijn, C.M.* AU - Econs, M.J.* AU - Gudnason, V.* AU - Kooner, J.S.* AU - Psaty, B.M.* AU - Spector, T.D.* AU - Stefansson, K.* AU - Rivadeneira, F.* AU - Uitterlinden, A.G.* AU - Wareham, N.J.* AU - Ossowski, V.* AU - Waterworth, D.* AU - Loos, R.J.F.* AU - Karasik, D.* AU - Harris, T.B.* AU - Ohlsson, C.* AU - Kiel, D.P.* C1 - 51564 C2 - 43311 CY - London TI - Large meta-analysis of genome-wide association studies identifies five loci for lean body mass. JO - Nat. Commun. VL - 8 IS - 1 PB - Nature Publishing Group PY - 2017 SN - 2041-1723 ER - TY - JOUR AB - A correction to this article has been published and is linked from the HTML version of this article. AU - Zillikens, M.C.* AU - Demissie, S.* AU - Hsu, Y.H.* AU - Yerges-Armstrong, L.M.* AU - Chou, W.C.* AU - Stolk, L.* AU - Livshits, G.* AU - Broer, L.* AU - Johnson, T.* AU - Koller, D.L.* AU - Kutalik, Z.* AU - Luan, J.* AU - Malkin, I.* AU - Ried, J.S. AU - Smith, A.V.* AU - Thorleifsson, G.* AU - Vandenput, L.* AU - Hua Zhao, J.* AU - Zhang, W.* AU - Aghdassi, A.* AU - Åkesson, K.* AU - Amin, N.* AU - Baier, L.J.* AU - Barroso, I.* AU - Bennett, D.A.* AU - Bertram, L.* AU - Biffar, R.* AU - Bochud, M.* AU - Boehnke, M.* AU - Borecki, I.B.* AU - Buchman, A.S.* AU - Byberg, L.* AU - Campbell, H.* AU - Campos Obanda, N.* AU - Cauley, J.A.* AU - Cawthon, P.M.* AU - Cederberg, H.* AU - Chen, Z.* AU - Cho, N.H.* AU - Jin Choi, H.* AU - Claussnitzer, M.* AU - Collins, F.C.* AU - Cummings, S.R.* AU - de Jager, P.L.* AU - Demuth, I.* AU - Dhonukshe-Rutten, R.A.M.* AU - Diatchenko, L.* AU - Eiriksdottir, G.* AU - Enneman, A.W.* AU - Erdos, M.R.* AU - Eriksson, J.G.* AU - Eriksson, J.* AU - Estrada, K.* AU - Evans, D.S.* AU - Feitosa, M.F.* AU - Fu, M.* AU - Garcia, M.* AU - Gieger, C. AU - Girke, T.* AU - Glazer, N.L.* AU - Grallert, H. AU - Grewal, J.* AU - Han, B.G.* AU - Hanson, R.L.* AU - Hayward, C.* AU - Hofman, A.* AU - Hoffman, E.P.* AU - Homuth, G.* AU - Hsueh, W.C.* AU - Hubal, M.J.* AU - Hubbard, A.* AU - Huffman, K.M.* AU - Husted, L.B.* AU - Illig, T. AU - Ingelsson, E.* AU - Ittermann, T.* AU - Jansson, J.O.* AU - Jordan, J.M.* AU - Jula, A.* AU - Karlsson, M.* AU - Khaw, K.T.* AU - Kilpeläinen, T.O.* AU - Klopp, N. AU - Kloth, J.S.L.* AU - Koistinen, H.A.* AU - Kraus, W.E.* AU - Kritchevsky, S.B.* AU - Kuulasmaa, T.* AU - Kuusisto, J.* AU - Laakso, M.* AU - Lahti, J.* AU - Lang, T.* AU - Langdahl, B.L.* AU - Launer, L.J.* AU - Lee, J.Y.* AU - Lerch, M.M.* AU - Lewis, J.R.* AU - Lind, L.* AU - Lindgren, C.* AU - Liu, Y.* AU - Liu, T.* AU - Ljunggren, O.* AU - Lorentzon, M.* AU - Luben, R.N.* AU - Maixner, W.* AU - McGuigan, F.E.* AU - Medina-Gomez, C.* AU - Meitinger, T. AU - Melhus, H.* AU - Mellström, D.* AU - Melov, S.* AU - Michaëlsson, K.* AU - Mitchell, B.D.* AU - Morris, A.P.* AU - Mosekilde, L.* AU - Newman, A.* AU - Nielson, C.M.* AU - O'Connell, J.R.* AU - Oostra, B.A.* AU - Orwoll, E.S.* AU - Palotie, A.* AU - Parker, S.C.J.* AU - Peacock, M.* AU - Perola, M.* AU - Peters, A. AU - Polasek, O.* AU - Prince, R.L.* AU - Räikkönen, K.* AU - Ralston, S.H.* AU - Ripatti, S.* AU - Robbins, J.A.* AU - Rotter, J.I.* AU - Rudan, I.* AU - Salomaa, V.* AU - Satterfield, S.* AU - Schadt, E.E.* AU - Schipf, S.* AU - Scott, L.J.* AU - Sehmi, J.* AU - Shen, J.* AU - Soo Shin, C.* AU - Sigurdsson, G.* AU - Smith, S.* AU - Soranzo, N.* AU - Stancáková, A.* AU - Steinhagen-Thiessen, E.* AU - Streeten, E.A.* AU - Styrkarsdottir, U.* AU - Swart, K.M.A.* AU - Tan, S.T.* AU - Tarnopolsky, M.A.* AU - Thompson, P.J.* AU - Thomson, C.A.* AU - Thorsteinsdottir, U.* AU - Tikkanen, E.* AU - Tranah, G.J.* AU - Tuomilehto, J.* AU - van Schoor, N.M.* AU - Verma, A.* AU - Vollenweider, P.* AU - Völzke, H.* AU - Wactawski-Wende, J.* AU - Walker, M.* AU - Weedon, M.N.* AU - Welch, R.* AU - Wichmann, H.-E. AU - Widen, E.* AU - Williams, F.M.K.* AU - Wilson, J.F.* AU - Wright, N.C.* AU - Xie, W.* AU - Yu, L.* AU - Zhou, Y.* AU - Chambers, J.C.* AU - Döring, A. AU - van Duijn, C.M.* AU - Econs, M.J.* AU - Gudnason, V.* AU - Kooner, J.S.* AU - Psaty, B.M.* AU - Spector, T.D.* AU - Stefansson, K.* AU - Rivadeneira, F.* AU - Uitterlinden, A.G.* AU - Wareham, N.J.* AU - Ossowski, V.* AU - Waterworth, D.* AU - Loos, R.J.F.* AU - Karasik, D.* AU - Harris, T.B.* AU - Ohlsson, C.* AU - Kiel, D.P.* C1 - 52296 C2 - 43889 CY - London TI - Erratum: Large meta-analysis of genome-wide association studies identifies five loci for lean body mass. JO - Nat. Commun. VL - 8 IS - 1 PB - Nature Publishing Group PY - 2017 SN - 2041-1723 ER - TY - JOUR AB - Malignant pleural effusion (MPE) is the lethal consequence of various human cancers metastatic to the pleural cavity. However, the mechanisms responsible for the development of MPE are still obscure. Here we show that mutant KRAS is important for MPE induction in mice. Pleural disseminated, mutant KRAS bearing tumour cells upregulate and systemically release chemokine ligand 2 (CCL2) into the bloodstream to mobilize myeloid cells from the host bone marrow to the pleural space via the spleen. These cells promote MPE formation, as indicated by splenectomy and splenocyte restoration experiments. In addition, KRAS mutations are frequently detected in human MPE and cell lines isolated thereof, but are often lost during automated analyses, as indicated by manual versus automated examination of Sanger sequencing traces. Finally, the novel KRAS inhibitor deltarasin and a monoclonal antibody directed against CCL2 are equally effective against an experimental mouse model of MPE, a result that holds promise for future efficient therapies against the human condition. AU - Αgalioti, T.* AU - Giannou, A.D.* AU - Krontira, A.C.* AU - Kanellakis, N.I.* AU - Kati, D.* AU - Vreka, M. AU - Pepe, M. AU - Spella, M.* AU - Lilis, I.* AU - Zazara, D.E.* AU - Nikolouli, E.* AU - Spiropoulou, N.* AU - Papadakis, A.* AU - Papadia, K.* AU - Voulgaridis, A.* AU - Harokopos, V.* AU - Stamou, P.* AU - Meiners, S. AU - Eickelberg, O. AU - Snyder, L.A.* AU - Antimisiaris, S.G.* AU - Kardamakis, D.* AU - Psallidas, I.* AU - Μarazioti, A.* AU - Stathopoulos, G.T. C1 - 51123 C2 - 43093 CY - London TI - Mutant KRAS promotes malignant pleural effusion formation. JO - Nat. Commun. VL - 8 PB - Nature Publishing Group PY - 2017 SN - 2041-1723 ER - TY - JOUR AB - Control of intestinal epithelial stemness is crucial for tissue homeostasis. Disturbances in epithelial function are implicated in inflammatory and neoplastic diseases of the gastrointestinal tract. Here we report that mitochondrial function plays a critical role in maintaining intestinal stemness and homeostasis. Using intestinal epithelial cell (IEC)-specific mouse models, we show that loss of HSP60, a mitochondrial chaperone, activates the mitochondrial unfolded protein response (MT-UPR) and results in mitochondrial dysfunction. HSP60-deficient crypts display loss of stemness and cell proliferation, accompanied by epithelial release of WNT10A and RSPO1. Sporadic failure of Cre-mediated Hsp60 deletion gives rise to hyperproliferative crypt foci originating from OLFM4(+) stem cells. These effects are independent of the MT-UPR-associated transcription factor CHOP. In conclusion, compensatory hyperproliferation of HSP60(+) escaper stem cells suggests paracrine release of WNT-related factors from HSP60-deficient, functionally impaired IEC to be pivotal in the control of the proliferative capacity of the stem cell niche. AU - Berger, E.* AU - Rath, E.* AU - Yuan, D.T. AU - Waldschmitt, N.* AU - Khaloian, S.* AU - Allgäuer, M.* AU - Staszewski, O.* AU - Lobner, E.M.* AU - Schöttl, T.* AU - Giesbertz, P.* AU - Coleman, O.I.* AU - Prinz, M.* AU - Weber, A.* AU - Gerhard, M.* AU - Klingenspor, M.* AU - Janssen, K.P.* AU - Heikenwälder, M. AU - Haller, D.* C1 - 49833 C2 - 40973 CY - London TI - Mitochondrial function controls intestinal epithelial stemness and proliferation. JO - Nat. Commun. VL - 7 PB - Nature Publishing Group PY - 2016 SN - 2041-1723 ER - TY - JOUR AB - Imaging flow cytometry combines the high-throughput capabilities of conventional flow cytometry with single-cell imaging. Here we demonstrate label-free prediction of DNA content and quantification of the mitotic cell cycle phases by applying supervised machine learning to morphological features extracted from brightfield and the typically ignored darkfield images of cells from an imaging flow cytometer. This method facilitates non-destructive monitoring of cells avoiding potentially confounding effects of fluorescent stains while maximizing available fluorescence channels. The method is effective in cell cycle analysis for mammalian cells, both fixed and live, and accurately assesses the impact of a cell cycle mitotic phase blocking agent. As the same method is effective in predicting the DNA content of fission yeast, it is likely to have a broad application to other cell types. AU - Blasi, T. AU - Hennig, H.* AU - Summers, H.D.* AU - Theis, F.J. AU - Cerveira, J.* AU - Patterson, J.O.* AU - Davies, D.* AU - Filby, A.* AU - Carpenter, A.E.* AU - Rees, P.* C1 - 47666 C2 - 39387 CY - London TI - Label-free cell cycle analysis for high-throughput imaging flow cytometry. JO - Nat. Commun. VL - 7 PB - Nature Publishing Group PY - 2016 SN - 2041-1723 ER - TY - JOUR AB - Cellular organelles provide opportunities to relate biological mechanisms to disease. Here we use affinity proteomics, genetics and cell biology to interrogate cilia: poorly understood organelles, where defects cause genetic diseases. Two hundred and seventeen tagged human ciliary proteins create a final landscape of 1,319 proteins, 4,905 interactions and 52 complexes. Reverse tagging, repetition of purifications and statistical analyses, produce a high-resolution network that reveals organelle-specific interactions and complexes not apparent in larger studies, and links vesicle transport, the cytoskeleton, signalling and ubiquitination to ciliary signalling and proteostasis. We observe sub-complexes in exocyst and intraflagellar transport complexes, which we validate biochemically, and by probing structurally predicted, disruptive, genetic variants from ciliary disease patients. The landscape suggests other genetic diseases could be ciliary including 3M syndrome. We show that 3M genes are involved in ciliogenesis, and that patient fibroblasts lack cilia. Overall, this organelle-specific targeting strategy shows considerable promise for Systems Medicine. AU - Boldt, K.* AU - van Reeuwijk, J.* AU - Lu, Q.* AU - Koutroumpas, K.* AU - Nguyen, T.M.* AU - Texier, Y. AU - van Beersum, S.E.* AU - Horn, N.* AU - Willer, J.R.* AU - Mans, D.A.* AU - Dougherty, G.* AU - Lamers, I.J.* AU - Coene, K.L.* AU - Arts, H.H.* AU - Betts, M.J.* AU - Beyer, T.* AU - Bolat, E.* AU - Gloeckner, C.J.* AU - Haidari, K.* AU - Hetterschijt, L.* AU - Iaconis, D.* AU - Jenkins, D.* AU - Klose, F.* AU - Knapp, B.* AU - Latour, B.* AU - Letteboer, S.J.* AU - Marcelis, C.L.* AU - Mitic, D.* AU - Morleo, M.* AU - Oud, M.M.* AU - Riemersma, M.* AU - Rix, S.* AU - Terhal, P.A.* AU - Toedt, G.* AU - van Dam, T.J.* AU - de Vrieze, E.* AU - Wissinger, Y.* AU - Wu, K.M.* AU - Apic, G.* AU - Beales, P.L.* AU - Blacque, O.E.* AU - Gibson, T.J.* AU - Huynen, M.A.* AU - Katsanis, N.* AU - Kremer, H.* AU - Omran, H.* AU - van Wijk, E. AU - Wolfrum, U.* AU - Kepes, F.* AU - Davis, E.E.* AU - Franco, B.* AU - Giles, R.H.* AU - Ueffing, M.* AU - Russell, R.B.* AU - Roepman, R.* C1 - 48658 C2 - 41245 CY - London TI - An organelle-specific protein landscape identifies novel diseases and molecular mechanisms. JO - Nat. Commun. VL - 7 PB - Nature Publishing Group PY - 2016 SN - 2041-1723 ER - TY - JOUR AB - Calcium signalling plays a critical role in the pathogenesis of heart failure. Here we describe a cardiac protein named Myoscape/FAM40B/STRIP2, which directly interacts with the L-type calcium channel. Knockdown of Myoscape in cardiomyocytes decreases calcium transients associated with smaller Ca(2+) amplitudes and a lower diastolic Ca(2+) content. Likewise, L-type calcium channel currents are significantly diminished on Myoscape ablation, and downregulation of Myoscape significantly reduces contractility of cardiomyocytes. Conversely, overexpression of Myoscape increases global Ca(2+) transients and enhances L-type Ca(2+) channel currents, and is sufficient to restore decreased currents in failing cardiomyocytes. In vivo, both Myoscape-depleted morphant zebrafish and Myoscape knockout (KO) mice display impairment of cardiac function progressing to advanced heart failure. Mechanistically, Myoscape-deficient mice show reduced L-type Ca(2+)currents, cell capacity and calcium current densities as a result of diminished LTCC surface expression. Finally, Myoscape expression is reduced in hearts from patients suffering of terminal heart failure, implying a role in human disease. AU - Eden, M.* AU - Meder, B.* AU - Völkers, M.* AU - Poomvanicha, M.* AU - Domes, K.* AU - Branchereau, M.* AU - Marck, P.* AU - Will, R.* AU - Bernt, A.* AU - Rangrez, A.* AU - Busch, M.* AU - German Mouse Clinic Consortium (Adler, T. AU - Aguilar-Pimentel, J.A. AU - Becker, L. AU - Beckers, J. AU - Busch, D.H. AU - Calzada-Wack, J. AU - Fuchs, H. AU - Gailus-Durner, V. AU - Garrett, L. AU - Graw, J. AU - Götz, A. AU - Hans, W. AU - Hölter, S.M. AU - Horsch, M. AU - Klein-Rodewald, T. AU - Lengger, C. AU - Leuchtenberger, S. AU - Maier, H. AU - Neff, F. AU - Ollert, M. AU - Prehn, C. AU - Puk, O. AU - Rácz, I. AU - Rathkolb, B. AU - Rozman, J. AU - Schrewe, A. AU - Schulz, H. AU - Stoeger, C. AU - Tost, M. AU - Wurst, W. AU - Frey, N.*) AU - Hrabě de Angelis, M. AU - Heymes, C.* AU - Rottbauer, W.* AU - Most, P.* AU - Hofmann, F.* C1 - 48502 C2 - 41115 CY - London TI - Myoscape controls cardiac calcium cycling and contractility via regulation of L-type calcium channel surface expression. JO - Nat. Commun. VL - 7 PB - Nature Publishing Group PY - 2016 SN - 2041-1723 ER - TY - JOUR AU - Eden, M.* AU - Meder, B.* AU - Völkers, M.* AU - Poomvanicha, M.* AU - Domes, K.* AU - Branchereau, M.* AU - Marck, P.* AU - Will, R.* AU - Bernt, A.* AU - Rangrez, A.* AU - Busch, M.* AU - German Mouse Clinic Consortium (Adler, T. AU - Aguilar-Pimentel, J.A. AU - Becker, L. AU - Beckers, J. AU - Busch, D.H. AU - Calzada-Wack, J. AU - Fuchs, H. AU - Gailus-Durner, V. AU - Garrett, L. AU - Graw, J. AU - Götz, A. AU - Hans, W. AU - Hölter, S.M. AU - Horsch, M. AU - Klein-Rodewald, T. AU - Lengger, C. AU - Leuchtenberger, S. AU - Maier, H. AU - Neff, F. AU - Ollert, M. AU - Prehn, C. AU - Puk, O. AU - Rácz, I. AU - Rathkolb, B. AU - Rozman, J. AU - Schrewe, A. AU - Schulz, H. AU - Stoeger, C. AU - Tost, M. AU - Wurst, W.) AU - Hrabě de Angelis, M. AU - Heymes, C.* AU - Rottbauer, W.* AU - Most, P.* AU - Hofmann, F.* AU - Frey, N.* C1 - 48754 C2 - 41331 CY - London TI - Erratum: Myoscape controls cardiac calcium cycling and contractility via regulation of L-type calcium channel surface expression. JO - Nat. Commun. VL - 7 PB - Nature Publishing Group PY - 2016 SN - 2041-1723 ER - TY - JOUR AB - Obesity-related insulin resistance represents the core component of the metabolic syndrome, promoting glucose intolerance, pancreatic beta cell failure and type 2 diabetes. Efficient and safe insulin sensitization and glucose control remain critical therapeutic aims to prevent diabetic late complications Here, we identify transforming growth factor beta-like stimulated clone (TSC) 22 D4 as a molecular determinant of insulin signalling and glucose handling. Hepatic TSC22D4 inhibition both prevents and reverses hyperglycaemia, glucose intolerance and insulin resistance in diabetes mouse models. TSC22D4 exerts its effects on systemic glucose homeostasis - at least in part - through the direct transcriptional regulation of the small secretory protein lipocalin 13 (LCN13). Human diabetic patients display elevated hepatic TSC22D4 expression, which correlates with decreased insulin sensitivity, hyperglycaemia and LCN13 serum levels. Our results establish TSC22D4 as a checkpoint in systemic glucose metabolism in both mice and humans, and propose TSC22D4 inhibition as an insulin sensitizing option in diabetes therapy. AU - Ekim Üstünel, B. AU - Friedrich, K. AU - Maida, A. AU - Wang, X. AU - Krones-Herzig, A. AU - Seibert, O. AU - Sommerfeld, A. AU - Jones, A. AU - Sijmonsma, T.P. AU - Sticht, C.* AU - Gretz, N.* AU - Fleming, T.* AU - Nawroth, P.P.* AU - Stremmel, W.* AU - Rose, A.J. AU - Berriel-Diaz, M. AU - Blüher, M.* AU - Herzig, S. C1 - 50033 C2 - 41986 CY - London TI - Control of diabetic hyperglycaemia and insulin resistance through TSC22D4. JO - Nat. Commun. VL - 7 PB - Nature Publishing Group PY - 2016 SN - 2041-1723 ER - TY - JOUR AB - Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P<8.5 × 10(-5)), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia. AU - Fan, Q.* AU - Verhoeven, V.J.* AU - Wojciechowski, R.* AU - Barathi, V.A.* AU - Hysi, P.G.* AU - Guggenheim, J.A.* AU - Höhn, R.* AU - Vitart, V.* AU - Khawaja, A.P.* AU - Yamashiro, K.* AU - Hosseini, S.M.* AU - Lehtimäki, T.* AU - Lu, Y.* AU - Haller, T.* AU - Xie, J.* AU - Delcourt, C.* AU - Pirastu, M.* AU - Wedenoja, J.* AU - Gharahkhani, P.* AU - Venturini, C.* AU - Miyake, M.* AU - Hewitt, A.W.* AU - Guo, X.* AU - Mazur, J.* AU - Huffman, J.E.* AU - Williams, K.M.* AU - Polasek, O.* AU - Campbell, H.* AU - Rudan, I.* AU - Vatavuk, Z.* AU - Wilson, J.F.* AU - Joshi, P.K.* AU - McMahon, G.* AU - St Pourcain, B.* AU - Evans, D.M* AU - Simpson, C.L.* AU - Schwantes-An, T.H.* AU - Igo, R.P.* AU - Mirshahi, A.* AU - Cougnard-Grégoire, A.* AU - Bellenguez, C.* AU - Blettner, M.* AU - Raitakari, O.* AU - Kähönen, M.* AU - Seppälä, I.* AU - Zeller, T.* AU - Meitinger, T. AU - Consortium for Refractive Error and Myopia (CREAM) (Döring, A.) AU - Ried, J.S. AU - Gieger, C. AU - Portas, L.* AU - van Leeuwen, E.M.* AU - Amin, N.* AU - Uitterlinden, A.G.* AU - Rivadeneira, F.* AU - Hofman, A.* AU - Vingerling, J.R.* AU - Wang, Y.X.* AU - Wang, X.* AU - Tai-Hui Boh, E.* AU - Ikram, M.K.* AU - Sabanayagam, C.* AU - Gupta, P.* AU - Tan, V.* AU - Zhou, L.* AU - Ho, C.E.* AU - Lim, W.Y.* AU - Beuerman, R.W.* AU - Siantar, R.G.* AU - Tai, E.S.* AU - Vithana, E.* AU - Mihailov, E.* AU - Khor, C.C.* AU - Hayward, C.* AU - Luben, R.N.* AU - Foster, P.J.* AU - Klein, B.E.* AU - Klein, R.* AU - Wong, H.S.* AU - Mitchell, P.* AU - Metspalu, A.* AU - Aung, T.* AU - Young, T.L.* AU - He, M.* AU - Pärssinen, O.* AU - van Duijn, C.M.* AU - Wang, J.J.* AU - Williams, C.* AU - Jonas, J.B.* AU - Teo, Y.Y.* AU - Mackey, D.A.* AU - Oexle, K.* AU - Yoshimura, N.* AU - Paterson, A.D.* AU - Pfeiffer, N.* AU - Wong, T.Y.* AU - Baird, P.N.* AU - Stambolian, D.* AU - Wilson, J.E.* AU - Cheng, C.Y.* AU - Hammond, C.J.* AU - Klaver, C.C.* AU - Saw, S.M.* C1 - 48205 C2 - 41045 CY - London TI - Meta-analysis of gene-environment-wide association scans accounting for education level identifies additional loci for refractive error. JO - Nat. Commun. VL - 7 PB - Nature Publishing Group PY - 2016 SN - 2041-1723 ER - TY - JOUR AB - Sam68 and T-STAR are members of the STAR family of proteins that directly link signal transduction with post-transcriptional gene regulation. Sam68 controls the alternative splicing of many oncogenic proteins. T-STAR is a tissue-specific paralogue that regulates the alternative splicing of neuronal pre-mRNAs. STAR proteins differ from most splicing factors, in that they contain a single RNA-binding domain. Their specificity of RNA recognition is thought to arise from their property to homodimerize, but how dimerization influences their function remains unknown. Here, we establish at atomic resolution how T-STAR and Sam68 bind to RNA, revealing an unexpected mode of dimerization different from other members of the STAR family. We further demonstrate that this unique dimerization interface is crucial for their biological activity in splicing regulation, and suggest that the increased RNA affinity through dimer formation is a crucial parameter enabling these proteins to select their functional targets within the transcriptome. AU - Feracci, M.* AU - Foot, J.N.* AU - Grellscheid, S.N.* AU - Danilenko, M.* AU - Stehle, R.* AU - Gonchar, O.* AU - Kang, H.-S. AU - Dalgliesh, C.* AU - Meyer, N.H. AU - Liu, Y.* AU - Lahat, A.* AU - Sattler, M. AU - Eperon, I.C.* AU - Elliott, D.J.* AU - Dominguez, C.* C1 - 47783 C2 - 39528 CY - London TI - Structural basis of RNA recognition and dimerization by the STAR proteins T-STAR and Sam68. JO - Nat. Commun. VL - 7 PB - Nature Publishing Group PY - 2016 SN - 2041-1723 ER - TY - JOUR AB - A population of monocytes, known as Ly6C(lo) monocytes, patrol blood vessels by crawling along the vascular endothelium. Here we show that endothelial cells control their origin through Notch signalling. Using combinations of conditional genetic deletion strategies and cell-fate tracking experiments we show that Notch2 regulates conversion of Ly6C(hi) monocytes into Ly6C(lo) monocytes in vivo and in vitro, thereby regulating monocyte cell fate under steady-state conditions. This process is controlled by Notch ligand delta-like 1 (Dll1) expressed by a population of endothelial cells that constitute distinct vascular niches in the bone marrow and spleen in vivo, while culture on recombinant DLL1 induces monocyte conversion in vitro. Thus, blood vessels regulate monocyte conversion, a form of committed myeloid cell fate regulation. AU - Gamrekelashvili, J.* AU - Giagnorio, R.* AU - Jussofie, J.* AU - Soehnlein, O.* AU - Duchene, J.* AU - Briseño, C.G.* AU - Ramasamy, S.K.* AU - Krishnasamy, K.* AU - Limbourg, A.* AU - Kapanadze, T.* AU - Ishifune, C.* AU - Hinkel, R.* AU - Radtke, F.* AU - Strobl, L.J. AU - Zimber-Strobl, U. AU - Napp, L.C.* AU - Bauersachs, J.* AU - Haller, H.* AU - Yasutomo, K.* AU - Kupatt, C.* AU - Murphy, K.M.* AU - Adams, R.H.* AU - Weber, C.* AU - Limbourg, F.P.* C1 - 49352 C2 - 41762 CY - London TI - Regulation of monocyte cell fate by blood vessels mediated by Notch signalling. JO - Nat. Commun. VL - 7 PB - Nature Publishing Group PY - 2016 SN - 2041-1723 ER - TY - JOUR AB - Receptor-interacting protein kinase 3 (RIPK3) mediates necroptosis, a form of programmed cell death that promotes inflammation in various pathological conditions, suggesting that it might be a privileged pharmacological target. However, its function in glucose homeostasis and obesity has been unknown. Here we show that RIPK3 is over expressed in the white adipose tissue (WAT) of obese mice fed with a choline-deficient high-fat diet. Genetic inactivation of Ripk3 promotes increased Caspase-8-dependent adipocyte apoptosis and WAT inflammation, associated with impaired insulin signalling in WAT as the basis for glucose intolerance. Similarly to mice, in visceral WAT of obese humans, RIPK3 is overexpressed and correlates with the body mass index and metabolic serum markers. Together, these findings provide evidence that RIPK3 in WAT maintains tissue homeostasis and suppresses inflammation and adipocyte apoptosis, suggesting that systemic targeting of necroptosis might be associated with the risk of promoting insulin resistance in obese patients. AU - Gautheron, J.* AU - Vucur, M.* AU - Schneider, A.T.* AU - Severi, I.* AU - Roderburg, C.* AU - Roy, S.* AU - Bartneck, M.* AU - Schrammen, P.* AU - Berriel Diaz, M. AU - Ehling, J.* AU - Gremse, F.* AU - Heymann, F.* AU - Koppe, C.* AU - Lammers, T.* AU - Kiessling, F.* AU - van Best, N.* AU - Pabst, O.* AU - Courtois, G.* AU - Linkermann, A.* AU - Krautwald, S.* AU - Neumann, U.P.* AU - Tacke, F.* AU - Trautwein, C.* AU - Green, D.R.* AU - Longerich, T.* AU - Frey, N.* AU - Luedde, M.* AU - Blüher, M.* AU - Herzig, S. AU - Heikenwälder, M.* AU - Luedde, T.* C1 - 48860 C2 - 41447 CY - London TI - The necroptosis-inducing kinase RIPK3 dampens adipose tissue inflammation and glucose intolerance. JO - Nat. Commun. VL - 7 PB - Nature Publishing Group PY - 2016 SN - 2041-1723 ER - TY - JOUR AB - The t(8;21) translocation is one of the most frequent cytogenetic abnormalities in acute myeloid leukaemia (AML) and results in the RUNX1/RUNX1T1 rearrangement. Despite the causative role of the RUNX1/RUNX1T1 fusion gene in leukaemia initiation, additional genetic lesions are required for disease development. Here we identify recurring ZBTB7A mutations in 23% (13/56) of AML t(8;21) patients, including missense and truncating mutations resulting in alteration or loss of the C-terminal zinc-finger domain of ZBTB7A. The transcription factor ZBTB7A is important for haematopoietic lineage fate decisions and for regulation of glycolysis. On a functional level, we show that ZBTB7A mutations disrupt the transcriptional repressor potential and the anti-proliferative effect of ZBTB7A. The specific association of ZBTB7A mutations with t(8;21) rearranged AML points towards leukaemogenic cooperativity between mutant ZBTB7A and the RUNX1/RUNX1T1 fusion. AU - Hartmann, L. AU - Dutta, S. AU - Opatz, S. AU - Vosberg, S. AU - Reiter, K. AU - Leubolt, G. AU - Metzeler, K.H. AU - Herold, T. AU - Bamopoulos, S.A.* AU - Bräundl, K.* AU - Zellmeier, E.* AU - Ksienzyk, B.* AU - Konstandin, N.P.* AU - Schneider, S.* AU - Hopfner, K.P.* AU - Graf, A.* AU - Krebs, S.* AU - Blum, H.* AU - Middeke, J.M.* AU - Stölzel, F.* AU - Thiede, C.* AU - Wolf, S.* AU - Bohlander, S.K.* AU - Preiss, C.* AU - Chen-Wichmann, L.* AU - Wichmann, C.* AU - Sauerland, M.C.* AU - Büchner, T.* AU - Berdel, W.E.* AU - Wörmann, B.J.* AU - Braess, J.* AU - Hiddemann, W. AU - Spiekermann, K. AU - Greif, P.A. C1 - 48760 C2 - 41325 CY - London TI - ZBTB7A mutations in acute myeloid leukaemia with t(8;21) translocation. JO - Nat. Commun. VL - 7 PB - Nature Publishing Group PY - 2016 SN - 2041-1723 ER - TY - JOUR AB - The RNA-binding protein Roquin is required to prevent autoimmunity. Roquin controls T-helper cell activation and differentiation by limiting the induced expression of costimulatory receptors such as tumor necrosis factor receptor superfamily 4 (Tnfrs4 or Ox40). A constitutive decay element (CDE) with a characteristic triloop hairpin was previously shown to be recognized by Roquin. Here we use SELEX assays to identify a novel U-rich hexaloop motif, representing an alternative decay element (ADE). Crystal structures and NMR data show that the Roquin-1 ROQ domain recognizes hexaloops in the SELEX-derived ADE and in an ADE-like variant present in the Ox40 3'-UTR with identical binding modes. In cells, ADE-like and CDE-like motifs cooperate in the repression of Ox40 by Roquin. Our data reveal an unexpected recognition of hexaloop cis elements for the posttranscriptional regulation of target messenger RNAs by Roquin. AU - Janowski, R. AU - Heinz, G.A. AU - Schlundt, A. AU - Wommelsdorf, N. AU - Brenner, S. AU - Gruber, A.R.* AU - Blank, M.* AU - Buch, T.* AU - Buhmann, R.* AU - Zavolan, M.* AU - Niessing, D. AU - Heissmeyer, V. AU - Sattler, M. C1 - 48189 C2 - 41079 CY - London TI - Roquin recognizes a non-canonical hexaloop structure in the 3'-UTR of Ox40. JO - Nat. Commun. VL - 7 PB - Nature Publishing Group PY - 2016 SN - 2041-1723 ER - TY - JOUR AB - Hypothalamic leptin signalling has a key role in food intake and energy-balance control and is often impaired in obese individuals. Here we identify histone deacetylase 5 (HDAC5) as a regulator of leptin signalling and organismal energy balance. Global HDAC5 KO mice have increased food intake and greater diet-induced obesity when fed high-fat diet. Pharmacological and genetic inhibition of HDAC5 activity in the mediobasal hypothalamus increases food intake and modulates pathways implicated in leptin signalling. We show HDAC5 directly regulates STAT3 localization and transcriptional activity via reciprocal STAT3 deacetylation at Lys685 and phosphorylation at Tyr705. In vivo, leptin sensitivity is substantially impaired in HDAC5 loss-of-function mice. Hypothalamic HDAC5 overexpression improves leptin action and partially protects against HFD-induced leptin resistance and obesity. Overall, our data suggest that hypothalamic HDAC5 activity is a regulator of leptin signalling that adapts food intake and body weight to our dietary environment. AU - Kabra, D.G. AU - Pfuhlmann, K. AU - García-Cáceres, C. AU - Schriever, S.C. AU - Casquero García, V. AU - Kebede, A.F.* AU - Fuente-Martin, E. AU - Trivedi, C.* AU - Heppner, K.* AU - Uhlenhaut, N.H. AU - Legutko, B. AU - Kabra, U.D. AU - Gao, Y. AU - Yi, C.-X. AU - Quarta, C. AU - Clemmensen, C. AU - Finan, B. AU - Müller, T.D. AU - Meyer, C.W. AU - Paez-Pereda, M.* AU - Stemmer, K. AU - Woods, S.C.* AU - Perez-Tilve, D.* AU - Schneider, R.* AU - Olson, E.N.* AU - Tschöp, M.H. AU - Pfluger, P.T. C1 - 47999 C2 - 39871 CY - London TI - Hypothalamic leptin action is mediated by histone deacetylase 5. JO - Nat. Commun. VL - 7 PB - Nature Publishing Group PY - 2016 SN - 2041-1723 ER - TY - JOUR AB - Genome-wide association studies have identified numerous loci linked with complex diseases, for which the molecular mechanisms remain largely unclear. Comprehensive molecular profiling of circulating metabolites captures highly heritable traits, which can help to uncover metabolic pathophysiology underlying established disease variants. We conduct an extended genome-wide association study of genetic influences on 123 circulating metabolic traits quantified by nuclear magnetic resonance metabolomics from up to 24,925 individuals and identify eight novel loci for amino acids, pyruvate and fatty acids. The LPA locus link with cardiovascular risk exemplifies how detailed metabolic profiling may inform underlying aetiology via extensive associations with very-low-density lipoprotein and triglyceride metabolism. Genetic fine mapping and Mendelian randomization uncover wide-spread causal effects of lipoprotein(a) on overall lipoprotein metabolism and we assess potential pleiotropic consequences of genetically elevated lipoprotein(a) on diverse morbidities via electronic health-care records. Our findings strengthen the argument for safe LPA-targeted intervention to reduce cardiovascular risk. AU - Kettunen, J.* AU - Demirkan, A.* AU - Würtz, P.* AU - Draisma, H.H.M.* AU - Haller, T.* AU - Rawal, R. AU - Vaarhorst, A.A.* AU - Kangas, A.J.* AU - Lyytikaeinen, L.* AU - Pirinen, M.* AU - Pool, R.* AU - Sarin, A.P.* AU - Soininen, P.* AU - Tukiainen, T.* AU - Wang, Q.* AU - Tiainen, M.* AU - Tynkkynen, T.* AU - Amin, N.* AU - Zeller, T.* AU - Beekman, M.* AU - Deelen, J.* AU - van Dijk, K.W.* AU - Esko, T.* AU - Hottenga, J.J.* AU - van Leeuwen, E.M.* AU - Lehtimäki, T.* AU - Mihailov, E.* AU - Rose, R.J.* AU - de Craen, A.J.M.* AU - Gieger, C. AU - Kähönen, M.* AU - Perola, M.* AU - Blankenberg, S.* AU - Savolainen, M.J.* AU - Verhoeven, A.* AU - Viikari, J.* AU - Willemsen, G.* AU - Boomsma, D.I.* AU - van Duijn, C.M.* AU - Eriksson, J.* AU - Jula, A.* AU - Jarvelin, M.R.* AU - Kaprio, J.* AU - Metspalu, A.* AU - Raitakari, O.* AU - Salomaa, V.* AU - Slagboom, P.E.* AU - Waldenberger, M. AU - Ripatti, S.* AU - Ala-Korpela, M.* C1 - 48406 C2 - 41066 TI - Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA. JO - Nat. Commun. VL - 7 PY - 2016 SN - 2041-1723 ER - TY - JOUR AB - Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health. AU - Kilpeläinen, T.O.* AU - Carli, J.F.* AU - Skowronski, A.A.* AU - Sun, Q.* AU - Kriebel, J. AU - Feitosa, M.F.* AU - Hedman, A.K.* AU - Drong, A.W.* AU - Hayes, J.E.* AU - Zhao, J.* AU - Pers, T.H.* AU - Schick, U.M.* AU - Grarup, N.* AU - Kutalik, Z.* AU - Trompet, S.* AU - Mangino, M.* AU - Kristiansson, K.* AU - Beekman, M.* AU - Lyytikäinen, L.-P.* AU - Eriksson, J.* AU - Henneman, P.* AU - Lahti, J.* AU - Tanaka, T.* AU - Luan, J.* AU - Greco M, F.D.* AU - Pasko, D.* AU - Renström, F.* AU - Willems, S.M.* AU - Mahajan, A.* AU - Rose, L.M.* AU - Guo, X.* AU - Liu, Y.* AU - Kleber, M.E.* AU - Perusse, L.* AU - Gaunt, T.R.* AU - Ahluwalia, T.S.* AU - Ju Sung, Y.* AU - Ramos, Y.F.* AU - Amin, N.* AU - Amuzu, A.* AU - Barroso, I.* AU - Bellis, C.* AU - Blangero, J.* AU - Buckley, B.M.* AU - Böhringer, S.* AU - Chen, Y.D.* AU - de Craen, A.J.* AU - Crosslin, D.R.* AU - Dale, C.E.* AU - Dastani, Z.* AU - Day, F.R.* AU - Deelen, J.* AU - Delgado, G.E.* AU - Demirkan, A.* AU - Finucane, F.M.* AU - Ford, I.* AU - Garcia, M.E.* AU - Gieger, C. AU - Gustafsson, S.* AU - Hallmans, G.* AU - Hankinson, S.E.* AU - Havulinna, A.S.* AU - Herder, C.* AU - Hernandez, D.* AU - Hicks, A.A.* AU - Hunter, D.J.* AU - Illig, T. AU - Ingelsson, E.* AU - Ioan-Facsinay, A.* AU - Jansson, J.O.* AU - Jenny, N.S.* AU - Jørgensen, M.E.* AU - Jørgensen, T.* AU - Karlsson, M.* AU - Koenig, W.* AU - Kraft, P.* AU - Kwekkeboom, J.* AU - Laatikainen, T.* AU - Ladwig, K.-H. AU - LeDuc, C.A.* AU - Lowe, G.* AU - Lu, Y.* AU - Marques-Vidal, P.* AU - Meisinger, C. AU - Menni, C.* AU - Morris, A.P.* AU - Myers, R.H.* AU - Männistö, S.* AU - Nalls, M.A.* AU - Paternoster, L.* AU - Peters, A. AU - Pradhan, A.D.* AU - Rankinen, T.* AU - Rasmussen-Torvik, L.J.* AU - Rathmann, W.* AU - Rice, T.K.* AU - Richards, J.B.* AU - Ridker, P.M.* AU - Sattar, N.* AU - Savage, D.B.* AU - Söderberg, S.* AU - Timpson, N.J.* AU - Vandenput, L.* AU - van Heemst, D.* AU - Uh, H.W.* AU - Vohl, M.C.* AU - Walker, M.* AU - Wichmann, H.-E. AU - Widen, E.* AU - Wood, A.R.* AU - Yao, J.* AU - Zeller, T.* AU - Zhang, Y.* AU - Meulenbelt, I.* AU - Kloppenburg, M.* AU - Astrup, A.* AU - Sørensen, T.I.* AU - Sarzynski, M.A.* AU - Rao, D.C.* AU - Jousilahti, P.* AU - Vartiainen, E.* AU - Hofman, A.* AU - Rivadeneira, F.* AU - Uitterlinden, A.G.* AU - Kajantie, E.* AU - Osmond, C.* AU - Palotie, A.* AU - Eriksson, J.G.* AU - Heliövaara, M.* AU - Knekt, P.B.* AU - Koskinen, S.* AU - Jula, A.* AU - Perola, M.* AU - Huupponen, R.K.* AU - Viikari, J.S.* AU - Kähönen, M.* AU - Lehtimäki, T.* AU - Raitakari, O.T.* AU - Mellström, D.* AU - Lorentzon, M.* AU - Casas, J.P.* AU - Bandinelli, S.* AU - Marz, W.* AU - Isaacs, A.* AU - van Dijk, K.W.* AU - van Duijn, C.M.* AU - Harris, T.B.* AU - Bouchard, C.* AU - Allison, M.A.* AU - Chasman, D.I.* AU - Ohlsson, C.* AU - Lind, L.* AU - Scott, R.A.* AU - Langenberg, C.* AU - Wareham, N.J.* AU - Ferrucci, L.* AU - Frayling, T.M.* AU - Pramstaller, P.P.* AU - Borecki, I.B.* AU - Waterworth, D.M.* AU - Bergmann, S.* AU - Waeber, G.* AU - Vollenweider, P.* AU - Vestergaard, H.* AU - Hansen, T.* AU - Pedersen, O.* AU - Hu, F.B.* AU - Slagboom, P.E.* AU - Grallert, H. AU - Spector, T.D.* AU - Jukema, J.W.* AU - Klein, R.J.* AU - Schaadt, E.* AU - Franks, P.W.* AU - Lindgren, C.M.* AU - Leibel, R.L.* AU - Loos, R.J.* C1 - 47863 C2 - 39599 CY - London TI - Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels. JO - Nat. Commun. VL - 7 PB - Nature Publishing Group PY - 2016 SN - 2041-1723 ER - TY - JOUR AB - An important question is how growing tissues establish a blood vessel network. Here we study vascular network formation in pancreatic islets, endocrine tissues derived from pancreatic epithelium. We find that depletion of integrin-linked kinase (ILK) in the pancreatic epithelial cells of mice results in glucose intolerance due to a loss of the intra-islet vasculature. In turn, blood vessels accumulate at the islet periphery. Neither alterations in endothelial cell proliferation, apoptosis, morphology, Vegfa expression and VEGF-A secretion nor empty sleeves' of vascular basement membrane are found. Instead, biophysical experiments reveal that the biomechanical properties of pancreatic islet cells, such as their actomyosin-mediated cortex tension and adhesive forces to endothelial cells, are significantly changed. These results suggest that a sorting event is driving the segregation of endothelial and epithelial cells and indicate that the epithelial biomechanical properties determine whether the blood vasculature invades or envelops a growing epithelial tissue. AU - Kragl, M.* AU - Schubert, R.* AU - Karsjens, H.* AU - Otter, S.* AU - Bartosinska, B.* AU - Jeruschke, K.* AU - Weiss, J.* AU - Chen, C. AU - Alsteens, D.* AU - Kuss, O.* AU - Speier, S. AU - Eberhard, D.* AU - Müller, D.J.* AU - Lammert, E.* C1 - 50245 C2 - 42254 CY - London TI - The biomechanical properties of an epithelial tissue determine the location of its vasculature. JO - Nat. Commun. VL - 7 PB - Nature Publishing Group PY - 2016 SN - 2041-1723 ER - TY - JOUR AB - Neutralization of the common p40-subunit of IL-12/23 in psoriasis patients has led to a breakthrough in the management of moderate to severe disease. Aside from neutralizing IL-23, which is thought to be responsible for the curative effect, anti-p40 therapy also interferes with IL-12 signalling and type 1 immunity. Here we dissect the individual contribution of these two cytokines to the formation of psoriatic lesions and understand the effect of therapeutic co-targeting of IL-12 and IL-23 in psoriasis. Using a preclinical model for psoriatic plaque formation we show that IL-12, in contrast to IL-23, has a regulatory function by restraining the invasion of an IL-17-committed gdT (gdT17) cell subset. We discover that IL-12 receptor signalling in keratinocytes initiates a protective transcriptional programme that limits skin inflammation, suggesting that collateral targeting of IL-12 by anti-p40 monoclonal antibodies is counterproductive in the therapy of psoriasis. AU - Kulig, P.* AU - Musiol, S. AU - Freiberger, S.N.* AU - Schreiner, B.* AU - Gyulveszi, G.* AU - Russo, G.* AU - Pantelyushin, S.* AU - Kishihara, K.* AU - Alessandrini, F. AU - Kundig, T.* AU - Sallusto, F.* AU - Hofbauer, G.F.L.* AU - Haak, S. AU - Becher, B.* C1 - 50176 C2 - 42059 CY - London TI - IL-12 protects from psoriasiform skin inflammation. JO - Nat. Commun. VL - 7 PB - Nature Publishing Group PY - 2016 SN - 2041-1723 ER - TY - JOUR AB - Ductal occlusion has been postulated to precipitate focal pancreatic inflammation, while the nature of the primary occluding agents has remained elusive. Neutrophils make use of histone citrullination by peptidyl arginine deiminase-4 (PADI4) in contact to particulate agents to extrude decondensed chromatin as neutrophil extracellular traps (NETs). In high cellular density, NETs form macroscopically visible aggregates. Here we show that such aggregates form inside pancreatic ducts in humans and mice occluding pancreatic ducts and thereby driving pancreatic inflammation. Experimental models indicate that PADI4 is critical for intraductal aggregate formation and that PADI4-deficiency abrogates disease progression. Mechanistically, we identify the pancreatic juice as a strong instigator of neutrophil chromatin extrusion. Characteristic single components of pancreatic juice, such as bicarbonate ions and calcium carbonate crystals, induce aggregated NET formation. Ductal occlusion by aggregated NETs emerges as a pathomechanism with relevance in a plethora of inflammatory conditions involving secretory ducts. AU - Leppkes, M.* AU - Maueroeder, C.* AU - Hirth, S.* AU - Nowecki, S.* AU - Günther, C.* AU - Billmeier, U.* AU - Paulus, S.* AU - Biermann, M.* AU - Munoz, L.E.* AU - Hoffmann, M.* AU - Wildner, D.* AU - Croxford, A.L.* AU - Waisman, A.* AU - Mowen, K.* AU - Jenne, D. AU - Krenn, V.* AU - Mayerle, J.* AU - Lerch, M.M.* AU - Schett, G.* AU - Wirtz, S.* AU - Neurath, M.F.* AU - Hermann, M.* AU - Becker, C.* C1 - 50303 C2 - 42080 TI - Externalized decondensed neutrophil chromatin occludes pancreatic ducts and drives pancreatitis. JO - Nat. Commun. VL - 7 PY - 2016 SN - 2041-1723 ER - TY - JOUR AB - To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk. AU - Lu, Y.* AU - Day, F.R.* AU - Gustafsson, S.* AU - Buchkovich, M.L.* AU - Na, J.* AU - Bataille, V.* AU - Cousminer, D.L.* AU - Dastani, Z.* AU - Drong, A.W.* AU - Esko, T.* AU - Evans, D.M* AU - Falchi, M.* AU - Feitosa, M.F.* AU - Ferreira, T.* AU - Hedman, A.K.* AU - Haring, R.* AU - Hysi, P.G.* AU - Iles, M.M.* AU - Justice, A.E.* AU - Kanoni, S.* AU - Lagou, V.* AU - Li, R.* AU - Li, X.* AU - Locke, A.* AU - Lu, C.* AU - Mägi, R.* AU - Perry, J.R.* AU - Pers, T.H.* AU - Qi, Q.* AU - Sanna, M.* AU - Schmidt, E.M.* AU - Scott, W.R.* AU - Shungin, D.* AU - Teumer, A.* AU - Vinkhuyzen, A.A.* AU - Walker, R.W.* AU - Westra, H.J.* AU - Zhang, M.* AU - Zhang, W.* AU - Zhao, J.H.* AU - Zhu, Z.* AU - Afzal, U.* AU - Ahluwalia, T.S.* AU - Bakker, S.J.* AU - Bellis, C.* AU - Bonnefond, A.* AU - Borodulin, K.* AU - Buchman, A.S.* AU - Cederholm, T.* AU - Choh, A.C.* AU - Choi, H.J.* AU - Curran, J.E.* AU - de Groot, L.C.* AU - de Jager, P.L.* AU - Dhonukshe-Rutten, R.A.* AU - Enneman, A.W.* AU - Eury, E.* AU - Evans, D.S.* AU - Forsen, T.* AU - Friedrich, N.* AU - Fumeron, F.* AU - Garcia, M.E.* AU - Gärtner, S.* AU - Han, B.G.* AU - Havulinna, A.S.* AU - Hayward, C.* AU - Hernandez, D.* AU - Hillege, H.* AU - Ittermann, T.* AU - Kent, J.W.* AU - Kolcic, I.* AU - Laatikainen, T.* AU - Lahti, J.* AU - Mateo Leach, I.* AU - Lee, C.G.* AU - Lee, J.Y.* AU - Liu, T.* AU - Liu, Y.* AU - Lobbens, S.* AU - Loh, M.* AU - Lyytikäinen, L.-P.* AU - Medina-Gomez, C.* AU - Michaelsson, K.* AU - Nalls, M.A.* AU - Nielson, C.M.* AU - Oozageer, L.* AU - Pascoe, L.* AU - Paternoster, L.* AU - Polasek, O.* AU - Ripatti, S.* AU - Sarzynski, M.A.* AU - Shin, C.S.* AU - Narančić, N.S.* AU - Spira, D.* AU - Srikanth, P.* AU - Steinhagen-Thiessen, E.* AU - Sung, Y.J.* AU - Swart, K.M.* AU - Taittonen, L.* AU - Tanaka, T.* AU - Tikkanen, E.* AU - van der Velde, N.* AU - van Schoor, N.M.* AU - Verweij, N.* AU - Wright, A.F.* AU - Yu, L.* AU - Zmuda, J.M.* AU - Eklund, N.* AU - Forrester, T.* AU - Grarup, N.* AU - Jackson, A.U.* AU - Kristiansson, K.* AU - Kuulasmaa, T.* AU - Kuusisto, J.* AU - Lichtner, P. AU - Luan, J.* AU - Mahajan, A.* AU - Männistö, S.* AU - Palmer, C.D.* AU - Ried, J.S. AU - Scott, R.A.* AU - Stancáková, A.* AU - Wagner, P.J.* AU - Demirkan, A.* AU - Döring, A. AU - Gudnason, V.* AU - Kiel, D.P.* AU - Kühnel, B. AU - Mangino, M.* AU - McKnight, B.* AU - Menni, C.* AU - O'Connell, J.R.* AU - Oostra, B.A.* AU - Shuldiner, A.R.* AU - Song, K.* AU - Vandenput, L.* AU - van Duijn, C.M.* AU - Vollenweider, P.* AU - White, C.C.* AU - Boehnke, M.* AU - Boettcher, Y.* AU - Cooper, R.S.* AU - Forouhi, N.G.* AU - Gieger, C. AU - Grallert, H. AU - Hingorani, A.* AU - Jørgensen, T.* AU - Jousilahti, P.* AU - Kivimaki, M.* AU - Kumari, M.* AU - Laakso, M.* AU - Langenberg, C.* AU - Linneberg, A.* AU - Luke, A.M.* AU - McKenzie, C.A.* AU - Palotie, A.* AU - Pedersen, O.* AU - Peters, A. AU - Strauch, K. AU - Tayo, B.O.* AU - Wareham, N.J.* AU - Bennett, D.A.* AU - Bertram, L.* AU - Blangero, J.* AU - Blüher, M.* AU - Bouchard, C.* AU - Campbell, H.* AU - Cho, N.H.* AU - Cummings, S.R.* AU - Czerwinski, S.A.* AU - Demuth, I.* AU - Eckardt, R.* AU - Eriksson, J.G.* AU - Ferrucci, L.* AU - Franco, O.H.* AU - Froguel, P.* AU - Gansevoort, R.T.* AU - Hansen, T.* AU - Harris, T.B.* AU - Hastie, N.* AU - Heliövaara, M.* AU - Hofman, A.* AU - Jordan, J.M.* AU - Jula, A.* AU - Kähönen, M.* AU - Kajantie, E.* AU - Knekt, P.B.* AU - Koskinen, S.* AU - Kovacs, P.* AU - Lehtimäki, T.* AU - Lind, L.* AU - Orwoll, E.S.* AU - Osmond, C.* AU - Perola, M.* AU - Perusse, L.* AU - Raitakari, O.T.* AU - Rankinen, T.* AU - Rao, D.C.* AU - Rice, T.K.* AU - Rivadeneira, F.* AU - Rudan, I.* AU - Salomaa, V.* AU - Sørensen, T.I.* AU - Stumvoll, M.* AU - Tönjes, A.* AU - Towne, B.* AU - Tranah, G.J.* AU - Tremblay, A.* AU - Uitterlinden, A.G.* AU - van der Harst, P.* AU - Vartiainen, E.* AU - Viikari, J.S.* AU - Vitart, V.* AU - Vohl, M.C.* AU - Völzke, H.* AU - Walker, M.* AU - Wallaschofski, H.* AU - Wild, S.* AU - Wilson, J.F.* AU - Yengo, L.* AU - Bishop, D.T.* AU - Borecki, I.B.* AU - Chambers, J.C.* AU - Cupples, L.A.* AU - Dehghan, A.* AU - Deloukas, P.* AU - Fatemifar, G.* AU - Fox, C.* AU - Furey, T.S.* AU - Franke, L.* AU - Han, J.* AU - Hunter, D.J.* AU - Karjalainen, J.* AU - Karpe, F.* AU - Kaplan, R.C.* AU - Kooner, J.S.* AU - McCarthy, M.I.* AU - Murabito, J.M.* AU - Morris, A.P.* AU - Bishop, J.A.* AU - North, K.E.* AU - Ohlsson, C.* AU - Ong, K.K.* AU - Prokopenko, I.* AU - Richards, J.B.* AU - Schadt, E.E.* AU - Spector, T.D.* AU - Widen, E.* AU - Willer, C.J.* AU - Yang, J.* AU - Ingelsson, E.* AU - Mohlke, K.L.* AU - Hirschhorn, J.N.* AU - Pospisilik, J.A.* AU - Zillikens, M.C.* AU - Lindgren, C.* AU - Kilpeläinen, T.O.* AU - Loos, R.J.* C1 - 47809 C2 - 39498 CY - London TI - New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk. JO - Nat. Commun. VL - 7 PB - Nature Publishing Group PY - 2016 SN - 2041-1723 ER - TY - JOUR AB - Recent studies revealed that mitochondrial Ca2+ channels, which control energy flow, cell signalling and death, are macromolecular complexes that basically consist of the pore-forming mitochondrial Ca2+ uniporter (MCU) protein, the essential MCU regulator (EMRE), and the mitochondrial Ca2+ uptake 1 (MICU1). MICU1 is a regulatory subunit that shields mitochondria from Ca2+ overload. Before the identification of these core elements, the novel uncoupling proteins 2 and 3 (UCP2/3) have been shown to be fundamental for mitochondrial Ca2+ uptake. Here we clarify the molecular mechanism that determines the UCP2/3 dependency of mitochondrial Ca2+ uptake. Our data demonstrate that mitochondrial Ca2+ uptake is controlled by protein arginine methyl transferase 1 (PRMT1) that asymmetrically methylates MICU1, resulting in decreased Ca2+ sensitivity. UCP2/3 normalize Ca2+ sensitivity of methylated MICU1 and, thus, re-establish mitochondrial Ca2+ uptake activity. These data provide novel insights in the complex regulation of the mitochondrial Ca2+ uniporter by PRMT1 and UCP2/3. AU - Madreiter-Sokolowski, C.T.* AU - Klec, C.* AU - Parichatikanond, W.* AU - Stryeck, S.* AU - Gottschalk, B.* AU - Pulido, S.* AU - Rost, R.* AU - Eroglu, E.* AU - Hofmann, N.A.* AU - Bondarenko, A.I.* AU - Madl, T. AU - Waldeck-Weiermair, M.* AU - Malli, R.* AU - Graier, W.F.* C1 - 49586 C2 - 40839 CY - London TI - PRMT1-mediated methylation of MICU1 determines the UCP2/3 dependency of mitochondrial Ca2+ uptake in immortalized cells. JO - Nat. Commun. VL - 7 PB - Nature Publishing Group PY - 2016 SN - 2041-1723 ER - TY - JOUR AB - Mouse transgenesis has provided fundamental insights into pancreatic cancer, but is limited by the long duration of allele/model generation. Here we show transfection-based multiplexed delivery of CRISPR/Cas9 to the pancreas of adult mice, allowing simultaneous editing of multiple gene sets in individual cells. We use the method to induce pancreatic cancer and exploit CRISPR/Cas9 mutational signatures for phylogenetic tracking of metastatic disease. Our results demonstrate that CRISPR/Cas9-multiplexing enables key applications, such as combinatorial gene-network analysis, in vivo synthetic lethality screening and chromosome engineering. Negative-selection screening in the pancreas using multiplexed-CRISPR/Cas9 confirms the vulnerability of pancreatic cells to Brca2-inactivation in a Kras-mutant context. We also demonstrate modelling of chromosomal deletions and targeted somatic engineering of inter-chromosomal translocations, offering multifaceted opportunities to study complex structural variation, a hallmark of pancreatic cancer. The low-frequency mosaic pattern of transfection-based CRISPR/Cas9 delivery faithfully recapitulates the stochastic nature of human tumorigenesis, supporting wide applicability for biological/preclinical research. AU - Maresch, R.* AU - Müller, S.* AU - Veltkamp, C.* AU - Öllinger, R.* AU - Friedrich, M.* AU - Heid, I.M.* AU - Steiger, K.* AU - Weber, J.* AU - Engleitner, T.* AU - Barenboim, M.* AU - Klein, S.* AU - Louzada, S.* AU - Banerjee, R.* AU - Strong, A.* AU - Stauber, T.* AU - Gross, N.* AU - Geumann, U.* AU - Lange, S.* AU - Ringelhan, M. AU - Varela, I.* AU - Unger, K. AU - Yang, F.* AU - Schmid, R.M.* AU - Vassiliou, G.S.* AU - Braren, R.* AU - Schneider, G.* AU - Heikenwälder, M. AU - Bradley, A.* AU - Saur, D.* AU - Rad, R.* C1 - 47985 C2 - 39801 CY - London TI - Multiplexed pancreatic genome engineering and cancer induction by transfection-based CRISPR/Cas9 delivery in mice. JO - Nat. Commun. VL - 7 PB - Nature Publishing Group PY - 2016 SN - 2041-1723 ER - TY - JOUR AB - The outer subventricular zone (OSVZ) is a germinal layer playing key roles in the development of the neocortex, with particular relevance in gyrencephalic species such as human and ferret, where it contains abundant basal radial glia cells (bRGCs) that promote cortical expansion. Here we identify a brief period in ferret embryonic development when apical RGCs generate a burst of bRGCs that become founders of the OSVZ. After this period, bRGCs in the OSVZ proliferate and self-renew exclusively locally, thereby forming a self-sustained lineage independent from the other germinal layers. The time window for the brief period of OSVZ bRGC production is delineated by the coincident downregulation of Cdh1 and Trnp1, and their upregulation reduces bRGC production and prevents OSVZ seeding. This mechanism in cortical development may have key relevance in brain evolution and disease. AU - Martínez-Martínez, M.Á.* AU - Romero, C.* AU - Fernandez, V.* AU - Cárdenas, A.* AU - Götz, M. AU - Borrell, V.* C1 - 48822 C2 - 41463 CY - London TI - A restricted period for formation of outer subventricular zone defined by Cdh1 and Trnp1 levels. JO - Nat. Commun. VL - 7 PB - Nature Publishing Group PY - 2016 SN - 2041-1723 ER - TY - JOUR AB - MALT1 channels proximal T-cell receptor (TCR) signalling to downstream signalling pathways. With MALT1A and MALT1B two conserved splice variants exist and we demonstrate here that MALT1 alternative splicing supports optimal T-cell activation. Inclusion of exon7 in MALT1A facilitates the recruitment of TRAF6, which augments MALT1 scaffolding function, but not protease activity. Naive CD4(+) T cells express almost exclusively MALT1B and MALT1A expression is induced by TCR stimulation. We identify hnRNP U as a suppressor of exon7 inclusion. Whereas selective depletion of MALT1A impairs T-cell signalling and activation, downregulation of hnRNP U enhances MALT1A expression and T-cell activation. Thus, TCR-induced alternative splicing augments MALT1 scaffolding to enhance downstream signalling and to promote optimal T-cell activation. AU - Meininger, I. AU - Griesbach, R.A. AU - Hu, D. AU - Gehring, T. AU - Seeholzer, T. AU - Bertossi, A. AU - Kranich, J.* AU - Oeckinghaus, A. AU - Eitelhuber, A.C. AU - Greczmiel, U. AU - Gewies, A.* AU - Schmidt-Supprian, M.* AU - Ruland, J.* AU - Brocker, T.* AU - Heissmeyer, V. AU - Heyd, F.* AU - Krappmann, D. C1 - 48396 C2 - 41018 CY - London TI - Alternative splicing of MALT1 controls signalling and activation of CD4+ T cells. JO - Nat. Commun. VL - 7 PB - Nature Publishing Group PY - 2016 SN - 2041-1723 ER - TY - JOUR AB - The myogenic regulatory factor MRF4 is highly expressed in adult skeletal muscle but its function is unknown. Here we show that Mrf4 knockdown in adult muscle induces hypertrophy and prevents denervation-induced atrophy. This effect is accompanied by increased protein synthesis and widespread activation of muscle-specific genes, many of which are targets of MEF2 transcription factors. MEF2-dependent genes represent the top-ranking gene set enriched after Mrf4 RNAi and a MEF2 reporter is inhibited by co-transfected MRF4 and activated by Mrf4 RNAi. The Mrf4 RNAi-dependent increase in fibre size is prevented by dominant negative MEF2, while constitutively active MEF2 is able to induce myofibre hypertrophy. The nuclear localization of the MEF2 corepressor HDAC4 is impaired by Mrf4 knockdown, suggesting that MRF4 acts by stabilizing a repressor complex that controls MEF2 activity. These findings open new perspectives in the search for therapeutic targets to prevent muscle wasting, in particular sarcopenia and cachexia. AU - Moretti, I.* AU - Ciciliot, S.* AU - Dyar, K.A. AU - Abraham, R.* AU - Murgia, M.* AU - Agatea, L.* AU - Akimoto, T.* AU - Bicciato, S.* AU - Forcato, M.* AU - Pierre, P.* AU - Uhlenhaut, N.H. AU - Rigby, P.W.* AU - Carvajal, J.J.* AU - Blaauw, B.* AU - Calabria, E.* AU - Schiaffino, S.* C1 - 49222 C2 - 34056 CY - London TI - MRF4 negatively regulates adult skeletal muscle growth by repressing MEF2 activity. JO - Nat. Commun. VL - 7 PB - Nature Publishing Group PY - 2016 SN - 2041-1723 ER - TY - JOUR AB - Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. AU - Pattaro, C.* AU - Teumer, A.* AU - Gorski, M.* AU - Chu, A.Y.* AU - Li, M.* AU - Mijatovic, V.* AU - Garnaas, M.* AU - Tin, A.* AU - Sorice, R.* AU - Li, Y.* AU - Taliun, D.* AU - Olden, M.* AU - Foster, M.* AU - Yang, Q.* AU - Chen, M.H.* AU - Pers, T.H.* AU - Johnson, A.D.* AU - Ko, Y.A.* AU - Fuchsberger, C.* AU - Tayo, B.O.* AU - Nalls, M.* AU - Feitosa, M.F.* AU - Isaacs, A.* AU - Dehghan, A.* AU - D'Adamo, P.* AU - Adeyemo, A.* AU - Dieffenbach, A.K.* AU - Zonderman, A.B.* AU - Nolte, I.M.* AU - van der Most, P.J.* AU - Wright, A.F.* AU - Shuldiner, A.R.* AU - Morrison, A.C.* AU - Hofman, A.* AU - Smith, A.V.* AU - Dreisbach, A.W.* AU - Franke, A.* AU - Uitterlinden, A.G.* AU - Metspalu, A.* AU - Tönjes, A.* AU - Lupo, A.* AU - Robino, A.* AU - Johansson, Å* AU - Demirkan, A.* AU - Kollerits, B.* AU - Freedman, B.I.* AU - Ponte, B.* AU - Oostra, B.A.* AU - Paulweber, B.* AU - Krämer, B.K.* AU - Mitchell, B.D.* AU - Buckley, B.M.* AU - Peralta, C.A.* AU - Hayward, C.* AU - Helmer, C.* AU - Rotimi, C.N.* AU - Shaffer, C.M.* AU - Müller, C.* AU - Sala, C.* AU - van Duijn, C.M.* AU - Saint-Pierre, A.* AU - Ackermann, D.* AU - Shriner, D.* AU - Ruggiero, D.* AU - Toniolo, D.* AU - Lu, Y.* AU - Cusi, D.* AU - Czamara, D.* AU - Ellinghaus, D.* AU - Siscovick, D.S.* AU - Ruderfer, D.* AU - Gieger, C. AU - Grallert, H. AU - Rochtchina, E.* AU - Atkinson, E.J.* AU - Holliday, E.G.* AU - Boerwinkle, E.* AU - Salvi, E.* AU - Bottinger, E.P.* AU - Murgia, F.* AU - Rivadeneira, F.* AU - Ernst, F.* AU - Kronenberg, F.* AU - Hu, F.B.* AU - Navis, G.J.* AU - Curhan, G.C.* AU - Ehret, G.B.* AU - Homuth, G.* AU - Coassin, S.* AU - Thun, G.A.* AU - Pistis, G.* AU - Gambaro, G.* AU - Malerba, G.* AU - Montgomery, G.W.* AU - Eiriksdottir, G.* AU - Jacobs, G.* AU - Li, G.* AU - Wichmann, H.-E. AU - Campbell, H.* AU - Schmidt, H.* AU - Wallaschofski, H.* AU - Völzke, H.* AU - Brenner, H.* AU - Kroemer, H.K.* AU - Kramer, H.* AU - Lin, H.* AU - Mateo Leach, I.* AU - Ford, I.* AU - Guessous, I.* AU - Rudan, I.* AU - Prokopenko, I.* AU - Borecki, I.* AU - Heid, I.M. AU - Kolcic, I.* AU - Persico, I.* AU - Jukema, J.W.* AU - Wilson, J.F.* AU - Felix, J.F.* AU - Divers, J.* AU - Lambert, J.C.* AU - Stafford, J.M.* AU - Gaspoz, J.M.* AU - Smith, J.A.* AU - Faul, J.D.* AU - Wang, J.J.* AU - Ding, J.* AU - Hirschhorn, J.N.* AU - Attia, J.* AU - Whitfield, J.B.* AU - Chalmers, J.* AU - Viikari, J.* AU - Coresh, J.* AU - Denny, J.C.* AU - Karjalainen, J.* AU - Fernandes, J.K.* AU - Endlich, K.* AU - Butterbach, K.* AU - Keene, K.L.* AU - Lohman, K.* AU - Portas, L.* AU - Launer, L.J.* AU - Lyytikäinen, L.-P.* AU - Yengo, L.* AU - Franke, L.* AU - Ferrucci, L.* AU - Rose, L.M.* AU - Kedenko, L.* AU - Rao, M.* AU - Struchalin, M.* AU - Kleber, M.E.* AU - Cavalieri, M.* AU - Haun, M.* AU - Cornelis, M.C.* AU - Ciullo, M.* AU - Pirastu, M.* AU - de Andrade, M.* AU - McEvoy, M.A.* AU - Woodward, M.* AU - Adam, M.* AU - Cocca, M.* AU - Nauck, M.* AU - Imboden, M.* AU - Waldenberger, M. AU - Pruijm, M.* AU - Metzger, M.* AU - Stumvoll, M.* AU - Evans, M.K.* AU - Sale, M.M.* AU - Kähönen, M.* AU - Boban, M.* AU - Bochud, M.* AU - Rheinberger, M.* AU - Verweij, N.* AU - Bouatia-Naji, N.* AU - Martin, N.G.* AU - Hastie, N.* AU - Probst-Hensch, N.* AU - Soranzo, N.* AU - Devuyst, O.* AU - Raitakari, O.* AU - Gottesman, O.* AU - Franco, O.H.* AU - Polasek, O.* AU - Gasparini, P.* AU - Munroe, P.B.* AU - Ridker, P.M.* AU - Mitchell, P.* AU - Muntner, P.* AU - Meisinger, C. AU - Smit, J.H.* AU - ICBP Consortium (Meitinger, T.) AU - AGEN Consortium (*) AU - CARDIoGRAM Consortium (Döring, A. AU - Klopp, N.) AU - CHARGE Consortium Heart Failure Group (Fox, C.S.*) AU - EchoGen Consortium (*) AU - Kovacs, P.* AU - Wild, P.S.* AU - Froguel, P.* AU - Rettig, R.* AU - Mägi, R.* AU - Biffar, R.* AU - Schmidt, R.* AU - Middelberg, R.P.* AU - Carroll, R.J.* AU - Penninx, B.W.* AU - Scott, R.J.* AU - Katz, R.* AU - Sedaghat, S.* AU - Wild, S.H.* AU - Kardia, S.L.* AU - Ulivi, S.* AU - Hwang, S.J.* AU - Enroth, S.* AU - Kloiber, S.* AU - Trompet, S.* AU - Stengel, B.* AU - Hancock, S.J.* AU - Turner, S.T.* AU - Rosas, S.E.* AU - Stracke, S.* AU - Harris, T.B.* AU - Zeller, T.* AU - Zemunik, T.* AU - Lehtimäki, T.* AU - Illig, T. AU - Aspelund, T.* AU - Nikopensius, T.* AU - Esko, T.* AU - Tanaka, T.* AU - Gyllensten, U.* AU - Völker, U.* AU - Emilsson, V.* AU - Vitart, V.* AU - Aalto, V.* AU - Gudnason, V.* AU - Chouraki, V.* AU - Chen, W.M.* AU - Igl, W.* AU - Marz, W.* AU - Koenig, W.* AU - Lieb, W.* AU - Loos, R.J.* AU - Liu, Y.* AU - Snieder, H.* AU - Pramstaller, P.P.* AU - Parsa, A.* AU - O'Connell, J.R.* AU - Susztak, K.* AU - Hamet, P.* AU - Tremblay, J.* AU - de Boer, I.H.* AU - Böger, C.A.* AU - Goessling, W.* AU - Chasman, D.I.* AU - Köttgen, A.* AU - Kao, W.H.L.* AU - Fox, C.S.* C1 - 47810 C2 - 39497 CY - London TI - Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function. JO - Nat. Commun. VL - 7 PB - Nature Publishing Group PY - 2016 SN - 2041-1723 ER - TY - JOUR AB - Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways. AU - Ried, J.S. AU - Jeff, J.M.* AU - Chu, A.Y.* AU - Bragg-Gresham, J.L.* AU - van Dongen, J.* AU - Huffman, J.E.* AU - Ahluwalia, T.S.* AU - Cadby, G.* AU - Eklund, N.* AU - Eriksson, J.* AU - Esko, T.* AU - Feitosa, M.F.* AU - Goel, A.* AU - Gorski, M.* AU - Hayward, C.* AU - Heard-Costa, N.L.* AU - Jackson, A.U.* AU - Jokinen, E.* AU - Kanoni, S.* AU - Kristiansson, K.* AU - Kutalik, Z.* AU - Lahti, J.* AU - Luan, J.* AU - Mägi, R.* AU - Mahajan, A.* AU - Mangino, M.* AU - Medina-Gomez, C.* AU - Monda, K.L.* AU - Nolte, I.M.* AU - Perusse, L.* AU - Prokopenko, I.* AU - Qi, L.* AU - Rose, L.M.* AU - Salvi, E.* AU - Smith, M.T.* AU - Snieder, H.* AU - Standáková, A.* AU - Ju Sung, Y.* AU - Tachmazidou, I.* AU - Teumer, A.* AU - Thorleifsson, G.* AU - van der Harst, P.* AU - Lichtner, P. AU - Gieger, C. AU - Loos, R.J.F.* AU - Willems, S.M.* AU - Wong, A.* AU - Zhang, W.* AU - Albrecht, E. AU - Couto Alves, A.* AU - Bakker, S.J.L.* AU - Barlassina, C.* AU - Bartz, T.M.* AU - Beilby, J.* AU - Bellis, C.* AU - Bergman, R.N.* AU - Bergmann, S.* AU - Blangero, J.* AU - Blüher, M.* AU - Boerwinkle, E.* AU - Bonnycastle, L.L.* AU - Bornstein, S.R.* AU - Bruinenberg, M.* AU - Campbell, H.* AU - Döring, A. AU - Grallert, H. AU - Strauch, K. AU - Peters, A. AU - Heid, I.M. AU - Müller-Nurasyid, M. C1 - 50136 C2 - 42035 CY - London TI - A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape. JO - Nat. Commun. VL - 7 PB - Nature Publishing Group PY - 2016 SN - 2041-1723 ER - TY - JOUR AB - Immune tolerance is executed partly by Foxp3(+)regulatory T (Treg) cells, which suppress autoreactive T cells. In autoimmune type 1 diabetes (T1D) impaired tolerance promotes destruction of insulin-producing β-cells. The development of autoantigen-specific vaccination strategies for Foxp3(+)Treg-induction and prevention of islet autoimmunity in patients is still in its infancy. Here, using human haematopoietic stem cell-engrafted NSG-HLA-DQ8 transgenic mice, we provide direct evidence for human autoantigen-specific Foxp3(+)Treg-induction in vivo. We identify HLA-DQ8-restricted insulin-specific CD4(+)T cells and demonstrate efficient human insulin-specific Foxp3(+)Treg-induction upon subimmunogenic vaccination with strong agonistic insulin mimetopes in vivo. Induced human Tregs are stable, show increased expression of Treg signature genes such as Foxp3, CTLA4, IL-2Rα and TIGIT and can efficiently suppress effector T cells. Such Foxp3(+)Treg-induction does not trigger any effector T cells. These T1D vaccine candidates could therefore represent an expedient improvement in the challenge to induce human Foxp3(+)Tregs and to develop novel precision medicines for prevention of islet autoimmunity in children at risk of T1D. AU - Serr, I. AU - Fürst, R. AU - Achenbach, P. AU - Scherm, M.G. AU - Gökmen, F. AU - Haupt, F. AU - Sedlmeier, E.-M. AU - Knopff, A. AU - Shultz, L.* AU - Willis, R.A.* AU - Ziegler, A.-G. AU - Daniel, C. C1 - 48112 C2 - 39913 CY - London TI - Type 1 diabetes vaccine candidates promote human Foxp3+Treg induction in humanized mice. JO - Nat. Commun. VL - 7 PB - Nature Publishing Group PY - 2016 SN - 2041-1723 ER - TY - JOUR AB - Although manganese is an essential trace metal, little is known about its transport and homeostatic regulation. Here we have identified a cohort of patients with a novel autosomal recessive manganese transporter defect caused by mutations in SLC39A14. Excessive accumulation of manganese in these patients results in rapidly progressive childhood-onset parkinsonism-dystonia with distinctive brain magnetic resonance imaging appearances and neurodegenerative features on post-mortem examination. We show that mutations in SLC39A14 impair manganese transport in vitro and lead to manganese dyshomeostasis and altered locomotor activity in zebrafish with CRISPR-induced slc39a14 null mutations. Chelation with disodium calcium edetate lowers blood manganese levels in patients and can lead to striking clinical improvement. Our results demonstrate that SLC39A14 functions as a pivotal manganese transporter in vertebrates. AU - Tuschl, K.* AU - Meyer, E.* AU - Valdivia, L.E.* AU - Zhao, N.* AU - Dadswell, C.* AU - Abdul-Sada, A.* AU - Hung, C.Y.* AU - Simpson, M.A.* AU - Chong, W.K.* AU - Jacques, T.S.* AU - Woltjer, R.L.* AU - Eaton, S.* AU - Gregory, A.* AU - Sanford, L.* AU - Kara, E.* AU - Houlden, H.* AU - Cuno, S.M. AU - Prokisch, H. AU - Valletta, L.* AU - Tiranti, V.* AU - Younis, R.* AU - Maher, E.R.* AU - Spencer, J.* AU - Straatman-Iwanowska, A.* AU - Gissen, P.* AU - Selim, L.A.M.* AU - Pintos-Morell, G.* AU - Coroleu-Lletget, W.* AU - Mohammad, S.S.* AU - Yoganathan, S.* AU - Dale, R.C.* AU - Thomas, M.* AU - Rihel, J.* AU - Bodamer, O.A.* AU - Enns, C.A.* AU - Hayflick, S.J.* AU - Clayton, P.T.* AU - Mills, P.B.* AU - Kurian, M.A.* AU - Wilson, S.W.* C1 - 48784 C2 - 41436 CY - London TI - Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia. JO - Nat. Commun. VL - 7 PB - Nature Publishing Group PY - 2016 SN - 2041-1723 ER - TY - JOUR AB - Light propagating in tissue attains a spectrum that varies with location due to wavelength-dependent fluence attenuation, an effect that causes spectral corruption. Spectral corruption has limited the quantification accuracy of optical and optoacoustic spectroscopic methods, and impeded the goal of imaging blood oxygen saturation (sO2) deep in tissues; a critical goal for the assessment of oxygenation in physiological processes and disease. Here we describe light fluence in the spectral domain and introduce eigenspectra multispectral optoacoustic tomography (eMSOT) to account for wavelength-dependent light attenuation, and estimate blood sO2 within deep tissue. We validate eMSOT in simulations, phantoms and animal measurements and spatially resolve sO2 in muscle and tumours, validating our measurements with histology data. eMSOT shows substantial sO2 accuracy enhancement over previous optoacoustic methods, potentially serving as a valuable tool for imaging tissue pathophysiology. AU - Tzoumas, S. AU - Nunes, A. AU - Olefir, I. AU - Stangl, S.* AU - Symvoulidis, P. AU - Glasl, S. AU - Bayer, C.* AU - Multhoff, G. AU - Ntziachristos, V. C1 - 48976 C2 - 41506 CY - London TI - Eigenspectra optoacoustic tomography achieves quantitative blood oxygenation imaging deep in tissues. JO - Nat. Commun. VL - 7 PB - Nature Publishing Group PY - 2016 SN - 2041-1723 ER - TY - JOUR AB - Epitranscriptome modifications are required for structure and function of RNA and defects in these pathways have been associated with human disease. Here we identify the RNA target for the previously uncharacterized 5-methylcytosine (m(5)C) methyltransferase NSun3 and link m(5)C RNA modifications with energy metabolism. Using whole-exome sequencing, we identified loss-of-function mutations in NSUN3 in a patient presenting with combined mitochondrial respiratory chain complex deficiency. Patient-derived fibroblasts exhibit severe defects in mitochondrial translation that can be rescued by exogenous expression of NSun3. We show that NSun3 is required for deposition of m(5)C at the anticodon loop in the mitochondrially encoded transfer RNA methionine (mt-tRNA(Met)). Further, we demonstrate that m(5)C deficiency in mt-tRNA(Met) results in the lack of 5-formylcytosine (f(5)C) at the same tRNA position. Our findings demonstrate that NSUN3 is necessary for efficient mitochondrial translation and reveal that f(5)C in human mitochondrial RNA is generated by oxidative processing of m(5)C. AU - van Haute, L.* AU - Dietmann, S.* AU - Kremer, L.S. AU - Hussain, S.* AU - Pearce, S.F.* AU - Powell, C.A.* AU - Rorbach, J.* AU - Lantaff, R.* AU - Blanco, S.* AU - Sauer, S.* AU - Kotzaeridou, U.* AU - Hoffmann, G.F.* AU - Memari, Y.* AU - Kolb-Kokocinski, A.* AU - Durbin, R.* AU - Mayr, J.A.* AU - Frye, M.* AU - Prokisch, H. AU - Minczuk, M.* C1 - 49026 C2 - 41556 CY - London TI - Deficient methylation and formylation of mt-tRNAMet wobble cytosine in a patient carrying mutations in NSUN3. JO - Nat. Commun. VL - 7 PB - Nature Publishing Group PY - 2016 SN - 2041-1723 ER - TY - JOUR AB - DNA (class 2) transposons are mobile genetic elements which move within their 'host' genome through excising and re-inserting elsewhere. Although the rice genome contains tens of thousands of such elements, their actual role in evolution is still unclear. Analysing over 650 transposon polymorphisms in the rice species Oryza sativa and Oryza glaberrima, we find that DNA repair following transposon excisions is associated with an increased number of mutations in the sequences neighbouring the transposon. Indeed, the 3,000 bp flanking the excised transposons can contain over 10 times more mutations than the genome-wide average. Since DNA transposons preferably insert near genes, this is correlated with increases in mutation rates in coding sequences and regulatory regions. Most importantly, we find this phenomenon also in maize, wheat and barley. Thus, these findings suggest that DNA transposon activity is a major evolutionary force in grasses which provide the basis of most food consumed by humankind. AU - Wicker, T.* AU - Yu, Y.* AU - Haberer, G. AU - Mayer, K.F.X. AU - Marri, P.R.* AU - Rounsley, S.* AU - Chen, M.* AU - Zuccolo, A.* AU - Panaud, O.* AU - Wing, R.A.* AU - Roffler, S.* C1 - 49390 C2 - 41807 CY - London TI - DNA transposon activity is associated with increased mutation rates in genes of rice and other grasses. JO - Nat. Commun. VL - 7 PB - Nature Publishing Group PY - 2016 SN - 2041-1723 ER - TY - JOUR AB - Ground levels of solar UV-B radiation induce DNA damage. Sessile phototrophic organisms such as vascular plants are recurrently exposed to sunlight and require UV-B photoreception, flavonols shielding, direct reversal of pyrimidine dimers and nucleotide excision repair for resistance against UV-B radiation. However, the frequency of UV-B-induced mutations is unknown in plants. Here we quantify the amount and types of mutations in the offspring of Arabidopsis thaliana wild-type and UV-B-hypersensitive mutants exposed to simulated natural UV-B over their entire life cycle. We show that reversal of pyrimidine dimers by UVR2 photolyase is the major mechanism required for sustaining plant genome stability across generations under UV-B. In addition to widespread somatic expression, germline-specific UVR2 activity occurs during late flower development, and is important for ensuring low mutation rates in male and female cell lineages. This allows plants to maintain genome integrity in the germline despite exposure to UV-B. AU - Willing, E.M.* AU - Piofczyk, T.* AU - Albert, A. AU - Winkler, J.B. AU - Schneeberger, K.* AU - Pecinka, A.* C1 - 50102 C2 - 42062 CY - London TI - UVR2 ensures transgenerational genome stability under simulated natural UV-B in Arabidopsis thaliana. JO - Nat. Commun. VL - 7 PB - Nature Publishing Group PY - 2016 SN - 2041-1723 ER - TY - JOUR AB - Centrioles and cilia are microtubule-based structures, whose precise formation requires controlled cytoplasmic tubulin incorporation. How cytoplasmic tubulin is recognized for centriolar/ciliary-microtubule construction remains poorly understood. Centrosomal-P4.1-associated-protein (CPAP) binds tubulin via its PN2-3 domain. Here, we show that a C-terminal loop-helix in PN2-3 targets β-tubulin at the microtubule outer surface, while an N-terminal helical motif caps microtubule's α-β surface of β-tubulin. Through this, PN2-3 forms a high-affinity complex with GTP-tubulin, crucial for defining numbers and lengths of centriolar/ciliary-microtubules. Surprisingly, two distinct mutations in PN2-3 exhibit opposite effects on centriolar/ciliary-microtubule lengths. CPAP F375A, with strongly reduced tubulin interaction, causes shorter centrioles and cilia exhibiting doublet- instead of triplet-microtubules. CPAP EE343RR that unmasks the β-tubulin polymerization surface displays slightly reduced tubulin-binding affinity inducing over-elongation of newly forming centriolar/ciliary-microtubules by enhanced dynamic release of its bound tubulin. Thus CPAP regulates delivery of its bound-tubulin to define the size of microtubule-based cellular structures using a €clutch-like' mechanism. AU - Zheng, X.* AU - Ramani, A.* AU - Soni, K. AU - Gottardo, M.* AU - Zheng, S.* AU - Gooi, L.M.* AU - Li, W.* AU - Feng, S.* AU - Mariappan, A.* AU - Wason, A.* AU - Widlund, P.* AU - Pozniakovsky, A.* AU - Poser, I.* AU - Deng, H.* AU - Ou, G.* AU - Riparbelli, M.* AU - Giuliano, C.* AU - Hyman, A.A.* AU - Sattler, M. AU - Gopalakrishnan, J.* AU - Li, H.* C1 - 48894 C2 - 41489 CY - London TI - Molecular basis for CPAP-tubulin interaction in controlling centriolar and ciliary length. JO - Nat. Commun. VL - 7 PB - Nature Publishing Group PY - 2016 SN - 2041-1723 ER - TY - JOUR AB - Non-protein-coding RNAs are a functionally versatile class of transcripts exerting their biological roles on the RNA level. Recently, we demonstrated that the vault complex-associated RNAs (vtRNAs) are significantly upregulated in Epstein-Barr virus (EBV)-infected human B cells. Very little is known about the function(s) of the vtRNAs or the vault complex. Here, we individually express latent EBV-encoded proteins in B cells and identify the latent membrane protein 1 (LMP1) as trigger for vtRNA upregulation. Ectopic expression of vtRNA1-1, but not of the other vtRNA paralogues, results in an improved viral establishment and reduced apoptosis, a function located in the central domain of vtRNA1-1. Knockdown of the major vault protein has no effect on these phenotypes revealing that vtRNA1-1 and not the vault complex contributes to general cell death resistance. This study describes a NF-κB-mediated role of the non-coding vtRNA1-1 in inhibiting both the extrinsic and intrinsic apoptotic pathways. AU - Amort, M.* AU - Nachbauer, B.* AU - Tuzlak, S.* AU - Kieser, A. AU - Schepers, A. AU - Villunger, A.* AU - Polacek, N.* C1 - 44808 C2 - 37037 CY - London TI - Expression of the vault RNA protects cells from undergoing apoptosis. JO - Nat. Commun. VL - 6 PB - Nature Publishing Group PY - 2015 SN - 2041-1723 ER - TY - JOUR AB - Lung function measures are used in the diagnosis of chronic obstructive pulmonary disease. In 38,199 European ancestry individuals, we studied genome-wide association of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC with 1000 Genomes Project (phase 1)-imputed genotypes and followed up top associations in 54,550 Europeans. We identify 14 novel loci (P<5 × 10(-8)) in or near ENSA, RNU5F-1, KCNS3, AK097794, ASTN2, LHX3, CCDC91, TBX3, TRIP11, RIN3, TEKT5, LTBP4, MN1 and AP1S2, and two novel signals at known loci NPNT and GPR126, providing a basis for new understanding of the genetic determinants of these traits and pulmonary diseases in which they are altered. AU - Artigas, M.S.* AU - Wain, L.V.* AU - Miller, S.* AU - Kheirallah, A.K.* AU - Huffman, J.E.* AU - Ntalla, I.* AU - Shrine, N.* AU - Obeidat, M.* AU - Trochet, H.* AU - McArdle, W.L.* AU - Alves, A.C.* AU - Hui, J.* AU - Zhao, J.H.* AU - Joshi, P.K.* AU - Teumer, A.* AU - Albrecht, E. AU - Imboden, M.* AU - Rawal, R. AU - Lopez, L.M.* AU - Marten, J.* AU - Enroth, S.* AU - Surakka, I.* AU - Polasek, O.* AU - Lyytikäinen, L.-P.* AU - Granell, R.* AU - Hysi, P.G.* AU - Flexeder, C. AU - Mahajan, A.* AU - Beilby, J.* AU - Bossé, Y.* AU - Brandsma, C.A.* AU - Campbell, H.* AU - Gieger, C. AU - Gläser, S.* AU - Gonzalez, J.R.* AU - Grallert, H. AU - Hammond, C.J.* AU - Harris, S.E.* AU - Hartikainen, A.L.* AU - Heliövaara, M.* AU - Henderson, J.* AU - Hocking, L.J.* AU - Horikoshi, M.* AU - Hutri-Kähönen, N.* AU - Ingelsson, E.* AU - Johansson, Å* AU - Kemp, J.P.* AU - Kolcic, I.* AU - Kumar, A.* AU - Lind, L.* AU - Melén, E.* AU - Musk, A.W.* AU - Navarro, P.* AU - Nickle, D.C.* AU - Padmanabhan, S.* AU - Raitakari, O.T.* AU - Ried, J.S. AU - Ripatti, S.* AU - Schulz, H. AU - Scott, R.A.* AU - Sin, D.D.* AU - Starr, J.M.* AU - Viñuela, A.* AU - Völzke, H.* AU - Wild, S.H.* AU - Wright, A.F.* AU - Zemunik, T.* AU - Jarvis, D.L.* AU - Spector, T.D.* AU - Evans, D.M* AU - Lehtimäki, T.* AU - Kähönen, M.* AU - Gyllensten, U.* AU - Rudan, I.* AU - Deary, I.J.* AU - Karrasch, S. AU - Probst-Hensch, N.M.* AU - Heinrich, J. AU - Stubbe, B.* AU - Wilson, J.F.* AU - Wareham, N.J.* AU - James, A.L.* AU - Morris, A.P.* AU - Jarvelin, M.R.* AU - Hayward, C.* AU - Sayers, I.* AU - Hall, I.P.* AU - Tobin, M.D.* C1 - 47500 C2 - 40606 TI - Sixteen new lung function signals identified through 1000 Genomes Project reference panel imputation. JO - Nat. Commun. VL - 6 PY - 2015 SN - 2041-1723 ER - TY - JOUR AU - Benyamin, B.* AU - Esko, T.* AU - Ried, J.S. AU - Radhakrishnan, A.* AU - Vermeulen, S.H.* AU - Traglia, M.* AU - Gögele, M.* AU - Anderson, D.* AU - Broer, L.* AU - Podmore, C.* AU - Luan, J.* AU - Kutalik, Z.* AU - Sanna, S.* AU - van der Meer, P.* AU - Tanaka, T.* AU - Wang, F.* AU - Westra, H.J.* AU - Franke, L.* AU - Mihailov, E.* AU - Milani, L.* AU - Hälldin, J.* AU - Winkelmann, J. AU - Meitinger, T. AU - Thiery, J.* AU - Peters, A. AU - Waldenberger, M. AU - Rendon, A.* AU - Jolley, J.* AU - Sambrook, J.* AU - Kiemeney, L.A.* AU - Sweep, F.C.* AU - Sala, C.F.* AU - Schwienbacher, C.* AU - Pichler, I.* AU - Hui, J.* AU - Demirkan, A.* AU - Isaacs, A.* AU - Amin, N.* AU - Steri, M.* AU - Waeber, G.* AU - Verweij, N.* AU - Powell, J.E.* AU - Nyholt, D.R.* AU - Heath, A.C.* AU - Madden, P.A.* AU - Visscher, P.M.* AU - Wright, M.J.* AU - Montgomery, G.W.* AU - Martin, N.G.* AU - Hernandez, D.* AU - Bandinelli, S.* AU - van der Harst, P.* AU - Uda, M.* AU - Vollenweider, P.* AU - Scott, R.A.* AU - Langenberg, C.* AU - Wareham, N.J.* AU - van Duijn, C.M.* AU - Beilby, J.* AU - Pramstaller, P.P.* AU - Hicks, A.A.* AU - Ouwehand, W.H.* AU - Oexle, K.* AU - Gieger, C. AU - Metspalu, A.* AU - Camaschella, C.* AU - Toniolo, D.* AU - Swinkels, D.W.* AU - Whitfield, J.B.* C1 - 44378 C2 - 36807 TI - Corrigendum: Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis. JO - Nat. Commun. VL - 6 PY - 2015 SN - 2041-1723 ER - TY - JOUR AB - Insulin regulates glycaemia, lipogenesis and increases mRNA translation. Cells with reduced eukaryotic initiation factor 6 (eIF6) do not increase translation in response to insulin. The role of insulin-regulated translation is unknown. Here we show that reduction of insulin-regulated translation in mice heterozygous for eIF6 results in normal glycaemia, but less blood cholesterol and triglycerides. eIF6 controls fatty acid synthesis and glycolysis in a cell autonomous fashion. eIF6 acts by exerting translational control of adipogenic transcription factors like C/EBPβ, C/EBPδ and ATF4 that have G/C rich or uORF sequences in their 5' UTR. The outcome of the translational activation by eIF6 is a reshaping of gene expression with increased levels of lipogenic and glycolytic enzymes. Finally, eIF6 levels modulate histone acetylation and amounts of rate-limiting fatty acid synthase (Fasn) mRNA. Since obesity, type 2 diabetes, and cancer require a Fasn-driven lipogenic state, we propose that eIF6 could be a therapeutic target for these diseases. AU - Brina, D.* AU - Miluzio, A.* AU - Ricciardi, S.* AU - Clarke, K.* AU - Davidsen, P.K.* AU - Viero, G.* AU - Tebaldi, T.* AU - Offenhäuser, N.* AU - Rozman, J. AU - Rathkolb, B. AU - Neschen, S. AU - Klingenspor, M. AU - Wolf, E. AU - Gailus-Durner, V. AU - Fuchs, H. AU - Hrabě de Angelis, M. AU - Quattrone, A.* AU - Falciani, F.* AU - Biffo, S.* C1 - 46938 C2 - 39069 TI - eIF6 coordinates insulin sensitivity and lipid metabolism by coupling translation to transcription. JO - Nat. Commun. VL - 6 PY - 2015 SN - 2041-1723 ER - TY - JOUR AB - An imbalance between neutrophil-derived proteases and extracellular inhibitors is widely regarded as an important pathogenic mechanism for lung injury. Despite intense efforts over the last three decades, attempts to develop small-molecule inhibitors for neutrophil elastase have failed in the clinic. Here we discover an intrinsic self-cleaving property of mouse neutrophil elastase that interferes with the action of elastase inhibitors. We show that conversion of the single-chain (sc) into a two-chain (tc) neutrophil elastase by self-cleavage near its S1 pocket altered substrate activity and impaired both inhibition by endogenous α-1-antitrypsin and synthetic small molecules. Our data indicate that autoconversion of neutrophil elastase decreases the inhibitory efficacy of natural α-1-antitrypsin and small-molecule inhibitors, while retaining its pathological potential in an experimental mouse model. The so-far overlooked occurrence and properties of a naturally occurring tc-form of neutrophil elastase necessitates the redesign of small-molecule inhibitors that target the sc-form as well as the tc-form of neutrophil elastase. AU - Dau, T. AU - Sarker, R.S. AU - Yildirim, A.Ö. AU - Eickelberg, O. AU - Jenne, D. C1 - 44341 C2 - 36874 CY - London TI - Autoprocessing of neutrophil elastase near its active site reduces the efficiency of natural and synthetic elastase inhibitors. JO - Nat. Commun. VL - 6 PB - Nature Publishing Group PY - 2015 SN - 2041-1723 ER - TY - JOUR AB - The mutualistic association of roots with ectomycorrhizal fungi promotes plant health and is a hallmark of boreal and temperate forests worldwide. In the pre-colonization phase, before direct contact, lateral root (LR) production is massively stimulated, yet little is known about the signals exchanged during this step. Here, we identify sesquiterpenes (SQTs) as biologically active agents emitted by Laccaria bicolor while interacting with Populus or Arabidopsis. We show that inhibition of fungal SQT production by lovastatin strongly reduces LR proliferation and that (-)-thujopsene, a low-abundance SQT, is sufficient to stimulate LR formation in the absence of the fungus. Further, we show that the ectomycorrhizal ascomycote, Cenococcum geophilum, which cannot synthesize SQTs, does not promote LRs. We propose that the LR-promoting SQT signal creates a win-win situation by enhancing the root surface area for plant nutrient uptake and by improving fungal access to plant-derived carbon via root exudates. AU - Ditengou, F.A.* AU - Müller, A.* AU - Rosenkranz, M. AU - Felten, J.* AU - Lasok, H.* AU - van Doorn, M.M. AU - Legué, V.* AU - Palme, K.* AU - Schnitzler, J.-P. AU - Polle, A.* C1 - 43448 C2 - 36540 CY - London TI - Volatile signalling by sesquiterpenes from ectomycorrhizal fungi reprogrammes root architecture. JO - Nat. Commun. VL - 6 PB - Nature Publishing Group PY - 2015 SN - 2041-1723 ER - TY - JOUR AB - Seasonal variations are rarely considered a contributing component to human tissue function or health, although many diseases and physiological process display annual periodicities. Here we find more than 4,000 protein-coding mRNAs in white blood cells and adipose tissue to have seasonal expression profiles, with inverted patterns observed between Europe and Oceania. We also find the cellular composition of blood to vary by season, and these changes, which differ between the United Kingdom and The Gambia, could explain the gene expression periodicity. With regards to tissue function, the immune system has a profound pro-inflammatory transcriptomic profile during European winter, with increased levels of soluble IL-6 receptor and C-reactive protein, risk biomarkers for cardiovascular, psychiatric and autoimmune diseases that have peak incidences in winter. Circannual rhythms thus require further exploration as contributors to various aspects of human physiology and disease. AU - Dopico, X.C.* AU - Evangelou, M.* AU - Ferreira, R.C.* AU - Guo, H.* AU - Pekalski, M.L.* AU - Smyth, D.J.* AU - Cooper, N.* AU - Burren, O.S.* AU - Fulford, A.J.* AU - Hennig, B.J.* AU - Prentice, A.M.* AU - Ziegler, A.-G. AU - Bonifacio, E.* AU - Wallace, C.* AU - Todd, J.A.* C1 - 44839 C2 - 37036 CY - London TI - Widespread seasonal gene expression reveals annual differences in human immunity and physiology. JO - Nat. Commun. VL - 6 PB - Nature Publishing Group PY - 2015 SN - 2041-1723 ER - TY - JOUR AB - Metabolites are small molecules involved in cellular metabolism, which can be detected in biological samples using metabolomic techniques. Here we present the results of genome-wide association and meta-analyses for variation in the blood serum levels of 129 metabolites as measured by the Biocrates metabolomic platform. In a discovery sample of 7,478 individuals of European descent, we find 4,068 genome- and metabolome-wide significant (Z-test, P<1.09 × 10(-9)) associations between single-nucleotide polymorphisms (SNPs) and metabolites, involving 59 independent SNPs and 85 metabolites. Five of the fifty-nine independent SNPs are new for serum metabolite levels, and were followed-up for replication in an independent sample (N=1,182). The novel SNPs are located in or near genes encoding metabolite transporter proteins or enzymes (SLC22A16, ARG1, AGPS and ACSL1) that have demonstrated biomedical or pharmaceutical importance. The further characterization of genetic influences on metabolic phenotypes is important for progress in biological and medical research. AU - Draisma, H.H.* AU - Pool, R.* AU - Kobl, M. AU - Jansen, R.C.* AU - Petersen, A.-K. AU - Vaarhorst, A.A.* AU - Yet, I.* AU - Haller, T.* AU - Demirkan, A.* AU - Esko, T.* AU - Zhu, G.* AU - Böhringer, S.* AU - Beekman, M.* AU - van Klinken, J.B.* AU - Römisch-Margl, W. AU - Prehn, C. AU - Adamski, J. AU - de Craen, A.J.* AU - van Leeuwen, E.M.* AU - Amin, N.* AU - Dharuri, H.* AU - Westra, H.J.* AU - Franke, L.* AU - de Geus, E.J.* AU - Hottenga, J.J.* AU - Willemsen, G.* AU - Henders, A.K.* AU - Montgomery, G.W.* AU - Nyholt, D.R.* AU - Whitfield, J.B.* AU - Penninx, B.W.* AU - Spector, T.D.* AU - Metspalu, A.* AU - Slagboom, P.E.* AU - van Dijk, K.W.* AU - 't Hoen, P.A.* AU - Strauch, K. AU - Martin, N.G.* AU - van Ommen, G.J.* AU - Illig, T. AU - Bell, J.T.* AU - Mangino, M.* AU - Suhre, K. AU - McCarthy, M.I.* AU - Gieger, C. AU - Isaacs, A.* AU - van Duijn, C.M.* AU - Boomsma, D.I.* C1 - 45182 C2 - 37260 CY - London TI - Genome-wide association study identifies novel genetic variants contributing to variation in blood metabolite levels. JO - Nat. Commun. VL - 6 PB - Nature Publishing Group PY - 2015 SN - 2041-1723 ER - TY - JOUR AB - The Clp protease complex degrades a multitude of substrates, which are engaged by a AAA+ chaperone such as ClpX and subsequently digested by the dynamic, barrel-shaped ClpP protease. Acyldepsipeptides (ADEPs) are natural product-derived antibiotics that activate ClpP for chaperone-independent protein digestion. Here we show that both protein and small-molecule activators of ClpP allosterically control the ClpP barrel conformation. We dissect the catalytic mechanism with chemical probes and show that ADEP in addition to opening the axial pore directly stimulates ClpP activity through cooperative binding. ClpP activation thus reaches beyond active site accessibility and also involves conformational control of the catalytic residues. Moreover, we demonstrate that substoichiometric amounts of ADEP potently prevent binding of ClpX to ClpP and, at the same time, partially inhibit ClpP through conformational perturbance. Collectively, our results establish the hydrophobic binding pocket as a major conformational regulatory site with implications for both ClpXP proteolysis and ADEP-based anti-bacterial activity. AU - Gersch, M.* AU - Famulla, K.* AU - Dahmen, M.* AU - Göbl, C. AU - Malik, I.* AU - Richter, K.* AU - Korotkov, V.S.* AU - Sass, P.* AU - Rübsamen-Schaeff, H.* AU - Madl, T. AU - Brötz-Oesterhelt, H.* AU - Sieber, S.A.* C1 - 43436 C2 - 36574 CY - London TI - AAA+ chaperones and acyldepsipeptides activate the ClpP protease via conformational control. JO - Nat. Commun. VL - 6 PB - Nature Publishing Group PY - 2015 SN - 2041-1723 ER - TY - JOUR AB - Canonical membrane protein biogenesis requires co-translational delivery of ribosome-associated proteins to the Sec translocase and depends on the signal recognition particle (SRP) and its receptor (SR). In contrast, high-throughput delivery of abundant light-harvesting chlorophyll a,b-binding proteins (LHCPs) in chloroplasts to the Alb3 insertase occurs post-translationally via a soluble transit complex including the cpSRP43/cpSRP54 heterodimer (cpSRP). Here we describe the molecular mechanisms of tethering cpSRP to the Alb3 insertase by specific interaction of cpSRP43 chromodomain 3 with a linear motif in the Alb3 C-terminal tail. Combining NMR spectroscopy, X-ray crystallography and biochemical analyses, we dissect the structural basis for selectivity of chromodomains 2 and 3 for their respective ligands cpSRP54 and Alb3, respectively. Negative cooperativity in ligand binding can be explained by dynamics in the chromodomain interface. Our study provides a model for membrane recruitment of the transit complex and may serve as a prototype for a functional gain by the tandem arrangement of chromodomains. AU - Horn, A.P.* AU - Hennig, J. AU - Ahmed, Y.L.* AU - Stier, G.* AU - Wild, K.* AU - Sattler, M. AU - Sinning, I.* C1 - 47405 C2 - 40512 TI - Structural basis for cpSRP43 chromodomain selectivity and dynamics in Alb3 insertase interaction. JO - Nat. Commun. VL - 6 PY - 2015 SN - 2041-1723 ER - TY - JOUR AB - Previous genome-wide association studies (GWASs) have shown that common genetic variation contributes to the heritable risk of glioma. To identify new glioma susceptibility loci, we conducted a meta-analysis of four GWAS (totalling 4,147 cases and 7,435 controls), with imputation using 1000 Genomes and UK10K Project data as reference. After genotyping an additional 1,490 cases and 1,723 controls we identify new risk loci for glioblastoma (GBM) at 12q23.33 (rs3851634, near POLR3B, P=3.02 × 10-9) and non-GBM at 10q25.2 (rs11196067, near VTI1A, P=4.32 × 10-8), 11q23.2 (rs648044, near ZBTB16, P=6.26 × 10-11), 12q21.2 (rs12230172, P=7.53 × 10-11) and 15q24.2 (rs1801591, near ETFA, P=5.71 × 10-9). Our findings provide further insights into the genetic basis of the different glioma subtypes. AU - Kinnersley, B.* AU - Labussière, M.* AU - Holroyd, A.* AU - di Stefano, A.L.* AU - Broderick, P.* AU - Vijayakrishnan, J.* AU - Mokhtari, K.* AU - Delattre, J.Y.* AU - Gousias, K.* AU - Schramm, J.* AU - Schoemaker, M.J.* AU - Fleming, S.J.* AU - Herms, S.* AU - Heilmann, S.* AU - Schreiber, S.* AU - Wichmann, H.-E. AU - Nöthen, M.M.* AU - Swerdlow, A.* AU - Lathrop, M* AU - Simon, M.* AU - Bondy, M.* AU - Sanson, M.* AU - Houlston, R.S.* C1 - 46977 C2 - 39109 TI - Genome-wide association study identifies multiple susceptibility loci for glioma. JO - Nat. Commun. VL - 6 PY - 2015 SN - 2041-1723 ER - TY - JOUR AB - Osteosarcomas are aggressive bone tumours with a high degree of genetic heterogeneity, which has historically complicated driver gene discovery. Here we sequence exomes of 31 tumours and decipher their evolutionary landscape by inferring clonality of the individual mutation events. Exome findings are interpreted in the context of mutation and SNP array data from a replication set of 92 tumours. We identify 14 genes as the main drivers, of which some were formerly unknown in the context of osteosarcoma. None of the drivers is clearly responsible for the majority of tumours and even TP53 mutations are frequently mapped into subclones. However, >80% of osteosarcomas exhibit a specific combination of single-base substitutions, LOH, or large-scale genome instability signatures characteristic of BRCA1/2-deficient tumours. Our findings imply that multiple oncogenic pathways drive chromosomal instability during osteosarcoma evolution and result in the acquisition of BRCA-like traits, which could be therapeutically exploited. AU - Kovac, M.* AU - Blattmann, C.* AU - Ribi, S.* AU - Smida, J. AU - Müller, N.S. AU - Engert, F.* AU - Castro-Giner, F.* AU - Weischenfeldt, J.* AU - Kovacova, M.* AU - Krieg, A.* AU - Andreou, D.* AU - Tunn, P.U.* AU - Dürr, H.R.* AU - Rechl, H.P.* AU - Schaser, K.D.* AU - Melcher, I.* AU - Burdach, S.* AU - Kulozik, A.* AU - Specht, K.* AU - Heinimann, K.* AU - Fulda, S.* AU - Bielack, S.* AU - Jundt, G.* AU - Tomlinson, I.* AU - Korbel, J.O.* AU - Nathrath, M. AU - Baumhoer, D.* C1 - 47496 C2 - 40607 TI - Exome sequencing of osteosarcoma reveals mutation signatures reminiscent of BRCA deficiency. JO - Nat. Commun. VL - 6 PY - 2015 SN - 2041-1723 ER - TY - JOUR AB - Juxtaglomerular neurons (JGNs) of the mammalian olfactory bulb are generated throughout life. Their integration into the preexisting neural network, their differentiation and survival therein depend on sensory activity, but when and how these adult-born cells acquire responsiveness to sensory stimuli remains unknown. In vivo two-photon imaging of retrovirally labelled adult-born JGNs reveals that ~90% of the cells arrive at the glomerular layer after day post injection (DPI) 7. After arrival, adult-born JGNs are still migrating, but at DPI 9, 52% of them have odour-evoked Ca(2+) signals. Their odourant sensitivity closely resembles that of the parent glomerulus and surrounding JGNs, and their spontaneous and odour-evoked spiking is similar to that of their resident neighbours. Our data reveal a remarkably rapid functional integration of adult-born cells into the preexisting neural network. The mature pattern of odour-evoked responses of these cells strongly contrasts with their molecular phenotype, which is typical of immature, migrating neuroblasts. AU - Kovalchuk, Y.* AU - Homma, R.* AU - Liang, Y.* AU - Maslyukov, A.* AU - Hermes, M.* AU - Thestrup, T.* AU - Griesbeck, O.* AU - Ninkovic, J. AU - Cohen, L.B.* AU - Garaschuk, O.* C1 - 43435 C2 - 36573 CY - London TI - In vivo odourant response properties of migrating adult-born neurons in the mouse olfactory bulb. JO - Nat. Commun. VL - 6 PB - Nature Publishing Group PY - 2015 SN - 2041-1723 ER - TY - JOUR AB - Survival of plasma cells is regulated by B-cell maturation antigen (BCMA), a membrane-bound receptor activated by its agonist ligands BAFF and APRIL. Here we report that γ-secretase directly cleaves BCMA, without prior truncation by another protease. This direct shedding is facilitated by the short length of BCMA's extracellular domain. In vitro, γ-secretase reduces BCMA-mediated NF-κB activation. In addition, γ-secretase releases soluble BCMA (sBCMA) that acts as a decoy neutralizing APRIL. In vivo, inhibition of γ-secretase enhances BCMA surface expression in plasma cells and increases their number in the bone marrow. Furthermore, in multiple sclerosis, sBCMA levels in spinal fluid are elevated and associated with intracerebral IgG production; in systemic lupus erythematosus, sBCMA levels in serum are elevated and correlate with disease activity. Together, shedding of BCMA by γ-secretase controls plasma cells in the bone marrow and yields a potential biomarker for B-cell involvement in human autoimmune diseases. AU - Laurent, S.A.* AU - Hoffmann, F.S.* AU - Kuhn, P.H.* AU - Cheng, Q.* AU - Chu, Y.* AU - Schmidt-Supprian, M.* AU - Hauck, S.M. AU - Schuh, E.* AU - Krumbholz, M.* AU - Rübsamen, H.* AU - Wanngren, J.* AU - Khademi, M.* AU - Olsson, T.* AU - Alexander, T.* AU - Hiepe, F.* AU - Pfister, H.W.* AU - Weber, F.* AU - Jenne, D. AU - Wekerle, H.* AU - Hohlfeld, R.* AU - Lichtenthaler, S.F.* AU - Meinl, E.* C1 - 45185 C2 - 37257 CY - London TI - γ-secretase directly sheds the survival receptor BCMA from plasma cells. JO - Nat. Commun. VL - 6 PB - Nature Publishing Group PY - 2015 SN - 2041-1723 ER - TY - JOUR AB - Linking microbial metabolomics and carbon sequestration in the ocean via refractory organic molecules has been hampered by the chemical complexity of dissolved organic matter (DOM). Here, using bioassay experiments and ultra-high resolution metabolic profiling, we demonstrate that marine bacteria rapidly utilize simple organic molecules and produce exometabolites of remarkable molecular and structural diversity. Bacterial DOM is similar in chemical composition and structural complexity to naturally occurring DOM in sea water. An appreciable fraction of bacterial DOM has molecular and structural properties that are consistent with those of refractory molecules in the ocean, indicating a dominant role for bacteria in shaping the refractory nature of marine DOM. The rapid production of chemically complex and persistent molecules from simple biochemicals demonstrates a positive feedback between primary production and refractory DOM formation. It appears that carbon sequestration in diverse and structurally complex dissolved molecules that persist in the environment is largely driven by bacteria. AU - Lechtenfeld, O.J.* AU - Hertkorn, N. AU - Shen, Y.* AU - Witt, M.* AU - Benner, R.* C1 - 44087 C2 - 36881 CY - London TI - Marine sequestration of carbon in bacterial metabolites. JO - Nat. Commun. VL - 6 PB - Nature Publishing Group PY - 2015 SN - 2041-1723 ER - TY - JOUR AB - Skeletal muscle is composed of both slow-twitch oxidative myofibers and fast-twitch glycolytic myofibers that differentially impact muscle metabolism, function and eventually whole-body physiology. Here we show that the mesodermal transcription factor T-box 15 (Tbx15) is highly and specifically expressed in glycolytic myofibers. Ablation of Tbx15 in vivo leads to a decrease in muscle size due to a decrease in the number of glycolytic fibres, associated with a small increase in the number of oxidative fibres. This shift in fibre composition results in muscles with slower myofiber contraction and relaxation, and also decreases whole-body oxygen consumption, reduces spontaneous activity, increases adiposity and glucose intolerance. Mechanistically, ablation of Tbx15 leads to activation of AMPK signalling and a decrease in Igf2 expression. Thus, Tbx15 is one of a limited number of transcription factors to be identified with a critical role in regulating glycolytic fibre identity and muscle metabolism. AU - Lee, K.Y.* AU - Singh, M.K.* AU - Ussar, S. AU - Wetzel, P.* AU - Hirshman, M.F.* AU - Goodyear, L.J.* AU - Kispert, A.* AU - Kahn, C.R.* C1 - 47149 C2 - 39116 TI - Tbx15 controls skeletal muscle fibre-type determination and muscle metabolism. JO - Nat. Commun. VL - 6 PY - 2015 SN - 2041-1723 ER - TY - JOUR AB - Common variable immunodeficiency disorder (CVID) is the most common symptomatic primary immunodeficiency in adults, characterized by B-cell abnormalities and inadequate antibody response. CVID patients have considerable autoimmune comorbidity and we therefore hypothesized that genetic susceptibility to CVID may overlap with autoimmune disorders. Here, in the largest genetic study performed in CVID to date, we compare 778 CVID cases with 10,999 controls across 123,127 single-nucleotide polymorphisms (SNPs) on the Immunochip. We identify the first non-HLA genome-wide significant risk locus at CLEC16A (rs17806056, P=2.0 × 10(-9)) and confirm the previously reported human leukocyte antigen (HLA) associations on chromosome 6p21 (rs1049225, P=4.8 × 10(-16)). Clec16a knockdown (KD) mice showed reduced number of B cells and elevated IgM levels compared with controls, suggesting that CLEC16A may be involved in immune regulatory pathways of relevance to CVID. In conclusion, the CLEC16A associations in CVID represent the first robust evidence of non-HLA associations in this immunodeficiency condition. AU - Li, J.* AU - Jørgensen, S.F.* AU - Maggadottir, S.M.* AU - Bakay, M.* AU - Warnatz, K.* AU - Glessner, J.T.* AU - Pandey, R.C.* AU - Salzer, U.* AU - Schmidt, R.E.* AU - Perez, E.* AU - Resnick, E.* AU - Goldacker, S.* AU - Buchta, M.* AU - Witte, T.* AU - Padyukov, L.* AU - Videm, V.* AU - Folseraas, T.* AU - Atschekzei, F.* AU - Elder, J.T.* AU - Nair, R.P.* AU - Winkelmann, J. AU - Gieger, C. AU - Nöthen, M.M.* AU - Büning, C.* AU - Brand, S.* AU - Sullivan, K.E.* AU - Orange, J.S.* AU - Fevang, B.* AU - Schreiber, S.* AU - Lieb, W.* AU - Aukrust, P.* AU - Chapel, H.* AU - Cunningham-Rundles, C.* AU - Franke, A.* AU - Karlsen, T.H.* AU - Grimbacher, B.* AU - Hakonarson, H.* AU - Hammarström, L.* AU - Ellinghaus, E.* C1 - 44461 C2 - 36864 CY - London TI - Association of CLEC16A with human common variable immunodeficiency disorder and role in murine B cells. JO - Nat. Commun. VL - 6 PB - Nature Publishing Group PY - 2015 SN - 2041-1723 ER - TY - JOUR AU - Lunetta, K.L.* AU - Day, F.R.* AU - Sulem, P.* AU - Ruth, K.S.* AU - Tung, J.Y.* AU - Hinds, D.A.* AU - Esko, T.* AU - Elks, C.E.* AU - Altmaier, E. AU - He, C.* AU - Huffman, J.E.* AU - Mihailov, E.* AU - Porcu, E.* AU - Robino, A.* AU - Rose, L.M.* AU - Schick, U.M.* AU - Stolk, L.* AU - Teumer, A.* AU - Thompson, D.J.* AU - Traglia, M.* AU - Wang, C.A.* AU - Yerges-Armstrong, L.M.* AU - Antoniou, A.C.* AU - Barbieri, C.* AU - Coviello, A.D.* AU - Cucca, F.* AU - Demerath, E.W.* AU - Dunning, A.M.* AU - Gandin, I.* AU - Grove, M.L.* AU - Gudbjartsson, D.F.* AU - Hocking, L.J.* AU - Hofman, A.* AU - Huang, J.* AU - Jackson, R.D.* AU - Karasik, D.* AU - Kriebel, J. AU - Lange, E.M.* AU - Lange, L.A.* AU - Langenberg, C.* AU - Li, X.* AU - Luan, J.* AU - Mägi, R.* AU - Morrison, A.C.* AU - Padmanabhan, S.* AU - Pirie, A.* AU - Polasek, O.* AU - Porteous, D.J.* AU - Reiner, A.P.* AU - Rivadeneira, F.* AU - Rudan, I.* AU - Sala, C.F.* AU - Schlessinger, D.* AU - Scott, R.A.* AU - Stöckl, D. AU - Visser, J.A.* AU - Völker, U.* AU - Vozzi, D.* AU - Wilson, J.G.* AU - Zygmunt, M.* AU - EPIC-Interact Consortium (*) AU - Generation Scotland Consortium (*) AU - Boerwinkle, E.* AU - Buring, J.E.* AU - Crisponi, L.* AU - Easton, D.F.* AU - Hayward, C.* AU - Hu, F.B.* AU - Liu, S.* AU - Metspalu, A.* AU - Pennell, C.E.* AU - Ridker, P.M.* AU - Strauch, K. AU - Streeten, E.A.* AU - Toniolo, D.* AU - Uitterlinden, A.G.* AU - Ulivi, S.* AU - Völzke, H.* AU - Wareham, N.J.* AU - Wellons, M.* AU - Franceschini, N.* AU - Chasman, D.I.* AU - Thorsteinsdottir, U.* AU - Murray, A.* AU - Stefansson, K.* AU - Murabito, J.M.* AU - Ong, K.K.* AU - Perry, J.R.* C1 - 47857 C2 - 39601 TI - Corrigendum: Rare coding variants and X-linked loci associated with age at menarche. JO - Nat. Commun. VL - 6 PY - 2015 SN - 2041-1723 ER - TY - JOUR AB - More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ∼3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P<5 × 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 × 10(-13)) and FAAH2 (rs5914101, P=4.9 × 10(-10)). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 × 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain ∼0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait. AU - Lunetta, K.L.* AU - Day, F.R.* AU - Sulem, P.* AU - Ruth, K.S.* AU - Tung, J.Y.* AU - Hinds, D.A.* AU - Esko, T.* AU - Elks, C.E.* AU - Altmaier, E. AU - He, C.* AU - Huffman, J.E.* AU - Mihailov, E.* AU - Porcu, E.* AU - Robino, A.* AU - Rose, L.M.* AU - Schick, U.M.* AU - Stolk, L.* AU - Teumer, A.* AU - Thompson, D.J.* AU - Traglia, M.* AU - Wang, C.A.* AU - Yerges-Armstrong, L.M.* AU - Antoniou, A.C.* AU - Barbieri, C.* AU - Coviello, A.D.* AU - Cucca, F.* AU - Demerath, E.W.* AU - Dunning, A.M.* AU - Gandin, I.* AU - Grove, M.L.* AU - Gudbjartsson, D.F.* AU - Hocking, L.J.* AU - Hofman, A.* AU - Huang, J.* AU - Jackson, R.D.* AU - Karasik, D.* AU - Kriebel, J. AU - Lange, E.M.* AU - Lange, L.A.* AU - Langenberg, C.* AU - Li, X.* AU - Luan, J.* AU - Mägi, R.* AU - Morrison, A.C.* AU - Padmanabhan, S.* AU - Pirie, A.* AU - Polasek, O.* AU - Porteous, D.J.* AU - Reiner, A.P.* AU - Rivadeneira, F.* AU - Rudan, I.* AU - Sala, C.F.* AU - Schlessinger, D.* AU - Scott, R.A.* AU - Stöckl, D. AU - Visser, J.A.* AU - Völker, U.* AU - Vozzi, D.* AU - Wilson, J.G.* AU - Zygmunt, M.* AU - EPIC-Interact Consortium (*) AU - Generation Scotland Consortium (*) AU - Boerwinkle, E.* AU - Buring, J.E.* AU - Crisponi, L.* AU - Easton, D.F.* AU - Hayward, C.* AU - Hu, F.B.* AU - Liu, S.* AU - Metspalu, A.* AU - Pennell, C.E.* AU - Ridker, P.M.* AU - Strauch, K. AU - Streeten, E.A.* AU - Toniolo, D.* AU - Uitterlinden, A.G.* AU - Ulivi, S.* AU - Völzke, H.* AU - Wareham, N.J.* AU - Wellons, M.* AU - Franceschini, N.* AU - Chasman, D.I.* AU - Thorsteinsdottir, U.* AU - Murray, A.* AU - Stefansson, K.* AU - Murabito, J.M.* AU - Ong, K.K.* AU - Perry, J.R.* C1 - 46510 C2 - 37723 CY - London TI - Rare coding variants and X-linked loci associated with age at menarche. JO - Nat. Commun. VL - 6 PB - Nature Publishing Group PY - 2015 SN - 2041-1723 ER - TY - JOUR AB - Eczema often precedes the development of asthma in a disease course called the 'atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10(-8)) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10(-9)). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema. AU - Marenholz, I.* AU - Esparza-Gordillo, J.* AU - Ruschendorf, F.* AU - Bauerfeind, A.* AU - Strachan, D.P.* AU - Spycher, B.D.* AU - Baurecht, H. AU - Margaritte-Jeannin, P.* AU - Saaf, A.* AU - Kerkhof, M.* AU - Ege, M.* AU - Baltic, S.* AU - Matheson, M.C.* AU - Li, J.* AU - Michel, S.* AU - Ang, W.Q.* AU - McArdle, W.* AU - Arnold, A.* AU - Homuth, G.* AU - Demenais, F.* AU - Bouzigon, E.* AU - Söderhäll, C.* AU - Pershagen, G.* AU - de Jongste, J.C.* AU - Postma, D.S.* AU - Braun-Fahrländer, C.* AU - Horak, E.* AU - Ogorodova, L.M.* AU - Puzyrev, V.P.* AU - Bragina, E.Y.* AU - Hudson, T.J.* AU - Morin, C.* AU - Duffy, D.L.* AU - Marks, G.B.* AU - Robertson, C.F.* AU - Montgomery, G.W.* AU - Musk, B.* AU - Thompson, P.J.* AU - Martin, N.G.* AU - James, A.* AU - Sleiman, P.M.* AU - Toskala, E. AU - Rodriguez, E.* AU - Fölster-Holst, R.* AU - Franke, A.* AU - Lieb, W.* AU - Gieger, C. AU - Heinzmann, A.* AU - Rietschel, E.* AU - Keil, T.* AU - Cichon, S.* AU - Nöthen, M.M.* AU - Pennell, C.E.* AU - Sly, P.D.* AU - Schmidt, C.O.* AU - Matanovic, A.* AU - Schneider, V.* AU - Heinig, M.* AU - Hubner, N.* AU - Holt, P.G.* AU - Lau, S.* AU - Kabesch, M.* AU - Weidinger, S.* AU - Hakonarson, H.* AU - Ferreira, M.A.* AU - Laprise, C.* AU - Freidin, M.B.* AU - Genuneit, J.* AU - Koppelman, G.H.* AU - Melén, E.* AU - Dizier, M.H.* AU - Henderson, A.J.* AU - Lee, Y.A.* C1 - 47220 C2 - 39184 TI - Meta-analysis identifies seven susceptibility loci involved in the atopic march. JO - Nat. Commun. VL - 6 PY - 2015 SN - 2041-1723 ER - TY - JOUR AB - Receptor families of the innate immune response engage in 'cross-talk' to tailor optimal immune responses against invading pathogens. However, these responses are subject to multiple levels of regulation to keep in check aberrant inflammatory signals. Here, we describe a role for the orphan receptor interleukin-17 receptor D (IL-17RD) in negatively regulating Toll-like receptor (TLR)-induced responses. Deficiency of IL-17RD expression in cells leads to enhanced pro-inflammatory signalling and gene expression in response to TLR stimulation, and Il17rd(-/-) mice are more susceptible to TLR-induced septic shock. We demonstrate that the intracellular Sef/IL-17R (SEFIR) domain of IL-17RD targets TIR adaptor proteins to inhibit TLR downstream signalling thus revealing a paradigm involving cross-regulation of members of the IL-17R and TLR families. AU - Mellett, M.* AU - Atzei, P.* AU - Bergin, R.* AU - Horgan, A.* AU - Floß, T. AU - Wurst, W. AU - Callanan, J.J.* AU - Moynagh, P.N.* C1 - 44021 C2 - 36729 CY - London TI - Orphan receptor IL-17RD regulates toll-like receptor signalling via SEFIR/TIR interactions. JO - Nat. Commun. VL - 6 PB - Nature Publishing Group PY - 2015 SN - 2041-1723 ER - TY - JOUR AB - The main challenge for gaining biological insights from genetic associations is identifying which genes and pathways explain the associations. Here we present DEPICT, an integrative tool that employs predicted gene functions to systematically prioritize the most likely causal genes at associated loci, highlight enriched pathways and identify tissues/cell types where genes from associated loci are highly expressed. DEPICT is not limited to genes with established functions and prioritizes relevant gene sets for many phenotypes. AU - Pers, T.H.* AU - Karjalainen, J.M.* AU - Chan, Y.* AU - Westra, H.J.* AU - Wood, A.R.* AU - Yang, J.* AU - Lui, J.C.* AU - Vedantam, S.* AU - Gustafsson, S.* AU - Esko, T.* AU - Frayling, T.* AU - Speliotes, E.K.* AU - GIANT Consortium (Albrecht, E. AU - Gieger, C. AU - Grallert, H. AU - Heid, I.M. AU - Illig, T. AU - Müller-Nurasyid, M. AU - Peters, A. AU - Thorand, B. AU - Wichmann, H.-E.) AU - Boehnke, M.* AU - Raychaudhuri, S.* AU - Fehrmann, R.S.N.* AU - Hirschhorn, J.N.* AU - Franke, L.* C1 - 44011 C2 - 36694 TI - Biological interpretation of genome-wide association studies using predicted gene functions. JO - Nat. Commun. VL - 6 PY - 2015 SN - 2041-1723 ER - TY - JOUR AB - Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the 'transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts. AU - Peters, M.J.* AU - Joehanes, R.* AU - Pilling, L.C.* AU - Schurmann, C.* AU - Conneely, K.N.* AU - Powell, J.* AU - Reinmaa, E.* AU - Sutphin, G.L.* AU - Zhernakova, A.* AU - Schramm, K. AU - Wilson, Y.A.* AU - Kobes, S.* AU - Tukiainen, T.* AU - Ramos, Y.F.* AU - Göring, H.H.H.* AU - Fornage, M.* AU - Liu, Y.* AU - Gharib, S.A.* AU - Stranger, B.E.* AU - de Jager, P.L.* AU - Aviv, A.* AU - Levy, D.* AU - Murabito, J.M.* AU - Munson, P.J.* AU - Huan, T.* AU - Hofman, A.* AU - Uitterlinden, A.G.* AU - Rivadeneira, F.* AU - van Rooij, J.* AU - Stolk, L.* AU - Broer, L.* AU - Verbiest, M.M.P.J.* AU - Jhamai, M.* AU - Arp, P.* AU - Metspalu, A.* AU - Tserel, L.* AU - Milani, L.* AU - Samani, N.J.* AU - Peterson, P.* AU - Kasela, S.* AU - Codd, V.* AU - Peters, A. AU - Ward-Caviness, C.K. AU - Herder, C.* AU - Waldenberger, M. AU - Roden, M.* AU - Singmann, P. AU - Zeilinger, S. AU - Illig, T.* AU - Homuth, G.* AU - Grabe, H.J.* AU - Völzke, H.* AU - Steil, L.* AU - Kocher, T.* AU - Martin, N.G.* AU - Smith, A.K.* AU - Mehta, D.* AU - Binder, E.B.* AU - Nylocks, K.M.* AU - Kennedy, E.M.* AU - Klengel, T.* AU - Ding, J.* AU - Suchy-Dicey, A.* AU - Enquobahrie, D.A.* AU - Houwing-Duistermaat, J.J.* AU - Slagboom, P.E.* AU - Helmer, Q.* AU - den Hollander, W.* AU - Raj, T.* AU - Oyston, L.J.* AU - Turner, S.T.* AU - Blangero, J.* AU - Brody, J.* AU - Rotter, J.I.* AU - Chen, Y.D.* AU - Kloppenburg, M.* AU - Bean, S.* AU - Bakhshi, N.* AU - Wang, Q.P.* AU - Psaty, B.M.* AU - Tracy, R.P.* AU - Montgomery, G.W.* AU - Meulenbelt, I.* AU - Ressler, K.J.* AU - Yang, J.* AU - Franke, L.* AU - Kettunen, J.* AU - Visscher, P.M.* AU - Neely, G.G.* AU - Korstanje, R.* AU - Hanson, R.L.* AU - Prokisch, H. AU - Ferrucci, L.* AU - Esko, T.* AU - Teumer, A.* AU - van Meurs, J.B.* AU - Johnson, A.D.* C1 - 47167 C2 - 39146 TI - The transcriptional landscape of age in human peripheral blood. JO - Nat. Commun. VL - 6 PY - 2015 SN - 2041-1723 ER - TY - JOUR AB - The cochaperone Sti1/Hop physically links Hsp70 and Hsp90. The protein exhibits one binding site for Hsp90 (TPR2A) and two binding sites for Hsp70 (TPR1 and TPR2B). How these sites are used remained enigmatic. Here we show that Sti1 is a dynamic, elongated protein that consists of a flexible N-terminal module, a long linker and a rigid C-terminal module. Binding of Hsp90 and Hsp70 regulates the Sti1 conformation with Hsp90 binding determining with which site Hsp70 interacts. Without Hsp90, Sti1 is more compact and TPR2B is the high-affinity interaction site for Hsp70. In the presence of Hsp90, Hsp70 shifts its preference. The linker connecting the two modules is crucial for the interaction with Hsp70 and for client activation in vivo. Our results suggest that the interaction of Hsp70 with Sti1 is tightly regulated by Hsp90 to assure transfer of Hsp70 between the modules, as a prerequisite for the efficient client handover. AU - Röhl, A.* AU - Wengler, D.* AU - Madl, T. AU - Lagleder, S.* AU - Tippel, F.* AU - Hermann, M.* AU - Hendrix, J.* AU - Richter, K.* AU - Hack, G.* AU - Schmid, A.B.* AU - Kessler, H.* AU - Lamb, D.C.* AU - Buchner, J.* C1 - 44335 C2 - 36771 CY - London TI - Hsp90 regulates the dynamics of its cochaperone Sti1 and the transfer of Hsp70 between modules. JO - Nat. Commun. VL - 6 PB - Nature Publishing Group PY - 2015 SN - 2041-1723 ER - TY - JOUR AB - Roquin is an RNA-binding protein that prevents autoimmunity and inflammation via repression of bound target mRNAs such as inducible costimulator (Icos). When Roquin is absent or mutated (Roquin(san)), Icos is overexpressed in T cells. Here we show that Roquin enhances Dicer-mediated processing of pre-miR-146a. Roquin also directly binds Argonaute2, a central component of the RNA-induced silencing complex, and miR-146a, a microRNA that targets Icos mRNA. In the absence of functional Roquin, miR-146a accumulates in T cells. Its accumulation is not due to increased transcription or processing, rather due to enhanced stability of mature miR-146a. This is associated with decreased 3' end uridylation of the miRNA. Crystallographic studies reveal that Roquin contains a unique HEPN domain and identify the structural basis of the 'san' mutation and Roquin's ability to bind multiple RNAs. Roquin emerges as a protein that can bind Ago2, miRNAs and target mRNAs, to control homeostasis of both RNA species. AU - Srivastava, M.* AU - Duan, G.* AU - Kershaw, N.J.* AU - Athanasopoulos, V.* AU - Yeo, J.H.* AU - Ose, T.* AU - Hu, D. AU - Brown, S.H.* AU - Jergic, S.* AU - Patel, H.R.* AU - Pratama, A.* AU - Richards, S.* AU - Verma, A.* AU - Jones, E.Y.* AU - Heissmeyer, V. AU - Preiss, T.* AU - Dixon, N.E.* AU - Chong, M.M.* AU - Babon, J.J.* AU - Vinuesa, C.G.* C1 - 43451 C2 - 36636 CY - London TI - Roquin binds microRNA-146a and Argonaute2 to regulate microRNA homeostasis. JO - Nat. Commun. VL - 6 PB - Nature Publishing Group PY - 2015 SN - 2041-1723 ER - TY - JOUR AB - Clonal proliferation in myeloproliferative neoplasms (MPN) is driven by somatic mutations in JAK2, CALR or MPL, but the contribution of inherited factors is poorly characterized. Using a three-stage genome-wide association study of 3,437 MPN cases and 10,083 controls, we identify two SNPs with genome-wide significance in JAK2(V617F)-negative MPN: rs12339666 (JAK2; meta-analysis P=1.27 × 10(-10)) and rs2201862 (MECOM; meta-analysis P=1.96 × 10(-9)). Two additional SNPs, rs2736100 (TERT) and rs9376092 (HBS1L/MYB), achieve genome-wide significance when including JAK2(V617F)-positive cases. rs9376092 has a stronger effect in JAK2(V617F)-negative cases with CALR and/or MPL mutations (Breslow-Day P=4.5 × 10(-7)), whereas in JAK2(V617F)-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelic χ(2) P=7.3 × 10(-7)). Reduced MYB expression, previously linked to development of an ET-like disease in model systems, associates with rs9376092 in normal myeloid cells. These findings demonstrate that multiple germline variants predispose to MPN and link constitutional differences in MYB expression to disease phenotype. AU - Tapper, W.* AU - Jones, A.V.* AU - Kralovics, R.* AU - Harutyunyan, A.S.* AU - Zoi, K.* AU - Leung, W.* AU - Godfrey, A.L.* AU - Guglielmelli, P.* AU - Callaway, A.* AU - Ward, D.* AU - Aranaz, P.* AU - White, H.E.* AU - Waghorn, K.* AU - Lin, F.* AU - Chase, A.J.* AU - Baxter, E.* AU - Maclean, C.* AU - Nangalia, J.* AU - Chen, E.* AU - Evans, P.* AU - Short, M.* AU - Jack, A.* AU - Wallis, L.* AU - Oscier, D.* AU - Duncombe, A.S.* AU - Schuh, A.* AU - Mead, A.J.* AU - Griffiths, M.* AU - Ewing, J.* AU - Gale, R.E.* AU - Schnittger, S.* AU - Haferlach, T.* AU - Stegelmann, F.* AU - Döhner, K.* AU - Grallert, H. AU - Strauch, K. AU - Tanaka, T.* AU - Bandinelli, S.* AU - Giannopoulos, A.* AU - Pieri, L.* AU - Mannarelli, C.* AU - Gisslinger, H.* AU - Barosi, G. AU - Cazzola, M.* AU - Reiter, A.* AU - Harrison, C.N.* AU - Campbell, P.J.* AU - Green, A.R.* AU - Vannucchi, A.M.* AU - Cross, N.C.P.* C1 - 44264 C2 - 36776 CY - London TI - Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms. JO - Nat. Commun. VL - 6 PB - Nature Publishing Group PY - 2015 SN - 2041-1723 ER - TY - JOUR AB - Acute lung injury (ALI) is a severe inflammatory disease for which no specific treatment exists. As glucocorticoids have potent immunosuppressive effects, their application in ALI is currently being tested in clinical trials. However, the benefits of this type of regimen remain unclear. Here we identify a mechanism of glucocorticoid action that challenges the long-standing dogma of cytokine repression by the glucocorticoid receptor. Contrarily, synergistic gene induction of sphingosine kinase 1 (SphK1) by glucocorticoids and pro-inflammatory stimuli via the glucocorticoid receptor in macrophages increases circulating sphingosine 1-phosphate levels, which proves essential for the inhibition of inflammation. Chemical or genetic inhibition of SphK1 abrogates the therapeutic effects of glucocorticoids. Inflammatory p38 MAPK- and mitogen- and stress-activated protein kinase 1 (MSK1)-dependent pathways cooperate with glucocorticoids to upregulate SphK1 expression. Our findings support a critical role for SphK1 induction in the suppression of lung inflammation by glucocorticoids, and therefore provide rationales for effective anti-inflammatory therapies. AU - Vettorazzi, S.* AU - Bode, C.* AU - Dejager, L.* AU - Frappart, L.* AU - Shelest, E.* AU - Klaßen, C.* AU - Tasdogan, A.* AU - Reichardt, H.M.* AU - Libert, C.* AU - Schneider, M.* AU - Weih, F.* AU - Uhlenhaut, N.H. AU - David, J.P.* AU - Gräler, M.H.* AU - Kleiman, A.* AU - Tuckermann, J.P.* C1 - 46375 C2 - 37558 CY - London TI - Glucocorticoids limit acute lung inflammation in concert with inflammatory stimuli by induction of SphK1. JO - Nat. Commun. VL - 6 PB - Nature Publishing Group PY - 2015 SN - 2041-1723 ER - TY - JOUR AB - Variation in body iron is associated with or causes diseases, including anaemia and iron overload. Here, we analyse genetic association data on biochemical markers of iron status from 11 European-population studies, with replication in eight additional cohorts (total up to 48,972 subjects). We find 11 genome-wide-significant (P<5 × 10(-8)) loci, some including known iron-related genes (HFE, SLC40A1, TF, TFR2, TFRC, TMPRSS6) and others novel (ABO, ARNTL, FADS2, NAT2, TEX14). SNPs at ARNTL, TF, and TFR2 affect iron markers in HFE C282Y homozygotes at risk for hemochromatosis. There is substantial overlap between our iron loci and loci affecting erythrocyte and lipid phenotypes. These results will facilitate investigation of the roles of iron in disease. AU - Benyamin, B.* AU - Esko, T.* AU - Ried, J.S. AU - Radhakrishnan, A.* AU - Vermeulen, S.H.* AU - Traglia, M.* AU - Gögele, M.* AU - Anderson, D.* AU - Broer, L.* AU - Podmore, C.* AU - Luan, J.* AU - Kutalik, Z.* AU - Sanna, S.* AU - van der Meer, P.* AU - Tanaka, T.* AU - Wang, F.* AU - Westra, H.J.* AU - Franke, L.* AU - Mihailov, E.* AU - Milani, L.* AU - Hälldin, J.* AU - Winkelmann, J. AU - Meitinger, T. AU - Thiery, J.* AU - Peters, A. AU - Waldenberger, M. AU - Rendon, A.* AU - Jolley, J.* AU - Sambrook, J.* AU - Kiemeney, L.A.* AU - Sweep, F.C.* AU - Sala, C.F.* AU - Schwienbacher, C.* AU - Pichler, I.* AU - Hui, J.* AU - Demirkan, A.* AU - Isaacs, A.* AU - Amin, N.* AU - Steri, M.* AU - Waeber, G.* AU - Verweij, N.* AU - Powell, J.E.* AU - Nyholt, D.R.* AU - Heath, A.C.* AU - Madden, P.A.* AU - Visscher, P.M.* AU - Wright, M.J.* AU - Montgomery, G.W.* AU - Martin, N.G.* AU - Hernandez, D.* AU - Bandinelli, S.* AU - van der Harst, P.* AU - Uda, M.* AU - Vollenweider, P.* AU - Scott, R.A.* AU - Langenberg, C.* AU - Wareham, N.J.* AU - van Duijn, C.M.* AU - Beilby, J.* AU - Pramstaller, P.P.* AU - Hicks, A.A.* AU - Ouwehand, W.H.* AU - Oexle, K.* AU - Gieger, C. AU - Metspalu, A.* AU - Camaschella, C.* AU - Toniolo, D.* AU - Swinkels, D.W.* AU - Whitfield, J.B.* C1 - 32643 C2 - 35192 CY - London TI - Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis. JO - Nat. Commun. VL - 5 PB - Nature Publishing Group PY - 2014 SN - 2041-1723 ER - TY - JOUR AB - Phosphorylation of the RNA polymerase II C-terminal domain (CTD) by cyclin-dependent kinases is important for productive transcription. Here we determine the crystal structure of Cdk12/CycK and analyse its requirements for substrate recognition. Active Cdk12/CycK is arranged in an open conformation similar to that of Cdk9/CycT but different from those of cell cycle kinases. Cdk12 contains a C-terminal extension that folds onto the N- and C-terminal lobes thereby contacting the ATP ribose. The interaction is mediated by an HE motif followed by a polybasic cluster that is conserved in transcriptional CDKs. Cdk12/CycK showed the highest activity on a CTD substrate prephosphorylated at position Ser7, whereas the common Lys7 substitution was not recognized. Flavopiridol is most potent towards Cdk12 but was still 10-fold more potent towards Cdk9. T-loop phosphorylation of Cdk12 required coexpression with a Cdk-activating kinase. These results suggest the regulation of Pol II elongation by a relay of transcriptionally active CTD kinases. AU - Bösken, C.A.* AU - Farnung, L.* AU - Hintermair, C. AU - Merzel Schachter, M.* AU - Vogel-Bachmayr, K.* AU - Blazek, D.* AU - Anand, K.* AU - Fisher, R.P.* AU - Eick, D. AU - Geyer, M.* C1 - 30855 C2 - 34000 CY - London TI - The structure and substrate specificity of human Cdk12/Cyclin K. JO - Nat. Commun. VL - 5 PB - Nature Publishing Group PY - 2014 SN - 2041-1723 ER - TY - JOUR AB - Type 2 diabetes mellitus is affecting more than 382 million people worldwide. Although much progress has been made, a comprehensive understanding of the underlying disease mechanism is still lacking. Here we report a role for the β-cell primary cilium in type 2 diabetes susceptibility. We find impaired ​glucose handling in young ​Bbs4−/− mice before the onset of obesity. Basal body/ciliary perturbation in murine pancreatic islets leads to impaired first phase insulin release ex and in vivo. ​Insulin receptor is recruited to the cilium of stimulated β-cells and ciliary/basal body integrity is required for activation of downstream targets of insulin signalling. We also observe a reduction in the number of ciliated β-cells along with misregulated ciliary/basal body gene expression in pancreatic islets in a diabetic rat model. We suggest that ciliary function is implicated in insulin secretion and insulin signalling in the β-cell and that ciliary dysfunction could contribute to type 2 diabetes susceptibility. AU - Gerdes, J.M. AU - Christou-Safina, S.* AU - Xiong, Y.* AU - Moede, T.* AU - Moruzzi, N. AU - Karlsson-Edlund, P.* AU - Leibiger, B.* AU - Leibiger, I.* AU - Ostenson, C.G.* AU - Beales, P.* AU - Berggren, P.O.* C1 - 32633 C2 - 35243 TI - Ciliary dysfunction impairs beta-cell insulin secretion and promotes development of type 2 diabetes in rodents. JO - Nat. Commun. VL - 5 PY - 2014 SN - 2041-1723 ER - TY - JOUR AB - Myogenic regulatory factors such as MyoD and Myf5 lie at the core of vertebrate muscle differentiation. However, E-boxes, the cognate binding sites for these transcription factors, are not restricted to the promoters/enhancers of muscle cell-specific genes. Thus, the specificity in myogenic transcription is poorly defined. Here we describe the transcription factor Ebf3 as a new determinant of muscle cell-specific transcription. In the absence of Ebf3 the lung does not unfold at birth, resulting in respiratory failure and perinatal death. This is due to a hypercontractile diaphragm with impaired Ca(2+) efflux-related muscle functions. Expression of the Ca(2+) pump Serca1 (Atp2a1) is downregulated in the absence of Ebf3, and its transgenic expression rescues this phenotype. Ebf3 binds directly to the promoter of Atp2a1 and synergises with MyoD in the induction of Atp2a1. In skeletal muscle, the homologous family member Ebf1 is strongly expressed and together with MyoD induces Atp2a1. Thus, Ebf3 is a new regulator of terminal muscle differentiation in the diaphragm, and Ebf factors cooperate with MyoD in the induction of muscle-specific genes. AU - Jin, S. AU - Kim, J. AU - Willert, T. AU - Klein-Rodewald, T. AU - Garcia-Dominguez, M.* AU - Mosqueira, M.* AU - Fink, R.* AU - Esposito, I. AU - Hofbauer, L.C.* AU - Charnay, P.* AU - Kieslinger, M. C1 - 31190 C2 - 34285 CY - London TI - Ebf factors and MyoD cooperate to regulate muscle relaxation via Atp2a1. JO - Nat. Commun. VL - 5 PB - Nature Publishing Group PY - 2014 SN - 2041-1723 ER - TY - JOUR AB - The hormone calcitonin (CT) is primarily known for its pharmacologic action as an inhibitor of bone resorption, yet CT-deficient mice display increased bone formation. These findings raised the question about the underlying cellular and molecular mechanism of CT action. Here we show that either ubiquitous or osteoclast-specific inactivation of the murine CT receptor (CTR) causes increased bone formation. CT negatively regulates the osteoclast expression of Spns2 gene, which encodes a transporter for the signalling lipid sphingosine 1-phosphate (S1P). CTR-deficient mice show increased S1P levels, and their skeletal phenotype is normalized by deletion of the S1P receptor S1P3. Finally, pharmacologic treatment with the nonselective S1P receptor agonist FTY720 causes increased bone formation in wild-type, but not in S1P3-deficient mice. This study redefines the role of CT in skeletal biology, confirms that S1P acts as an osteoanabolic molecule in vivo and provides evidence for a pharmacologically exploitable crosstalk between osteoclasts and osteoblasts. AU - Keller, J.* AU - Catala-Lehnen, P.* AU - Huebner, A.K.* AU - Jeschke, A.* AU - Heckt, T.* AU - Lueth, A.* AU - Krause, M.* AU - Koehne, T.* AU - Albers, J.* AU - Schulze, J.* AU - Schilling, S.* AU - Haberland, M.* AU - Denninger, H.* AU - Neven, M.* AU - Hermans-Borgmeyer, I.* AU - Streichert, T.* AU - Breer, S.* AU - Barvencik, F.* AU - Levkau, B.* AU - Rathkolb, B. AU - Wolf, E.* AU - Calzada-Wack, J. AU - Neff, F. AU - Gailus-Durner, V. AU - Fuchs, H. AU - Hrabě de Angelis, M. AU - Klutmann, S.* AU - Tsourdi, E.* AU - Hofbauer, L.C.* AU - Kleuser, B.* AU - Chun, J.* AU - Schinke, T.* AU - Amling, M.* C1 - 32600 C2 - 35168 CY - London TI - Calcitonin controls bone formation by inhibiting the release of sphingosine 1-phosphate from osteoclasts. JO - Nat. Commun. VL - 5 PB - Nature Publishing Group PY - 2014 SN - 2041-1723 ER - TY - JOUR AB - DNA damage and telomere dysfunction shorten organismal lifespan. Here we show that oral glucose administration at advanced age increases health and lifespan of telomere dysfunctional mice. The study reveals that energy consumption increases in telomere dysfunctional cells resulting in enhanced glucose metabolism both in glycolysis and in the tricarboxylic acid cycle at organismal level. In ageing telomere dysfunctional mice, normal diet provides insufficient amounts of glucose thus leading to impaired energy homeostasis, catabolism, suppression of IGF-1/mTOR signalling, suppression of mitochondrial biogenesis and tissue atrophy. A glucose-enriched diet reverts these defects by activating glycolysis, mitochondrial biogenesis and oxidative glucose metabolism. The beneficial effects of glucose substitution on mitochondrial function and glucose metabolism are blocked by mTOR inhibition but mimicked by IGF-1 application. Together, these results provide the first experimental evidence that telomere dysfunction enhances the requirement of glucose substitution for the maintenance of energy homeostasis and IGF-1/mTOR-dependent mitochondrial biogenesis in ageing tissues. AU - Missios, P.* AU - Zhou, Y.* AU - Guachalla, L.M.* AU - von Figura, G.* AU - Wegner, A.* AU - Chakkarappan, S.R.* AU - Binz, T.* AU - Gompf, A.* AU - Hartleben, G.* AU - Burkhalter, M.D.* AU - Wulff, V.* AU - Günes, C.* AU - Wang-Sattler, R. AU - Song, Z.* AU - Illig, T. AU - Klaus, S.* AU - Böhm, B.O.* AU - Wenz, T.* AU - Hiller, K.* AU - Rudolph, K.L.* C1 - 32493 C2 - 35073 TI - Glucose substitution prolongs maintenance of energy homeostasis and lifespan of telomere dysfunctional mice. JO - Nat. Commun. VL - 5 PY - 2014 SN - 2041-1723 ER - TY - JOUR AB - Fossil fuel-powered vehicles emit significant particulate matter, for example, black carbon and primary organic aerosol, and produce secondary organic aerosol. Here we quantify secondary organic aerosol production from two-stroke scooters. Cars and trucks, particularly diesel vehicles, are thought to be the main vehicular pollution sources. This needs re-thinking, as we show that elevated particulate matter levels can be a consequence of 'asymmetric pollution' from two-stroke scooters, vehicles that constitute a small fraction of the fleet, but can dominate urban vehicular pollution through organic aerosol and aromatic emission factors up to thousands of times higher than from other vehicle classes. Further, we demonstrate that oxidation processes producing secondary organic aerosol from vehicle exhaust also form potentially toxic 'reactive oxygen species'. AU - Platt, S.M.* AU - Haddad, I.E.* AU - Pieber, S.M.* AU - Huang, R.J.* AU - Zardini, A.A.* AU - Clairotte, M.* AU - Suarez-Bertoa, R.* AU - Barmet, P.* AU - Pfaffenberger, L.* AU - Wolf, R.* AU - Slowik, J.G.* AU - Fuller, S.J.* AU - Kalberer, M.* AU - Chirico, R.* AU - Dommen, J.* AU - Astorga, C.* AU - Zimmermann, R. AU - Marchand, N.* AU - Hellebust, S.* AU - Temime-Roussel, B.* AU - Baltensperger, U.* AU - Prévôt, A.S.* C1 - 31286 C2 - 34303 CY - London TI - Two-stroke scooters are a dominant source of air pollution in many cities. JO - Nat. Commun. VL - 5 PB - Nature Publishing Group PY - 2014 SN - 2041-1723 ER - TY - JOUR AB - Efficient delivery of short interfering RNAs reflects a prerequisite for the development of RNA interference therapeutics. Here, we describe highly specific nanoparticles, based on near infrared fluorescent polymethine dye-derived targeting moieties coupled to biodegradable polymers. The fluorescent dye, even when coupled to a nanoparticle, mimics a ligand for hepatic parenchymal uptake transporters resulting in hepatobiliary clearance of approximately 95% of the dye within 45 min. Body distribution, hepatocyte uptake and excretion into bile of the dye itself, or dye-coupled nanoparticles can be tracked by intravital microscopy or even non-invasively by multispectral optoacoustic tomography. Efficacy of delivery is demonstrated in vivo using 3-hydroxy-3-methyl-glutaryl-CoA reductase siRNA as an active payload resulting in a reduction of plasma cholesterol levels if siRNA was formulated into dye-functionalised nanoparticles. This suggests that organ-selective uptake of a near infrared dye can be efficiently transferred to theranostic nanoparticles allowing novel possibilities for personalised silencing of disease-associated genes. AU - Press, A.T.* AU - Traeger, A.* AU - Pietsch, C.* AU - Mosig, A.* AU - Wagner, M.* AU - Clemens, M.G.* AU - Jbeily, N.* AU - Koch, N.* AU - Gottschaldt, M.* AU - Bézière, N. AU - Ermolayev, V. AU - Ntziachristos, V. AU - Popp, J.* AU - Kessels, M.M.* AU - Qualmann, B.* AU - Schubert, U.S.* AU - Bauer, M.* C1 - 42898 C2 - 35731 TI - Cell type-specific delivery of short interfering RNAs by dye-functionalised theranostic nanoparticles. JO - Nat. Commun. VL - 5 PY - 2014 SN - 2041-1723 ER - TY - JOUR AB - Dietary restriction (DR) increases healthspan and longevity in many species, including primates, but it is often accompanied by impaired reproductive function. Whether signals associated with the reproductive system contribute to or are required for DR effects on lifespan has not been established. Here we show that expression of the cytochrome P450 DAF-9/CYP450 and production of the steroid hormone Δ(7)-dafachronic acid (DA) are increased in C. elegans subjected to DR. DA signalling through the non-canonical nuclear hormone receptor NHR-8/NHR and the nutrient-responsive kinase let-363/mTOR is essential for DR-mediated longevity. Steroid signalling also affects germline plasticity in response to nutrient deprivation and this is required to achieve lifespan extension. These data demonstrate that steroid signalling links germline physiology to lifespan when nutrients are limited, and establish a central role for let-363/mTOR in integrating signals derived from nutrients and steroid hormones. AU - Thondamal, M.* AU - Witting, M. AU - Schmitt-Kopplin, P. AU - Aguilaniu, H.* C1 - 32500 C2 - 35079 CY - London TI - Steroid hormone signalling links reproduction to lifespan in dietary-restricted Caenorhabditis elegans. JO - Nat. Commun. VL - 5 PB - Nature Publishing Group PY - 2014 SN - 2041-1723 ER - TY - JOUR AB - Misfolded ER proteins are retrotranslocated into the cytosol for degradation via the ubiquitin-proteasome system. The human cytomegalovirus protein US11 exploits this ER-associated protein degradation (ERAD) pathway to downregulate HLA class I molecules in virus-infected cells, thereby evading elimination by cytotoxic T-lymphocytes. US11-mediated degradation of HLA class I has been instrumental in the identification of key components of mammalian ERAD, including Derlin-1, p97, VIMP and SEL1L. Despite this, the process governing retrotranslocation of the substrate is still poorly understood. Here using a high-coverage genome-wide shRNA library, we identify the uncharacterized protein TMEM129 and the ubiquitin-conjugating E2 enzyme UBE2J2 to be essential for US11-mediated HLA class I downregulation. TMEM129 is an unconventional C4C4-type RING finger E3 ubiquitin ligase that resides within a complex containing various other ERAD components, including Derlin-1, Derlin-2, VIMP and p97, indicating that TMEM129 is an integral part of the ER-resident dislocation complex mediating US11-induced HLA class I degradation. AU - van de Weijer, M.L.* AU - Bassik, M.C.* AU - Luteijn, R.D.* AU - Voorburg, C.M.* AU - Lohuis, M.A.* AU - Kremmer, E. AU - Hoeben, R.C.* AU - Leproust, E.M.* AU - Chen, S.* AU - Hoelen, H.* AU - Ressing, M.E.* AU - Patena, W.* AU - Weissman, J.S.* AU - McManus, M.T.* AU - Wiertz, E.J.* AU - Lebbink, R.J.* C1 - 31249 C2 - 34250 CY - London TI - A high-coverage shRNA screen identifies TMEM129 as an E3 ligase involved in ER-associated protein degradation. JO - Nat. Commun. VL - 5 PB - Nature Publishing Group PY - 2014 SN - 2041-1723 ER - TY - JOUR AB - The sequestration of carbon and nitrogen by clay-sized particles in soils is well established, and clay content or mineral surface area has been used to estimate the sequestration potential of soils. Here, via incubation of a sieved (<2 mm) topsoil with labelled litter, we find that only some of the clay-sized surfaces bind organic matter (OM). Surprisingly, <19% of the visible mineral areas show an OM attachment. OM is preferentially associated with organo-mineral clusters with rough surfaces. By combining nano-scale secondary ion mass spectrometry and isotopic tracing, we distinguish between new labelled and pre-existing OM and show that new OM is preferentially attached to already present organo-mineral clusters. These results, which provide evidence that only a limited proportion of the clay-sized surfaces contribute to OM sequestration, revolutionize our view of carbon sequestration in soils and the widely used carbon saturation estimates. AU - Vogel, C.* AU - Mueller, C.W.* AU - Höschen, C.* AU - Buegger, F. AU - Heister, K.* AU - Schulz, S. AU - Schloter, M. AU - Kögel-Knabner, I.* C1 - 28894 C2 - 33564 CY - London TI - Submicron structures provide preferential spots for carbon and nitrogen sequestration in soils. JO - Nat. Commun. VL - 5 PB - Nature Publishing Group PY - 2014 SN - 2041-1723 ER - TY - JOUR AB - The subfamily of the Lemnoideae belongs to a different order than other monocotyledonous species that have been sequenced and comprises aquatic plants that grow rapidly on the water surface. Here we select Spirodela polyrhiza for whole-genome sequencing. We show that Spirodela has a genome with no signs of recent retrotranspositions but signatures of two ancient whole-genome duplications, possibly 95 million years ago (mya), older than those in Arabidopsis and rice. Its genome has only 19,623 predicted protein-coding genes, which is 28% less than the dicotyledonous Arabidopsis thaliana and 50% less than monocotyledonous rice. We propose that at least in part, the neotenous reduction of these aquatic plants is based on readjusted copy numbers of promoters and repressors of the juvenile-to-adult transition. The Spirodela genome, along with its unique biology and physiology, will stimulate new insights into environmental adaptation, ecology, evolution and plant development, and will be instrumental for future bioenergy applications. AU - Wang, W.* AU - Haberer, G. AU - Gundlach, H. AU - Gläßer, C. AU - Nussbaumer, T. AU - Luo, M.C.* AU - Lomsadze, A.* AU - Borodovsky, M.* AU - Kerstetter, R.A.* AU - Shanklin, J.* AU - Byrant, D.W.* AU - Mockler, T.C.* AU - Appenroth, K.J.* AU - Grimwood, J.* AU - Jenkins, J.* AU - Chow, J.* AU - Choi, C.* AU - Adam, C.* AU - Cao, X.H.* AU - Fuchs, J.* AU - Schubert, I.* AU - Rokhsar, D.* AU - Schmutz, J.* AU - Michael, T.P.* AU - Mayer, K.F.X. AU - Messing, J.* C1 - 30603 C2 - 33744 CY - London TI - The Spirodela polyrhiza genome reveals insights into its neotenous reduction fast growth and aquatic lifestyle. JO - Nat. Commun. VL - 5 PB - Nature Publishing Group PY - 2014 SN - 2041-1723 ER - TY - JOUR AB - The non-essential cation caesium (Cs+) is assimilated by all organisms. Thus, anthropogenically released radiocaesium is of concern to agriculture. Cs+ accumulates owing to its chemical similarity to the potassium ion (K+). The apparent lack of a Cs+-specific uptake mechanism has obstructed attempts to manipulate Cs+ accumulation without causing pleiotropic effects. Here we show that the SNARE protein Sec22p/SEC22 specifically impacts Cs+ accumulation in yeast and in plants. Loss of Saccharomyces cerevisiae Sec22p does not affect K+ homeostasis, yet halves Cs+ concentration compared with the wild type. Mathematical modelling of the uptake time course predicts a compromised vacuolar Cs+ deposition in sec22Δ. Biochemical fractionation confirms this and indicates a new feature of Sec22p in enhancing non-selective cation deposition. A developmentally controlled loss-of-function mutant of the orthologous Arabidopsis thaliana SEC22 phenocopies the reduced Cs+ uptake without affecting plant growth. This finding provides a new strategy to reduce radiocaesium entry into the food chain. AU - Dräxl, S. AU - Müller, J. AU - Li, W.B. AU - Michalke, B. AU - Scherb, H. AU - Hense, B.A. AU - Tschiersch, J. AU - Kanter, U. AU - Schäffner, A. C1 - 25216 C2 - 31841 TI - Caesium accumulation in yeast and plants is selectively repressed by loss of the SNARE Sec22p/SEC22. JO - Nat. Commun. VL - 4 PB - Nature Publishing PY - 2013 SN - 2041-1723 ER - TY - JOUR AB - The G protein-coupled receptor 83 (Gpr83) is widely expressed in brain regions regulating energy metabolism. Here we report that hypothalamic expression of Gpr83 is regulated in response to nutrient availability and is decreased in obese mice compared with lean mice. In the arcuate nucleus, Gpr83 colocalizes with the ghrelin receptor (Ghsr1a) and the agouti-related protein. In vitro analyses show heterodimerization of Gpr83 with Ghsr1a diminishes activation of Ghsr1a by acyl-ghrelin. The orexigenic and adipogenic effect of ghrelin is accordingly potentiated in Gpr83-deficient mice. Interestingly, Gpr83 knock-out mice have normal body weight and glucose tolerance when fed a regular chow diet, but are protected from obesity and glucose intolerance when challenged with a high-fat diet, despite hyperphagia and increased hypothalamic expression of agouti-related protein, Npy, Hcrt and Ghsr1a. Together, our data suggest that Gpr83 modulates ghrelin action but also indicate that Gpr83 regulates systemic metabolism through other ghrelin-independent pathways. AU - Müller, T.D. AU - Müller, A.* AU - Yi, C.-X. AU - Habegger, K.M.* AU - Meyer, C.W. AU - Gaylinn, B.D.* AU - Finan, B. AU - Heppner, K.* AU - Trivedi, C.* AU - Bielohuby, M.* AU - Abplanalp, W.* AU - Meyer, F.* AU - Piechowski, C.L.* AU - Pratzka, J.* AU - Stemmer, K. AU - Holland, J.* AU - Hembree, J.* AU - Bhardwaj, N.* AU - Raver, C.* AU - Ottaway, N.* AU - Krishna, R.* AU - Sah, R.* AU - Sallee, F.R.* AU - Woods, S.C.* AU - Perez-Tilve, D.* AU - Bidlingmaier, M.* AU - Thorner, M.O.* AU - Krude, H.* AU - Smiley, D.* AU - DiMarchi, R.* AU - Hofmann, S. AU - Pfluger, P.T. AU - Kleinau, G.* AU - Biebermann, H.* AU - Tschöp, M.H. C1 - 24783 C2 - 31676 TI - The orphan receptor Gpr83 regulates systemic energy metabolism via ghrelin-dependent and ghrelin-independent mechanisms. JO - Nat. Commun. VL - 4 PB - Nature Publishing PY - 2013 SN - 2041-1723 ER - TY - JOUR AB - Endothermy has facilitated mammalian species radiation, but the sequence of events leading to sustained thermogenesis is debated in multiple evolutionary models. Here we study the Lesser hedgehog tenrec (Echinops telfairi), a phylogenetically ancient, 'protoendothermic' eutherian mammal, in which constantly high body temperatures are reported only during reproduction. Evidence for nonshivering thermogenesis is found in vivo during periodic ectothermic-endothermic transitions. Anatomical studies reveal large brown fat-like structures in the proximity of the reproductive organs, suggesting physiological significance for parental care. Biochemical analysis demonstrates high mitochondrial proton leak catalysed by an uncoupling protein 1 ortholog. Strikingly, bioenergetic profiling of tenrec uncoupling protein 1 reveals similar thermogenic potency as modern mouse uncoupling protein 1, despite the large phylogenetic distance. The discovery of functional brown adipose tissue in this 'protoendothermic' mammal links nonshivering thermogenesis directly to the roots of eutherian evolution, suggesting physiological importance prior to sustained body temperatures and migration to the cold. AU - Oelkrug, R.* AU - Goetze, N.* AU - Exner, C.* AU - Lee, Y.* AU - Ganjam, G.K.* AU - Kutschke, M. AU - Müller, S. AU - Stöhr, S.* AU - Tschöp, M.H. AU - Crichton, P.G.* AU - Heldmaier, G.* AU - Jastroch, M. AU - Meyer, C.W. C1 - 26188 C2 - 32113 TI - Brown fat in a protoendothermic mammal fuels eutherian evolution. JO - Nat. Commun. VL - 4 PB - Nature Publishing PY - 2013 SN - 2041-1723 ER - TY - JOUR AB - The mechanisms governing the expansion of neuron number in specific brain regions are still poorly understood. Enlarged neuron numbers in different species are often anticipated by increased numbers of progenitors dividing in the subventricular zone. Here we present live imaging analysis of radial glial cells and their progeny in the ventral telencephalon, the region with the largest subventricular zone in the murine brain during neurogenesis. We observe lineage amplification by a new type of progenitor, including bipolar radial glial cells dividing at subapical positions and generating further proliferating progeny. The frequency of this new type of progenitor is increased not only in larger clones of the mouse lateral ganglionic eminence but also in cerebral cortices of gyrated species, and upon inducing gyrification in the murine cerebral cortex. This implies key roles of this new type of radial glia in ontogeny and phylogeny. AU - Pilz, G.-A. AU - Shitamukai, A.* AU - Reillo, I.* AU - Pacary, E.* AU - Schwausch, J. AU - Stahl, R.* AU - Ninkovic, J. AU - Snippert, H.J.* AU - Clevers, H.* AU - Godinho, L. AU - Guillemot, F.* AU - Borrell, V.* AU - Matsuzaki, F.* AU - Götz, M. C1 - 25868 C2 - 31963 TI - Amplification of progenitors in the mammalian telencephalon includes a new radial glial cell type. JO - Nat. Commun. VL - 4 PB - Nature Publishing PY - 2013 SN - 2041-1723 ER - TY - JOUR AB - Emerging evidence suggests that new cells, including neurons, can be generated within the adult hypothalamus, suggesting the existence of a local neural stem/progenitor cell niche. Here, we identify α-tanycytes as key components of a hypothalamic niche in the adult mouse. Long-term lineage tracing in vivo using a GLAST::CreER(T2) conditional driver indicates that α-tanycytes are self-renewing cells that constitutively give rise to new tanycytes, astrocytes and sparse numbers of neurons. In vitro studies demonstrate that α-tanycytes, but not β-tanycytes or parenchymal cells, are neurospherogenic. Distinct subpopulations of α-tanycytes exist, amongst which only GFAP-positive dorsal α2-tanycytes possess stem-like neurospherogenic activity. Fgf-10 and Fgf-18 are expressed specifically within ventral tanycyte subpopulations; α-tanycytes require fibroblast growth factor signalling to maintain their proliferation ex vivo and elevated fibroblast growth factor levels lead to enhanced proliferation of α-tanycytes in vivo. Our results suggest that α-tanycytes form the critical component of a hypothalamic stem cell niche, and that local fibroblast growth factor signalling governs their proliferation. AU - Robins, S.C.* AU - Stewart, I.* AU - McNay, D.E.* AU - Taylor, V.* AU - Giachino, C.* AU - Götz, M. AU - Ninkovic, J. AU - Briancon, N.* AU - Maratos-Flier, E.* AU - Flier, J.S.* AU - Kokoeva, M.V.* AU - Placzek, M.* C1 - 28235 C2 - 33019 TI - α-Tanycytes of the adult hypothalamic third ventricle include distinct populations of FGF-responsive neural progenitors. JO - Nat. Commun. VL - 4 PB - Nature Publishing PY - 2013 SN - 2041-1723 ER - TY - JOUR AB - Haematopoietic stem cells (HSCs) are the founding cells of the adult haematopoietic system, born during ontogeny from a specialized subset of endothelium, the haemogenic endothelium (HE) via an endothelial-to-haematopoietic transition (EHT). Although recently imaged in real time, the underlying mechanism of EHT is still poorly understood. We have generated a Runx1 +23 enhancer-reporter transgenic mouse (23GFP) for the prospective isolation of HE throughout embryonic development. Here we perform functional analysis of over 1,800 and transcriptional analysis of 268 single 23GFP(+) HE cells to explore the onset of EHT at the single-cell level. We show that initiation of the haematopoietic programme occurs in cells still embedded in the endothelial layer, and is accompanied by a previously unrecognized early loss of endothelial potential before HSCs emerge. Our data therefore provide important insights on the timeline of early haematopoietic commitment. AU - Swiers, G.* AU - Baumann, C.* AU - O'Rourke, J.* AU - Giannoulatou, E.* AU - Taylor, S.* AU - Joshi, A.* AU - Moignard, V.* AU - Pina, C.* AU - Bee, T.* AU - Kokkaliaris, K.D. AU - Yoshimoto, M.* AU - Yoder, M.C.* AU - Frampton, J.* AU - Schroeder, T. AU - Enver, T.* AU - Göttgens, B.* AU - de Bruijn, M.F.* C1 - 28738 C2 - 33533 TI - Early dynamic fate changes in haemogenic endothelium characterized at the single-cell level. JO - Nat. Commun. VL - 4 PB - Nature Publishing PY - 2013 SN - 2041-1723 ER - TY - JOUR AB - Invasive and biomaterial-associated infections in humans are often difficult to diagnose and treat. Here, guided by recent advances in clinically relevant optical imaging technologies, we explore the use of fluorescently labelled vancomycin (vanco-800CW) to specifically target and detect infections caused by Gram-positive bacteria. The application potential of vanco-800CW for real-time in vivo imaging of bacterial infections is assessed in a mouse myositis model and a human post-mortem implant model. We show that vanco-800CW can specifically detect Gram-positive bacterial infections in our mouse myositis model, discriminate bacterial infections from sterile inflammation in vivo and detect biomaterial-associated infections in the lower leg of a human cadaver. We conclude that vanco-800CW has a high potential for enhanced non-invasive diagnosis of infections with Gram-positive bacteria and is a promising candidate for early-phase clinical trials. AU - van Oosten, M.* AU - Schäfer, T.* AU - Gazendam, J.A.* AU - Ohlsen, K.* AU - Tsompanidou, E.* AU - de Goffau, M.C.* AU - Harmsen, H.J.* AU - Crane, L.M.* AU - Lim, E.* AU - Francis, K.P.* AU - Cheung, L.* AU - Olive, M.* AU - Ntziachristos, V. AU - van Dijl, J.M.* AU - van Dam, G.M.* C1 - 28025 C2 - 32908 TI - Real-time in vivo imaging of invasive- and biomaterial-associated bacterial infections using fluorescently labelled vancomycin. JO - Nat. Commun. VL - 4 PB - Nature Publishing PY - 2013 SN - 2041-1723 ER - TY - JOUR AB - Adenosine diphosphate-ribosylation is a post-translational modification mediated by intracellular and membrane-associated extracellular enzymes and many bacterial toxins. The intracellular enzymes modify their substrates either by poly-ADP-ribosylation, exemplified by ARTD1/PARP1, or by mono-ADP-ribosylation. The latter has been discovered only recently, and little is known about its physiological relevance. The founding member of mono-AD-Pribosyltransferases is ARTD10/PARP10. It possesses two ubiquitin-interaction motifs, a unique feature among ARTD/PARP enzymes. Here, we find that the ARTD10 ubiquitin-interaction motifs bind to K63-linked poly-ubiquitin, a modification that is essential for NF-kappa B signalling. We therefore studied the role of ARTD10 in this pathway. ARTD10 inhibits the activation of NF-kB and downstream target genes in response to interleukin-1 beta and tumour necrosis factor-a, dependent on catalytic activity and poly-ubiquitin binding of ARTD10. Mechanistically ARTD10 interferes with poly-ubiquitination of NEMO, which interacts with and is a substrate of ARTD10. Our findings identify a novel regulator of NF-kB signalling and provide evidence for cross-talk between K63-linked poly-ubiquitination and mono-ADP-ribosylation. AU - Verheugd, P.* AU - Forst, A.H.* AU - Milke, L.* AU - Herzog, N.* AU - Feijs, K.L.H.* AU - Kremmer, E. AU - Kleine, H.* AU - Lüscher, B.* C1 - 25139 C2 - 31828 TI - Regulation of NF-κB signalling by the mono-ADP-ribosyltransferase ARTD10. JO - Nat. Commun. VL - 4 PB - Nature Publishing PY - 2013 SN - 2041-1723 ER - TY - JOUR AB - Current approaches to monitor and quantify cell division in live cells, and reliably distinguish between acytokinesis and endoreduplication, are limited and complicate determination of stem cell pool identities. Here we overcome these limitations by generating an in vivo reporter system using the scaffolding protein anillin fused to enhanced green fluorescent protein, to provide high spatiotemporal resolution of mitotic phase. This approach visualizes cytokinesis and midbody formation as hallmarks of expansion of stem and somatic cells, and enables distinction from cell cycle variations. High-resolution microscopy in embryonic heart and brain tissues of enhanced green fluorescent protein-anillin transgenic mice allows live monitoring of cell division and quantitation of cell cycle kinetics. Analysis of cell division in hearts post injury shows that border zone cardiomyocytes in the infarct respond with increasing ploidy, but not cell division. Thus, the enhanced green fluorescent protein-anillin system enables monitoring and measurement of cell division in vivo and markedly simplifies in vitro analysis in fixed cells. AU - Hesse, M.* AU - Raulf, A.* AU - Pilz, G.-A. AU - Haberlandt, C.* AU - Klein, A.M.* AU - Jabs, R.* AU - Zaehres, H.* AU - Fügemann, C.J.* AU - Zimmermann, K.* AU - Trebicka, J.* AU - Welz, A.* AU - Pfeifer, A.* AU - Röll, W.* AU - Kotlikoff, M.I.* AU - Steinhauser, C.* AU - Götz, M. AU - Schöler, H.R.* AU - Fleischmann, B.K.* C1 - 10578 C2 - 30301 TI - Direct visualization of cell division using high-resolution imaging of M-phase of the cell cycle. JO - Nat. Commun. VL - 3 PB - Nature Pub. Group PY - 2012 SN - 2041-1723 ER - TY - JOUR AB - Interleukin-17A, the prototypical member of the interleukin-17 cytokine family, coordinates local tissue inflammation by recruiting neutrophils to sites of infection. Dysregulation of interleukin-17 signalling has been linked to the pathogenesis of inflammatory diseases and autoimmunity. The interleukin-17 receptor family members (A-E) have a broad range of functional effects in immune signalling yet no known role has been described for the remaining orphan receptor, interleukin-17 receptor D, in regulating interleukin-17A-induced signalling pathways. Here we demonstrate that interleukin-17 receptor D can differentially regulate the various pathways employed by interleukin-17A. Neutrophil recruitment, in response to in vivo administration of interleukin-17A, is abolished in interleukin-17 receptor D-deficient mice, correlating with reduced interleukin-17A-induced activation of p38 mitogen-activated protein kinase and expression of the neutrophil chemokine MIP-2. In contrast, interleukin-17 receptor D deficiency results in enhanced interleukin-17A-induced activation of nuclear factor-kappa B and interleukin-6 and keratinocyte chemoattractant expression. Interleukin-17 receptor D disrupts the interaction of Act1 and TRAF6 causing differential regulation of nuclear factor-kappa B and p38 mitogen-activated protein kinase signalling pathways. AU - Mellett, M.* AU - Atzei, P.* AU - Horgan, A.* AU - Hams, E.* AU - Floß, T. AU - Wurst, W. AU - Fallon, P.G.* AU - Moynagh, P.N.* C1 - 11172 C2 - 30533 TI - Orphan receptor IL-17RD tunes IL-17A signalling and is required for neutrophilia. JO - Nat. Commun. VL - 3 PB - Nature Publishing Group PY - 2012 SN - 2041-1723 ER - TY - JOUR AB - High attrition rates of novel anti-cancer drugs highlight the need for improved models to predict toxicity. Although polo-like kinase 1 (Plk1) inhibitors are attractive candidates for drug development, the role of Plk1 in primary cells remains widely unexplored. Therefore, we evaluated the utility of an RNA interference-based model to assess responses to an inducible knockdown (iKD) of Plk1 in adult mice. Here we show that Plk1 silencing can be achieved in several organs, although adverse events are rare. We compared responses in Plk1-iKD mice with those in primary cells kept under controlled culture conditions. In contrast to the addiction of many cancer cell lines to the non-oncogene Plk1, the primary cells' proliferation, spindle assembly and apoptosis exhibit only a low dependency on Plk1. Responses to Plk1-depletion, both in cultured primary cells and in our iKD-mouse model, correspond well and thus provide the basis for using validated iKD mice in predicting responses to therapeutic interventions. AU - Raab, M.* AU - Kappel, S.* AU - Krämer, A.* AU - Sanhaji, M.* AU - Matthess, Y.* AU - Kurunci-Csacsko, E.* AU - Calzada-Wack, J. AU - Rathkolb, B. AU - Rozman, J. AU - Adler, T. AU - Busch, D.H.* AU - Esposito, I. AU - Fuchs, H. AU - Gailus-Durner, V. AU - Klingenspor, M.* AU - Wolf, E.* AU - Sänger, N.* AU - Prinz, F.* AU - Hrabě de Angelis, M. AU - Seibler, J.* AU - Yuan, J.* AU - Bergmann, M.* AU - Knecht, R.* AU - Kreft, B.* AU - Strebhardt, K.* C1 - 4212 C2 - 28794 TI - Toxicity modelling of Plk1-targeted therapies in genetically engineered mice and cultured primary mammalian cells. JO - Nat. Commun. VL - 2 IS - 1 PB - Nature Publ. Group PY - 2011 SN - 2041-1723 ER -