TY  - JOUR
AB  - Establishing a unified theory of cognition has been an important goal in psychology1,2. A first step towards such a theory is to create a computational model that can predict human behaviour in a wide range of settings. Here we introduce Centaur, a computational model that can predict and simulate human behaviour in any experiment expressible in natural language. We derived Centaur by fine-tuning a state-of-the-art language model on a large-scale dataset called Psych-101. Psych-101 has an unprecedented scale, covering trial-by-trial data from more than 60,000 participants performing in excess of 10,000,000 choices in 160 experiments. Centaur not only captures the behaviour of held-out participants better than existing cognitive models, but it also generalizes to previously unseen cover stories, structural task modifications and entirely new domains. Furthermore, the model's internal representations become more aligned with human neural activity after fine-tuning. Taken together, our results demonstrate that it is possible to discover computational models that capture human behaviour across a wide range of domains. We believe that such models provide tremendous potential for guiding the development of cognitive theories, and we present a case study to demonstrate this.
AU  - Binz, M.
AU  - Akata, E.
AU  - Bethge, M.*
AU  - Brändle, F.*
AU  - Callaway, F.*
AU  - Coda-Forno, J.
AU  - Dayan, P.*
AU  - Demircan, C.
AU  - Eckstein, M.K.*
AU  - Éltető, N.*
AU  - Griffiths, T.L.*
AU  - Haridi, S.
AU  - Jagadish, A.K.
AU  - Ji-An, L.*
AU  - Kipnis, A.
AU  - Kumar, S.*
AU  - Ludwig, T.*
AU  - Mathony. M.
AU  - Mattar, M.*
AU  - Modirshanechi, A.
AU  - Nath, S.S.*
AU  - Peterson, J.C.*
AU  - Rmus, M.
AU  - Russek, E.M.*
AU  - Saanum, T.
AU  - Schubert, J.A.*
AU  - Schulze Buschoff, L.M.
AU  - Singhi, N.*
AU  - Sui, X.*
AU  - Thalmann, M.
AU  - Theis, F.J.
AU  - Truong, V.*
AU  - Udandarao, V.*
AU  - Voudouris, K.
AU  - Wilson, R.*
AU  - Witte, K.
AU  - Wu, S.
AU  - Wulff, D.U.*
AU  - Xiong, H.*
AU  - Schulz, E.
C1  - 75065
C2  - 57755
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - A foundation model to predict and capture human cognition.
JO  - Nature
PB  - Nature Portfolio
PY  - 2025
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Iron catalyses the oxidation of lipids in biological membranes and promotes a form of cell death called ferroptosis1. Defining where this chemistry occurs in the cell can inform the design of drugs capable of inducing or inhibiting ferroptosis in various disease-relevant settings. Genetic approaches have revealed suppressors of ferroptosis2-4; by contrast, small molecules can provide spatiotemporal control of the chemistry at work5. Here we show that the ferroptosis inhibitor liproxstatin-1 exerts cytoprotective effects by inactivating iron in lysosomes. We also show that the ferroptosis inducer RSL3 initiates membrane lipid oxidation in lysosomes. We designed a small-molecule activator of lysosomal iron-fentomycin-1-to induce the oxidative degradation of phospholipids and ultimately ferroptosis. Fentomycin-1 is able to kill iron-rich CD44high primary sarcoma and pancreatic ductal adenocarcinoma cells, which can promote metastasis and fuel drug tolerance. In such cells, iron regulates cell adaptation6,7 while conferring vulnerability to ferroptosis8,9. Sarcoma cells exposed to sublethal doses of fentomycin-1 acquire a ferroptosis-resistant cell state characterized by the downregulation of mesenchymal markers and the activation of a membrane-damage response. This phospholipid degrader can eradicate drug-tolerant persister cancer cells in vitro and reduces intranodal tumour growth in a mouse model of breast cancer metastasis. Together, these results show that control of iron reactivity confers therapeutic benefits, establish lysosomal iron as a druggable target and highlight the value of targeting cell states10.
AU  - Cañeque, T.*
AU  - Baron, L.*
AU  - Müller, S.*
AU  - Carmona, A.*
AU  - Colombeau, L.*
AU  - Versini, A.*
AU  - Solier, S.*
AU  - Gaillet, C.*
AU  - Sindikubwabo, F.*
AU  - Sampaio, J.L.*
AU  - Sabatier, M.*
AU  - Mishima, E.
AU  - Picard-Bernes, A.*
AU  - Syx, L.*
AU  - Servant, N.*
AU  - Lombard, B.*
AU  - Loew, D.*
AU  - Zheng, J.
AU  - Proneth, B.
AU  - Thoidingjam, L.K.*
AU  - Grimaud, L.*
AU  - Fraser, C.S.*
AU  - Szylo, K.J.*
AU  - Der Kazarian, E.*
AU  - Bonnet, C.*
AU  - Charafe-Jauffret, E.*
AU  - Ginestier, C.*
AU  - Santofimia-Castaño, P.*
AU  - Estaras, M.*
AU  - Dusetti, N.*
AU  - Iovanna, J.L.*
AU  - Cunha, A.S.*
AU  - Pittau, G.*
AU  - Hammel, P.*
AU  - Tzanis, D.*
AU  - Bonvalot, S.*
AU  - Watson, S.*
AU  - Gandon, V.*
AU  - Upadhyay, A.*
AU  - Pratt, D.A.*
AU  - Freitas, F.P.*
AU  - Friedmann Angeli, J.P.*
AU  - Stockwell, B.R.*
AU  - Conrad, M.
AU  - Ubellacker, J.M.*
AU  - Rodriguez, R.*
C1  - 74333
C2  - 57478
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Activation of lysosomal iron triggers ferroptosis in cancer.
JO  - Nature
PB  - Nature Portfolio
PY  - 2025
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - T cell exhaustion limits effector T cell function in chronic infection and tumors1,2. The development of these hypofunctional T cells and of their precursors was considered to require stimulatory conditions met only upon persisting exposure to antigen and inflammation. In sharp contrast, we found similar T cell populations in the early phase of acute infections1,2. At that stage early developing TCF1+ precursor population shows an unexpected diversity, which includes precursors of normal memory T cells but also cells with a phenotype, gene-expression, and epigenetic profile that resembles precursors of exhausted T cells found in chronic infections. We demonstrate that high ligand affinity promotes, and PD-1 signaling restricts the development of these precursors. While these exhausted precursors are initially frequently found, they decline without being completely lost in infections the immune system resolves. We therefore concluded that precursor T cells with at least two distinct phenotypes are preemptively generated irrespectively of the outcome of the infection.
AU  - Chu, T.*
AU  - Wu, M.*
AU  - Höllbacher, B.
AU  - de Almeida, G.P.*
AU  - Wurmser, C.*
AU  - Berner, J.*
AU  - Donhauser, L.V.*
AU  - Ann-Katrin, G.*
AU  - Lin, S.*
AU  - Cepeda-Mayorga, J.D.*
AU  - Kilb, I.I.*
AU  - Bongers, L.*
AU  - Toppeta, F.*
AU  - Strobl, P.*
AU  - Youngblood, B.*
AU  - Schulz, A.M.*
AU  - Zippelius, A.*
AU  - Knolle, P.A.*
AU  - Heinig, M.
AU  - Hackstein, C.P.*
AU  - Zehn, D.*
C1  - 72994
C2  - 56881
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 782-792
TI  - Precursors of exhausted T cells are preemptively formed in acute infection.
JO  - Nature
VL  - 640
IS  - 8059
PB  - Nature Portfolio
PY  - 2025
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - The rapid advent of high-throughput omics technologies has created an exponential growth in biological data, often outpacing our ability to derive molecular insights. Large-language models have shown a way out of this data deluge in natural language processing by integrating massive datasets into a joint model with manifold downstream use cases. Here we envision developing multimodal foundation models, pretrained on diverse omics datasets, including genomics, transcriptomics, epigenomics, proteomics, metabolomics and spatial profiling. These models are expected to exhibit unprecedented potential for characterizing the molecular states of cells across a broad continuum, thereby facilitating the creation of holistic maps of cells, genes and tissues. Context-specific transfer learning of the foundation models can empower diverse applications from novel cell-type recognition, biomarker discovery and gene regulation inference, to in silico perturbations. This new paradigm could launch an era of artificial intelligence-empowered analyses, one that promises to unravel the intricate complexities of molecular cell biology, to support experimental design and, more broadly, to profoundly extend our understanding of life sciences.
AU  - Cui, H.*
AU  - Tejada Lapuerta, A.
AU  - Brbic, M.*
AU  - Saez-Rodriguez, J.*
AU  - Cristea, S.*
AU  - Goodarzi, H.*
AU  - Lotfollahi, M.*
AU  - Theis, F.J.
AU  - Wang, B.*
C1  - 74140
C2  - 57341
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 623-633
TI  - Towards multimodal foundation models in molecular cell biology.
JO  - Nature
VL  - 640
IS  - 8059
PB  - Nature Portfolio
PY  - 2025
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Wild plants can contribute valuable genes to their domesticated relatives1. Fertility barriers and a lack of genomic resources have hindered the effective use of crop-wild introgressions. Decades of research into barley's closest wild relative, Hordeum bulbosum, a grass native to the Mediterranean basin and Western Asia, have yet to manifest themselves in the release of a cultivar bearing alien genes2. Here we construct a pangenome of bulbous barley comprising 10 phased genome sequence assemblies amounting to 32 distinct haplotypes. Autotetraploid cytotypes, among which the donors of resistance-conferring introgressions are found, arose at least twice, and are connected among each other and to diploid forms through gene flow. The differential amplification of transposable elements after barley and H. bulbosum diverged from each other is responsible for genome size differences between them. We illustrate the translational value of our resource by mapping non-host resistance to a viral pathogen to a structurally diverse multigene cluster that has been implicated in diverse immune responses in wheat and barley.
AU  - Feng, J.W.*
AU  - Pidon, H.*
AU  - Cuacos, M.*
AU  - Lux, T.
AU  - Himmelbach, A.*
AU  - Haghi, R.*
AU  - Fuchs, J.*
AU  - Haberer, G.
AU  - Kuo, Y.T.*
AU  - Guo, Y.*
AU  - Jayakodi, M.*
AU  - Toegelová, H.*
AU  - Harpke, D.*
AU  - Knauft, M.*
AU  - Fiebig, A.*
AU  - Maruschewski, M.*
AU  - Ronen, M.*
AU  - Sharon, A.*
AU  - Šimková, H.*
AU  - Mayer, K.F.X.
AU  - Spannagl, M.
AU  - Kumlehn, J.*
AU  - Heckmann, S.*
AU  - Houben, A.*
AU  - Blattner, F.R.*
AU  - Stein, N.*
AU  - Mascher, M.*
C1  - 75117
C2  - 57757
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - A haplotype-resolved pangenome of the barley wild relative Hordeum bulbosum.
JO  - Nature
PB  - Nature Portfolio
PY  - 2025
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Osteoarthritis is the third most rapidly growing health condition associated with disability, after dementia and diabetes1. By 2050, the total number of patients with osteoarthritis is estimated to reach 1 billion worldwide2. As no disease-modifying treatments exist for osteoarthritis, a better understanding of disease aetiopathology is urgently needed. Here we perform a genome-wide association study meta-analyses across up to 489,975 cases and 1,472,094 controls, establishing 962 independent associations, 513 of which have not been previously reported. Using single-cell multiomics data, we identify signal enrichment in embryonic skeletal development pathways. We integrate orthogonal lines of evidence, including transcriptome, proteome and epigenome profiles of primary joint tissues, and implicate 700 effector genes. Within these, we find rare coding-variant burden associations with effect sizes that are consistently higher than common frequency variant associations. We highlight eight biological processes in which we find convergent involvement of multiple effector genes, including the circadian clock, glial-cell-related processes and pathways with an established role in osteoarthritis (TGFβ, FGF, WNT, BMP and retinoic acid signalling, and extracellular matrix organization). We find that 10% of the effector genes express a protein that is the target of approved drugs, offering repurposing opportunities, which can accelerate translation.
AU  - Hatzikotoulas, K.
AU  - Southam, L.
AU  - Stefansdottir, L.*
AU  - Boer, C.G.*
AU  - McDonald, M.L.*
AU  - Pett, J.P.*
AU  - Park, Y.-C.
AU  - Tuerlings, M.*
AU  - Mulders, R.*
AU  - Barysenka, A.
AU  - Arruda, A.L.
AU  - Tragante, V.*
AU  - Rocco, A.*
AU  - Bittner, N.
AU  - Chen, S.
AU  - Horn, S.
AU  - Srinivasasainagendra, V.*
AU  - To, K.*
AU  - Katsoula, G.
AU  - Kreitmaier, P.
AU  - Tenghe, A.M.M.*
AU  - Gilly, A.*
AU  - Arbeeva, L.*
AU  - Chen, L.G.*
AU  - de Pins, A.M.*
AU  - Dochtermann, D.*
AU  - Henkel, C.*
AU  - Höijer, J.*
AU  - Ito, S.*
AU  - Lind, P.A.*
AU  - Lukusa-Sawalena, B.*
AU  - Minn, A.K.K.*
AU  - Mola-Caminal, M.*
AU  - Narita, A.*
AU  - Nguyen, C.*
AU  - Reimann, E.*
AU  - Silberstein, M.D.*
AU  - Skogholt, A.H.*
AU  - Tiwari, H.K.*
AU  - Yau, M.S.*
AU  - Yue, M.*
AU  - Zhao, W.*
AU  - Zhou, J.J.*
AU  - Alexiadis, G.*
AU  - Banasik, K.*
AU  - Brunak, S.*
AU  - Campbell, A.*
AU  - Cheung, J.T.S.*
AU  - Dowsett, J.*
AU  - Faquih, T.O.*
AU  - Faul, J.D.*
AU  - Fei, L.*
AU  - Fenstad, A.M.*
AU  - Funayama, T.*
AU  - Gabrielsen, M.E.*
AU  - Gocho, C.*
AU  - Gromov, K.*
AU  - Hansen, T.*
AU  - Hudjashov, G.*
AU  - Ingvarsson, T.*
AU  - Johnson, J.S.*
AU  - Jonsson, H.*
AU  - Kakehi, S.*
AU  - Karjalainen, J.*
AU  - Kasbohm, E.*
AU  - Lemmelä, S.*
AU  - Lin, K.*
AU  - Liu, X.*
AU  - Loef, M.*
AU  - Mangino, M.*
AU  - McCartney, D.L.*
AU  - Millwood, I.Y.*
AU  - Richman, J.*
AU  - Roberts, M.B.*
AU  - Ryan, K.A.*
AU  - Samartzis, D.*
AU  - Shivakumar, M.*
AU  - Skou, S.T.*
AU  - Sugimoto, S.*
AU  - Suzuki, K.*
AU  - Takuwa, H.*
AU  - Teder-Laving, M.*
AU  - Thomas, L.*
AU  - Tomizuka, K.*
AU  - Turman, C.*
AU  - Weiss, S.*
AU  - Wu, T.T.*
AU  - Zengini, E.*
AU  - Zhang, Y.*
AU  - Ferreira, M.A.R.*
AU  - Babis, G.C.*
AU  - Baras, A.*
AU  - Barker, T.*
AU  - Carey, D.J.*
AU  - Cheah, K.S.E.*
AU  - Chen, Z.*
AU  - Cheung, J.P.Y.*
AU  - Daly, M.*
AU  - de Mutsert, R.*
AU  - Eaton, C.B.*
AU  - Erikstrup, C.*
AU  - Furnes, O.N.*
AU  - Golightly, Y.M.*
AU  - Gudbjartsson, D.F.*
AU  - Hailer, N.P.*
AU  - Hayward, C.*
AU  - Hochberg, M.C.*
AU  - Homuth, G.*
AU  - Huckins, L.M.*
AU  - Hveem, K.*
AU  - Ikegawa, S.*
AU  - Ishijima, M.*
AU  - Isomura, M.*
AU  - Jones, M.*
AU  - Kang, J.H.*
AU  - Kardia, S.L.R.*
AU  - Kloppenburg, M.*
AU  - Kraft, P.*
AU  - Kumahashi, N.*
AU  - Kuwata, S.*
AU  - Lee, M.T.M.*
AU  - Lee, P.H.*
AU  - Lerner, R.*
AU  - Li, L.*
AU  - Lietman, S.A.*
AU  - Lotta, L.A.*
AU  - Lupton, M.K.*
AU  - Mägi, R.*
AU  - Martin, N.G.*
AU  - McAlindon, T.E.*
AU  - Medland, S.E.*
AU  - Michaëlsson, K.*
AU  - Mitchell, B.D.*
AU  - Mook-Kanamori, D.O.*
AU  - Morris, A.P.
AU  - Nabika, T.*
AU  - Nagami, F.*
AU  - Nelson, A.E.*
AU  - Ostrowski, S.R.*
AU  - Palotie, A.*
AU  - Pedersen, O.B.*
AU  - Rosendaal, F.R.*
AU  - Sakurai-Yageta, M.*
AU  - Schmidt, C.O.*
AU  - Sham, P.C.*
AU  - Singh, J.A.*
AU  - Smelser, D.T.*
AU  - Smith, J.A.*
AU  - Song, Y.Q.*
AU  - Sørensen, E.*
AU  - Tamiya, G.*
AU  - Tamura, Y.*
AU  - Terao, C.*
AU  - Thorleifsson, G.*
AU  - Troelsen, A.*
AU  - Tsezou, A.*
AU  - Uchio, Y.*
AU  - Uitterlinden, A.G.*
AU  - Ullum, H.*
AU  - Valdes, A.M.*
AU  - van Heel, D.A.*
AU  - Walters, R.G.*
AU  - Weir, D.R.*
AU  - Wilkinson, J.M.*
AU  - Winsvold, B.S.*
AU  - Yamamoto, M.*
AU  - Zwart, J.A.*
AU  - Stefansson, K.*
AU  - Meulenbelt, I.*
AU  - Teichmann, S.A.*
AU  - van Meurs, J.B.J.*
AU  - Styrkarsdottir, U.*
AU  - Zeggini, E.
C1  - 74042
C2  - 57305
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 26
TI  - Translational genomics of osteoarthritis in 1,962,069 individuals.
JO  - Nature
PB  - Nature Portfolio
PY  - 2025
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Correction to: Naturehttps://doi.org/10.1038/s41586-024-08165-7 Published online 18 November 2024 In the version of the article initially published, in Fig. 2e and f the label “HCC” should have read “HHC” and has now been corrected. In Extended Data Fig. 5z, the label “CC” should have read “CC_s”. In Extended Data Fig. 10j the “HCH” label was illegible and has been amended. Additionally, the Source data for this figure has been corrected because one column reflected the data for HHC mice (displayed in Extended Data Fig. 5m) and not HCH mice. In Extended Data Fig. 10k the label “HHC” should have read “HCH”. In the “Epigenetic obesogenic memory in mice” section, in the sentence now reading “Many of these epigenetic changes were also reflected in the translatome (Fig. 3h) and nuclear transcriptome (Fig. 2g,h)”, the citation to Fig. 2g,h originally referred to Fig. 2f. In the “Metabolic memory primes adipocytes” section, a citation to Fig. 2f has been removed from the sentence, which now reads “Interestingly, these overlapped with promoters and enhancers carrying epigenetic memory (Figs. 3h and 5k,l)”. These errors, which do not affect the underlying data and interpretations of the article, have been corrected in the HTML and PDF versions of the article.
AU  - Hinte, L.C.*
AU  - Castellano-Castillo, D.*
AU  - Ghosh, A.*
AU  - Melrose, K.*
AU  - Gasser, E.*
AU  - Noé, F.*
AU  - Massier, L.
AU  - Dong, H.*
AU  - Sun, W.*
AU  - Hoffmann, A.
AU  - Wolfrum, C.*
AU  - Rydén, M.*
AU  - Mejhert, N.*
AU  - Blüher, M.
AU  - von Meyenn, F.*
C1  - 75091
C2  - 57752
TI  - Author Correction: Adipose tissue retains an epigenetic memory of obesity after weight loss.
JO  - Nature
PY  - 2025
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Impaired differentiation is a hallmark of myeloid malignancies1,2. Therapies that enable cells to circumvent the differentiation block, such as all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), are by and large curative in acute promyelocytic leukaemia3, but whether 'differentiation therapy' is a generalizable therapeutic approach for acute myeloid leukaemia (AML) and beyond remains incompletely understood. Here we demonstrate that simultaneous inhibition of the histone demethylase LSD1 (LSD1i) and the WNT pathway antagonist GSK3 kinase4 (GSK3i) robustly promotes therapeutic differentiation of established AML cell lines and primary human AML cells, as well as reducing tumour burden and significantly extending survival in a patient-derived xenograft mouse model. Mechanistically, this combination promotes differentiation by activating genes in the type I interferon pathway via inducing expression of transcription factors such as IRF7 (LSD1i) and the co-activator β-catenin (GSK3i), and their selective co-occupancy at targets such as STAT1, which is necessary for combination-induced differentiation. Combination treatment also suppresses the canonical, pro-oncogenic WNT pathway and cell cycle genes. Analysis of datasets from patients with AML suggests a correlation between the combination-induced transcription signature and better prognosis, highlighting clinical potential of this strategy. Collectively, this combination strategy rewires transcriptional programs to suppress stemness and to promote differentiation, which may have important therapeutic implications for AML and WNT-driven cancers beyond AML.
AU  - Hosseini, A.*
AU  - Dhall, A.*
AU  - Ikonen, N.*
AU  - Sikora, N.*
AU  - Nguyen, S.*
AU  - Shen, Y.*
AU  - Amaral, M.L.J.*
AU  - Jiao, A.L.*
AU  - Wallner, F.*
AU  - Sergeev, P.*
AU  - Lim, Y.H.*
AU  - Yang, Y.*
AU  - Vick, B.
AU  - Kawabata, K.C.*
AU  - Melnick, A.*
AU  - Vyas, P.*
AU  - Ren, B.*
AU  - Jeremias, I.
AU  - Psaila, B.*
AU  - Heckman, C.A.*
AU  - Blanco, M.A.*
AU  - Shi, Y.*
C1  - 74142
C2  - 57107
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 40
TI  - Perturbing LSD1 and WNT rewires transcription to synergistically induce AML differentiation.
JO  - Nature
PB  - Nature Portfolio
PY  - 2025
SN  - 0028-0836
ER  - 

TY  - JOUR
AU  - Kamal, N.
AU  - Spannagl, M.
C1  - 73694
C2  - 57179
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 44-45
TI  - Genus-wide plant pangenome could inform next-generation crop design.
JO  - Nature
VL  - 640
IS  - 8057
PB  - Nature Portfolio
PY  - 2025
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Antigenic variation is an immune evasion strategy used by many different pathogens. It involves the periodic, non-random switch in the expression of different antigens throughout an infection. How the observed hierarchy in antigen expression is achieved has remained a mystery1,2. A key challenge in uncovering this process has been the inability to track transcriptome changes and potential genomic rearrangements in individual cells during a switch event. Here we report the establishment of a highly sensitive single-cell RNA sequencing approach for the model protozoan parasite Trypanosoma brucei. This approach has revealed genomic rearrangements that occur in individual cells during a switch event. Our data show that following a double-strand break in the transcribed antigen-coding gene-an important trigger for antigen switching-the type of repair mechanism and the resultant antigen expression depend on the availability of a homologous repair template in the genome. When such a template was available, repair proceeded through segmental gene conversion, creating new, mosaic antigen-coding genes. Conversely, in the absence of a suitable template, a telomere-adjacent antigen-coding gene from a different part of the genome was activated by break-induced replication. Our results show the critical role of repair sequence availability in the antigen selection mechanism. Furthermore, our study demonstrates the power of highly sensitive single-cell RNA sequencing methods in detecting genomic rearrangements that drive transcriptional changes at the single-cell level.
AU  - Keneskhanova, Z.*
AU  - McWilliam, K.R.*
AU  - Cosentino, R.O.*
AU  - Barcons-Simon, A.*
AU  - Dobrynin, A.
AU  - Smith, J.E.*
AU  - Subota, I.*
AU  - Mugnier, M.R.*
AU  - Colomé-Tatché, M.
AU  - Siegel, T.N.*
C1  - 73671
C2  - 56977
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Genomic determinants of antigen expression hierarchy in African trypanosomes.
JO  - Nature
PB  - Nature Portfolio
PY  - 2025
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Single-cell genomic technologies enable the multimodal profiling of millions of cells across temporal and spatial dimensions. However, experimental limitations hinder the comprehensive measurement of cells under native temporal dynamics and in their native spatial tissue niche. Optimal transport has emerged as a powerful tool to address these constraints and has facilitated the recovery of the original cellular context1-4. Yet, most optimal transport applications are unable to incorporate multimodal information or scale to single-cell atlases. Here we introduce multi-omics single-cell optimal transport (moscot), a scalable framework for optimal transport in single-cell genomics that supports multimodality across all applications. We demonstrate the capability of moscot to efficiently reconstruct developmental trajectories of 1.7 million cells from mouse embryos across 20 time points. To illustrate the capability of moscot in space, we enrich spatial transcriptomic datasets by mapping multimodal information from single-cell profiles in a mouse liver sample and align multiple coronal sections of the mouse brain. We present moscot.spatiotemporal, an approach that leverages gene-expression data across both spatial and temporal dimensions to uncover the spatiotemporal dynamics of mouse embryogenesis. We also resolve endocrine-lineage relationships of delta and epsilon cells in a previously unpublished mouse, time-resolved pancreas development dataset using paired measurements of gene expression and chromatin accessibility. Our findings are confirmed through experimental validation of NEUROD2 as a regulator of epsilon progenitor cells in a model of human induced pluripotent stem cell islet cell differentiation. Moscot is available as open-source software, accompanied by extensive documentation.
AU  - Klein, D.
AU  - Palla, G.
AU  - Lange, M.
AU  - Klein, M.*
AU  - Piran, Z.*
AU  - Gander, M.
AU  - Meng-Papaxanthos, L.*
AU  - Sterr, M.
AU  - Saber, L.
AU  - Jing, C.
AU  - Bastidas-Ponce, A.
AU  - Cota, P.
AU  - Tarquis Medina, M.
AU  - Parikh, S.
AU  - Gold, I.
AU  - Lickert, H.
AU  - Bakhti, M.
AU  - Nitzan, M.*
AU  - Cuturi, M.C.*
AU  - Theis, F.J.
C1  - 73154
C2  - 56935
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 1065–1075
TI  - Mapping cells through time and space with moscot.
JO  - Nature
VL  - 638
PB  - Nature Portfolio
PY  - 2025
SN  - 0028-0836
ER  - 

TY  - JOUR
AU  - Klein, D.
AU  - Theis, F.J.
C1  - 73260
C2  - 56974
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Multimodal cell mapping with optimal transport.
JO  - Nature
PB  - Nature Portfolio
PY  - 2025
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Epidemiological data have identified Epstein-Barr virus (EBV) infection as the main environmental risk factor for multiple sclerosis, the predominant autoimmune disease of the central nervous system (CNS)1. However, how EBV infection initiates multiple sclerosis pathogenesis remains unclear. Here we demonstrate that EBV expands oligoclonal T-bet+CXCR3+ B cells that home to the CNS in humanized mice. Effector memory CD8+ T cells and CD4+ TH1 cells as well as CD4+ TH17 cells co-migrate to the brain of EBV-infected humanized mice. T-bet+CXCR3+ B cells can colonize submeningeal brain regions in the absence of other lymphocytes and attract T cells. Depletion of B cells with rituximab or blocking of CXCR3 significantly decreases lymphocyte infiltration into the CNS. Thus, we suggest that symptomatic primary EBV infection generates B cell subsets that gain access to the CNS, attract T cells and thereby initiate multiple sclerosis.
AU  - Läderach, F.*
AU  - Piteros, I.*
AU  - Fennell, E.*
AU  - Bremer, E.*
AU  - Last, M.
AU  - Schmid, S.*
AU  - Rieble, L.*
AU  - Campbell, C.D.*
AU  - Ludwig-Portugall, I.*
AU  - Bornemann, L.*
AU  - Gruhl, A.*
AU  - Eulitz, K.*
AU  - Gueguen, P.*
AU  - Mietz, J.*
AU  - Müller, A.*
AU  - Pezzino, G.*
AU  - Schmitz, J.*
AU  - Ferlazzo, G.*
AU  - Mautner, J.
AU  - Münz, C.*
C1  - 75319
C2  - 57933
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 171-179
TI  - EBV induces CNS homing of B cells attracting inflammatory T cells.
JO  - Nature
VL  - 646
IS  - 8083
PB  - Nature Portfolio
PY  - 2025
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Methyl-coenzyme M reductase (MCR) is the enzyme responsible for nearly all biologically generated methane1. Its active site comprises coenzyme F430, a porphyrin-based cofactor with a central nickel ion that is active exclusively in the Ni(I) state2,3. How methanogenic archaea perform the reductive activation of F430 represents a major gap in our understanding of one of the most ancient bioenergetic systems in nature. Here we purified and characterized the MCR activation complex from Methanococcus maripaludis. McrC, a small subunit encoded in the mcr operon, co-purifies with the methanogenic marker proteins Mmp7, Mmp17, Mmp3 and the A2 component. We demonstrated that this complex can activate MCR in vitro in a strictly ATP-dependent manner, enabling the formation of methane. In addition, we determined the cryo-electron microscopy structure of the MCR activation complex exhibiting different functional states with local resolutions reaching 1.8-2.1 Å. Our data revealed three complex iron-sulfur clusters that formed an electron transfer pathway towards F430. Topology and electron paramagnetic resonance spectroscopy analyses indicate that these clusters are similar to the [8Fe-9S-C] cluster, a maturation intermediate of the catalytic cofactor in nitrogenase. Altogether, our findings offer insights into the activation mechanism of MCR and prospects on the early evolution of nitrogenase.
AU  - Ramírez-Amador, F.*
AU  - Paul, S.*
AU  - Kumar, A.*
AU  - Lorent, C.*
AU  - Keller, S.*
AU  - Bohn, S.
AU  - Nguyen, T.*
AU  - Lometto, S.*
AU  - Vlegels, D.*
AU  - Kahnt, J.*
AU  - Deobald, D.*
AU  - Abendroth, F.*
AU  - Vázquez, O.*
AU  - Hochberg, G.K.A.*
AU  - Scheller, S.*
AU  - Stripp, S.T.*
AU  - Schuller, J.M.*
C1  - 74141
C2  - 57342
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Structure of the ATP-driven methyl-coenzyme M reductase activation complex.
JO  - Nature
PB  - Nature Portfolio
PY  - 2025
SN  - 0028-0836
ER  - 

TY  - JOUR
AU  - Southam, L.
AU  - Zeggini, E.
C1  - 74527
C2  - 57495
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 47-49
TI  - Twenty years of genome-wide association studies.
JO  - Nature
VL  - 641
IS  - 8061
PB  - Nature Portfolio
PY  - 2025
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Greenlandic Inuit and other indigenous populations are underrepresented in genetic research1,2, leading to inequity in healthcare opportunities. To address this, we performed analyses of sequenced or imputed genomes of 5,996 Greenlanders with extensive phenotypes. We quantified their historical population bottleneck and how it has shaped their genetic architecture to have fewer, but more common, variable sites. Consequently, we find twice as many high-impact genome-wide associations to metabolic traits in Greenland compared with Europe. We infer that the high-impact variants arose after the population split from Native Americans and thus are Arctic-specific, and show that some of them are common due to not only genetic drift but also selection. We also find that European-derived polygenic scores for metabolic traits are only half as accurate in Greenlanders as in Europeans, and that adding Arctic-specific variants improves the overall accuracy to the same level as in Europeans. Similarly, lack of representation in public genetic databases makes genetic clinical screening harder in Greenlandic Inuit, but inclusion of Greenlandic data remedies this by reducing the number of non-causal candidate variants by sixfold. Finally, we identify pronounced genetic fine structure that explains differences in prevalence of monogenic diseases in Greenland and, together with recent changes in mobility, leads to a predicted future reduction in risk for certain recessive diseases. These results illustrate how including data from Greenlanders can greatly reduce inequity in genomic-based healthcare.
AU  - Stæger, F.F.*
AU  - Andersen, M.K.*
AU  - Li, Z.*
AU  - Hjerresen, J.P.*
AU  - He, S.*
AU  - Santander, C.G.*
AU  - Jensen, R.T.*
AU  - Rex, K.F.*
AU  - Thuesen, A.C.B.*
AU  - Hanghøj, K.*
AU  - Seiding, I.H.*
AU  - Jørsboe, E.*
AU  - Stinson, S.E.*
AU  - Rasmussen, M.S.*
AU  - Balboa, R.F.*
AU  - Larsen, C.V.L.*
AU  - Bjerregaard, P.*
AU  - Schubert, M.*
AU  - Meisner, J.*
AU  - Linneberg, A.*
AU  - Grarup, N.*
AU  - Zeggini, E.
AU  - Nielsen, R.*
AU  - Jørgensen, M.E.*
AU  - Hansen, T.*
AU  - Moltke, I.*
AU  - Albrechtsen, A.*
C1  - 73381
C2  - 57032
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 404-410
TI  - Genetic architecture in Greenland is shaped by demography, structure and selection.
JO  - Nature
VL  - 639
IS  - 8054
PB  - Nature Portfolio
PY  - 2025
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Acute tubular necrosis mediates acute kidney injury (AKI) and nephron loss1, the hallmark of end-stage renal disease2-4. For decades, it has been known that female kidneys are less sensitive to AKI5,6. Acute tubular necrosis involves dynamic cell death propagation by ferroptosis along the tubular compartment7,8. Here we demonstrate abrogated ferroptotic cell death propagation in female kidney tubules. 17β-oestradiol establishes an anti-ferroptotic state through non-genomic and genomic mechanisms. These include the potent direct inhibition of ferroptosis by hydroxyoestradiol derivatives, which function as radical trapping antioxidants, are present at high concentrations in kidney tubules and, when exogenously applied, protect male mice from AKI. In cells, the oxidized hydroxyoestradiols are recycled by FSP19,10, but FSP1-deficient female mice were not sensitive to AKI. At the genomic level, female ESR1-deficient kidney tubules partially lose their anti-ferroptotic capacity, similar to ovariectomized mice. While ESR1 promotes the anti-ferroptotic hydropersulfide system, male tubules express pro-ferroptotic proteins of the ether lipid pathway which are suppressed by ESR1 in female tissues until menopause. In summary, we identified non-genomic and genomic mechanisms that collectively explain ferroptosis resistance in female tubules and may function as therapeutic targets for male and postmenopausal female individuals.
AU  - Tonnus, W.*
AU  - Maremonti, F.*
AU  - Gavali, S.*
AU  - Schlecht, M.N.*
AU  - Gembardt, F.*
AU  - Belavgeni, A.*
AU  - Leinung, N.*
AU  - Flade, K.*
AU  - Bethe, N.*
AU  - Traikov, S.*
AU  - Haag, A.*
AU  - Schilling, D.*
AU  - Penkov, S.P.*
AU  - Mallais, M.*
AU  - Gaillet, C.*
AU  - Meyer, C.*
AU  - Katebi, M.*
AU  - Ray, A.*
AU  - Gerhardt, L.M.S.*
AU  - Brucker, A.J.*
AU  - Becker, J.N.*
AU  - Tmava, M.*
AU  - Schlicker, L.*
AU  - Schulze, A.*
AU  - Himmerkus, N.*
AU  - Shevchenko, A.*
AU  - Peitzsch, M.*
AU  - Barayeu, U.*
AU  - Nasi, S.*
AU  - Putz, J.*
AU  - Korach, K.S.*
AU  - Neugarten, J.*
AU  - Golestaneh, L.*
AU  - Hugo, C.*
AU  - Becker, J.U.*
AU  - Weinberg, J.M.*
AU  - Lorenz, S.
AU  - Proneth, B.
AU  - Conrad, M.
AU  - Wolf, E.*
AU  - Plietker, B.*
AU  - Rodriguez, R.*
AU  - Pratt, D.A.*
AU  - Dick, T.P.*
AU  - Fedorova, M.*
AU  - Bornstein, S.R.
AU  - Linkermann, A.*
C1  - 75351
C2  - 57945
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 1011-1019
TI  - Multiple oestradiol functions inhibit ferroptosis and acute kidney injury.
JO  - Nature
VL  - 645
IS  - 8082
PB  - Nature Portfolio
PY  - 2025
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Correction to: Naturehttps://doi.org/10.1038/s41586-025-09389-x Published online 13 August 2025 In the version of this article initially published, due to a processing error, text from a reference title was inserted into the seventh sentence of the Discussion, which has now been amended to read “In conclusion, ferroptosis sensitivity explains the higher susceptibility of male individuals to AKI” in the HTML and PDF versions of the article.
AU  - Tonnus, W.*
AU  - Maremonti, F.*
AU  - Gavali, S.*
AU  - Schlecht, M.N.*
AU  - Gembardt, F.*
AU  - Belavgeni, A.*
AU  - Leinung, N.*
AU  - Flade, K.*
AU  - Bethe, N.*
AU  - Traikov, S.*
AU  - Haag, A.*
AU  - Schilling, D.*
AU  - Penkov, S.P.*
AU  - Mallais, M.*
AU  - Gaillet, C.*
AU  - Meyer, C.*
AU  - Katebi, M.*
AU  - Ray, A.*
AU  - Gerhardt, L.M.S.*
AU  - Brucker, A.J.*
AU  - Becker, J.N.*
AU  - Tmava, M.*
AU  - Schlicker, L.*
AU  - Schulze, A.*
AU  - Himmerkus, N.*
AU  - Shevchenko, A.*
AU  - Peitzsch, M.*
AU  - Barayeu, U.*
AU  - Nasi, S.*
AU  - Putz, J.*
AU  - Korach, K.S.*
AU  - Neugarten, J.*
AU  - Golestaneh, L.*
AU  - Hugo, C.*
AU  - Becker, J.U.*
AU  - Weinberg, J.M.*
AU  - Lorenz, S.
AU  - Proneth, B.
AU  - Conrad, M.
AU  - Wolf, E.*
AU  - Plietker, B.*
AU  - Rodriguez, R.*
AU  - Pratt, D.A.*
AU  - Dick, T.P.*
AU  - Fedorova, M.*
AU  - Bornstein, S.R.
AU  - Linkermann, A.*
C1  - 75407
C2  - 57959
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Publisher Correction: Multiple oestradiol functions inhibit ferroptosis and acute kidney injury.
JO  - Nature
VL  - 645
PB  - Nature Portfolio
PY  - 2025
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Herpes simplex virus 1 (HSV-1) and Influenza A viruses (IAV) induce Z-form nucleic acid Binding Protein 1 (ZBP1)-initiated cell death1-8. ZBP1 is activated by Z-RNA1,7,9, and the Z-RNAs which trigger ZBP1 during HSV-1 and IAV infections were assumed to be of viral origin1. However, we show here that host cell-encoded Z-RNAs are major and sufficient ZBP1 activating ligands following infection by these two human pathogens. The majority of cellular Z-RNAs mapped to intergenic endogenous retroelements (EREs) embedded within abnormally long 3' extensions of host cell mRNAs. These aberrant host cell transcripts arose as a consequence of Disruption of Transcription Termination (DoTT), a virus-driven phenomenon which disables Cleavage and Polyadenylation Specificity Factor (CPSF)-mediated 3' processing of nascent pre-mRNAs10-15. Mutant viruses lacking ICP27 or NS1, the virus-encoded proteins responsible for inhibiting CPSF and triggering DoTT13,15, failed to induce host cell Z-RNA accrual and were attenuated in their ability to stimulate ZBP1. Ectopic expression of HSV-1 ICP27 or IAV NS1, or pharmacological blockade of CPSF activity, induced accumulation of host cell Z-RNAs and activated ZBP1. These results demonstrate that DoTT-generated cellular Z-RNAs are bona fide ZBP1 ligands, and position ZBP1-activated cell death as a host response to counter viral disruption of the cellular transcriptional machinery.
AU  - Yin, C.*
AU  - Fedorov, A.*
AU  - Guo, H.*
AU  - Crawford, J.C.*
AU  - Rousseau, C.*
AU  - Zhong, X.*
AU  - Williams, R.M.*
AU  - Gautam, A.K.*
AU  - Koehler, H.S.*
AU  - Whisnant, A.W.*
AU  - Hennig, T.*
AU  - Rozina, A.*
AU  - Zhong, Y.*
AU  - Lv, S.*
AU  - Bergant, V.*
AU  - Wang, S.*
AU  - Dröge, P.*
AU  - Miller, S.*
AU  - Poptsova, M.*
AU  - Rehwinkel, J.*
AU  - Pichlmair, A.
AU  - Mocarski, E.S.*
AU  - Thomas, P.G.*
AU  - Dölken, L.*
AU  - Zhang, T.*
AU  - Herbert, A.*
AU  - Balachandran, S.*
C1  - 75777
C2  - 57988
TI  - Host cell Z-RNAs activate ZBP1 during virus infections.
JO  - Nature
PY  - 2025
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Neuromyelitis optica is a paradigmatic autoimmune disease of the central nervous system, in which the water-channel protein AQP4 is the target antigen1. The immunopathology in neuromyelitis optica is largely driven by autoantibodies to AQP42. However, the T cell response that is required for the generation of these anti-AQP4 antibodies is not well understood. Here we show that B cells endogenously express AQP4 in response to activation with anti-CD40 and IL-21 and are able to present their endogenous AQP4 to T cells with an AQP4-specific T cell receptor (TCR). A population of thymic B cells emulates a CD40-stimulated B cell transcriptome, including AQP4 (in mice and humans), and efficiently purges the thymic TCR repertoire of AQP4-reactive clones. Genetic ablation of Aqp4 in B cells rescues AQP4-specific TCRs despite sufficient expression of AQP4 in medullary thymic epithelial cells, and B-cell-conditional AQP4-deficient mice are fully competent to raise AQP4-specific antibodies in productive germinal-centre responses. Thus, the negative selection of AQP4-specific thymocytes is dependent on the expression and presentation of AQP4 by thymic B cells. As AQP4 is expressed in B cells in a CD40-dependent (but not AIRE-dependent) manner, we propose that thymic B cells might tolerize against a group of germinal-centre-associated antigens, including disease-relevant autoantigens such as AQP4.
AU  - Afzali, A.M.*
AU  - Nirschl, L.*
AU  - Sie, C.*
AU  - Pfaller, M.*
AU  - Ulianov, O.*
AU  - Hassler, T.*
AU  - Federle, C.*
AU  - Petrozziello, E.*
AU  - Kalluri, S.R.*
AU  - Chen, H.H.*
AU  - Tyystjärvi, S.*
AU  - Muschaweckh, A.*
AU  - Lammens, K.*
AU  - Delbridge, C.*
AU  - Büttner, A.*
AU  - Steiger, K.*
AU  - Seyhan, G.*
AU  - Ottersen, O.P.*
AU  - Öllinger, R.*
AU  - Rad, R.*
AU  - Jarosch, S.*
AU  - Straub, A.*
AU  - Mühlbauer, A.*
AU  - Grassmann, S.*
AU  - Hemmer, B.*
AU  - Böttcher, J.P.*
AU  - Wagner, I.*
AU  - Kreutzfeldt, M.*
AU  - Merkler, D.*
AU  - Bonafonte Pardás, I.
AU  - Schmidt Supprian, M.*
AU  - Buchholz, V.R.*
AU  - Heink, S.*
AU  - Busch, D.H.*
AU  - Klein, L.*
AU  - Korn, T.*
C1  - 70047
C2  - 55381
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 407-415
TI  - B cells orchestrate tolerance to the neuromyelitis optica autoantigen AQP4.
JO  - Nature
VL  - 627
IS  - 8003
PB  - Nature Portfolio
PY  - 2024
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Plants exposed to incidences of excessive temperatures activate heat-stress responses to cope with the physiological challenge and stimulate long-term acclimation1,2. The mechanism that senses cellular temperature for inducing thermotolerance is still unclear3. Here we show that TWA1 is a temperature-sensing transcriptional co-regulator that is needed for basal and acquired thermotolerance in Arabidopsis thaliana. At elevated temperatures, TWA1 changes its conformation and allows physical interaction with JASMONATE-ASSOCIATED MYC-LIKE (JAM) transcription factors and TOPLESS (TPL) and TOPLESS-RELATED (TPR) proteins for repressor complex assembly. TWA1 is a predicted intrinsically disordered protein that has a key thermosensory role functioning through an amino-terminal highly variable region. At elevated temperatures, TWA1 accumulates in nuclear subdomains, and physical interactions with JAM2 and TPL appear to be restricted to these nuclear subdomains. The transcriptional upregulation of the heat shock transcription factor A2 (HSFA2) and heat shock proteins depended on TWA1, and TWA1 orthologues provided different temperature thresholds, consistent with the sensor function in early signalling of heat stress. The identification of the plant thermosensors offers a molecular tool for adjusting thermal acclimation responses of crops by breeding and biotechnology, and a sensitive temperature switch for thermogenetics.
AU  - Bohn, L.*
AU  - Huang, J.*
AU  - Weidig, S.*
AU  - Yang, Z.*
AU  - Heidersberger, C.*
AU  - Genty, B.*
AU  - Falter-Braun, P.
AU  - Christmann, A.*
AU  - Grill, E.*
C1  - 70689
C2  - 55710
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 1126-1132
TI  - The temperature sensor TWA1 is required for thermotolerance in Arabidopsis.
JO  - Nature
VL  - 629
IS  - 8014
PB  - Nature Portfolio
PY  - 2024
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Chronic hepatitis B virus (HBV) infection affects 300 million patients worldwide1,2, in whom virus-specific CD8 T cells by still ill-defined mechanisms lose their function and cannot eliminate HBV-infected hepatocytes3-7. Here we demonstrate that a liver immune rheostat renders virus-specific CD8 T cells refractory to activation and leads to their loss of effector functions. In preclinical models of persistent infection with hepatotropic viruses such as HBV, dysfunctional virus-specific CXCR6+ CD8 T cells accumulated in the liver and, as a characteristic hallmark, showed enhanced transcriptional activity of cAMP-responsive element modulator (CREM) distinct from T cell exhaustion. In patients with chronic hepatitis B, circulating and intrahepatic HBV-specific CXCR6+ CD8 T cells with enhanced CREM expression and transcriptional activity were detected at a frequency of 12-22% of HBV-specific CD8 T cells. Knocking out the inhibitory CREM/ICER isoform in T cells, however, failed to rescue T cell immunity. This indicates that CREM activity was a consequence, rather than the cause, of loss in T cell function, further supported by the observation of enhanced phosphorylation of protein kinase A (PKA) which is upstream of CREM. Indeed, we found that enhanced cAMP-PKA-signalling from increased T cell adenylyl cyclase activity augmented CREM activity and curbed T cell activation and effector function in persistent hepatic infection. Mechanistically, CD8 T cells recognizing their antigen on hepatocytes established close and extensive contact with liver sinusoidal endothelial cells, thereby enhancing adenylyl cyclase-cAMP-PKA signalling in T cells. In these hepatic CD8 T cells, which recognize their antigen on hepatocytes, phosphorylation of key signalling kinases of the T cell receptor signalling pathway was impaired, which rendered them refractory to activation. Thus, close contact with liver sinusoidal endothelial cells curbs the activation and effector function of HBV-specific CD8 T cells that target hepatocytes expressing viral antigens by means of the adenylyl cyclase-cAMP-PKA axis in an immune rheostat-like fashion.
AU  - Bosch, M.*
AU  - Kallin, N.*
AU  - Donakonda, S.*
AU  - Zhang, J.D.*
AU  - Wintersteller, H.*
AU  - Hegenbarth, S.*
AU  - Heim, K.*
AU  - Ramirez, C.*
AU  - Fürst, A.*
AU  - Lattouf, E.I.*
AU  - Feuerherd, M.*
AU  - Chattopadhyay, S.*
AU  - Kumpesa, N.*
AU  - Griesser, V.*
AU  - Hoflack, J.C.*
AU  - Siebourg-Polster, J.*
AU  - Mogler, C.*
AU  - Swadling, L.*
AU  - Pallett, L.J.*
AU  - Meiser, P.*
AU  - Manske, K.*
AU  - de Almeida, G.P.*
AU  - Kosinska, A.
AU  - Sandu, I.*
AU  - Schneider, A.*
AU  - Steinbacher, V.*
AU  - Teng, Y.*
AU  - Schnabel, J.A.
AU  - Theis, F.*
AU  - Gehring, A.J.*
AU  - Boonstra, A.*
AU  - Janssen, H.L.A.*
AU  - Vandenbosch, M.*
AU  - Cuypers, E.*
AU  - Öllinger, R.*
AU  - Engleitner, T.*
AU  - Rad, R.*
AU  - Steiger, K.*
AU  - Oxenius, A.*
AU  - Lo, W.L.*
AU  - Klepsch, V.*
AU  - Baier, G.*
AU  - Holzmann, B.*
AU  - Maini, M.K.*
AU  - Heeren, R.*
AU  - Murray, P.J.*
AU  - Thimme, R.*
AU  - Herrmann, C.*
AU  - Protzer, U.
AU  - Böttcher, J.P.*
AU  - Zehn, D.*
AU  - Wohlleber, D.*
AU  - Lauer, G.M.*
AU  - Hofmann, M.*
AU  - Luangsay, S.*
AU  - Knolle, P.A.*
C1  - 71095
C2  - 55914
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 867–875 
TI  - A liver immune rheostat regulates CD8 T cell immunity in chronic HBV infection.
JO  - Nature
VL  - 631
IS  - 8022
PB  - Nature Portfolio
PY  - 2024
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Correction to: Nature Published online 15 November 2023 In the version of the article initially published, the surname of Thomas Volz appeared incorrectly as Voltz. This has now been corrected in the HTML and PDF versions of the article.
AU  - Correa-Gallegos, D.
AU  - Ye, H.
AU  - Dasgupta, B.
AU  - Sardogan, A.
AU  - Kadri, S.
AU  - Kandi, R.
AU  - Dai, R.
AU  - Lin, Y.
AU  - Kopplin, R.
AU  - Shantaram Shenai, D.
AU  - Wannemacher, J.
AU  - Ichijo, R.
AU  - Jiang, D.
AU  - Strunz, M.
AU  - Ansari, M.
AU  - Angelidis, I.
AU  - Schiller, H. B.
AU  - Volz, T.*
AU  - Machens, H.G.*
AU  - Rinkevich, Y.
C1  - 68941
C2  - 53892
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Author Correction: CD201+ fascia progenitors choreograph injury repair.
JO  - Nature
VL  - 625
PB  - Nature Portfolio
PY  - 2024
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Ferroptosis is a form of cell death that has received considerable attention not only as a means to eradicate defined tumour entities but also because it provides unforeseen insights into the metabolic adaptation that tumours exploit to counteract phospholipid oxidation1,2. Here, we identify proferroptotic activity of 7-dehydrocholesterol reductase (DHCR7) and an unexpected prosurvival function of its substrate, 7-dehydrocholesterol (7-DHC). Although previous studies suggested that high concentrations of 7-DHC are cytotoxic to developing neurons by favouring lipid peroxidation3, we now show that 7-DHC accumulation confers a robust prosurvival function in cancer cells. Because of its far superior reactivity towards peroxyl radicals, 7-DHC effectively shields (phospho)lipids from autoxidation and subsequent fragmentation. We provide validation in neuroblastoma and Burkitt's lymphoma xenografts where we demonstrate that the accumulation of 7-DHC is capable of inducing a shift towards a ferroptosis-resistant state in these tumours ultimately resulting in a more aggressive phenotype. Conclusively, our findings provide compelling evidence of a yet-unrecognized antiferroptotic activity of 7-DHC as a cell-intrinsic mechanism that could be exploited by cancer cells to escape ferroptosis.
AU  - Freitas, F.P.*
AU  - Alborzinia, H.*
AU  - Dos Santos, A.F.*
AU  - Nepachalovich, P.*
AU  - Pedrera, L.*
AU  - Zilka, O.*
AU  - Inague, A.*
AU  - Klein, C.*
AU  - Aroua, N.*
AU  - Kaushal, K.*
AU  - Kast, B.*
AU  - Lorenz, S.
AU  - Kunz, V.*
AU  - Nehring, H.*
AU  - Xavier da Silva, T.N.*
AU  - Chen, Z.*
AU  - Atici, S.*
AU  - Doll, S.
AU  - Schaefer, E.L.*
AU  - Ekpo, I.*
AU  - Schmitz, W.*
AU  - Horling, A.*
AU  - Imming, P.*
AU  - Miyamoto, S.*
AU  - Wehman, A.M.*
AU  - Genaro-Mattos, T.C.*
AU  - Mirnics, K.*
AU  - Kumar, L.*
AU  - Klein-Seetharaman, J.*
AU  - Meierjohann, S.*
AU  - Weigand, I.*
AU  - Kroiss, M.*
AU  - Bornkamm, G.W.*
AU  - Gomes, F.*
AU  - Netto, L.E.S.*
AU  - Sathian, M.B.*
AU  - Konrad, D.B.*
AU  - Covey, D.F.*
AU  - Michalke, B.
AU  - Bommert, K.*
AU  - Bargou, R.C.*
AU  - García-Sáez, A.J.*
AU  - Pratt, D.A.*
AU  - Fedorova, M.*
AU  - Trumpp, A.*
AU  - Conrad, M.
AU  - Friedmann Angeli, J.P.*
C1  - 69896
C2  - 55313
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 401-410
TI  - 7-Dehydrocholesterol is an endogenous suppressor of ferroptosis.
JO  - Nature
VL  - 626
IS  - 7998
PB  - Nature Portfolio
PY  - 2024
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Platelet homeostasis is essential for vascular integrity and immune defence1,2. Although the process of platelet formation by fragmenting megakaryocytes (MKs; thrombopoiesis) has been extensively studied, the cellular and molecular mechanisms required to constantly replenish the pool of MKs by their progenitor cells (megakaryopoiesis) remains unclear3,4. Here we use intravital imaging to track the cellular dynamics of megakaryopoiesis over days. We identify plasmacytoid dendritic cells (pDCs) as homeostatic sensors that monitor the bone marrow for apoptotic MKs and deliver IFNα to the MK niche triggering local on-demand proliferation and maturation of MK progenitors. This pDC-dependent feedback loop is crucial for MK and platelet homeostasis at steady state and under stress. pDCs are best known for their ability to function as vigilant detectors of viral infection5. We show that virus-induced activation of pDCs interferes with their function as homeostatic sensors of megakaryopoiesis. Consequently, activation of pDCs by SARS-CoV-2 leads to excessive megakaryopoiesis. Together, we identify a pDC-dependent homeostatic circuit that involves innate immune sensing and demand-adapted release of inflammatory mediators to maintain homeostasis of the megakaryocytic lineage.
AU  - Gaertner, F.*
AU  - Ishikawa-Ankerhold, H.*
AU  - Stutte, S.*
AU  - Fu, W.*
AU  - Weitz, J.*
AU  - Dueck, A.*
AU  - Nelakuditi, B.
AU  - Fumagalli, V.*
AU  - van den Heuvel, D.*
AU  - Belz, L.*
AU  - Sobirova, G.*
AU  - Zhang, Z.*
AU  - Titova, A.*
AU  - Navarro, A.M.*
AU  - Pekayvaz, K.*
AU  - Lorenz, M.*
AU  - von Baumgarten, L.*
AU  - Kranich, J.*
AU  - Straub, T.*
AU  - Popper, B.*
AU  - Zheden, V.*
AU  - Kaufmann, W.A.*
AU  - Guo, C.*
AU  - Piontek, G.*
AU  - von Stillfried, S.*
AU  - Boor, P.*
AU  - Colonna, M.*
AU  - Clauß, S.*
AU  - Schulz, C.*
AU  - Brocker, T.*
AU  - Walzog, B.*
AU  - Scheiermann, C.*
AU  - Aird, W.C.*
AU  - Nerlov, C.*
AU  - Stark, K.*
AU  - Petzold, T.*
AU  - Engelhardt, S.*
AU  - Sixt, M.*
AU  - Hauschild, R.*
AU  - Rudelius, M.*
AU  - Oostendorp, R.A.J.*
AU  - Iannacone, M.*
AU  - Heinig, M.
AU  - Massberg, S.*
C1  - 71094
C2  - 55929
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 645-653
TI  - Plasmacytoid dendritic cells control homeostasis of megakaryopoiesis.
JO  - Nature
VL  - 631
IS  - 8021
PB  - Nature Portfolio
PY  - 2024
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Human neural organoids, generated from pluripotent stem cells in vitro, are useful tools to study human brain development, evolution and disease. However, it is unclear which parts of the human brain are covered by existing protocols, and it has been difficult to quantitatively assess organoid variation and fidelity. Here we integrate 36 single-cell transcriptomic datasets spanning 26 protocols into one integrated human neural organoid cell atlas totalling more than 1.7 million cells1-26. Mapping to developing human brain references27-30 shows primary cell types and states that have been generated in vitro, and estimates transcriptomic similarity between primary and organoid counterparts across protocols. We provide a programmatic interface to browse the atlas and query new datasets, and showcase the power of the atlas to annotate organoid cell types and evaluate new organoid protocols. Finally, we show that the atlas can be used as a diverse control cohort to annotate and compare organoid models of neural disease, identifying genes and pathways that may underlie pathological mechanisms with the neural models. The human neural organoid cell atlas will be useful to assess organoid fidelity, characterize perturbed and diseased states and facilitate protocol development.
AU  - He, Z.*
AU  - Dony, L.
AU  - Fleck, J.S.*
AU  - Szałata, A.
AU  - Li, K.
AU  - Slišković, I.
AU  - Lin, H.C.*
AU  - Santel, M.*
AU  - Atamian, A.*
AU  - Quadrato, G.*
AU  - Sun, J.*
AU  - Pașca, S.P.*
AU  - Camp, J.G.*
AU  - Theis, F.J.
AU  - Treutlein, B.*
C1  - 72465
C2  - 56586
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 690-698
TI  - An integrated transcriptomic cell atlas of human neural organoids.
JO  - Nature
VL  - 635
IS  - 8039
PB  - Nature Portfolio
PY  - 2024
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Correction to: Naturehttps://doi.org/10.1038/s41586-024-08172-8 Published online 20 November 2024 In the version of the article initially published, Artur Szałata, Katelyn X. Li and Irena Slišković were mistakenly listed as having equally contributed along with Zhisong He, Leander Dony and Jonas Simon Fleck. This has now been amended in the HTML and PDF versions of the article.
AU  - He, Z.*
AU  - Dony, L.
AU  - Fleck, J.S.*
AU  - Szałata, A.
AU  - Li, K.
AU  - Slišković, I.
AU  - Lin, H.C.*
AU  - Santel, M.*
AU  - Atamian, A.*
AU  - Quadrato, G.*
AU  - Sun, J.*
AU  - Pașca, S.P.*
AU  - Camp, J.G.*
AU  - Theis, F.J.
AU  - Treutlein, B.*
C1  - 72739
C2  - 56723
TI  - Publisher Correction: An integrated transcriptomic cell atlas of human neural organoids.
JO  - Nature
PY  - 2024
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Our genomes influence nearly every aspect of human biology-from molecular and cellular functions to phenotypes in health and disease. Studying the differences in DNA sequence between individuals (genomic variation) could reveal previously unknown mechanisms of human biology, uncover the basis of genetic predispositions to diseases, and guide the development of new diagnostic tools and therapeutic agents. Yet, understanding how genomic variation alters genome function to influence phenotype has proved challenging. To unlock these insights, we need a systematic and comprehensive catalogue of genome function and the molecular and cellular effects of genomic variants. Towards this goal, the Impact of Genomic Variation on Function (IGVF) Consortium will combine approaches in single-cell mapping, genomic perturbations and predictive modelling to investigate the relationships among genomic variation, genome function and phenotypes. IGVF will create maps across hundreds of cell types and states describing how coding variants alter protein activity, how noncoding variants change the regulation of gene expression, and how such effects connect through gene-regulatory and protein-interaction networks. These experimental data, computational predictions and accompanying standards and pipelines will be integrated into an open resource that will catalyse community efforts to explore how our genomes influence biology and disease across populations.
AU  - IGVF Affiliate Member Projects (Heinig, M.)
C1  - 72980
C2  - 56756
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 47-57
TI  - Deciphering the impact of genomic variation on function.
JO  - Nature
VL  - 633
IS  - 8028
PB  - Nature Portfolio
PY  - 2024
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Reducing body weight to improve metabolic health and related comorbidities is a primary goal in treating obesity1,2. However, maintaining weight loss is a considerable challenge, especially as the body seems to retain an obesogenic memory that defends against body weight changes3,4. Overcoming this barrier for long-term treatment success is difficult because the molecular mechanisms underpinning this phenomenon remain largely unknown. Here, by using single-nucleus RNA sequencing, we show that both human and mouse adipose tissues retain cellular transcriptional changes after appreciable weight loss. Furthermore, we find persistent obesity-induced alterations in the epigenome of mouse adipocytes that negatively affect their function and response to metabolic stimuli. Mice carrying this obesogenic memory show accelerated rebound weight gain, and the epigenetic memory can explain future transcriptional deregulation in adipocytes in response to further high-fat diet feeding. In summary, our findings indicate the existence of an obesogenic memory, largely on the basis of stable epigenetic changes, in mouse adipocytes and probably other cell types. These changes seem to prime cells for pathological responses in an obesogenic environment, contributing to the problematic 'yo-yo' effect often seen with dieting. Targeting these changes in the future could improve long-term weight management and health outcomes.
AU  - Hinte, L.C.*
AU  - Castellano-Castillo, D.*
AU  - Ghosh, A.*
AU  - Melrose, K.*
AU  - Gasser, E.*
AU  - Noé, F.*
AU  - Massier, L.
AU  - Dong, H.*
AU  - Sun, W.*
AU  - Hoffmann, A.
AU  - Wolfrum, C.*
AU  - Rydén, M.*
AU  - Mejhert, N.*
AU  - Blüher, M.
AU  - von Meyenn, F.*
C1  - 72420
C2  - 56583
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 457-465
TI  - Adipose tissue retains an epigenetic memory of obesity after weight loss.
JO  - Nature
VL  - 636
IS  - 8042
PB  - Nature Portfolio
PY  - 2024
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Pangenomes are collections of annotated genome sequences of multiple individuals of a species1. The structural variants uncovered by these datasets are a major asset to genetic analysis in crop plants2. Here we report a pangenome of barley comprising long-read sequence assemblies of 76 wild and domesticated genomes and short-read sequence data of 1,315 genotypes. An expanded catalogue of sequence variation in the crop includes structurally complex loci that are rich in gene copy number variation. To demonstrate the utility of the pangenome, we focus on four loci involved in disease resistance, plant architecture, nutrient release and trichome development. Novel allelic variation at a powdery mildew resistance locus and population-specific copy number gains in a regulator of vegetative branching were found. Expansion of a family of starch-cleaving enzymes in elite malting barleys was linked to shifts in enzymatic activity in micro-malting trials. Deletion of an enhancer motif is likely to change the developmental trajectory of the hairy appendages on barley grains. Our findings indicate that allelic diversity at structurally complex loci may have helped crop plants to adapt to new selective regimes in agricultural ecosystems.
AU  - Jayakodi, M.*
AU  - Lu, Q.*
AU  - Pidon, H.*
AU  - Rabanus-Wallace, M.T.*
AU  - Bayer, M.*
AU  - Lux, T.
AU  - Guo, Y.*
AU  - Jaegle, B.*
AU  - Badea, A.*
AU  - Bekele, W.A.*
AU  - Brar, G.S.*
AU  - Braune, K.*
AU  - Bunk, B.*
AU  - Chalmers, K.J.*
AU  - Chapman, B.*
AU  - Jørgensen, M.E.*
AU  - Feng, J.W.*
AU  - Feser, M.*
AU  - Fiebig, A.*
AU  - Gundlach, H.
AU  - Guo, W.*
AU  - Haberer, G.
AU  - Hansson, M.*
AU  - Himmelbach, A.*
AU  - Hoffie, I.*
AU  - Hoffie, R.E.*
AU  - Hu, H.*
AU  - Isobe, S.*
AU  - König, P.*
AU  - Kale, S.M.*
AU  - Kamal, N.
AU  - Keeble-Gagnère, G.*
AU  - Keller, B.*
AU  - Knauft, M.*
AU  - Koppolu, R.*
AU  - Krattinger, S.G.*
AU  - Kumlehn, J.*
AU  - Langridge, P.*
AU  - Li, C.*
AU  - Marone, M.P.*
AU  - Maurer, A.*
AU  - Mayer, K.F.X.
AU  - Melzer, M.*
AU  - Muehlbauer, G.J.*
AU  - Murozuka, E.*
AU  - Padmarasu, S.*
AU  - Perovic, D.*
AU  - Pillen, K.*
AU  - Pin, P.A.*
AU  - Pozniak, C.J.*
AU  - Ramsay, L.*
AU  - Pedas, P.R.*
AU  - Rutten, T.*
AU  - Sakuma, S.*
AU  - Sato, K.*
AU  - Schuler, D.*
AU  - Schmutzer, T.*
AU  - Scholz, U.*
AU  - Schreiber, M.*
AU  - Shirasawa, K.*
AU  - Simpson, C.*
AU  - Skadhauge, B.*
AU  - Spannagl, M.
AU  - Steffenson, B.J.*
AU  - Thomsen, H.C.*
AU  - Tibbits, J.F.*
AU  - Nielsen, M.T.S.*
AU  - Trautewig, C.*
AU  - Vequaud, D.*
AU  - Voss, C.*
AU  - Wang, P.*
AU  - Waugh, R.*
AU  - Westcott, S.*
AU  - Rasmussen, M.W.*
AU  - Zhang, R.*
AU  - Zhang, X.Q.*
AU  - Wicker, T.*
AU  - Dockter, C.*
AU  - Mascher, M.*
AU  - Stein, N.*
C1  - 72332
C2  - 56578
TI  - Structural variation in the pangenome of wild and domesticated barley.
JO  - Nature
PY  - 2024
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism1-7. This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases8-11. Here we present a genome-wide association study for 233 circulating metabolic traits quantified by nuclear magnetic resonance spectroscopy in up to 136,016 participants from 33 cohorts. We identify more than 400 independent loci and assign probable causal genes at two-thirds of these using manual curation of plausible biological candidates. We highlight the importance of sample and participant characteristics that can have significant effects on genetic associations. We use detailed metabolic profiling of lipoprotein- and lipid-associated variants to better characterize how known lipid loci and novel loci affect lipoprotein metabolism at a granular level. We demonstrate the translational utility of comprehensively phenotyped molecular data, characterizing the metabolic associations of intrahepatic cholestasis of pregnancy. Finally, we observe substantial genetic pleiotropy for multiple metabolic pathways and illustrate the importance of careful instrument selection in Mendelian randomization analysis, revealing a putative causal relationship between acetone and hypertension. Our publicly available results provide a foundational resource for the community to examine the role of metabolism across diverse diseases.
AU  - Karjalainen, M.K.*
AU  - Karthikeyan, S.*
AU  - Oliver-Williams, C.*
AU  - Sliz, E.*
AU  - Allara, E.*
AU  - Fung, W.T.*
AU  - Surendran, P.*
AU  - Zhang, W.*
AU  - Jousilahti, P.*
AU  - Kristiansson, K.*
AU  - Salomaa, V.*
AU  - Goodwin, M.*
AU  - Hughes, D.A.*
AU  - Boehnke, M.*
AU  - Fernandes Silva, L.*
AU  - Yin, X.*
AU  - Mahajan, A.*
AU  - Neville, M.J.*
AU  - van Zuydam, N.R.*
AU  - de Mutsert, R.*
AU  - Li-Gao, R.*
AU  - Mook-Kanamori, D.O.*
AU  - Demirkan, A.*
AU  - Liu, J.*
AU  - Noordam, R.*
AU  - Trompet, S.*
AU  - Chen, Z.*
AU  - Kartsonaki, C.*
AU  - Li, L.*
AU  - Lin, K.*
AU  - Hagenbeek, F.A.*
AU  - Hottenga, J.J.*
AU  - Pool, R.*
AU  - Ikram, M.A.*
AU  - van Meurs, J.*
AU  - Haller, T.*
AU  - Milaneschi, Y.*
AU  - Kähönen, M.*
AU  - Mishra, P.P.*
AU  - Joshi, P.K.*
AU  - Macdonald-Dunlop, E.*
AU  - Mangino, M.*
AU  - Zierer, J.*
AU  - Acar, I.E.*
AU  - Hoyng, C.B.*
AU  - Lechanteur, Y.T.E.*
AU  - Franke, L.*
AU  - Kurilshikov, A.*
AU  - Zhernakova, A.*
AU  - Beekman, M.*
AU  - van den Akker, E.B.*
AU  - Kolcic, I.*
AU  - Polasek, O.*
AU  - Rudan, I.*
AU  - Gieger, C.
AU  - Waldenberger, M.
AU  - Asselbergs, F.W.*
AU  - Hayward, C.*
AU  - Fu, J.*
AU  - den Hollander, A.I.*
AU  - Menni, C.*
AU  - Spector, T.D.*
AU  - Wilson, J.F.*
AU  - Lehtimäki, T.*
AU  - Raitakari, O.T.*
AU  - Penninx, B.W.J.H.*
AU  - Esko, T.*
AU  - Walters, R.G.*
AU  - Jukema, J.W.*
AU  - Sattar, N.*
AU  - Ghanbari, M.*
AU  - Willems van Dijk, K.*
AU  - Karpe, F.*
AU  - McCarthy, M.I.*
AU  - Laakso, M.*
AU  - Järvelin, M.R.*
AU  - Timpson, N.J.*
AU  - Perola, M.*
AU  - Kooner, J.S.*
AU  - Chambers, J.C.*
AU  - van Duijn, C.M.*
AU  - Slagboom, P.E.*
AU  - Boomsma, D.I.*
AU  - Danesh, J.*
AU  - Ala-Korpela, M.*
AU  - Butterworth, A.S.*
AU  - Kettunen, J.*
C1  - 70178
C2  - 55231
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 130-138
TI  - Genome-wide characterization of circulating metabolic biomarkers.
JO  - Nature
VL  - 628
IS  - 8006
PB  - Nature Portfolio
PY  - 2024
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Cancer-specific TCF1+ stem-like CD8+ T cells can drive protective anticancer immunity through expansion and effector cell differentiation1-4; however, this response is dysfunctional in tumours. Current cancer immunotherapies2,5-9 can promote anticancer responses through TCF1+ stem-like CD8+ T cells in some but not all patients. This variation points towards currently ill-defined mechanisms that limit TCF1+CD8+ T cell-mediated anticancer immunity. Here we demonstrate that tumour-derived prostaglandin E2 (PGE2) restricts the proliferative expansion and effector differentiation of TCF1+CD8+ T cells within tumours, which promotes cancer immune escape. PGE2 does not affect the priming of TCF1+CD8+ T cells in draining lymph nodes. PGE2 acts through EP2 and EP4 (EP2/EP4) receptor signalling in CD8+ T cells to limit the intratumoural generation of early and late effector T cell populations that originate from TCF1+ tumour-infiltrating CD8+ T lymphocytes (TILs). Ablation of EP2/EP4 signalling in cancer-specific CD8+ T cells rescues their expansion and effector differentiation within tumours and leads to tumour elimination in multiple mouse cancer models. Mechanistically, suppression of the interleukin-2 (IL-2) signalling pathway underlies the PGE2-mediated inhibition of TCF1+ TIL responses. Altogether, we uncover a key mechanism that restricts the IL-2 responsiveness of TCF1+ TILs and prevents anticancer T cell responses that originate from these cells. This study identifies the PGE2-EP2/EP4 axis as a molecular target to restore IL-2 responsiveness in anticancer TILs to achieve cancer immune control.
AU  - Lacher, S.B.*
AU  - Dörr, J.*
AU  - de Almeida, G.P.*
AU  - Hönninger, J.*
AU  - Bayerl, F.*
AU  - Hirschberger, A.*
AU  - Pedde, A.M.*
AU  - Meiser, P.*
AU  - Ramsauer, L.*
AU  - Rudolph, T.J.*
AU  - Spranger, N.*
AU  - Morotti, M.*
AU  - Grimm, A.J.*
AU  - Jarosch, S.*
AU  - Oner, A.*
AU  - Gregor, L.*
AU  - Lesch, S.*
AU  - Michaelides, S.*
AU  - Fertig, L.*
AU  - Briukhovetska, D.*
AU  - Majed, L.*
AU  - Stock, S.*
AU  - Kobold, S.
AU  - Böttcher, J.P.*
C1  - 70564
C2  - 55690
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 417-425
TI  - PGE2 limits effector expansion of tumour-infiltrating stem-like CD8+ T cells.
JO  - Nature
VL  - 629
IS  - 8011
PB  - Nature Portfolio
PY  - 2024
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Dissolved organic matter (DOM) is one of the most complex, dynamic and abundant sources of organic carbon, but its chemical reactivity remains uncertain1-3. Greater insights into DOM structural features could facilitate understanding its synthesis, turnover and processing in the global carbon cycle4,5. Here we use complementary multiplicity-edited 13C nuclear magnetic resonance (NMR) spectra to quantify key substructures assembling the carbon skeletons of DOM from four main Amazon rivers and two mid-size Swedish boreal lakes. We find that one type of reaction mechanism, oxidative dearomatization (ODA), widely used in organic synthetic chemistry to create natural product scaffolds6-10, is probably a key driver for generating structural diversity during processing of DOM that are rich in suitable polyphenolic precursor molecules. Our data suggest a high abundance of tetrahedral quaternary carbons bound to one oxygen and three carbon atoms (OCqC3 units). These units are rare in common biomolecules but could be readily produced by ODA of lignin-derived and tannin-derived polyphenols. Tautomerization of (poly)phenols by ODA creates non-planar cyclohexadienones, which are subject to immediate and parallel cycloadditions. This combination leads to a proliferation of structural diversity of DOM compounds from early stages of DOM processing, with an increase in oxygenated aliphatic structures. Overall, we propose that ODA is a key reaction mechanism for complexity acceleration in the processing of DOM molecules, creation of new oxygenated aliphatic molecules and that it could be prevalent in nature.
AU  - Li, S.
AU  - Harir, M.
AU  - Bastviken, D.*
AU  - Schmitt-Kopplin, P.
AU  - Gonsior, M.*
AU  - Enrich-Prast, A.*
AU  - Valle Das Neves, J.
AU  - Hertkorn, N.
C1  - 70565
C2  - 55691
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 776-781
TI  - Dearomatization drives complexity generation in freshwater organic matter.
JO  - Nature
VL  - 628
IS  - 8009
PB  - Nature Portfolio
PY  - 2024
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - DNA and histone modifications combine into characteristic patterns that demarcate functional regions of the genome1,2. While many 'readers' of individual modifications have been described3-5, how chromatin states comprising composite modification signatures, histone variants and internucleosomal linker DNA are interpreted is a major open question. Here we use a multidimensional proteomics strategy to systematically examine the interaction of around 2,000 nuclear proteins with over 80 modified dinucleosomes representing promoter, enhancer and heterochromatin states. By deconvoluting complex nucleosome-binding profiles into networks of co-regulated proteins and distinct nucleosomal features driving protein recruitment or exclusion, we show comprehensively how chromatin states are decoded by chromatin readers. We find highly distinctive binding responses to different features, many factors that recognize multiple features, and that nucleosomal modifications and linker DNA operate largely independently in regulating protein binding to chromatin. Our online resource, the Modification Atlas of Regulation by Chromatin States (MARCS), provides in-depth analysis tools to engage with our results and advance the discovery of fundamental principles of genome regulation by chromatin states.
AU  - Lukauskas, S.
AU  - Tvardovskiy, A.
AU  - Nguyen, N.V.*
AU  - Stadler, M.
AU  - Faull, P.*
AU  - Ravnsborg, T.*
AU  - Özdemir Aygenli, B.
AU  - Dornauer, S.
AU  - Flynn, H.*
AU  - Lindeboom, R.G.H.*
AU  - Barth, T.K.
AU  - Brockers, K.
AU  - Hauck, S.M.
AU  - Vermeulen, M.*
AU  - Snijders, A.P.*
AU  - Müller, C.L.
AU  - DiMaggio, P.A.*
AU  - Jensen, O.N.*
AU  - Schneider, R.
AU  - Bartke, T.
C1  - 70179
C2  - 55444
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 671-679
TI  - Decoding chromatin states by proteomic profiling of nucleosome readers.
JO  - Nature
VL  - 627
IS  - 8004
PB  - Nature Portfolio
PY  - 2024
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Correction to: Naturehttps://doi.org/10.1038/s41586-024-07141-5 Published online 6 March 2024 In the version of the article initially published, the first column of data points for RNF2 and EZH2 on the left-hand side of Fig. 1e were mistakenly shifted to the far right. In Fig. 4d, “6” was missing from the x axis and in Fig. 5e the left “+” was missing from the “H4ac” row. These errors have now been corrected in the HTML and PDF versions of the article.
AU  - Lukauskas, S.
AU  - Tvardovskiy, A.
AU  - Nguyen, N.V.*
AU  - Stadler, M.
AU  - Faull, P.*
AU  - Ravnsborg, T.*
AU  - Özdemir Aygenli, B.
AU  - Dornauer, S.
AU  - Flynn, H.*
AU  - Lindeboom, R.G.H.*
AU  - Barth, T.K.
AU  - Brockers, K.
AU  - Hauck, S.M.
AU  - Vermeulen, M.*
AU  - Snijders, A.P.*
AU  - Müller, C.L.
AU  - DiMaggio, P.A.*
AU  - Jensen, O.N.*
AU  - Schneider, R.
AU  - Bartke, T.
C1  - 70504
C2  - 55642
TI  - Publisher Correction: Decoding chromatin states by proteomic profiling of nucleosome readers.
JO  - Nature
VL  - 628
IS  - 8009
PY  - 2024
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Expansion of antigen-experienced CD8+ T cells is critical for the success of tumour-infiltrating lymphocyte (TIL)-adoptive cell therapy (ACT) in patients with cancer1. Interleukin-2 (IL-2) acts as a key regulator of CD8+ cytotoxic T lymphocyte functions by promoting expansion and cytotoxic capability2,3. Therefore, it is essential to comprehend mechanistic barriers to IL-2 sensing in the tumour microenvironment to implement strategies to reinvigorate IL-2 responsiveness and T cell antitumour responses. Here we report that prostaglandin E2 (PGE2), a known negative regulator of immune response in the tumour microenvironment4,5, is present at high concentrations in tumour tissue from patients and leads to impaired IL-2 sensing in human CD8+ TILs via the PGE2 receptors EP2 and EP4. Mechanistically, PGE2 inhibits IL-2 sensing in TILs by downregulating the IL-2Rγc chain, resulting in defective assembly of IL-2Rβ-IL2Rγc membrane dimers. This results in impaired IL-2-mTOR adaptation and PGC1α transcriptional repression, causing oxidative stress and ferroptotic cell death in tumour-reactive TILs. Inhibition of PGE2 signalling to EP2 and EP4 during TIL expansion for ACT resulted in increased IL-2 sensing, leading to enhanced proliferation of tumour-reactive TILs and enhanced tumour control once the cells were transferred in vivo. Our study reveals fundamental features that underlie impairment of human TILs mediated by PGE2 in the tumour microenvironment. These findings have therapeutic implications for cancer immunotherapy and cell therapy, and enable the development of targeted strategies to enhance IL-2 sensing and amplify the IL-2 response in TILs, thereby promoting the expansion of effector T cells with enhanced therapeutic potential.
AU  - Morotti, M.*
AU  - Grimm, A.J.*
AU  - Hope, H.C.*
AU  - Arnaud, M.*
AU  - Desbuisson, M.*
AU  - Rayroux, N.*
AU  - Barras, D.*
AU  - Masid, M.*
AU  - Murgues, B.*
AU  - Chap, B.S.*
AU  - Ongaro, M.*
AU  - Rota, I.A.*
AU  - Ronet, C.*
AU  - Minasyan, A.*
AU  - Chiffelle, J.*
AU  - Lacher, S.B.*
AU  - Bobisse, S.*
AU  - Murgues, C.*
AU  - Ghisoni, E.*
AU  - Ouchen, K.*
AU  - Bou Mjahed, R.*
AU  - Benedetti, F.*
AU  - Abdellaoui, N.*
AU  - Turrini, R.*
AU  - Gannon, P.O.*
AU  - Zaman, K.S.*
AU  - Mathevet, P.*
AU  - Lelievre, L.*
AU  - Crespo, I.*
AU  - Conrad, M.
AU  - Verdeil, G.*
AU  - Kandalaft, L.E.*
AU  - Dagher, J.*
AU  - Corria-Osorio, J.*
AU  - Doucey, M.A.*
AU  - Ho, P.C.*
AU  - Harari, A.*
AU  - Vannini, N.*
AU  - Böttcher, J.P.*
AU  - Dangaj Laniti, D.*
AU  - Coukos, G.*
C1  - 70563
C2  - 55689
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 426-434
TI  - PGE2 inhibits TIL expansion by disrupting IL-2 signalling and mitochondrial function.
JO  - Nature
VL  - 629
IS  - 8011
PB  - Nature Portfolio
PY  - 2024
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - The N-methyl-D-aspartate (NMDA) receptor is a glutamate-activated cation channel that is critical to many processes in the brain. Genome-wide association studies suggest that glutamatergic neurotransmission and NMDA receptor-mediated synaptic plasticity are important for body weight homeostasis1. Here we report the engineering and preclinical development of a bimodal molecule that integrates NMDA receptor antagonism with glucagon-like peptide-1 (GLP-1) receptor agonism to effectively reverse obesity, hyperglycaemia and dyslipidaemia in rodent models of metabolic disease. GLP-1-directed delivery of the NMDA receptor antagonist MK-801 affects neuroplasticity in the hypothalamus and brainstem. Importantly, targeting of MK-801 to GLP-1 receptor-expressing brain regions circumvents adverse physiological and behavioural effects associated with MK-801 monotherapy. In summary, our approach demonstrates the feasibility of using peptide-mediated targeting to achieve cell-specific ionotropic receptor modulation and highlights the therapeutic potential of unimolecular mixed GLP-1 receptor agonism and NMDA receptor antagonism for safe and effective obesity treatment.
AU  - Petersen, J.*
AU  - Ludwig, M.Q.*
AU  - Juozaityte, V.*
AU  - Ranea-Robles, P.*
AU  - Svendsen, C.*
AU  - Hwang, E.*
AU  - Kristensen, A.W.*
AU  - Fadahunsi, N.*
AU  - Lund, J.*
AU  - Breum, A.W.*
AU  - Mathiesen, C.V.*
AU  - Sachs, L.*
AU  - Moreno-Justicia, R.*
AU  - Rohlfs, R.*
AU  - Ford, J.C.*
AU  - Douros, J.D.*
AU  - Finan, B.*
AU  - Portillo, B.*
AU  - Grose, K.*
AU  - Petersen, J.E.*
AU  - Trauelsen, M.*
AU  - Feuchtinger, A.
AU  - DiMarchi, R.D.*
AU  - Schwartz, T.W.*
AU  - Deshmukh, A.S.*
AU  - Thomsen, M.B.*
AU  - Kohlmeier, K.A.*
AU  - Williams, K.W.*
AU  - Pers, T.H.*
AU  - Frølund, B.*
AU  - Strømgaard, K.*
AU  - Klein, A.B.*
AU  - Clemmensen, C.*
C1  - 70688
C2  - 55709
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 1133-1141
TI  - GLP-1-directed NMDA receptor antagonism for obesity treatment.
JO  - Nature
VL  - 629
IS  - 8014
PB  - Nature Portfolio
PY  - 2024
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Fractals are patterns that are self-similar across multiple length-scales1. Macroscopic fractals are common in nature2-4; however, so far, molecular assembly into fractals is restricted to synthetic systems5-12. Here we report the discovery of a natural protein, citrate synthase from the cyanobacterium Synechococcus elongatus, which self-assembles into Sierpiński triangles. Using cryo-electron microscopy, we reveal how the fractal assembles from a hexameric building block. Although different stimuli modulate the formation of fractal complexes and these complexes can regulate the enzymatic activity of citrate synthase in vitro, the fractal may not serve a physiological function in vivo. We use ancestral sequence reconstruction to retrace how the citrate synthase fractal evolved from non-fractal precursors, and the results suggest it may have emerged as a harmless evolutionary accident. Our findings expand the space of possible protein complexes and demonstrate that intricate and regulatable assemblies can evolve in a single substitution.
AU  - Sendker, F.L.*
AU  - Lo, Y.K.*
AU  - Heimerl, T.*
AU  - Bohn, S.
AU  - Persson, L.J.*
AU  - Mais, C.N.*
AU  - Sadowska, W.*
AU  - Paczia, N.*
AU  - Nußbaum, E.*
AU  - Del Carmen Sánchez Olmos, M.*
AU  - Forchhammer, K.*
AU  - Schindler, D.*
AU  - Erb, T.J.*
AU  - Benesch, J.L.P.*
AU  - Marklund, E.G.*
AU  - Bange, G.*
AU  - Schuller, J.M.*
AU  - Hochberg, G.K.A.*
C1  - 70501
C2  - 55640
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 894-900
TI  - Emergence of fractal geometries in the evolution of a metabolic enzyme.
JO  - Nature
VL  - 628
IS  - 8009
PB  - Nature Portfolio
PY  - 2024
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.
AU  - Suzuki, K.*
AU  - Hatzikotoulas, K.
AU  - Southam, L.
AU  - Taylor, H.J.*
AU  - Yin, X.*
AU  - Lorenz, K.M.*
AU  - Mandla, R.*
AU  - Huerta-Chagoya, A.*
AU  - Melloni, G.E.M.*
AU  - Kanoni, S.*
AU  - Rayner, N.W.
AU  - Bocher, O.
AU  - Arruda, A.L.
AU  - Sonehara, K.*
AU  - Namba, S.*
AU  - Lee, S.S.K.*
AU  - Preuss, M.H.*
AU  - Petty, L.E.*
AU  - Schroeder, P.*
AU  - Vanderwerff, B.R.*
AU  - Kals, M.*
AU  - Bragg, F.*
AU  - Lin, K.*
AU  - Guo, X.*
AU  - Zhang, W.*
AU  - Yao, J.*
AU  - Kim, Y.J.*
AU  - Graff, M.*
AU  - Takeuchi, F.*
AU  - Nano, J.
AU  - Lamri, A.*
AU  - Nakatochi, M.*
AU  - Moon, S.*
AU  - Scott, R.A.*
AU  - Cook, J.P.*
AU  - Lee, J.J.*
AU  - Pan, I.*
AU  - Taliun, D.*
AU  - Parra, E.J.*
AU  - Chai, J.F.*
AU  - Bielak, L.F.*
AU  - Tabara, Y.*
AU  - Hai, Y.*
AU  - Thorleifsson, G.*
AU  - Grarup, N.*
AU  - Sofer, T.*
AU  - Wuttke, M.*
AU  - Sarnowski, C.*
AU  - Gieger, C.
AU  - Nousome, D.*
AU  - Trompet, S.*
AU  - Kwak, S.H.*
AU  - Long, J.*
AU  - Sun, M.*
AU  - Tong, L.*
AU  - Chen, W.M.*
AU  - Nongmaithem, S.S.*
AU  - Noordam, R.*
AU  - Lim, V.J.Y.*
AU  - Tam, C.H.T.*
AU  - Joo, Y.Y.*
AU  - Chen, C.H.*
AU  - Raffield, L.M.*
AU  - Prins, B.P.*
AU  - Nicolas, A.*
AU  - Yanek, L.R.*
AU  - Chen, G.*
AU  - Brody, J.A.*
AU  - Kabagambe, E.K.*
AU  - An, P.*
AU  - Xiang, A.H.*
AU  - Choi, H.S.*
AU  - Cade, B.E.*
AU  - Tan, J.*
AU  - Broadaway, K.A.*
AU  - Williamson, A.*
AU  - Kamali, Z.*
AU  - Cui, J.*
AU  - Thangam, M.*
AU  - Adair, L.S.*
AU  - Adeyemo, A.*
AU  - Aguilar-Salinas, C.A.*
AU  - Ahluwalia, T.S.*
AU  - Anand, S.S.*
AU  - Bertoni, A.G.*
AU  - Bork-Jensen, J.*
AU  - Brandslund, I.*
AU  - Buchanan, T.A.*
AU  - Burant, C.F.*
AU  - Butterworth, A.S.*
AU  - Canouil, M.*
AU  - Chan, J.C.N.*
AU  - Chang, L.C.*
AU  - Chee, M.L.*
AU  - Chen, J.*
AU  - Chen, S.H.*
AU  - Chen, Y.T.*
AU  - Chen, Z.*
AU  - Chuang, L.M.*
AU  - Cushman, M.*
AU  - Danesh, J.*
AU  - Das, S.K.*
AU  - de Silva, H.J.*
AU  - Dedoussis, G.*
AU  - Dimitrov, L.*
AU  - Doumatey, A.P.*
AU  - Du, S.*
AU  - Duan, Q.*
AU  - Eckardt, K.U.*
AU  - Emery, L.S.*
AU  - Evans, D.S.*
AU  - Evans, M.K.*
AU  - Fischer, K.*
AU  - Floyd, J.S.*
AU  - Ford, I.*
AU  - Franco, O.H.*
AU  - Frayling, T.M.*
AU  - Freedman, B.I.*
AU  - Genter, P.*
AU  - Gerstein, H.C.*
AU  - Giedraitis, V.*
AU  - González-Villalpando, C.*
AU  - Gonzalez-Villalpando, M.E.*
AU  - Gordon-Larsen, P.*
AU  - Gross, M.*
AU  - Guare, L.A.*
AU  - Hackinger, S.*
AU  - Hakaste, L.*
AU  - Han, S.*
AU  - Hattersley, A.T.*
AU  - Herder, C.*
AU  - Horikoshi, M.*
AU  - Howard, A.G.*
AU  - Hsueh, W.A.*
AU  - Huang, M.*
AU  - Huang, W.*
AU  - Hung, Y.J.*
AU  - Hwang, M.Y.*
AU  - Hwu, C.M.*
AU  - Ichihara, S.*
AU  - Ikram, M.A.*
AU  - Ingelsson, M.*
AU  - Islam, M.T.*
AU  - Isono, M.*
AU  - Jang, H.M.*
AU  - Jasmine, F.*
AU  - Jiang, G.*
AU  - Jonas, J.B.*
AU  - Jørgensen, T.*
AU  - Kamanu, F.K.*
AU  - Kandeel, F.R.*
AU  - Kasturiratne, A.*
AU  - Katsuya, T.*
AU  - Kaur, V.*
AU  - Kawaguchi, T.*
AU  - Keaton, J.M.*
AU  - Kho, A.N.*
AU  - Khor, C.C.*
AU  - Kibriya, M.G.*
AU  - Kim, D.H.*
AU  - Kronenberg, F.*
AU  - Kuusisto, J.*
AU  - Läll, K.*
AU  - Lange, L.A.*
AU  - Lee, K.M.*
AU  - Lee, M.S.*
AU  - Lee, N.R.*
AU  - Leong, A.*
AU  - Li, L.*
AU  - Li, Y.*
AU  - Li-Gao, R.*
AU  - Ligthart, S.*
AU  - Lindgren, C.M.*
AU  - Linneberg, A.*
AU  - Liu, C.T.*
AU  - Liu, J.*
AU  - Locke, A.E.*
AU  - Louie, T.*
AU  - Luan, J.*
AU  - Luk, A.O.Y.*
AU  - Luo, X.*
AU  - Lv, J.*
AU  - Lynch, J.A.*
AU  - Lyssenko, V.*
AU  - Maeda, S.*
AU  - Mamakou, V.*
AU  - Mansuri, S.R.*
AU  - Matsuda, K.*
AU  - Meitinger, T.
AU  - Melander, O.*
AU  - Metspalu, A.*
AU  - Mo, H.*
AU  - Morris, A.D.*
AU  - Moura, F.A.*
AU  - Nadler, J.L.*
AU  - Nalls, M.A.*
AU  - Nayak, U.*
AU  - Ntalla, I.*
AU  - Okada, Y.*
AU  - Orozco, L.*
AU  - Patel, S.R.*
AU  - Patil, S.*
AU  - Pei, P.*
AU  - Pereira, M.A.*
AU  - Peters, A.
AU  - Pirie, F.J.*
AU  - Polikowsky, H.G.*
AU  - Porneala, B.C.*
AU  - Prasad, G.*
AU  - Rasmussen-Torvik, L.J.*
AU  - Reiner, A.P.*
AU  - Roden, M.*
AU  - Rohde, R.*
AU  - Roll, K.*
AU  - Sabanayagam, C.*
AU  - Sandow, K.*
AU  - Sankareswaran, A.*
AU  - Sattar, N.*
AU  - Schönherr, S.*
AU  - Shahriar, M.*
AU  - Shen, B.*
AU  - Shi, J.*
AU  - Shin, D.M.*
AU  - Shojima, N.*
AU  - Smith, J.A.*
AU  - So, W.Y.*
AU  - Stancáková, A.*
AU  - Steinthorsdottir, V.*
AU  - Stilp, A.M.*
AU  - Strauch, K.
AU  - Taylor, K.D.*
AU  - Thorand, B.
AU  - Thorsteinsdottir, U.*
AU  - Tomlinson, B.*
AU  - Tran, T.C.*
AU  - Tsai, F.J.*
AU  - Tuomilehto, J.*
AU  - Tusié-Luna, T.*
AU  - Udler, M.S.*
AU  - Valladares-Salgado, A.*
AU  - van Dam, R.M.*
AU  - van Klinken, J.B.*
AU  - Varma, R.*
AU  - Wacher-Rodarte, N.*
AU  - Wheeler, E.*
AU  - Wickremasinghe, A.R.*
AU  - van Dijk, K.W.*
AU  - Witte, D.R.*
AU  - Yajnik, C.S.*
AU  - Yamamoto, K.*
AU  - Yoon, K.*
AU  - Yu, C.*
AU  - Yuan, J.M.*
AU  - Yusuf, S.*
AU  - Zawistowski, M.*
AU  - Zhang, L.*
AU  - Zheng, W.*
AU  - Raffel, L.J.*
AU  - Igase, M.*
AU  - Ipp, E.*
AU  - Redline, S.*
AU  - Cho, Y.S.*
AU  - Lind, L.*
AU  - Province, M.A.*
AU  - Fornage, M.*
AU  - Hanis, C.L.*
AU  - Ingelsson, E.*
AU  - Zonderman, A.B.*
AU  - Psaty, B.M.*
AU  - Wang, Y.X.*
AU  - Rotimi, C.N.*
AU  - Becker, D.M.*
AU  - Matsuda, F.*
AU  - Liu, Y.*
AU  - Yokota, M.*
AU  - Kardia, S.L.R.*
AU  - Peyser, P.A.*
AU  - Pankow, J.S.*
AU  - Engert, J.C.*
AU  - Bonnefond, A.*
AU  - Froguel, P.*
AU  - Wilson, J.G.*
AU  - Sheu, W.H.H.*
AU  - Wu, J.Y.*
AU  - Hayes, M.G.*
AU  - Ma, R.C.W.*
AU  - Wong, T.Y.*
AU  - Mook-Kanamori, D.O.*
AU  - Tuomi, T.*
AU  - Chandak, G.R.*
AU  - Collins, F.S.*
AU  - Bharadwaj, D.*
AU  - Paré, G.*
AU  - Sale, M.M.*
AU  - Ahsan, H.*
AU  - Motala, A.A.*
AU  - Shu, X.O.*
AU  - Park, K.S.*
AU  - Jukema, J.W.*
AU  - Cruz, M.*
AU  - Chen, Y.I.*
AU  - Rich, S.S.*
AU  - McKean-Cowdin, R.*
AU  - Grallert, H.
AU  - Cheng, C.Y.*
AU  - Ghanbari, M.*
AU  - Tai, E.S.*
AU  - Dupuis, J.*
AU  - Kato, N.*
AU  - Laakso, M.*
AU  - Köttgen, A.*
AU  - Koh, W.P.*
AU  - Bowden, D.W.*
AU  - Palmer, C.N.A.*
AU  - Kooner, J.S.*
AU  - Kooperberg, C.*
AU  - Liu, S.*
AU  - North, K.E.*
AU  - Saleheen, D.*
AU  - Hansen, T.*
AU  - Pedersen, O.*
AU  - Wareham, N.J.*
AU  - Lee, J.*
AU  - Kim, B.J.*
AU  - Millwood, I.Y.*
AU  - Walters, R.G.*
AU  - Stefansson, K.*
AU  - Ahlqvist, E.*
AU  - Goodarzi, M.O.*
AU  - Mohlke, K.L.*
AU  - Langenberg, C.*
AU  - Haiman, C.A.*
AU  - Loos, R.J.F.*
AU  - Florez, J.C.*
AU  - Rader, D.J.*
AU  - Ritchie, M.D.*
AU  - Zöllner, S.*
AU  - Mägi, R.*
AU  - Marston, N.A.*
AU  - Ruff, C.T.*
AU  - van Heel, D.A.*
AU  - Finer, S.*
AU  - Denny, J.C.*
AU  - Yamauchi, T.*
AU  - Kadowaki, T.*
AU  - Chambers, J.C.*
AU  - Ng, M.C.Y.*
AU  - Sim, X.*
AU  - Below, J.E.*
AU  - Tsao, P.S.*
AU  - Chang, K.M.*
AU  - McCarthy, M.I.*
AU  - Meigs, J.B.*
AU  - Mahajan, A.*
AU  - Spracklen, C.N.*
AU  - Mercader, J.M.*
AU  - Boehnke, M.*
AU  - Rotter, J.I.*
AU  - Vujkovic, M.R.*
AU  - Voight, B.F.*
AU  - Morris, A.P.
AU  - Zeggini, E.
C1  - 72502
C2  - 56601
SP  - 347-357
TI  - Genetic drivers of heterogeneity in type 2 diabetes pathophysiology.
JO  - Nature
VL  - 627
IS  - 8003
PY  - 2024
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Spermatozoa harbour a complex and environment-sensitive pool of small non-coding RNAs (sncRNAs)1, which influences offspring development and adult phenotypes1-7. Whether spermatozoa in the epididymis are directly susceptible to environmental cues is not fully understood8. Here we used two distinct paradigms of preconception acute high-fat diet to dissect epididymal versus testicular contributions to the sperm sncRNA pool and offspring health. We show that epididymal spermatozoa, but not developing germ cells, are sensitive to the environment and identify mitochondrial tRNAs (mt-tRNAs) and their fragments (mt-tsRNAs) as sperm-borne factors. In humans, mt-tsRNAs in spermatozoa correlate with body mass index, and paternal overweight at conception doubles offspring obesity risk and compromises metabolic health. Sperm sncRNA sequencing of mice mutant for genes involved in mitochondrial function, and metabolic phenotyping of their wild-type offspring, suggest that the upregulation of mt-tsRNAs is downstream of mitochondrial dysfunction. Single-embryo transcriptomics of genetically hybrid two-cell embryos demonstrated sperm-to-oocyte transfer of mt-tRNAs at fertilization and suggested their involvement in the control of early-embryo transcription. Our study supports the importance of paternal health at conception for offspring metabolism, shows that mt-tRNAs are diet-induced and sperm-borne and demonstrates, in a physiological setting, father-to-offspring transfer of sperm mitochondrial RNAs at fertilization.
AU  - Tomar, A.
AU  - Gómez Velázquez, M.
AU  - Gerlini, R.
AU  - Comas-Armangue, G.
AU  - Makharadze, L.
AU  - Kolbe, T.*
AU  - Boersma, A.*
AU  - Dahlhoff, M.*
AU  - Burgstaller, J.P.*
AU  - Lassi, M.
AU  - Darr, J.
AU  - Toppari, J.*
AU  - Virtanen, H.*
AU  - Kühnapfel, A.*
AU  - Scholz, M.*
AU  - Landgraf, K.*
AU  - Kiess, W.*
AU  - Vogel, M.*
AU  - Gailus-Durner, V.
AU  - Fuchs, H.
AU  - Marschall, S.
AU  - Hrabě de Angelis, M.
AU  - Kotaja, N.*
AU  - Körner, A.
AU  - Teperino, R.
C1  - 70808
C2  - 55703
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 720-727
TI  - Epigenetic inheritance of diet-induced and sperm-borne mitochondrial RNAs.
JO  - Nature
VL  - 638
PB  - Nature Portfolio
PY  - 2024
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Chaperonins are large barrel-shaped complexes that mediate ATP-dependent protein folding1-3. The bacterial chaperonin GroEL forms juxtaposed rings that bind unfolded protein and the lid-shaped cofactor GroES at their apertures. In vitro analyses of the chaperonin reaction have shown that substrate protein folds, unimpaired by aggregation, while transiently encapsulated in the GroEL central cavity by GroES4-6. To determine the functional stoichiometry of GroEL, GroES and client protein in situ, here we visualized chaperonin complexes in their natural cellular environment using cryo-electron tomography. We find that, under various growth conditions, around 55-70% of GroEL binds GroES asymmetrically on one ring, with the remainder populating symmetrical complexes. Bound substrate protein is detected on the free ring of the asymmetrical complex, defining the substrate acceptor state. In situ analysis of GroEL-GroES chambers, validated by high-resolution structures obtained in vitro, showed the presence of encapsulated substrate protein in a folded state before release into the cytosol. Based on a comprehensive quantification and conformational analysis of chaperonin complexes, we propose a GroEL-GroES reaction cycle that consists of linked asymmetrical and symmetrical subreactions mediating protein folding. Our findings illuminate the native conformational and functional chaperonin cycle directly within cells.
AU  - Wagner, J.*
AU  - Carvajal, A.I.*
AU  - Bracher, A.*
AU  - Beck, F.*
AU  - Wan, W.*
AU  - Bohn, S.
AU  - Körner, R.*
AU  - Baumeister, W.*
AU  - Fernandez-Busnadiego, R.*
AU  - Hartl, F.U.*
C1  - 71511
C2  - 56223
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 459–464 
TI  - Visualizing chaperonin function in situ by cryo-electron tomography.
JO  - Nature
VL  - 633
PB  - Nature Portfolio
PY  - 2024
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - The largest genome-wide association study for type 2 diabetes so far, which included several ancestry groups, led to the identification of eight clusters of genetic risk variants. The clusters capture different biological pathways that contribute to the disease, and some clusters are associated with vascular complications.
AU  - Zeggini, E.
AU  - Morris, A.P.*
C1  - 70637
C2  - 55521
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Genetic risk variants lead to type 2 diabetes development through different pathways.
JO  - Nature
PB  - Nature Portfolio
PY  - 2024
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Optimal tissue recovery and organismal survival are achieved by spatiotemporal tuning of tissue inflammation, contraction and scar formation1. Here we identify a multipotent fibroblast progenitor marked by CD201 expression in the fascia, the deepest connective tissue layer of the skin. Using skin injury models in mice, single-cell transcriptomics and genetic lineage tracing, ablation and gene deletion models, we demonstrate that CD201+ progenitors control the pace of wound healing by generating multiple specialized cell types, from proinflammatory fibroblasts to myofibroblasts, in a spatiotemporally tuned sequence. We identified retinoic acid and hypoxia signalling as the entry checkpoints into proinflammatory and myofibroblast states. Modulating CD201+ progenitor differentiation impaired the spatiotemporal appearances of fibroblasts and chronically delayed wound healing. The discovery of proinflammatory and myofibroblast progenitors and their differentiation pathways provide a new roadmap to understand and clinically treat impaired wound healing.
AU  - Correa-Gallegos, D.
AU  - Ye, H.
AU  - Dasgupta, B.
AU  - Sardogan, A.
AU  - Kadri, S.
AU  - Kandi, R.
AU  - Dai, R.
AU  - Lin, Y.
AU  - Kopplin, R.
AU  - Shantaram Shenai, D.
AU  - Wannemacher, J.
AU  - Ichijo, R.
AU  - Jiang, D.
AU  - Strunz, M.
AU  - Ansari, M.
AU  - Angelidis, I.
AU  - Schiller, H.
AU  - Voltz, T.*
AU  - Machens, H.G.*
AU  - Rinkevich, Y.
C1  - 68772
C2  - 54982
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 792-802
TI  - CD201+ fascia progenitors choreograph injury repair.
JO  - Nature
VL  - 623
IS  - 7988
PB  - Nature Portfolio
PY  - 2023
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Optimal growth and development in childhood and adolescence is crucial for lifelong health and well-being1-6.
       Here we used data from 2,325 population-based studies, with 
      measurements of height and weight from 71 million participants, to 
      report the height and body-mass index (BMI) of children and adolescents 
      aged 5-19 years on the basis of rural and urban place of residence in 
      200 countries and territories from 1990 to 2020. In 1990, children and 
      adolescents residing in cities were taller than their rural counterparts
       in all but a few high-income countries. By 2020, the urban height 
      advantage became smaller in most countries, and in many high-income 
      western countries it reversed into a small urban-based disadvantage. The
       exception was for boys in most countries in sub-Saharan Africa and in 
      some countries in Oceania, south Asia and the region of central Asia, 
      Middle East and north Africa. In these countries, successive cohorts of 
      boys from rural places either did not gain height or possibly became 
      shorter, and hence fell further behind their urban peers. The difference
       between the age-standardized mean BMI of children in urban and rural 
      areas was <1.1 kg m-2 in the vast majority of countries. 
      Within this small range, BMI increased slightly more in cities than in 
      rural areas, except in south Asia, sub-Saharan Africa and some countries
       in central and eastern Europe. Our results show that in much of the 
      world, the growth and developmental advantages of living in cities have 
      diminished in the twenty-first century, whereas in much of sub-Saharan 
      Africa they have amplified.
AU  - NCD Risk Factors Collaboration (Döring, A.
AU  - Gieger, C.
AU  - Heier, M.
AU  - Linkohr, B.
AU  - Meisinger, C.
AU  - Schneider, A.
AU  - Stieber, J.
AU  - Peters, A.
AU  - Stöckl, D.
AU  - Thorand, B.
AU  - Wolf, K.)
C1  - 68591
C2  - 53729
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 874-883
TI  - Diminishing benefits of urban living for children and adolescents’ growth and development.
JO  - Nature
VL  - 615
IS  - 7954
PB  - Nature Portfolio
PY  - 2023
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Mouse models are a critical tool for studying human diseases, particularly developmental disorders1. However, conventional approaches for phenotyping may fail to detect subtle defects throughout the developing mouse2. Here we set out to establish single-cell RNA sequencing of the whole embryo as a scalable platform for the systematic phenotyping of mouse genetic models. We applied combinatorial indexing-based single-cell RNA sequencing3 to profile 101 embryos of 22 mutant and 4 wild-type genotypes at embryonic day 13.5, altogether profiling more than 1.6 million nuclei. The 22 mutants represent a range of anticipated phenotypic severities, from established multisystem disorders to deletions of individual regulatory regions4,5. We developed and applied several analytical frameworks for detecting differences in composition and/or gene expression across 52 cell types or trajectories. Some mutants exhibit changes in dozens of trajectories whereas others exhibit changes in only a few cell types. We also identify differences between widely used wild-type strains, compare phenotyping of gain- versus loss-of-function mutants and characterize deletions of topological associating domain boundaries. Notably, some changes are shared among mutants, suggesting that developmental pleiotropy might be 'decomposable' through further scaling of this approach. Overall, our findings show how single-cell profiling of whole embryos can enable the systematic molecular and cellular phenotypic characterization of mouse mutants with unprecedented breadth and resolution.
AU  - Huang, X.*
AU  - Henck, J.*
AU  - Qiu, C.*
AU  - Sreenivasan, V.K.A.*
AU  - Balachandran, S.*
AU  - Amarie, O.V.
AU  - Hrabě de Angelis, M.
AU  - Behncke, R.Y.*
AU  - Chan, W.L.*
AU  - Despang, A.*
AU  - Dickel, D.E.*
AU  - Duran, M.*
AU  - Feuchtinger, A.
AU  - Fuchs, H.
AU  - Gailus-Durner, V.
AU  - Haag, N.*
AU  - Hägerling, R.*
AU  - Hansmeier, N.*
AU  - Hennig, F.*
AU  - Marshall, C.*
AU  - Rajderkar, S.*
AU  - Ringel, A.*
AU  - Robson, M.*
AU  - Saunders, L.M.*
AU  - da Silva Buttkus, P.
AU  - Spielmann, N.
AU  - Srivatsan, S.R.*
AU  - Ulferts, S.*
AU  - Wittler, L.*
AU  - Zhu, Y.*
AU  - Kalscheuer, V.M.*
AU  - Ibrahim, D.M.*
AU  - Kurth, I.*
AU  - Kornak, U.*
AU  - Visel, A.*
AU  - Pennacchio, L.A.*
AU  - Beier, D.R.*
AU  - Trapnell, C.*
AU  - Cao, J.*
AU  - Shendure, J.*
AU  - Spielmann, M.*
C1  - 68773
C2  - 54983
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 772-781
TI  - Single-cell, whole-embryo phenotyping of mammalian developmental disorders.
JO  - Nature
VL  - 623
IS  - 7988
PB  - Nature Portfolio
PY  - 2023
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Increasing the proportion of locally produced plant protein in currently meat-rich diets could substantially reduce greenhouse gas emissions and loss of biodiversity1. However, plant protein production is hampered by the lack of a cool-season legume equivalent to soybean in agronomic value2. Faba bean (Vicia faba L.) has a high yield potential and is well suited for cultivation in temperate regions, but genomic resources are scarce. Here, we report a high-quality chromosome-scale assembly of the faba bean genome and show that it has expanded to a massive 13 Gb in size through an imbalance between the rates of amplification and elimination of retrotransposons and satellite repeats. Genes and recombination events are evenly dispersed across chromosomes and the gene space is remarkably compact considering the genome size, although with substantial copy number variation driven by tandem duplication. Demonstrating practical application of the genome sequence, we develop a targeted genotyping assay and use high-resolution genome-wide association analysis to dissect the genetic basis of seed size and hilum colour. The resources presented constitute a genomics-based breeding platform for faba bean, enabling breeders and geneticists to accelerate the improvement of sustainable protein production across the Mediterranean, subtropical and northern temperate agroecological zones.
AU  - Jayakodi, M.*
AU  - Golicz, A.A.*
AU  - Kreplak, J.*
AU  - Fechete, L.I.*
AU  - Angra, D.*
AU  - Bednář, P.*
AU  - Bornhofen, E.*
AU  - Zhang, H.*
AU  - Boussageon, R.*
AU  - Kaur, S.*
AU  - Cheung, K.*
AU  - Čížková, J.*
AU  - Gundlach, H.
AU  - Hallab, A.*
AU  - Imbert, B.*
AU  - Keeble-Gagnère, G.*
AU  - Koblížková, A.*
AU  - Kobrlová, L.*
AU  - Krejčí, P.*
AU  - Mouritzen, T.W.*
AU  - Neumann, P.*
AU  - Nadzieja, M.*
AU  - Nielsen, L.K.*
AU  - Novak, P.*
AU  - Orabi, J.*
AU  - Padmarasu, S.*
AU  - Robertson-Shersby-Harvie, T.*
AU  - Robledillo, L.*
AU  - Schiemann, A.*
AU  - Tanskanen, J.*
AU  - Törönen, P.*
AU  - Warsame, A.O.*
AU  - Wittenberg, A.H.J.*
AU  - Himmelbach, A.*
AU  - Aubert, G.*
AU  - Courty, P.E.*
AU  - Dolezel, J.*
AU  - Holm, L.U.*
AU  - Janss, L.L.*
AU  - Khazaei, H.*
AU  - Macas, J.*
AU  - Mascher, M.*
AU  - Smýkal, P.*
AU  - Snowdon, R.J.*
AU  - Stein, N.*
AU  - Stoddard, F.L.*
AU  - Stougaard, J.*
AU  - Tayeh, N.*
AU  - Torres, A.M.*
AU  - Usadel, B.*
AU  - Schubert, I.*
AU  - O'Sullivan, D.M.*
AU  - Schulman, A.H.*
AU  - Andersen, S.U.*
C1  - 67746
C2  - 54056
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 652-659
TI  - The giant diploid faba genome unlocks variation in a global protein crop.
JO  - Nature
VL  - 615
IS  - 7953
PB  - Nature Portfolio
PY  - 2023
SN  - 0028-0836
ER  - 

TY  - JOUR
AU  - Mishima, E.
AU  - Nakamura, T.
AU  - Zheng, J.
AU  - Zhang, W.
AU  - Mourao, A.
AU  - Sennhenn, P.*
AU  - Conrad, M.
C1  - 68430
C2  - 54626
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - E9-E18
TI  - DHODH inhibitors sensitize to ferroptosis by FSP1 inhibition.
JO  - Nature
VL  - 619
IS  - 7968
PB  - Nature Portfolio
PY  - 2023
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Ferroptosis is evolving as a highly promising approach to combat difficult-to-treat tumour entities including therapy-refractory and dedifferentiating cancers1–3. Recently, ferroptosis suppressor protein-1 (FSP1), along with extramitochondrial ubiquinone or exogenous vitamin K and NAD(P)H/H+ as an electron donor, has been identified as the second ferroptosis-suppressing system, which efficiently prevents lipid peroxidation independently of the cyst(e)ine–glutathione (GSH)–glutathione peroxidase 4 (GPX4) axis4–6. To develop FSP1 inhibitors as next-generation therapeutic ferroptosis inducers, here we performed a small molecule library screen and identified the compound class of 3-phenylquinazolinones (represented by icFSP1) as potent FSP1 inhibitors. We show that icFSP1, unlike iFSP1, the first described on-target FSP1 inhibitor5, does not competitively inhibit FSP1 enzyme activity, but instead triggers subcellular relocalization of FSP1 from the membrane and FSP1 condensation before ferroptosis induction, in synergism with GPX4 inhibition. icFSP1-induced FSP1 condensates show droplet-like properties consistent with phase separation, an emerging and widespread mechanism to modulate biological activity7. N-terminal myristoylation, distinct amino acid residues and intrinsically disordered, low-complexity regions in FSP1 were identified to be essential for FSP1-dependent phase separation in cells and in vitro. We further demonstrate that icFSP1 impairs tumour growth and induces FSP1 condensates in tumours in vivo. Hence, our results suggest that icFSP1 exhibits a unique mechanism of action and synergizes with ferroptosis-inducing agents to potentiate the ferroptotic cell death response, thus providing a rationale for targeting FSP1-dependent phase separation as an efficient anti-cancer therapy.
AU  - Nakamura, T.
AU  - Hipp, C.
AU  - Santos Dias Mourão, A.*
AU  - Borggräfe, J.
AU  - Aldrovandi, M.
AU  - Henkelmann, B.
AU  - Wanninger, J.
AU  - Mishima, E.
AU  - Lytton, E.
AU  - Emler, D.
AU  - Proneth, B.
AU  - Sattler, M.
AU  - Conrad, M.
C1  - 68461
C2  - 54648
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 371-377
TI  - Phase separation of FSP1 promotes ferroptosis.
JO  - Nature
VL  - 619
IS  - 7969
PB  - Nature Portfolio
PY  - 2023
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - DNA replication enables genetic inheritance across the kingdoms of life. Replication occurs with a defined temporal order known as the replication timing (RT) programme, leading to organization of the genome into early- or late-replicating regions. RT is cell-type specific, is tightly linked to the three-dimensional nuclear organization of the genome1,2 and is considered an epigenetic fingerprint3. In spite of its importance in maintaining the epigenome4, the developmental regulation of RT in mammals in vivo has not been explored. Here, using single-cell Repli-seq5, we generated genome-wide RT maps of mouse embryos from the zygote to the blastocyst stage. Our data show that RT is initially not well defined but becomes defined progressively from the 4-cell stage, coinciding with strengthening of the A and B compartments. We show that transcription contributes to the precision of the RT programme and that the difference in RT between the A and B compartments depends on RNA polymerase II at zygotic genome activation. Our data indicate that the establishment of nuclear organization precedes the acquisition of defined RT features and primes the partitioning of the genome into early- and late-replicating domains. Our work sheds light on the establishment of the epigenome at the beginning of mammalian development and reveals the organizing principles of genome organization.
AU  - Nakatani, T.
AU  - Schauer, T.
AU  - Altamirano-Pacheco, L.
AU  - Klein, K.N.*
AU  - Ettinger, A.
AU  - Pal, M.
AU  - Gilbert, D.M.*
AU  - Torres-Padilla, M.E.
C1  - 69056
C2  - 53834
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 401–409
TI  - Emergence of replication timing during early mammalian development.
JO  - Nature
VL  - 625
IS  - 7994
PB  - Nature Portfolio
PY  - 2023
SN  - 0028-0836
ER  - 

TY  - JOUR
AU  - COVID-19 Host Genetics Initiative (Schulte, E.C.
AU  - Protzer, U.
AU  - Müller, N.S.)
C1  - 68966
C2  - 55166
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - E7-E26
TI  - A second update on mapping the human genetic architecture of COVID-19.
JO  - Nature
VL  - 621
IS  - 7977
PB  - Nature Portfolio
PY  - 2023
SN  - 0028-0836
ER  - 

TY  - JOUR
AU  - COVID-19 Host Genetics Initiative (Schulte, E.C.)
C1  - 72995
C2  - 56786
SP  - E7-E26
TI  - Erratum to: Mapping the human genetic architecture of COVID-19 (Nature, (2021), 600, 7889, (472-477), 10.1038/s41586-021-03767-x).
JO  - Nature
VL  - 621
IS  - 7977
PY  - 2023
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - The Pharma Proteomics Project is a precompetitive biopharmaceutical consortium characterizing the plasma proteomic profiles of 54,219 UK Biobank participants. Here we provide a detailed summary of this initiative, including technical and biological validations, insights into proteomic disease signatures, and prediction modelling for various demographic and health indicators. We present comprehensive protein quantitative trait locus (pQTL) mapping of 2,923 proteins that identifies 14,287 primary genetic associations, of which 81% are previously undescribed, alongside ancestry-specific pQTL mapping in non-European individuals. The study provides an updated characterization of the genetic architecture of the plasma proteome, contextualized with projected pQTL discovery rates as sample sizes and proteomic assay coverages increase over time. We offer extensive insights into trans pQTLs across multiple biological domains, highlight genetic influences on ligand–receptor interactions and pathway perturbations across a diverse collection of cytokines and complement networks, and illustrate long-range epistatic effects of ABO blood group and FUT2 secretor status on proteins with gastrointestinal tissue-enriched expression. We demonstrate the utility of these data for drug discovery by extending the genetic proxied effects of protein targets, such as PCSK9, on additional endpoints, and disentangle specific genes and proteins perturbed at loci associated with COVID-19 susceptibility. This public–private partnership provides the scientific community with an open-access proteomics resource of considerable breadth and depth to help to elucidate the biological mechanisms underlying proteo-genomic discoveries and accelerate the development of biomarkers, predictive models and therapeutics1.
AU  - Sun, B.B.*
AU  - Chiou, J.*
AU  - Traylor, M.*
AU  - Benner, C.*
AU  - Hsu, Y.H.*
AU  - Richardson, T.G.*
AU  - Surendran, P.*
AU  - Mahajan, A.*
AU  - Robins, C.*
AU  - Vasquez-Grinnell, S.G.*
AU  - Hou, L.*
AU  - Kvikstad, E.M.*
AU  - Burren, O.S.*
AU  - Davitte, J.*
AU  - Ferber, K.L.*
AU  - Gillies, C.E.*
AU  - Hedman, A.K.*
AU  - Hu, S.*
AU  - Lin, T.*
AU  - Mikkilineni, R.*
AU  - Pendergrass, R.K.*
AU  - Pickering, C.*
AU  - Prins, B.*
AU  - Baird, D.*
AU  - Chen, C.Y.*
AU  - Ward, L.D.*
AU  - Deaton, A.M.*
AU  - Welsh, S.*
AU  - Willis, C.M.*
AU  - Lehner, N.
AU  - Arnold, M.
AU  - Wörheide, M.
AU  - Suhre, K.*
AU  - Kastenmüller, G.
AU  - Sethi, A.*
AU  - Cule, M.*
AU  - Raj, A.*
AU  - Kang, H.M.*
AU  - Burkitt-Gray, L.*
AU  - Melamud, E.*
AU  - Black, M.H.*
AU  - Fauman, E.B.*
AU  - Howson, J.M.M.*
AU  - McCarthy, M.I.*
AU  - Nioi, P.*
AU  - Petrovski, S.*
AU  - Scott, R.A.*
AU  - Smith, E.N.*
AU  - Szalma, S.*
AU  - Waterworth, D.M.*
AU  - Mitnaul, L.J.*
AU  - Szustakowski, J.D.*
AU  - Gibson, B.W.*
AU  - Miller, M.R.*
AU  - Whelan, C.D.*
C1  - 68184
C2  - 54810
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 329-338
TI  - Plasma proteomic associations with genetics and health in the UK Biobank.
JO  - Nature
VL  - 622
IS  - 7982
PB  - Nature Portfolio
PY  - 2023
SN  - 0028-0836
ER  - 

TY  - JOUR
AU  - Urban, L.
AU  - Mehta, D.*
C1  - 70197
C2  - 55045
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 249-249
TI  - eLife: Community support for a new publishing model.
JO  - Nature
VL  - 616
IS  - 7956
PB  - Nature Portfolio
PY  - 2023
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Artificial sweeteners are used as calorie-free sugar substitutes in many food products and their consumption has increased substantially over the past years1. Although generally regarded as safe, some concerns have been raised about the long-term safety of the consumption of certain sweeteners2-5. In this study, we show that the intake of high doses of sucralose in mice results in immunomodulatory effects by limiting T cell proliferation and T cell differentiation. Mechanistically, sucralose affects the membrane order of T cells, accompanied by a reduced efficiency of T cell receptor signalling and intracellular calcium mobilization. Mice given sucralose show decreased CD8+ T cell antigen-specific responses in subcutaneous cancer models and bacterial infection models, and reduced T cell function in models of T cell-mediated autoimmunity. Overall, these findings suggest that a high intake of sucralose can dampen T cell-mediated responses, an effect that could be used in therapy to mitigate T cell-dependent autoimmune disorders.
AU  - Zani, F.*
AU  - Blagih, J.*
AU  - Gruber, T.
AU  - Buck, M.D.*
AU  - Jones, N.*
AU  - Hennequart, M.*
AU  - Newell, C.L.*
AU  - Pilley, S.E.*
AU  - Soro-Barrio, P.*
AU  - Kelly, G.*
AU  - Legrave, N.M.*
AU  - Cheung, E.C.*
AU  - Gilmore, I.S.*
AU  - Gould, A.P.*
AU  - García-Cáceres, C.
AU  - Vousden, K.H.*
C1  - 67721
C2  - 54029
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 705-711
TI  - The dietary sweetener sucralose is a negative modulator of T cell-mediated responses.
JO  - Nature
VL  - 615
IS  - 7953
PB  - Nature Portfolio
PY  - 2023
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Filamentous enzymes have been found in all domains of life, but the advantage of filamentation is often elusive1. Some anaerobic, autotrophic bacteria have an unusual filamentous enzyme for CO2 fixation-hydrogen-dependent CO2 reductase (HDCR)2,3-which directly converts H2 and CO2 into formic acid. HDCR reduces CO2 with a higher activity than any other known biological or chemical catalyst4,5, and it has therefore gained considerable interest in two areas of global relevance: hydrogen storage and combating climate change by capturing atmospheric CO2. However, the mechanistic basis of the high catalytic turnover rate of HDCR has remained unknown. Here we use cryo-electron microscopy to reveal the structure of a short HDCR filament from the acetogenic bacterium Thermoanaerobacter kivui. The minimum repeating unit is a hexamer that consists of a formate dehydrogenase (FdhF) and two hydrogenases (HydA2) bound around a central core of hydrogenase Fe-S subunits, one HycB3 and two HycB4. These small bacterial polyferredoxin-like proteins oligomerize through their C-terminal helices to form the backbone of the filament. By combining structure-directed mutagenesis with enzymatic analysis, we show that filamentation and rapid electron transfer through the filament enhance the activity of HDCR. To investigate the structure of HDCR in situ, we imaged T. kivui cells with cryo-electron tomography and found that HDCR filaments bundle into large ring-shaped superstructures attached to the plasma membrane. This supramolecular organization may further enhance the stability and connectivity of HDCR to form a specialized metabolic subcompartment within the cell.
AU  - Dietrich, H.M.*
AU  - Righetto, R.D.
AU  - Kumar, A.*
AU  - Wietrzynski, W.
AU  - Trischler, R.*
AU  - Schuller, S.K.*
AU  - Wagner, J.*
AU  - Schwarz, F.M.*
AU  - Engel, B.D.
AU  - Müller, V.*
AU  - Schuller, J.M.*
C1  - 65762
C2  - 52904
SP  - 823-830
TI  - Membrane-anchored HDCR nanowires drive hydrogen-powered CO2 fixation.
JO  - Nature
VL  - 607
IS  - 7920
PY  - 2022
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Cultivated oat (Avena sativa L.) is an allohexaploid (AACCDD, 2n = 6x = 42) thought to have been domesticated more than 3,000 years ago while growing as a weed in wheat, emmer and barley fields in Anatolia1,2. Oat has a low carbon footprint, substantial health benefits and the potential to replace animal-based food products. However, the lack of a fully annotated reference genome has hampered efforts to deconvolute its complex evolutionary history and functional gene dynamics. Here we present a high-quality reference genome of A. sativa and close relatives of its diploid (Avena longiglumis, AA, 2n = 14) and tetraploid (Avena insularis, CCDD, 2n = 4x = 28) progenitors. We reveal the mosaic structure of the oat genome, trace large-scale genomic reorganizations in the polyploidization history of oat and illustrate a breeding barrier associated with the genome architecture of oat. We showcase detailed analyses of gene families implicated in human health and nutrition, which adds to the evidence supporting oat safety in gluten-free diets, and we perform mapping-by-sequencing of an agronomic trait related to water-use efficiency. This resource for the Avena genus will help to leverage knowledge from other cereal genomes, improve understanding of basic oat biology and accelerate genomics-assisted breeding and reanalysis of quantitative trait studies.
AU  - Kamal, N.
AU  - Tsardakas Renhuldt, N.*
AU  - Bentzer, J.*
AU  - Gundlach, H.
AU  - Haberer, G.
AU  - Juhász, A.*
AU  - Lux, T.
AU  - Bose, U.*
AU  - Tye-Din, J.A.*
AU  - Lang, D.
AU  - van Gessel, N.*
AU  - Reski, R.*
AU  - Fu, Y.B.*
AU  - Spégel, P.*
AU  - Ceplitis, A.*
AU  - Himmelbach, A.*
AU  - Waters, A.J.*
AU  - Bekele, W.A.*
AU  - Colgrave, M.L.*
AU  - Hansson, M.*
AU  - Stein, N.*
AU  - Mayer, K.F.X.
AU  - Jellen, E.N.*
AU  - Maughan, P.J.*
AU  - Tinker, N.A.*
AU  - Mascher, M.*
AU  - Olsson, O.*
AU  - Spannagl, M.
AU  - Sirijovski, N.*
C1  - 65084
C2  - 52127
SP  - 113-119
TI  - The mosaic oat genome gives insights into a uniquely healthy cereal crop.
JO  - Nature
VL  - 606
IS  - 7912
PY  - 2022
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Ferroptosis, a non-apoptotic form of cell death marked by iron-dependent lipid peroxidation1, has a key role in organ injury, degenerative disease and vulnerability of therapy-resistant cancers2. Although substantial progress has been made in understanding the molecular processes relevant to ferroptosis, additional cell-extrinsic and cell-intrinsic processes that determine cell sensitivity toward ferroptosis remain unknown. Here we show that the fully reduced forms of vitamin K—a group of naphthoquinones that includes menaquinone and phylloquinone3—confer a strong anti-ferroptotic function, in addition to the conventional function linked to blood clotting by acting as a cofactor for γ-glutamyl carboxylase. Ferroptosis suppressor protein 1 (FSP1), a NAD(P)H-ubiquinone reductase and the second mainstay of ferroptosis control after glutathione peroxidase-44,5, was found to efficiently reduce vitamin K to its hydroquinone, a potent radical-trapping antioxidant and inhibitor of (phospho)lipid peroxidation. The FSP1-mediated reduction of vitamin K was also responsible for the antidotal effect of vitamin K against warfarin poisoning. It follows that FSP1 is the enzyme mediating warfarin-resistant vitamin K reduction in the canonical vitamin K cycle6. The FSP1-dependent non-canonical vitamin K cycle can act to protect cells against detrimental lipid peroxidation and ferroptosis.
AU  - Mishima, E.
AU  - Ito, J.*
AU  - Wu, Z.*
AU  - Nakamura, T.
AU  - Wahida, A.
AU  - Doll, S.
AU  - Tonnus, W.*
AU  - Nepachalovich, P.*
AU  - Eggenhofer, E.*
AU  - Aldrovandi, M.
AU  - Henkelmann, B.
AU  - Yamada, K.i.*
AU  - Wanninger, J.
AU  - Zilka, O.*
AU  - Sato, E.*
AU  - Feederle, R.
AU  - Hass, D,
AU  - Maida, A.
AU  - Mourao, A.
AU  - Linkermann, A.*
AU  - Geissler, E.K.*
AU  - Nakagawa, K.*
AU  - Abe, T.*
AU  - Fedorova, M.*
AU  - Proneth, B.
AU  - Pratt, D.A.*
AU  - Conrad, M.
C1  - 65847
C2  - 52533
SP  - 778-783
TI  - A non-canonical vitamin K cycle is a potent ferroptosis suppressor.
JO  - Nature
VL  - 608
IS  - 7924
PY  - 2022
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
AU  - Mishra, A.*
AU  - Malik, R.*
AU  - Hachiya, T.*
AU  - Jürgenson, T.*
AU  - Namba, S.*
AU  - Posner, D.C.*
AU  - Kamanu, F.K.*
AU  - Koido, M.*
AU  - Le Grand, Q.*
AU  - Shi, M.*
AU  - He, Y.*
AU  - Georgakis, M.K.*
AU  - Caro, I.*
AU  - Krebs, K.*
AU  - Liaw, Y.C.*
AU  - Vaura, F.C.*
AU  - Lin, K.*
AU  - Winsvold, B.S.*
AU  - Srinivasasainagendra, V.*
AU  - Parodi, L.*
AU  - Bae, H.J.*
AU  - Chauhan, G.*
AU  - Chong, M.R.*
AU  - Tomppo, L.*
AU  - Akinyemi, R.*
AU  - Roshchupkin, G.V.*
AU  - Habib, N.*
AU  - Jee, Y.H.*
AU  - Thomassen, J.Q.*
AU  - Abedi, V.*
AU  - Cárcel-Márquez, J.*
AU  - Nygaard, M.*
AU  - Leonard, H.L.*
AU  - Yang, C.*
AU  - Yonova-Doing, E.*
AU  - Knol, M.J.*
AU  - Lewis, A.J.*
AU  - Judy, R.L.*
AU  - Ago, T.*
AU  - Amouyel, P.*
AU  - Armstrong, N.D.*
AU  - Bakker, M.K.*
AU  - Bartz, T.M.*
AU  - Bennett, D.A.*
AU  - Bis, J.C.*
AU  - Bordes, C.*
AU  - Børte, S.*
AU  - Cain, A.*
AU  - Ridker, P.M.*
AU  - Cho, K.*
AU  - Chen, Z.*
AU  - Cruchaga, C.*
AU  - Cole, J.W.*
AU  - de Jager, P.L.*
AU  - de Cid, R.*
AU  - Endres, M.*
AU  - Ferreira, L.E.*
AU  - Geerlings, M.I.*
AU  - Gasca, N.C.*
AU  - Gudnason, V.*
AU  - Hata, J.*
AU  - He, J.*
AU  - Heath, A.K.*
AU  - Ho, Y.L.*
AU  - Havulinna, A.S.*
AU  - Hopewell, J.C.*
AU  - Hyacinth, H.I.*
AU  - Jacob, M.A.*
AU  - Jeon, C.E.*
AU  - Jern, C.*
AU  - Kamouchi, M.*
AU  - Keene, K.L.*
AU  - Kitazono, T.*
AU  - Kittner, S.J.*
AU  - Konuma, T.*
AU  - Kumar, A.*
AU  - Lacaze, P.*
AU  - Launer, L.J.*
AU  - Lee, K.J.D.*
AU  - Lepik, K.*
AU  - Li, J.*
AU  - Li, L.*
AU  - Manichaikul, A.*
AU  - Markus, H.S.*
AU  - Marston, N.A.*
AU  - Meitinger, T.
AU  - Mitchell, B.D.*
AU  - Montellano, F.A.*
AU  - Morisaki, T.*
AU  - Mosley, T.H.*
AU  - Nalls, M.A.*
AU  - Nordestgaard, B.G.*
AU  - O'Donnell, M.J.*
AU  - Onland-Moret, N.C.*
AU  - Ovbiagele, B.*
AU  - Peters, A.
AU  - Psaty, B.M.*
AU  - Rich, S.S.*
AU  - Rosand, J.*
AU  - Sabatine, M.S.*
AU  - Sacco, R.L.*
AU  - Saleheen, D.*
AU  - Sandset, E.C.*
AU  - Salomaa, V.*
AU  - Sargurupremraj, M.*
AU  - Sasaki, M.*
AU  - Satizabal, C.L.*
AU  - Schmidt, C.O.*
AU  - Shimizu, A.*
AU  - Smith, N.L.*
AU  - Sloane, K.L.*
AU  - Sutoh, Y.*
AU  - Sun, Y.V.*
AU  - Tanno, K.*
AU  - Tiedt, S.*
AU  - Tatlisumak, T.*
AU  - Torres-Aguila, N.P.*
AU  - Tiwari, H.K.*
AU  - Tregouet, D.A.*
AU  - Trompet, S.*
AU  - Tuladhar, A.M.*
AU  - Tybjærg-Hansen, A.*
AU  - van Vugt, M.*
AU  - Vibo, R.*
AU  - Verma, S.S.*
AU  - Wiggins, K.L.*
AU  - Wennberg, P.*
AU  - Woo, D.*
AU  - Wilson, P.W.F.*
AU  - Xu, H.*
AU  - Yang, Q.*
AU  - Yoon, K.*
AU  - Millwood, I.Y.*
AU  - Gieger, C.
AU  - Ninomiya, T.*
AU  - Grabe, H.J.*
AU  - Jukema, J.W.*
AU  - Rissanen, I.L.*
AU  - Strbian, D.*
AU  - Kim, Y.J.*
AU  - Chen, P.H.*
AU  - Mayerhofer, E.*
AU  - Howson, J.M.M.*
AU  - Irvin, M.R.*
AU  - Adams, H.H.*
AU  - Wassertheil-Smoller, S.*
AU  - Christensen, K.*
AU  - Ikram, M.A.*
AU  - Rundek, T.*
AU  - Worrall, B.B.*
AU  - Lathrop, G.M.*
AU  - Riaz, M.*
AU  - Simonsick, E.M.*
AU  - Kõrv, J.*
AU  - França, P.H.C.*
AU  - Zand, R.*
AU  - Prasad, K.*
AU  - Frikke-Schmidt, R.*
AU  - de Leeuw, F.E.*
AU  - Liman, T.*
AU  - Haeusler, K.G.*
AU  - Ruigrok, Y.M.*
AU  - Heuschmann, P.U.*
AU  - Longstreth, W.T. Jr.*
AU  - Jung, K.J.*
AU  - Bastarache, L.*
AU  - Paré, G.*
AU  - Damrauer, S.M.*
AU  - Chasman, D.I.*
AU  - Rotter, J.I.*
AU  - Anderson, C.D.*
AU  - Zwart, J.A.*
AU  - Niiranen, T.J.*
AU  - Fornage, M.*
AU  - Liaw, Y.P.*
AU  - Seshadri, S.*
AU  - Fernandez-Cadenas, I.*
AU  - Walters, R.G.*
AU  - Ruff, C.T.*
AU  - Owolabi, M.O.*
AU  - Huffman, J.E.*
AU  - Milani, L.*
AU  - Kamatani, Y.*
AU  - Dichgans, M.*
AU  - Debette, S.*
AU  - MEGASTROKE Consortium (Müller-Nurasyid, M.
AU  - Strauch, K.)
C1  - 66369
C2  - 52806
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 115-123
TI  - Stroke genetics informs drug discovery and risk prediction across ancestries.
JO  - Nature
VL  - 611
IS  - 7934
PB  - Nature Portfolio
PY  - 2022
SN  - 0028-0836
ER  - 

TY  - JOUR
AU  - Mishra, A.*
AU  - Malik, R.*
AU  - Hachiya, T.*
AU  - Jürgenson, T.*
AU  - Namba, S.*
AU  - Posner, D.C.*
AU  - Kamanu, F.K.*
AU  - Koido, M.*
AU  - Le Grand, Q.*
AU  - Shi, M.*
AU  - He, Y.*
AU  - Georgakis, M.K.*
AU  - Caro, I.*
AU  - Krebs, K.*
AU  - Liaw, Y.C.*
AU  - Vaura, F.C.*
AU  - Lin, K.*
AU  - Winsvold, B.S.*
AU  - Srinivasasainagendra, V.*
AU  - Parodi, L.*
AU  - Bae, H.J.*
AU  - Chauhan, G.*
AU  - Chong, M.R.*
AU  - Tomppo, L.*
AU  - Akinyemi, R.*
AU  - Roshchupkin, G.V.*
AU  - Habib, N.*
AU  - Jee, Y.H.*
AU  - Thomassen, J.Q.*
AU  - Abedi, V.*
AU  - Cárcel-Márquez, J.*
AU  - Nygaard, M.*
AU  - Leonard, H.L.*
AU  - Yang, C.*
AU  - Yonova-Doing, E.*
AU  - Knol, M.J.*
AU  - Lewis, A.J.*
AU  - Judy, R.L.*
AU  - Ago, T.*
AU  - Amouyel, P.*
AU  - Armstrong, N.D.*
AU  - Bakker, M.K.*
AU  - Bartz, T.M.*
AU  - Bennett, D.A.*
AU  - Bis, J.C.*
AU  - Bordes, C.*
AU  - Børte, S.*
AU  - Cain, A.*
AU  - Ridker, P.M.*
AU  - Cho, K.*
AU  - Chen, Z.*
AU  - Cruchaga, C.*
AU  - Cole, J.W.*
AU  - de Jager, P.L.*
AU  - de Cid, R.*
AU  - Endres, M.*
AU  - Ferreira, L.E.*
AU  - Geerlings, M.I.*
AU  - Gasca, N.C.*
AU  - Gudnason, V.*
AU  - Hata, J.*
AU  - He, J.*
AU  - Heath, A.K.*
AU  - Ho, Y.L.*
AU  - Havulinna, A.S.*
AU  - Hopewell, J.C.*
AU  - Hyacinth, H.I.*
AU  - Jacob, M.A.*
AU  - Jeon, C.E.*
AU  - Jern, C.*
AU  - Kamouchi, M.*
AU  - Keene, K.L.*
AU  - Kitazono, T.*
AU  - Kittner, S.J.*
AU  - Konuma, T.*
AU  - Kumar, A.*
AU  - Lacaze, P.*
AU  - Launer, L.J.*
AU  - Lee, K.J.D.*
AU  - Lepik, K.*
AU  - Li, J.*
AU  - Li, L.*
AU  - Manichaikul, A.*
AU  - Markus, H.S.*
AU  - Marston, N.A.*
AU  - Meitinger, T.
AU  - Mitchell, B.D.*
AU  - Montellano, F.A.*
AU  - Morisaki, T.*
AU  - Mosley, T.H.*
AU  - Nalls, M.A.*
AU  - Nordestgaard, B.G.*
AU  - O'Donnell, M.J.*
AU  - Onland-Moret, N.C.*
AU  - Ovbiagele, B.*
AU  - Peters, A.
AU  - Psaty, B.M.*
AU  - Rich, S.S.*
AU  - Rosand, J.*
AU  - Sabatine, M.S.*
AU  - Sacco, R.L.*
AU  - Saleheen, D.*
AU  - Sandset, E.C.*
AU  - Salomaa, V.*
AU  - Sargurupremraj, M.*
AU  - Sasaki, M.*
AU  - Satizabal, C.L.*
AU  - Schmidt, C.O.*
AU  - Shimizu, A.*
AU  - Smith, N.L.*
AU  - Sloane, K.L.*
AU  - Sutoh, Y.*
AU  - Sun, Y.V.*
AU  - Tanno, K.*
AU  - Tiedt, S.*
AU  - Tatlisumak, T.*
AU  - Torres-Aguila, N.P.*
AU  - Tiwari, H.K.*
AU  - Trégouët, D.A.*
AU  - Trompet, S.*
AU  - Tuladhar, A.M.*
AU  - Tybjærg-Hansen, A.*
AU  - van Vugt, M.*
AU  - Vibo, R.*
AU  - Verma, S.S.*
AU  - Wiggins, K.L.*
AU  - Wennberg, P.*
AU  - Woo, D.*
AU  - Wilson, P.W.F.*
AU  - Xu, H.*
AU  - Yang, Q.*
AU  - Yoon, K.*
AU  - Millwood, I.Y.*
AU  - Gieger, C.
AU  - Ninomiya, T.*
AU  - Grabe, H.J.*
AU  - Jukema, J.W.*
AU  - Rissanen, I.L.*
AU  - Strbian, D.*
AU  - Kim, Y.J.*
AU  - Chen, P.H.*
AU  - Mayerhofer, E.*
AU  - Howson, J.M.M.*
AU  - Irvin, M.R.*
AU  - Adams, H.H.*
AU  - Wassertheil-Smoller, S.*
AU  - Christensen, K.*
AU  - Ikram, M.A.*
AU  - Rundek, T.*
AU  - Worrall, B.B.*
AU  - Lathrop, G.M.*
AU  - Riaz, M.*
AU  - Simonsick, E.M.*
AU  - Kõrv, J.*
AU  - França, P.H.C.*
AU  - Zand, R.*
AU  - Prasad, K.*
AU  - Frikke-Schmidt, R.*
AU  - de Leeuw, F.E.*
AU  - Liman, T.*
AU  - Haeusler, K.G.*
AU  - Ruigrok, Y.M.*
AU  - Heuschmann, P.U.*
AU  - Longstreth, W.T. Jr.*
AU  - Jung, K.J.*
AU  - Bastarache, L.*
AU  - Paré, G.*
AU  - Damrauer, S.M.*
AU  - Chasman, D.I.*
AU  - Rotter, J.I.*
AU  - Anderson, C.D.*
AU  - Zwart, J.A.*
AU  - Niiranen, T.J.*
AU  - Fornage, M.*
AU  - Liaw, Y.P.*
AU  - Seshadri, S.*
AU  - Fernandez-Cadenas, I.*
AU  - Walters, R.G.*
AU  - Ruff, C.T.*
AU  - Owolabi, M.O.*
AU  - Huffman, J.E.*
AU  - Milani, L.*
AU  - Kamatani, Y.*
AU  - Dichgans, M.*
AU  - Debette, S.*
C1  - 66669
C2  - 53260
TI  - Publisher Correction: Stroke genetics informs drug discovery and risk prediction across ancestries.
JO  - Nature
VL  - 612
IS  - 7938
PY  - 2022
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Atherosclerotic plaques develop in the inner intimal layer of arteries and can cause heart attacks and strokes1.
       As plaques lack innervation, the effects of neuronal control on 
      atherosclerosis remain unclear. However, the immune system responds to 
      plaques by forming leukocyte infiltrates in the outer connective tissue 
      coat of arteries (the adventitia)2,3,4,5,6. Here, because the peripheral nervous system uses the adventitia as its principal conduit to reach distant targets7,8,9,
       we postulated that the peripheral nervous system may directly interact 
      with diseased arteries. Unexpectedly, widespread 
      neuroimmune cardiovascular interfaces (NICIs) arose in mouse and human 
      atherosclerosis-diseased adventitia segments showed expanded axon 
      networks, including growth cones at axon endings near immune cells and 
      media smooth muscle cells. Mouse NICIs established a structural 
      artery–brain circuit (ABC): abdominal adventitia nociceptive afferents10,11,12,13,14 entered the central nervous system through spinal cord T6–T13
       dorsal root ganglia and were traced to higher brain regions, including 
      the parabrachial and central amygdala neurons; and sympathetic efferent 
      neurons projected from medullary and hypothalamic neurons to the 
      adventitia through spinal intermediolateral neurons and both coeliac and
       sympathetic chain ganglia. Moreover, ABC peripheral nervous system 
      components were activated: splenic sympathetic and coeliac vagus nerve 
      activities increased in parallel to disease progression, whereas coeliac
       ganglionectomy led to the disintegration of adventitial NICIs, reduced 
      disease progression and enhanced plaque stability. Thus, the peripheral 
      nervous system uses NICIs to assemble a structural ABC, and therapeutic 
      intervention in the ABC attenuates atherosclerosis.
AU  - Mohanta, S.K.*
AU  - Peng, L.*
AU  - Li, Y.*
AU  - Lu, S.*
AU  - Sun, T.*
AU  - Carnevale, L.*
AU  - Perrotta, M.*
AU  - Ma, Z.*
AU  - Foerstera, B.*
AU  - Stanic, K.*
AU  - Zhang, C.*
AU  - Zhang, X.*
AU  - Szczepaniak, P.*
AU  - Bianchini, M.*
AU  - Saeed, B.R.*
AU  - Carnevale, R.*
AU  - Hu, D.
AU  - Nosalski, R.*
AU  - Pallante, F.*
AU  - Beer, M.*
AU  - Santovito, D.*
AU  - Ertürk, A.*
AU  - Mettenleiter, T.C.*
AU  - Klupp, B.G.*
AU  - Megens, R.T.A.*
AU  - Steffens, S.*
AU  - Pelisek, J.*
AU  - Eckstein, H.H.*
AU  - Kleemann, R.*
AU  - Habenicht, L.*
AU  - Mallat, Z.*
AU  - Michel, J.*
AU  - Bernhagen, J.*
AU  - Dichgans, M.*
AU  - D'Agostino, G.*
AU  - Guzik, T.J.*
AU  - Olofsson, P.S.*
AU  - Yin, C.*
AU  - Weber, C.*
AU  - Lembo, G.*
AU  - Carnevale, D.*
AU  - Habenicht, A.J.R.*
C1  - 64918
C2  - 51982
SP  - 152–159
TI  - Neuroimmune cardiovascular interfaces control atherosclerosis.
JO  - Nature
VL  - 650
IS  - 7908
PY  - 2022
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Brown adipose tissue (BAT) dissipates energy1,2 and promotes cardio-metabolic health3. Loss of BAT during obesity and aging is a principal hurdle for BAT-centered obesity therapies, but not much is known about BAT apoptosis. Here, untargeted metabolomics demonstrated that apoptotic brown adipocytes release a specific pattern of metabolites with purine metabolites being highly enriched. Interestingly, this apoptotic secretome enhances expression of the thermogenic program in healthy adipocytes. This effect is mediated by the purine inosine which stimulates energy expenditure (EE) in brown adipocytes via the cAMP/protein kinase A signaling pathway. Treatment of mice with inosine increased BAT-dependent EE and induced "browning" of white adipose tissue. Mechanistically, the equilibrative nucleoside transporter 1 (ENT1, SLC29A1) regulates inosine levels in BAT: ENT1-deficiency increases extracellular inosine levels and consequently enhances thermogenic adipocyte differentiation. In mice, pharmacological inhibition of ENT1 as well as global and adipose-specific ablation enhanced BAT activity and counteracted diet-induced obesity, respectively. In human brown adipocytes, knockdown or blockade of ENT1 increased extracellular inosine, which enhanced thermogenic capacity. Conversely, high ENT1 levels correlated with lower expression of the thermogenic marker UCP1 in human adipose tissues. Finally, the Ile216Thr loss of function mutation in human ENT1 was associated with significantly lower BMI and 59% lower odds of obesity for individuals carrying the Thr variant. Our data identify inosine as a metabolite released during apoptosis with "replace me" signaling function that regulates thermogenic fat and counteracts obesity.
AU  - Niemann, B.*
AU  - Haufs-Brusberg, S.*
AU  - Puetz, L.*
AU  - Feickert, M.*
AU  - Jaeckstein, M.Y.*
AU  - Hoffmann, A.
AU  - Zurkovic, J.*
AU  - Heine, M.*
AU  - Trautmann, E.-M.
AU  - Müller, C.E.*
AU  - Tönjes, A.*
AU  - Schlein, C.*
AU  - Jafari, A.*
AU  - Eltzschig, H.K.*
AU  - Gnad, T.*
AU  - Blüher, M.
AU  - Krahmer, N.
AU  - Kovacs, P.*
AU  - Heeren, J.*
AU  - Pfeifer, A.*
C1  - 65664
C2  - 52876
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 361–368
TI  - Apoptotic brown adipocytes enhance energy expenditure via extracellular inosine.
JO  - Nature
VL  - 609
IS  - 7926
PB  - Nature Portfolio
PY  - 2022
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury1–4. These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries5. Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.
AU  - Saunders, G.R.B.*
AU  - Wang, X.*
AU  - Chen, F.*
AU  - Jang, S.K.*
AU  - Liu, M.*
AU  - Wang, C.*
AU  - Gao, S.*
AU  - Jiang, Y.*
AU  - Khunsriraksakul, C.*
AU  - Otto, J.M.*
AU  - Addison, C.*
AU  - Akiyama, M.*
AU  - Albert, C.M.*
AU  - Aliev, F.*
AU  - Alonso, A.*
AU  - Arnett, D.K.*
AU  - Ashley-Koch, A.E.*
AU  - Ashrani, A.A.*
AU  - Barnes, K.C.*
AU  - Barr, R.G.*
AU  - Bartz, T.M.*
AU  - Becker, D.M.*
AU  - Bielak, L.F.*
AU  - Benjamin, E.J.*
AU  - Bis, J.C.*
AU  - Bjornsdottir, G.*
AU  - Blangero, J.*
AU  - Bleecker, E.R.*
AU  - Boardman, J.D.*
AU  - Boerwinkle, E.*
AU  - Boomsma, D.I.*
AU  - Boorgula, M.P.*
AU  - Bowden, D.W.*
AU  - Brody, J.A.*
AU  - Cade, B.E.*
AU  - Chasman, D.I.*
AU  - Chavan, S.*
AU  - Chen, Y.D.I.*
AU  - Chen, Z.*
AU  - Cheng, I.*
AU  - Cho, M.H.*
AU  - Choquet, H.*
AU  - Cole, J.W.*
AU  - Cornelis, M.C.*
AU  - Cucca, F.*
AU  - Curran, J.E.*
AU  - de Andrade, M.*
AU  - Dick, D.M.*
AU  - Docherty, A.R.*
AU  - Duggirala, R.*
AU  - Eaton, C.B.*
AU  - Ehringer, M.A.*
AU  - Esko, T.*
AU  - Faul, J.D.*
AU  - Silva, L.F.D.*
AU  - Fiorillo, E.*
AU  - Fornage, M.*
AU  - Freedman, B.I.*
AU  - Gabrielsen, M.E.*
AU  - Garrett, M.E.*
AU  - Gharib, S.A.*
AU  - Gieger, C.
AU  - Gillespie, N.A.*
AU  - Glahn, D.C.*
AU  - Gordon, S.D.*
AU  - Gu, C.C.*
AU  - Gu, D.*
AU  - Gudbjartsson, D.F.*
AU  - Guo, X.*
AU  - Haessler, J.*
AU  - Hall, M.E.*
AU  - Haller, T.*
AU  - Harris, K.M.*
AU  - He, J.*
AU  - Herd, P.*
AU  - Hewitt, J.K.*
AU  - Hickie, I.B.*
AU  - Hidalgo, B.*
AU  - Hokanson, J.E.*
AU  - Hopfer, C.J.*
AU  - Hottenga, J.J.*
AU  - Hou, L.*
AU  - Huang, H.*
AU  - Hung, Y.J.*
AU  - Hunter, D.J.*
AU  - Hveem, K.*
AU  - Hwang, S.J.*
AU  - Hwu, C.M.*
AU  - Iacono, W.G.*
AU  - Irvin, M.R.*
AU  - Jee, Y.H.*
AU  - Johnson, E.O.*
AU  - Joo, Y.Y.*
AU  - Jorgenson, E.*
AU  - Justice, A.E.*
AU  - Kamatani, Y.*
AU  - Kaplan, R.C.*
AU  - Kaprio, J.*
AU  - Kardia, S.L.R.*
AU  - Keller, M.C.*
AU  - Peters, A.
AU  - Peyser, P.A.*
AU  - Polderman, T.J.C.*
AU  - Redline, S.*
AU  - Reiner, A.P.*
AU  - Rice, J.P.*
AU  - Rich, S.S.*
AU  - Richmond, N.E.*
AU  - Schwartz, D.A.*
AU  - Shadyab, A.H.*
AU  - Sicinski, K.*
AU  - Sotoodehnia, N.*
AU  - Stallings, M.C.*
AU  - Stefánsson, H.*
AU  - Sun, X.*
AU  - Tal-Singer, R.*
AU  - Taylor, K.D.*
AU  - Turman, C.*
AU  - Tyrfingsson, T.*
AU  - Wall, T.L.*
AU  - Walters, R.G.*
AU  - Weiss, S.T.*
AU  - Whitfield, J.B.*
AU  - Wiggins, K.L.*
AU  - Willemsen, G.*
AU  - Winsvold, B.S.*
AU  - Yanek, L.R.*
AU  - Zhao, W.*
AU  - Zöllner, S.*
AU  - Zuccolo, L.*
AU  - Batini, C.*
AU  - Bergen, A.W.*
AU  - Bierut, L.J.*
AU  - David, S.P.*
AU  - Gagliano Taliun, S.A.*
AU  - Hancock, D.B.*
AU  - Munafò, M.R.*
AU  - Thorgeirsson, T.E.*
AU  - Liu, D.J.*
AU  - Vrieze, S.*
C1  - 66948
C2  - 53371
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 720–724
TI  - Genetic diversity fuels gene discovery for tobacco and alcohol use.
JO  - Nature
VL  - 612
IS  - 7941
PB  - Nature Portfolio
PY  - 2022
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Bacterial cell wall components provide various unique molecular structures that are detected by pattern recognition receptors (PRRs) of the innate immune system as non-self. Most bacterial species form a cell wall that consists of peptidoglycan (PGN), a polymeric structure comprising alternating amino sugars that form strands cross-linked by short peptides. Muramyl dipeptide (MDP) has been well documented as a minimal immunogenic component of peptidoglycan1-3. MDP is sensed by the cytosolic nucleotide-binding oligomerization domain-containing protein 24 (NOD2). Upon engagement, it triggers pro-inflammatory gene expression, and this functionality is of critical importance in maintaining a healthy intestinal barrier function5. Here, using a forward genetic screen to identify factors required for MDP detection, we identified N-acetylglucosamine kinase (NAGK) as being essential for the immunostimulatory activity of MDP. NAGK is broadly expressed in immune cells and has previously been described to contribute to the hexosamine biosynthetic salvage pathway6. Mechanistically, NAGK functions upstream of NOD2 by directly phosphorylating the N-acetylmuramic acid moiety of MDP at the hydroxyl group of its C6 position, yielding 6-O-phospho-MDP. NAGK-phosphorylated MDP-but not unmodified MDP-constitutes an agonist for NOD2. Macrophages from mice deficient in NAGK are completely deficient in MDP sensing. These results reveal a link between amino sugar metabolism and innate immunity to bacterial cell walls.
AU  - Stafford, C.A.*
AU  - Gassauer, A.M.*
AU  - de Oliveira Mann, C.C.*
AU  - Tanzer, M.C.*
AU  - Fessler, E.*
AU  - Wefers, B.
AU  - Nagl, D.*
AU  - Kuut, G.*
AU  - Sulek, K.*
AU  - Vasilopoulou, C.G.*
AU  - Schwojer, S.J.*
AU  - Wiest, A.*
AU  - Pfautsch, M.K.*
AU  - Wurst, W.
AU  - Yabal, M.*
AU  - Fröhlich, T.*
AU  - Mann, M.*
AU  - Gisch, N.*
AU  - Jae, L.T.*
AU  - Hornung, V.*
C1  - 65986
C2  - 53028
SP  - 590-596
TI  - Phosphorylation of muramyl peptides by NAGK is required for NOD2 activation.
JO  - Nature
VL  - 609
IS  - 7927
PY  - 2022
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Aggregates of medin amyloid (a fragment of the protein MFG-E8, also known as lactadherin) are found in the vasculature of almost all humans over 50 years of age1,2, making it the most common amyloid currently known. We recently reported that medin also aggregates in blood vessels of ageing wild-type mice, causing cerebrovascular dysfunction3. Here we demonstrate in amyloid-β precursor protein (APP) transgenic mice and in patients with Alzheimer’s disease that medin co-localizes with vascular amyloid-β deposits, and that in mice, medin deficiency reduces vascular amyloid-β deposition by half. Moreover, in both the mouse and human brain, MFG-E8 is highly enriched in the vasculature and both MFG-E8 and medin levels increase with the severity of vascular amyloid-β burden. Additionally, analysing data from 566 individuals in the ROSMAP cohort, we find that patients with Alzheimer’s disease have higher MFGE8 expression levels, which are attributable to vascular cells and are associated with increased measures of cognitive decline, independent of plaque and tau pathology. Mechanistically, we demonstrate that medin interacts directly with amyloid-β to promote its aggregation, as medin forms heterologous fibrils with amyloid-β, affects amyloid-β fibril structure, and cross-seeds amyloid-β aggregation both in vitro and in vivo. Thus, medin could be a therapeutic target for prevention of vascular damage and cognitive decline resulting from amyloid-β deposition in the blood vessels of the brain.
AU  - Wagner, J.*
AU  - Degenhardt, K.*
AU  - Veit, M.*
AU  - Louros, N.*
AU  - Konstantoulea, K.*
AU  - Skodras, A.*
AU  - Wild, K.*
AU  - Liu, P.*
AU  - Obermüller, U.*
AU  - Bansal, V.*
AU  - Dalmia, A.*
AU  - Häsler, L.M.*
AU  - Lambert, M.*
AU  - De Vleeschouwer, M.*
AU  - Davies, H.A.*
AU  - Madine, J.*
AU  - Kronenberg-Versteeg, D.*
AU  - Feederle, R.
AU  - Del Turco, D.*
AU  - Nilsson, K.P.R.*
AU  - Lashley, T.*
AU  - Deller, T.*
AU  - Gearing, M.*
AU  - Walker, L.C.*
AU  - Heutink, P.*
AU  - Rousseau, F.*
AU  - Schymkowitz, J.*
AU  - Jucker, M.*
AU  - Neher, J.J.*
C1  - 66731
C2  - 53283
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 123-131
TI  - Medin co-aggregates with vascular amyloid-β in Alzheimer’s disease.
JO  - Nature
VL  - 612
IS  - 7938
PB  - Nature Portfolio
PY  - 2022
SN  - 0028-0836
ER  - 

TY  - JOUR
AU  - Yengo, L.*
AU  - Vedantam, S.*
AU  - Marouli, E.*
AU  - Sidorenko, J.*
AU  - Bartell, E.*
AU  - Sakaue, S.*
AU  - Graff, M.*
AU  - Eliasen, A.U.*
AU  - Jiang, Y.*
AU  - Raghavan, S.*
AU  - Miao, J.*
AU  - Arias, J.D.*
AU  - Graham, S.E.*
AU  - Mukamel, R.E.*
AU  - Spracklen, C.N.*
AU  - Yin, X.*
AU  - Chen, S.H.*
AU  - Ferreira, T.*
AU  - Highland, H.H.*
AU  - Ji, Y.*
AU  - Karaderi, T.*
AU  - Lin, K.*
AU  - Lüll, K.*
AU  - Malden, D.E.*
AU  - Medina-Gomez, C.*
AU  - Machado, M.*
AU  - Moore, A.*
AU  - Rüeger, S.*
AU  - Sim, X.*
AU  - Vrieze, S.*
AU  - Ahluwalia, T.S.*
AU  - Akiyama, M.*
AU  - Allison, M.A.*
AU  - Alvarez, M.*
AU  - Andersen, M.K.*
AU  - Ani, A.*
AU  - Appadurai, V.*
AU  - Arbeeva, L.*
AU  - Bhaskar, S.*
AU  - Bielak, L.F.*
AU  - Bollepalli, S.*
AU  - Bonnycastle, L.L.*
AU  - Bork-Jensen, J.*
AU  - Bradfield, J.P.*
AU  - Bradford, Y.*
AU  - Braund, P.S.*
AU  - Brody, J.A.*
AU  - Burgdorf, K.S.*
AU  - Cade, B.E.*
AU  - Cai, H.*
AU  - Cai, Q.*
AU  - Campbell, A.*
AU  - Cañadas-Garre, M.*
AU  - Catamo, E.*
AU  - Chai, J.F.*
AU  - Chai, X.*
AU  - Chang, L.C.*
AU  - Chang, Y.C.*
AU  - Chen, C.H.*
AU  - Chesi, A.*
AU  - Choi, S.H.*
AU  - Chung, R.H.*
AU  - Cocca, M.*
AU  - Concas, M.P.*
AU  - Couture, C.*
AU  - Cuellar-Partida, G.*
AU  - Danning, R.*
AU  - Daw, E.W.*
AU  - Degenhard, F.*
AU  - Delgado, G.E.*
AU  - Delitala, A.*
AU  - Demirkan, A.*
AU  - Deng, X.*
AU  - Devineni, P.*
AU  - Dietl, A.*
AU  - Dimitriou, M.*
AU  - Dimitrov, L.*
AU  - Dorajoo, R.*
AU  - Ekici, A.B.*
AU  - Engmann, J.E.L.*
AU  - Fairhurst-Hunter, Z.*
AU  - Farmaki, A.E.*
AU  - Faul, J.D.*
AU  - Fernandez-Lopez, J.C.*
AU  - Forer, L.*
AU  - Francescatto, M.*
AU  - Freitag-Wolf, S.*
AU  - Fuchsberger, C.*
AU  - Galesloot, T.E.*
AU  - Gao, Y.*
AU  - Gao, Z.
AU  - Geller, F.*
AU  - Giannakopoulou, O.*
AU  - Giulianini, F.*
AU  - Gjesing, A.P.*
AU  - Goel, A.*
AU  - Gordon, S.D.*
AU  - Gorski, M.*
AU  - Grove, J.*
AU  - Guo, X.*
AU  - Hebbar, P.*
AU  - Hindy, G.*
AU  - Hottenga, J.-J.*
AU  - Gieger, C.
AU  - Girotto, G.*
AU  - Golightly, Y.M.*
AU  - Grallert, H.
AU  - Grarup, N.*
AU  - Hengstenberg , C.*
AU  - Pattaro, C.*
AU  - Peters, A.
AU  - Raitakari, O.*
AU  - Redline, S.*
AU  - Rayner, N.W.
AU  - Sidore, C.*
AU  - Sitlani, C.M.*
AU  - Southam, L.
AU  - Steinthorsdottir, V.*
AU  - Sun, L.*
AU  - Zeggini, E.
AU  - Zemel, B.S.*
AU  - Zheng, W.*
AU  - Zmuda, J.M*
AU  - Zonderman, A.B.*
AU  - Rivadeneira, F.*
AU  - Thorsteinsdottir, U.*
AU  - Stefansson, K.*
AU  - Walters, R.G.*
AU  - Esko, T.*
AU  - Assimes, T.L.*
AU  - Auton, A.*
AU  - Abecasis, G.R.*
AU  - Berndt, S.I*
AU  - Lettre, G.*
AU  - Frayling, T.M.*
AU  - Okada, Y.*
AU  - Wood, A.R.*
AU  - Visscher, P.M.*
AU  - Hirschhorn, J.N.*
C1  - 66442
C2  - 52832
SP  - 704-712
TI  - A saturated map of common genetic variants associated with human height.
JO  - Nature
VL  - 610
IS  - 7933
PY  - 2022
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - In this Article, the affiliations for author Ünal Coskun were incorrect. They should be ‘German Center for Diabetes Research (DZD), Neuherberg, Germany’, ‘Paul Langerhans Institute Dresden of Helmholtz Center Munich, Technical University Dresden, Dresden, Germany’ and ‘Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine and University Clinic Carl Gustav Carus, Technical University Dresden, Dresden, Germany’ (affiliations 2, 10 and 14, respectively), and not ‘Department of Microsystems Engineering (IMTEK), University of Freiburg, Freiburg, Germany’ (affiliation 5). The original Article has been corrected online.
AU  - Ansarullah
AU  - Jain, C.
AU  - Far, F.F.
AU  - Homberg, S.
AU  - Wißmiller, K.
AU  - von Hahn, F.
AU  - Raducanu, A.
AU  - Schirge, S.
AU  - Sterr, M.
AU  - Bilekova, S.
AU  - Siehler, J.
AU  - Wiener, J.
AU  - Oppenländer, L.
AU  - Morshedi, A.
AU  - Bastidas-Ponce, A.
AU  - Collden, G.
AU  - Irmler, M.
AU  - Beckers, J.
AU  - Feuchtinger, A.
AU  - Grzybek, M.
AU  - Ahlbrecht, C.
AU  - Feederle, R.
AU  - Plettenburg, O.
AU  - Müller, T.D.
AU  - Meier, M.
AU  - Tschöp, M.H.
AU  - Coskun, Ü.
AU  - Lickert, H.
C1  - 61542
C2  - 50332
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Author Correction: Inceptor counteracts insulin signalling in β-cells to control glycaemia.
JO  - Nature
VL  - 592
PB  - Nature Research
PY  - 2021
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Resistance to insulin and insulin-like growth factor 1 (IGF1) in pancreatic β-cells causes overt diabetes in mice; thus, therapies that sensitize β-cells to insulin may protect patients with diabetes against β-cell failure1–3. Here we identify an inhibitor of insulin receptor (INSR) and IGF1 receptor (IGF1R) signalling in mouse β-cells, which we name the insulin inhibitory receptor (inceptor; encoded by the gene Iir). Inceptor contains an extracellular cysteine-rich domain with similarities to INSR and IGF1R4, and a mannose 6-phosphate receptor domain that is also found in the IGF2 receptor (IGF2R)5. Knockout mice that lack inceptor (Iir−/−) exhibit signs of hyperinsulinaemia and hypoglycaemia, and die within a few hours of birth. Molecular and cellular analyses of embryonic and postnatal pancreases from Iir−/− mice showed an increase in the activation of INSR–IGF1R in Iir−/− pancreatic tissue, resulting in an increase in the proliferation and mass of β-cells. Similarly, inducible β-cell-specific Iir−/− knockout in adult mice and in ex vivo islets led to an increase in the activation of INSR–IGF1R and increased proliferation of β-cells, resulting in improved glucose tolerance in vivo. Mechanistically, inceptor interacts with INSR–IGF1R to facilitate clathrin-mediated endocytosis for receptor desensitization. Blocking this physical interaction using monoclonal antibodies against the extracellular domain of inceptor resulted in the retention of inceptor and INSR at the plasma membrane to sustain the activation of INSR–IGF1R in β-cells. Together, our findings show that inceptor shields insulin-producing β-cells from constitutive pathway activation, and identify inceptor as a potential molecular target for INSR–IGF1R sensitization and diabetes therapy.
AU  - Ansarullah
AU  - Jain, C.
AU  - Far, F.F.
AU  - Homberg, S.
AU  - Wissmiller, K.
AU  - Gräfin von Hahn, F.
AU  - Raducanu, A.
AU  - Schirge, S.
AU  - Sterr, M.
AU  - Bilekova, S.
AU  - Siehler, J.
AU  - Wiener, J.
AU  - Oppenländer, L.
AU  - Morshedi, A.
AU  - Bastidas-Ponce, A.
AU  - Collden, G.
AU  - Irmler, M.
AU  - Beckers, J.
AU  - Feuchtinger, A.
AU  - Grzybek, M.
AU  - Ahlbrecht, C.
AU  - Feederle, R.
AU  - Plettenburg, O.
AU  - Müller, T.D.
AU  - Meier, M.
AU  - Tschöp, M.H.
AU  - Coskun, Ü.
AU  - Lickert, H.
C1  - 61144
C2  - 49992
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 326–331
TI  - Inceptor counteracts insulin signalling in β-cells to control glycaemia.
JO  - Nature
VL  - 590
PB  - Nature Research
PY  - 2021
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - In the HTML version of this Article, owing to a typesetting error, the affiliations for author Indrabahadur Singh were incorrect. The correct affiliation is ‘Emmy Noether Research Group Epigenetic Machineries and Cancer, Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany’. The PDF and print versions of the Article are correct. In addition, Ilias Angelidis should have been listed as an author, with the affiliation: ‘Comprehensive Pneumology Center (CPC), Institute of Lung Biology and Disease, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Neuherberg, Germany’. They designed, undertook, and analysed scRNA-seq experiments, and analysed and interpreted data (see ‘Author contributions’). Finally, in the original Article, authors Mathias Heikenwalder and Ali Önder Yildirim were listed as ‘jointly supervising’ authors instead of ‘equally contributing’ authors, alongside authors Thomas M. Conlon and Gerrit John-Schuster. The original Article has been corrected online.
AU  - Conlon, T.M.
AU  - John-Schuster, G.
AU  - Heide, D.*
AU  - Pfister, D.*
AU  - Lehmann, M.
AU  - Hu, Y.*
AU  - Ertüz, Z.
AU  - López, M.A.*
AU  - Ansari, M.
AU  - Strunz, M.
AU  - Mayr, C.
AU  - Angelidis, I.
AU  - Ciminieri, C.*
AU  - Costa, R.
AU  - Kohlhepp, M.S.*
AU  - Guillot, A.*
AU  - Güneş, G.
AU  - Jeridi, A.
AU  - Funk, M.C.*
AU  - Beroshvili, G.
AU  - Prokosch, S.*
AU  - Hetzer, J.*
AU  - Verleden, S.E.*
AU  - Alsafadi, H.N.
AU  - Lindner, M.
AU  - Burgstaller, G.
AU  - Becker, L.
AU  - Irmler, M.
AU  - Dudek, M.*
AU  - Janzen, J.*
AU  - Goffin, E.*
AU  - Gosens, R.*
AU  - Knolle, P.*
AU  - Pirotte, B.*
AU  - Stöger, T.
AU  - Beckers, J.
AU  - Wagner, D.E.
AU  - Singh, I.*
AU  - Theis, F.J.
AU  - Hrabě de Angelis, M.
AU  - O’Connor, T.*
AU  - Tacke, F.*
AU  - Boutros, M.*
AU  - Dejardin, E.*
AU  - Eickelberg, O.*
AU  - Schiller, H. B.
AU  - Königshoff, M.
AU  - Heikenwalder, M.*
AU  - Yildirim, A.Ö.
C1  - 60844
C2  - 50264
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - E6
TI  - Publisher Correction: Inhibition of LTβR signalling activates WNT-induced regeneration in lung (Nature, (2020), 588, 7836, (151-156), 10.1038/s41586-020-2882-8).
JO  - Nature
VL  - 589
IS  - 7842
PB  - Nature Research
PY  - 2021
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - In this Article, the surname of Tobias Boettler was incorrectly shown as ‘Böttler’, and the surname of author Jan-Philipp Mallm was incorrectly shown as ‘Malm’. The original Article has been corrected online.
AU  - Dudek, M.*
AU  - Pfister, D.*
AU  - Donakonda, S.*
AU  - Filpe, P.*
AU  - Schneider, A.*
AU  - Laschinger, M.*
AU  - Hartmann, D.*
AU  - Hüser, N.*
AU  - Meiser, P.*
AU  - Bayerl, F.*
AU  - Inverso, D.*
AU  - Wigger, J.*
AU  - Sebode, M.*
AU  - Öllinger, R.*
AU  - Rad, R.*
AU  - Hegenbarth, S.*
AU  - Anton, M.*
AU  - Guillot, A.*
AU  - Bowman, A.*
AU  - Heide, D.*
AU  - Müller, F.*
AU  - Ramadori, P.*
AU  - Leone, V.
AU  - García-Cáceres, C.
AU  - Gruber, T.
AU  - Seifert, G.*
AU  - Kabat, A.M.*
AU  - Mallm, J.P.*
AU  - Reider, S.*
AU  - Effenberger, M.*
AU  - Roth, S.*
AU  - Billeter, A.T.*
AU  - Müller-Stich, B.*
AU  - Pearce, E.J.*
AU  - Koch-Nolte, F.*
AU  - Käser, R.*
AU  - Tilg, H.*
AU  - Thimme, R.*
AU  - Boettler, T.*
AU  - Tacke, F.*
AU  - Dufour, J.F.*
AU  - Haller, D.*
AU  - Murray, P.J.*
AU  - Heeren, R.*
AU  - Zehn, D.*
AU  - Böttcher, J.P.*
AU  - Heikenwalder, M.*
AU  - Knolle, P.A.*
C1  - 62041
C2  - 50630
TI  - Author Correction: Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH.
JO  - Nature
VL  - 593
PY  - 2021
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Nonalcoholic steatohepatitis (NASH) is a manifestation of systemic metabolic disease related to obesity, and causes liver disease and cancer1,2. The accumulation of metabolites leads to cell stress and inflammation in the liver3, but mechanistic understandings of liver damage in NASH are incomplete. Here, using a preclinical mouse model that displays key features of human NASH (hereafter, NASH mice), we found an indispensable role for T cells in liver immunopathology. We detected the hepatic accumulation of CD8 T cells with phenotypes that combined tissue residency (CXCR6) with effector (granzyme) and exhaustion (PD1) characteristics. Liver CXCR6+ CD8 T cells were characterized by low activity of the FOXO1 transcription factor, and were abundant in NASH mice and in patients with NASH. Mechanistically, IL-15 induced FOXO1 downregulation and CXCR6 upregulation, which together rendered liver-resident CXCR6+ CD8 T cells susceptible to metabolic stimuli (including acetate and extracellular ATP) and collectively triggered auto-aggression. CXCR6+ CD8 T cells from the livers of NASH mice or of patients with NASH had similar transcriptional signatures, and showed auto-aggressive killing of cells in an MHC-class-I-independent fashion after signalling through P2X7 purinergic receptors. This killing by auto-aggressive CD8 T cells fundamentally differed from that by antigen-specific cells, which mechanistically distinguishes auto-aggressive and protective T cell immunity.
AU  - Dudek, M.*
AU  - Pfister, D.*
AU  - Donakonda, S.*
AU  - Filpe, P.*
AU  - Schneider, A.*
AU  - Laschinger, M.*
AU  - Hartmann, D.*
AU  - Hüser, N.*
AU  - Meiser, P.*
AU  - Bayerl, F.*
AU  - Inverso, D.*
AU  - Wigger, J.*
AU  - Sebode, M.*
AU  - Öllinger, R.*
AU  - Rad, R.*
AU  - Hegenbarth, S.*
AU  - Anton, M.*
AU  - Guillot, A.*
AU  - Bowman, A.*
AU  - Heide, D.*
AU  - Müller, F.*
AU  - Ramadori, P.*
AU  - Leone, V.
AU  - García-Cáceres, C.
AU  - Gruber, T.
AU  - Seifert, G.*
AU  - Kabat, A.M.*
AU  - Malm, J.P.*
AU  - Reider, S.*
AU  - Effenberger, M.*
AU  - Roth, S.*
AU  - Billeter, A.T.*
AU  - Müller-Stich, B.*
AU  - Pearce, E.J.*
AU  - Koch-Nolte, F.*
AU  - Käser, R.*
AU  - Tilg, H.*
AU  - Thimme, R.*
AU  - Böttler, T.*
AU  - Tacke, F.*
AU  - Dufour, J.F.*
AU  - Haller, D.*
AU  - Murray, P.J.*
AU  - Heeren, R.*
AU  - Zehn, D.*
AU  - Böttcher, J.P.*
AU  - Heikenwälder, M.*
AU  - Knolle, P.A.*
C1  - 61688
C2  - 50396
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 444-449
TI  - Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH.
JO  - Nature
VL  - 592
IS  - 7854
PB  - Nature Research
PY  - 2021
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - During the transition from a healthy state to cardiometabolic disease, patients become heavily medicated, which leads to an increasingly aberrant gut microbiome and serum metabolome, and complicates biomarker discovery1-5. Here, through integrated multi-omics analyses of 2,173 European residents from the MetaCardis cohort, we show that the explanatory power of drugs for the variability in both host and gut microbiome features exceeds that of disease. We quantify inferred effects of single medications, their combinations as well as additive effects, and show that the latter shift the metabolome and microbiome towards a healthier state, exemplified in synergistic reduction in serum atherogenic lipoproteins by statins combined with aspirin, or enrichment of intestinal Roseburia by diuretic agents combined with beta-blockers. Several antibiotics exhibit a quantitative relationship between the number of courses prescribed and progression towards a microbiome state that is associated with the severity of cardiometabolic disease. We also report a relationship between cardiometabolic drug dosage, improvement in clinical markers and microbiome composition, supporting direct drug effects. Taken together, our computational framework and resulting resources enable the disentanglement of the effects of drugs and disease on host and microbiome features in multimedicated individuals. Furthermore, the robust signatures identified using our framework provide new hypotheses for drug-host-microbiome interactions in cardiometabolic disease.
AU  - Forslund, S.K.*
AU  - Chakaroun, R.*
AU  - Zimmermann-Kogadeeva, M.*
AU  - Markó, L.*
AU  - Aron-Wisnewsky, J.*
AU  - Nielsen, T.*
AU  - Moitinho-Silva, L.*
AU  - Schmidt, T.S.B.*
AU  - Falony, G.*
AU  - Vieira-Silva, S.*
AU  - Adriouch, S.*
AU  - Alves, R.J.*
AU  - Assmann, K.*
AU  - Bastard, J.P.*
AU  - Birkner, T.*
AU  - Caesar, R.*
AU  - Chilloux, J.*
AU  - Coelho, L.P.*
AU  - Fezeu, F.*
AU  - Galleron, N.*
AU  - Helft, G.*
AU  - Isnard, R.*
AU  - Ji, B.*
AU  - Kuhn, M.*
AU  - Le Chatelier, E.*
AU  - Myridakis, A.*
AU  - Olsson, L.*
AU  - Pons, N.*
AU  - Prifti, E.*
AU  - Quinquis, B.*
AU  - Roume, H.*
AU  - Salem, J.E.*
AU  - Sokolovska, N.*
AU  - Tremaroli, V.*
AU  - Valles-Colomer, M.*
AU  - Lewinter, C.*
AU  - Søndertoft, N.B.*
AU  - Pedersen, H.K.*
AU  - Hansen, T.H.*
AU  - Gøtze, J.P.*
AU  - Køber, L.*
AU  - Vestergaard, H.*
AU  - Hansen, T.*
AU  - Zucker, J.D.*
AU  - Hercberg, S.*
AU  - Oppert, J.M.*
AU  - Letunic, I.*
AU  - Nielsen, J.*
AU  - Bäckhed, F.*
AU  - Ehrlich, S.D.*
AU  - Dumas, M.E.*
AU  - Raes, J.*
AU  - Pedersen, O.*
AU  - Clément, K.*
AU  - Stumvoll, M.
AU  - Bork, P.*
C1  - 63800
C2  - 51764
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 500-505
TI  - Combinatorial, additive and dose-dependent drug-microbiome associations.
JO  - Nature
VL  - 600
IS  - 7889
PB  - Nature Portfolio
PY  - 2021
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use1. Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels2, heart disease remains the leading cause of death worldwide3. Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS4-23 have been conducted in European ancestry populations and may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. These include differences in allele frequencies, effect sizes and linkage-disequilibrium patterns24. Here we conduct a multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65 million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support the expansion of recruitment of additional ancestries, even with relatively small sample sizes. We find that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in approximately 295,000 individuals from 7 ancestry groupings). Modest gains in the number of discovered loci and ancestry-specific variants were also achieved. As GWAS expand emphasis beyond the identification of genes and fundamental biology towards the use of genetic variants for preventive and precision medicine25, we anticipate that increased diversity of participants will lead to more accurate and equitable26 application of polygenic scores in clinical practice.
AU  - Graham, S.E.*
AU  - Clarke, S.L.*
AU  - Wu, K.H.*
AU  - Kanoni, S.*
AU  - Zajac, G.J.M.*
AU  - Ramdas, S.*
AU  - Surakka, I.*
AU  - Ntalla, I.*
AU  - Vedantam, S.*
AU  - Winkler, T.W.*
AU  - Locke, A.E.*
AU  - Marouli, E.*
AU  - Hwang, M.Y.*
AU  - Han, S.*
AU  - Narita, A.*
AU  - Choudhury, A.*
AU  - Bentley, A.R.*
AU  - Ekoru, K.*
AU  - Verma, A.*
AU  - Trivedi, B.*
AU  - Martin, H.C.*
AU  - Hunt, K.A.*
AU  - Hui, Q.*
AU  - Klarin, D.*
AU  - Zhu, X.*
AU  - Thorleifsson, G.*
AU  - Helgadottir, A.*
AU  - Gudbjartsson, D.F.*
AU  - Holm, H.*
AU  - Olafsson, I.*
AU  - Akiyama, M.*
AU  - Sakaue, S.*
AU  - Terao, C.*
AU  - Kanai, M.*
AU  - Zhou, W.*
AU  - Brumpton, B.M.*
AU  - Rasheed, H.*
AU  - Ruotsalainen, S.E.*
AU  - Havulinna, A.S.*
AU  - Veturi, Y.*
AU  - Feng, Q.*
AU  - Rosenthal, E.A.*
AU  - Lingren, T.*
AU  - Pacheco, J.A.*
AU  - Pendergrass, S.A.*
AU  - Haessler, J.*
AU  - Giulianini, F.*
AU  - Bradford, Y.*
AU  - Miller, J.E.*
AU  - Campbell, A.*
AU  - Lin, K.*
AU  - Millwood, I.Y.*
AU  - Hindy, G.*
AU  - Rasheed, A.*
AU  - Faul, J.D.*
AU  - Zhao, W.*
AU  - Weir, D.R.*
AU  - Turman, C.*
AU  - Huang, H.*
AU  - Graff, M.*
AU  - Mahajan, A.*
AU  - Brown, M.R.*
AU  - Zhang, W.*
AU  - Yu, K.*
AU  - Schmidt, E.M.*
AU  - Pandit, A.*
AU  - Gustafsson, S.*
AU  - Yin, X.*
AU  - Luan, J.*
AU  - Zhao, J.H.*
AU  - Matsuda, F.*
AU  - Jang, H.M.*
AU  - Yoon, K.*
AU  - Medina-Gomez, C.*
AU  - Pitsillides, A.*
AU  - Hottenga, J.J.*
AU  - Willemsen, G.*
AU  - Wood, A.R.*
AU  - Ji, Y.*
AU  - Gao, Z.
AU  - Haworth, S.*
AU  - Mitchell, R.E.*
AU  - Chai, J.F.*
AU  - Aadahl, M.*
AU  - Yao, J.*
AU  - Manichaikul, A.*
AU  - Warren, H.R.*
AU  - Ramirez, J.*
AU  - Bork-Jensen, J.*
AU  - Kårhus, L.L.*
AU  - Goel, A.*
AU  - Sabater-Lleal, M.*
AU  - Noordam, R.*
AU  - Sidore, C.*
AU  - Fiorillo, E.*
AU  - McDaid, A.F.*
AU  - Marques-Vidal, P.*
AU  - Wielscher, M.*
AU  - Trompet, S.*
AU  - Sattar, N.*
AU  - Møllehave, L.T.*
AU  - Thuesen, B.H.*
AU  - Munz, M.*
AU  - Zeng, L.*
AU  - Huang, J.*
AU  - Yang, B.*
AU  - Poveda, A.*
AU  - Kurbasic, A.*
AU  - Lamina, C.*
AU  - Forer, L.*
AU  - Scholz, M.*
AU  - Galesloot, T.E.*
AU  - Bradfield, J.P.*
AU  - Daw, E.W.*
AU  - Zmuda, J.M.*
AU  - Mitchell, J.S.*
AU  - Fuchsberger, C.*
AU  - Christensen, H.*
AU  - Brody, J.A.*
AU  - Feitosa, M.F.*
AU  - Wojczynski, M.K.*
AU  - Preuss, M.*
AU  - Mangino, M.*
AU  - Christofidou, P.*
AU  - Verweij, N.*
AU  - Engmann, J.*
AU  - Kember, R.L.*
AU  - Slieker, R.C.*
AU  - Lo, K.S.*
AU  - Zilhao, N.R.*
AU  - Le, P.*
AU  - Kleber, M.E.*
AU  - Delgado, G.E.*
AU  - Huo, S.*
AU  - Ikeda, D.D.*
AU  - Iha, H.*
AU  - Yang, J.*
AU  - Liu, J.*
AU  - Leonard, H.L.*
AU  - Marten, J.*
AU  - Schmidt, B.*
AU  - Arendt, M.*
AU  - Smyth, L.J.*
AU  - Cañadas-Garre, M.*
AU  - Wang, C.*
AU  - Nakatochi, M.*
AU  - Wong, A.*
AU  - Hutri-Kähönen, N.*
AU  - Sim, X.*
AU  - Xia, R.*
AU  - Huerta-Chagoya, A.*
AU  - Fernandez-Lopez, J.C.*
AU  - Lyssenko, V.*
AU  - Ahmed, M.*
AU  - Jackson, A.U.*
AU  - Irvin, M.R.*
AU  - Oldmeadow, C.*
AU  - Kim, H.N.*
AU  - Ryu, S.*
AU  - Timmers, P.R.H.J.*
AU  - Arbeeva, L.*
AU  - Dorajoo, R.*
AU  - Lange, L.A.*
AU  - Chai, X.*
AU  - Prasad, G.*
AU  - Lorés-Motta, L.*
AU  - Pauper, M.*
AU  - Long, J.*
AU  - Li, X.*
AU  - Theusch, E.*
AU  - Takeuchi, F.*
AU  - Spracklen, C.N.*
AU  - Loukola, A.*
AU  - Bollepalli, S.*
AU  - Warner, S.C.*
AU  - Wang, Y.X.*
AU  - Wei, W.B.*
AU  - Nutile, T.*
AU  - Ruggiero, D.*
AU  - Sung, Y.J.*
AU  - Hung, Y.J.*
AU  - Chen, S.*
AU  - Liu, F.*
AU  - Kentistou, K.A.*
AU  - Gorski, M.*
AU  - Brumat, M.*
AU  - Meidtner, K.*
AU  - Bielak, L.F.*
AU  - Smith, J.A.*
AU  - Hebbar, P.*
AU  - Farmaki, A.E.*
AU  - Hofer, E.*
AU  - Lin, M.*
AU  - Xue, C.*
AU  - Zhang, J.*
AU  - Concas, M.P.*
AU  - Vaccargiu, S.*
AU  - van der Most, P.J.*
AU  - Pitkänen, N.*
AU  - Cade, B.E.*
AU  - Lee, J.*
AU  - van der Laan, S.W.*
AU  - Chitrala, K.N.*
AU  - Weiss, S.*
AU  - Zimmermann, M.E.*
AU  - Lee, J.Y.*
AU  - Choi, H.S.*
AU  - Nethander, M.*
AU  - Freitag-Wolf, S.*
AU  - Southam, L.
AU  - Rayner, N.W.
AU  - Wang, C.A.*
AU  - Lin, S.Y.*
AU  - Wang, J.S.*
AU  - Couture, C.*
AU  - Lyytikäinen, L.P.*
AU  - Nikus, K.*
AU  - Cuellar-Partida, G.*
AU  - Vestergaard, H.*
AU  - Hildalgo, B.*
AU  - Giannakopoulou, O.*
AU  - Cai, Q.*
AU  - Obura, M.O.*
AU  - van Setten, J.*
AU  - Schwander, K.*
AU  - Terzikhan, N.*
AU  - Shin, J.H.*
AU  - Jackson, R.D.*
AU  - Reiner, A.P.*
AU  - Martin, L.W.*
AU  - Chen, Z.*
AU  - Li, L.*
AU  - Highland, H.M.*
AU  - Young, K.L.*
AU  - Kawaguchi, T.*
AU  - Thiery, J.*
AU  - Bis, J.C.*
AU  - Nadkarni, G.N.*
AU  - Launer, L.J.*
AU  - Li, H.*
AU  - Nalls, M.A.*
AU  - Raitakari, O.T.*
AU  - Ichihara, S.*
AU  - Wild, S.H.*
AU  - Nelson, C.P.*
AU  - Campbell, H.*
AU  - Jäger, S.*
AU  - Nabika, T.*
AU  - Al-Mulla, F.*
AU  - Niinikoski, H.*
AU  - Braund, P.S.*
AU  - Kolcic, I.*
AU  - Kovacs, P.*
AU  - Giardoglou, T.*
AU  - Katsuya, T.*
AU  - Bhatti, K.F.*
AU  - de Kleijn, D.P.*
AU  - de Borst, G.J.*
AU  - Kim, E.K.*
AU  - Adams, H.H.H.*
AU  - Ikram, M.A.*
AU  - Asselbergs, F.W.*
AU  - Kraaijeveld, A.O.*
AU  - Beulens, J.W.J.*
AU  - Shu, X.O.*
AU  - Rallidis, L.S.*
AU  - Pedersen, O.*
AU  - Hansen, T.*
AU  - Mitchell, P.*
AU  - Hewitt, A.W.*
AU  - Kähönen, M.*
AU  - Perusse, L.*
AU  - Bouchard, C.*
AU  - Tönjes, A.*
AU  - Chen, Y.I.*
AU  - Pennell, C.E.*
AU  - Mori, T.A.*
AU  - Lieb, W.*
AU  - Franke, A.*
AU  - Ohlsson, C.*
AU  - Mellström, D.*
AU  - Cho, Y.S.*
AU  - Lee, H.*
AU  - Yuan, J.M.*
AU  - Koh, W.P.*
AU  - Rhee, S.Y.*
AU  - Woo, J.T.*
AU  - Heid, I.M.*
AU  - Stark, K.J.*
AU  - Völzke, H.*
AU  - Homuth, G.*
AU  - Evans, M.K.*
AU  - Zonderman, A.B.*
AU  - Polasek, O.*
AU  - Pasterkamp, G.*
AU  - Hoefer, I.E.*
AU  - Redline, S.*
AU  - Pahkala, K.*
AU  - Oldehinkel, A.J.*
AU  - Snieder, H.*
AU  - Biino, G.*
AU  - Schmidt, R.*
AU  - Schmidt, H.*
AU  - Chen, Y.E.*
AU  - Bandinelli, S.*
AU  - Dedoussis, G.*
AU  - Thanaraj, T.A.*
AU  - Kardia, S.L.R.*
AU  - Kato, N.*
AU  - Schulze, M.B.*
AU  - Girotto, G.*
AU  - Jung, B.*
AU  - Böger, C.A.*
AU  - Joshi, P.K.*
AU  - Bennett, D.A.*
AU  - de Jager, P.L.*
AU  - Lu, X.*
AU  - Mamakou, V.*
AU  - Brown, M.*
AU  - Caulfield, M.J.*
AU  - Munroe, P.B.*
AU  - Guo, X.*
AU  - Ciullo, M.*
AU  - Jonas, J.B.*
AU  - Samani, N.J.*
AU  - Kaprio, J.*
AU  - Pajukanta, P.*
AU  - Adair, L.S.*
AU  - Bechayda, S.A.*
AU  - de Silva, H.J.*
AU  - Wickremasinghe, A.R.*
AU  - Krauss, R.M.*
AU  - Wu, J.Y.*
AU  - Zheng, W.*
AU  - den Hollander, A.I.*
AU  - Bharadwaj, D.*
AU  - Correa, A.*
AU  - Wilson, J.G.*
AU  - Lind, L.*
AU  - Heng, C.K.*
AU  - Nelson, A.E.*
AU  - Golightly, Y.M.*
AU  - Wilson, J.F.*
AU  - Penninx, B.*
AU  - Kim, H.L.*
AU  - Attia, J.*
AU  - Scott, R.J.*
AU  - Rao, D.C.*
AU  - Arnett, D.K.*
AU  - Walker, M.*
AU  - Koistinen, H.A.*
AU  - Chandak, G.R.*
AU  - Yajnik, C.S.*
AU  - Mercader, J.M.*
AU  - Tusié-Luna, T.*
AU  - Aguilar-Salinas, C.A.*
AU  - Villalpando, C.G.*
AU  - Orozco, L.*
AU  - Fornage, M.*
AU  - Tai, E.S.*
AU  - van Dam, R.M.*
AU  - Lehtimäki, T.*
AU  - Chaturvedi, N.*
AU  - Yokota, M.*
AU  - Reilly, D.F.*
AU  - McKnight, A.J.*
AU  - Kee, F.*
AU  - Jöckel, K.H.*
AU  - McCarthy, M.I.*
AU  - Palmer, C.N.A.*
AU  - Vitart, V.*
AU  - Hayward, C.*
AU  - Simonsick, E.*
AU  - van Duijn, C.M.*
AU  - Lu, F.*
AU  - Qu, J.*
AU  - Hishigaki, H.*
AU  - Lin, X.*
AU  - März, W.*
AU  - Parra, E.J.*
AU  - Cruz, M.*
AU  - Gudnason, V.*
AU  - Tardif, J.C.*
AU  - Lettre, G.*
AU  - 't Hart, L.M.*
AU  - Elders, P.J.M.*
AU  - Damrauer, S.M.*
AU  - Kumari, M.*
AU  - Kivimaki, M.*
AU  - van der Harst, P.*
AU  - Spector, T.D.*
AU  - Loos, R.J.F.*
AU  - Province, M.A.*
AU  - Psaty, B.M.*
AU  - Brandslund, I.*
AU  - Pramstaller, P.P.*
AU  - Christensen, K.*
AU  - Ripatti, S.*
AU  - Widen, E.*
AU  - Hakonarson, H.*
AU  - Grant, S.F.A.*
AU  - Kiemeney, L.A.L.M.*
AU  - de Graaf, J.*
AU  - Loeffler, M.*
AU  - Kronenberg, F.*
AU  - Gu, D.*
AU  - Erdmann, J.*
AU  - Schunkert, H.*
AU  - Franks, P.W.*
AU  - Linneberg, A.*
AU  - Jukema, J.W.*
AU  - Khera, A.V.*
AU  - Männikkö, M.*
AU  - Jarvelin, M.R.*
AU  - Kutalik, Z.*
AU  - Cucca, F.*
AU  - Mook-Kanamori, D.O.*
AU  - van Dijk, K.W.*
AU  - Watkins, H.*
AU  - Strachan, D.P.*
AU  - Grarup, N.*
AU  - Sever, P.*
AU  - Poulter, N.*
AU  - Rotter, J.I.*
AU  - Dantoft, T.M.*
AU  - Karpe, F.*
AU  - Neville, M.J.*
AU  - Timpson, N.J.*
AU  - Cheng, C.Y.*
AU  - Wong, T.Y.*
AU  - Khor, C.C.*
AU  - Sabanayagam, C.*
AU  - Peters, A.
AU  - Gieger, C.
AU  - Hattersley, A.T.*
AU  - Pedersen, N.L.*
AU  - Magnusson, P.K.E.*
AU  - Boomsma, D.I.*
AU  - de Geus, E.J.C.*
AU  - Cupples, L.A.*
AU  - van Meurs, J.B.J.*
AU  - Ghanbari, M.*
AU  - Gordon-Larsen, P.*
AU  - Huang, W.*
AU  - Kim, Y.J.*
AU  - Tabara, Y.*
AU  - Wareham, N.J.*
AU  - Langenberg, C.*
AU  - Zeggini, E.
AU  - Kuusisto, J.*
AU  - Laakso, M.*
AU  - Ingelsson, E.*
AU  - Abecasis, G.*
AU  - Chambers, J.C.*
AU  - Kooner, J.S.*
AU  - de Vries, P.S.*
AU  - Morrison, A.C.*
AU  - North, K.E.*
AU  - Daviglus, M.*
AU  - Kraft, P.*
AU  - Martin, N.G.*
AU  - Whitfield, J.B.*
AU  - Abbas, S.*
AU  - Saleheen, D.*
AU  - Walters, R.G.*
AU  - Holmes, M.V.*
AU  - Black, C.*
AU  - Smith, B.H.*
AU  - Justice, A.E.*
AU  - Baras, A.*
AU  - Buring, J.E.*
AU  - Ridker, P.M.*
AU  - Chasman, D.I.*
AU  - Kooperberg, C.*
AU  - Wei, W.Q.*
AU  - Jarvik, G.P.*
AU  - Namjou, B.*
AU  - Hayes, M.G.*
AU  - Ritchie, M.D.*
AU  - Jousilahti, P.*
AU  - Salomaa, V.*
AU  - Hveem, K.*
AU  - Asvold, B.O.*
AU  - Kubo, M.*
AU  - Kamatani, Y.*
AU  - Okada, Y.*
AU  - Murakami, Y.*
AU  - Thorsteinsdottir, U.*
AU  - Stefansson, K.*
AU  - Ho, Y.L.*
AU  - Lynch, J.A.*
AU  - Rader, D.J.*
AU  - Tsao, P.S.*
AU  - Chang, K.M.*
AU  - Cho, K.*
AU  - O'Donnell, C.J.*
AU  - Gaziano, J.M.*
AU  - Wilson, P.F.*
AU  - Rotimi, C.N.*
AU  - Hazelhurst, S.*
AU  - Ramsay, M.*
AU  - Trembath, R.C.*
AU  - van Heel, D.A.*
AU  - Tamiya, G.*
AU  - Yamamoto, M.*
AU  - Kim, B.J.*
AU  - Mohlke, K.L.*
AU  - Frayling, T.M.*
AU  - Hirschhorn, J.N.*
AU  - Kathiresan, S.*
AU  - VA Million Veteran Program*
AU  - Global Lipids Genetics Consortium**
AU  - Boehnke, M.*
AU  - Natarajan, P.*
AU  - Peloso, G.M.*
AU  - Brown, C.D.*
AU  - Morris, A.P.*
AU  - Assimes, T.L.*
AU  - Deloukas, P.*
AU  - Sun, Y.V.*
AU  - Willer, C.J.*
C1  - 63787
C2  - 51664
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 675-679
TI  - The power of genetic diversity in genome-wide association studies of lipids.
JO  - Nature
VL  - 600
IS  - 7890
PB  - Nature Portfolio
PY  - 2021
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - In a brain structure called the hippocampus, sharp wave-ripples - oscillatory hallmarks of an 'offline' mode of cognitive processing - have been found to predict dips in glucose concentrations in the body.
AU  - Hallschmid, M.
AU  - Born, J.
C1  - 62814
C2  - 50999
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 39-40
TI  - A brain signal that coordinates thought with metabolism.
JO  - Nature
VL  - 597
IS  - 7874
PB  - Nature Portfolio
PY  - 2021
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - One of the most important regulatory small molecules in plants is indole-3-acetic acid, also known as auxin. Its dynamic redistribution has an essential role in almost every aspect of plant life, ranging from cell shape and division to organogenesis and responses to light and gravity1,2. So far, it has not been possible to directly determine the spatial and temporal distribution of auxin at a cellular resolution. Instead it is inferred from the visualization of irreversible processes that involve the endogenous auxin-response machinery3-7; however, such a system cannot detect transient changes. Here we report a genetically encoded biosensor for the quantitative in vivo visualization of auxin distribution. The sensor is based on the Escherichia coli tryptophan repressor8, the binding pocket of which is engineered to be specific to auxin. Coupling of the auxin-binding moiety with selected fluorescent proteins enables the use of a fluorescence resonance energy transfer signal as a readout. Unlike previous systems, this sensor enables direct monitoring of the rapid uptake and clearance of auxin by individual cells and within cell compartments in planta. By responding to the graded spatial distribution along the root axis and its perturbation by transport inhibitors-as well as the rapid and reversible redistribution of endogenous auxin in response to changes in gravity vectors-our sensor enables real-time monitoring of auxin concentrations at a (sub)cellular resolution and their spatial and temporal changes during the lifespan of a plant.
AU  - Herud-Sikimić, O.*
AU  - Stiel, A.-C.
AU  - Kolb, M.*
AU  - Shanmugaratnam, S.*
AU  - Berendzen, K.W.*
AU  - Feldhaus, C.*
AU  - Höcker, B.*
AU  - Jürgens, G.*
C1  - 61792
C2  - 50128
SP  - 768–772
TI  - A biosensor for the direct visualization of auxin.
JO  - Nature
VL  - 592
PY  - 2021
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Hepatocellular carcinoma (HCC) can have viral or non-viral causes1-5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.
AU  - Pfister, D.*
AU  - Núñez, N.G.*
AU  - Pinyol, R.*
AU  - Govaere, O.*
AU  - Pinter, M.*
AU  - Szydlowska, M.*
AU  - Gupta, R.*
AU  - Qiu, M.*
AU  - Deczkowska, A.*
AU  - Weiner, A.*
AU  - Müller, F.*
AU  - Sinha, A.*
AU  - Friebel, E.*
AU  - Engleitner, T.*
AU  - Lenggenhager, D.*
AU  - Moncsek, A.*
AU  - Heide, D.*
AU  - Stirm, K.*
AU  - Kosla, J.*
AU  - Kotsiliti, E.*
AU  - Leone, V.
AU  - Dudek, M.*
AU  - Yousuf, S.*
AU  - Inverso, D.*
AU  - Singh, I.*
AU  - Teijeiro, A.*
AU  - Castet, F.*
AU  - Montironi, C.*
AU  - Haber, P.K.*
AU  - Tiniakos, D.*
AU  - Bedossa, P.*
AU  - Cockell, S.*
AU  - Younes, R.*
AU  - Vacca, M.*
AU  - Marra, F.*
AU  - Schattenberg, J.M.*
AU  - Allison, M.*
AU  - Bugianesi, E.*
AU  - Ratziu, V.*
AU  - Pressiani, T.*
AU  - D'Alessio, A.*
AU  - Personeni, N.*
AU  - Rimassa, L.*
AU  - Daly, A.K.*
AU  - Scheiner, B.*
AU  - Pomej, K.*
AU  - Kirstein, M.M.*
AU  - Vogel, A.*
AU  - Peck-Radosavljevic, M.*
AU  - Hucke, F.*
AU  - Finkelmeier, F.*
AU  - Waidmann, O.*
AU  - Trojan, J.*
AU  - Schulze, K.*
AU  - Wege, H.*
AU  - Koch, S.*
AU  - Weinmann, A.*
AU  - Bueter, M.*
AU  - Rössler, F.*
AU  - Siebenhüner, A.*
AU  - Dosso, S.*
AU  - Mallm, J.P.*
AU  - Umansky, V.*
AU  - Jugold, M.*
AU  - Luedde, T.*
AU  - Schietinger, A.*
AU  - Schirmacher, P.*
AU  - Emu, B.*
AU  - Augustin, H.G.*
AU  - Billeter, A.T.*
AU  - Müller-Stich, B.*
AU  - Kikuchi, H.*
AU  - Duda, D.G.*
AU  - Kütting, F.*
AU  - Waldschmidt, D.T.*
AU  - Ebert, M.P.*
AU  - Rahbari, N.*
AU  - Mei, H.E.*
AU  - Schulz, A.R.*
AU  - Ringelhan, M.
AU  - Malek, N.*
AU  - Spahn, S.*
AU  - Bitzer, M.*
AU  - Ruiz de Galarreta, M.*
AU  - Lujambio, A.*
AU  - Dufour, J.F.*
AU  - Marron, T.U.*
AU  - Kaseb, A.*
AU  - Kudo, M.*
AU  - Huang, Y.H.*
AU  - Djouder, N.*
AU  - Wolter, K.*
AU  - Zender, L.*
AU  - Marche, P.N.*
AU  - Decaens, T.*
AU  - Pinato, D.J.*
AU  - Rad, R.*
AU  - Mertens, J.C.*
AU  - Weber, A.*
AU  - Unger, K.
AU  - Meissner, F.*
AU  - Roth, S.*
AU  - Jilkova, Z.M.*
AU  - Claassen, M.*
AU  - Anstee, Q.M.*
AU  - Amit, I.*
AU  - Knolle, P.*
AU  - Becher, B.*
AU  - Llovet, J.M.*
AU  - Heikenwalder, M.*
C1  - 61689
C2  - 50397
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 450–456
TI  - NASH limits anti-tumour surveillance in immunotherapy-treated HCC.
JO  - Nature
VL  - 592
IS  - 7854
PB  - Nature Research
PY  - 2021
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - The liberation of energy stores from adipocytes is critical to support survival in times of energy deficit; however, uncontrolled or chronic lipolysis associated with insulin resistance and/or insulin insufficiency disrupts metabolic homeostasis1,2. Coupled to lipolysis is the release of a recently identified hormone, fatty-acid-binding protein 4 (FABP4)3. Although circulating FABP4 levels have been strongly associated with cardiometabolic diseases in both preclinical models and humans4-7, no mechanism of action has yet been described8-10. Here we show that hormonal FABP4 forms a functional hormone complex with adenosine kinase (ADK) and nucleoside diphosphate kinase (NDPK) to regulate extracellular ATP and ADP levels. We identify a substantial effect of this hormone on beta cells and given the central role of beta-cell function in both the control of lipolysis and development of diabetes, postulate that hormonal FABP4 is a key regulator of an adipose-beta-cell endocrine axis. Antibody-mediated targeting of this hormone complex improves metabolic outcomes, enhances beta-cell function and preserves beta-cell integrity to prevent both type 1 and type 2 diabetes. Thus, the FABP4-ADK-NDPK complex, Fabkin, represents a previously unknown hormone and mechanism of action that integrates energy status with the function of metabolic organs, and represents a promising target against metabolic disease.
AU  - Prentice, K.J.*
AU  - Saksi, J.*
AU  - Robertson, L.T.*
AU  - Lee, G.Y.*
AU  - Inouye, K.E.*
AU  - Eguchi, K.*
AU  - Lee, A.*
AU  - Cakici, O.*
AU  - Otterbeck, E.*
AU  - Cedillo, P.*
AU  - Achenbach, P.
AU  - Ziegler, A.-G.
AU  - Calay, E.S.*
AU  - Engin, F.*
AU  - Hotamisligil, G.S.*
C1  - 63799
C2  - 51627
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 720–726
TI  - A hormone complex of FABP4 and nucleoside kinases regulates islet function.
JO  - Nature
VL  - 600
IS  - 7890
PB  - Nature Portfolio
PY  - 2021
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - In this Perspective, owing to an error in the HTML, the surname of author Alejandro López-Tobón of the LifeTime Community Working Groups consortium was indexed as ‘Tobon’ rather than ‘López-Tobón’ and the accents were missing. The HTML version of the original Perspective has been corrected; the PDF and print versions were always correct. *A list of authors and their affiliations appears online.
AU  - Rajewsky, N.*
AU  - Almouzni, G.*
AU  - Gorski, S.A.*
AU  - Aerts, S.*
AU  - Amit, I.*
AU  - Bertero, M.G.*
AU  - Bock, C.*
AU  - Bredenoord, A.L.*
AU  - Cavalli, G.*
AU  - Chiocca, S.*
AU  - Clevers, H.*
AU  - de Strooper, B.*
AU  - Eggert, A.*
AU  - Ellenberg, J.*
AU  - Fernández, X.M.*
AU  - Figlerowicz, M.*
AU  - Gasser, S.M.*
AU  - Hubner, N.*
AU  - Kjems, J.*
AU  - Knoblich, J.A.*
AU  - Krabbe, G.*
AU  - Lichter, P.*
AU  - Linnarsson, S.*
AU  - Marine, J.C.*
AU  - Marioni, J.C.*
AU  - Marti-Renom, M.A.*
AU  - Netea, M.G.*
AU  - Nickel, D.*
AU  - Nollmann, M.*
AU  - Novak, H.R.*
AU  - Parkinson, H.*
AU  - Piccolo, S.*
AU  - Pinheiro, I.*
AU  - Pombo, A.*
AU  - Popp, C.*
AU  - Reik, W.*
AU  - Roman-Roman, S.*
AU  - Rosenstiel, P.*
AU  - Schultze, J.L.*
AU  - Stegle, O.*
AU  - Tanay, A.*
AU  - Testa, G.*
AU  - Thanos, D.*
AU  - Theis, F.J.
AU  - Torres-Padilla, M.E.
AU  - Valencia, A.*
AU  - Vallot, C.*
AU  - van Oudenaarden, A.*
AU  - Vidal, M.*
AU  - Voet, T.*
AU  - LifeTime Community (Schiller, H. B.
AU  - Ziegler, A.-G.)
C1  - 61643
C2  - 50248
TI  - Publisher Correction: LifeTime and improving European healthcare through cell-based interceptive medicine (Nature, (2020), 587, 7834, (377-386), 10.1038/s41586-020-2715-9).
JO  - Nature
VL  - 592
IS  - 7852
PY  - 2021
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
AU  - Ruth, K.S.*
AU  - Day, F.R.*
AU  - Hussain, J.*
AU  - Martínez-Marchal, A.*
AU  - Aiken, C.E.*
AU  - Azad, A.*
AU  - Thompson, D.J.*
AU  - Knoblochova, L.*
AU  - Abe, H.*
AU  - Tarry-Adkins, J.L.*
AU  - Gonzalez, J.M.*
AU  - Fontanillas, P.*
AU  - Claringbould, A.*
AU  - Bakker, O.B.*
AU  - Sulem, P.*
AU  - Walters, R.G.*
AU  - Terao, C.*
AU  - Turon, S.*
AU  - Horikoshi, M.*
AU  - Lin, K.*
AU  - Onland-Moret, N.C.*
AU  - Sankar, A.*
AU  - Hertz, E.P.T.*
AU  - Timshel, P.N.*
AU  - Shukla, V.*
AU  - Borup, R.*
AU  - Olsen, K.W.*
AU  - Aguilera, P.*
AU  - Ferrer-Roda, M.*
AU  - Huang, Y.*
AU  - Stankovic, S.*
AU  - Timmers, P.R.H.J.*
AU  - Ahearn, T.U.*
AU  - Alizadeh, B.Z.*
AU  - Naderi, E.*
AU  - Andrulis, I.L.*
AU  - Arnold, A.M.*
AU  - Aronson, K.J.*
AU  - Augustinsson, A.*
AU  - Bandinelli, S.*
AU  - Barbieri, C.M.*
AU  - Beaumont, R.N.*
AU  - Becher, H.*
AU  - Beckmann, M.W.*
AU  - Benonisdottir, S.*
AU  - Bergmann, S.*
AU  - Bochud, M.*
AU  - Boerwinkle, E.*
AU  - Bojesen, S.E.*
AU  - Bolla, M.K.*
AU  - Boomsma, D.I.*
AU  - Bowker, N.*
AU  - Brody, J.A.*
AU  - Broer, L.*
AU  - Buring, J.E.*
AU  - Campbell, A.*
AU  - Campbell, H.*
AU  - Castelao, J.E.*
AU  - Catamo, E.*
AU  - Chanock, S.J.*
AU  - Chenevix-Trench, G.*
AU  - Ciullo, M.*
AU  - Corre, T.*
AU  - Couch, F.J.*
AU  - Cox, A.*
AU  - Crisponi, L.*
AU  - Cross, S.S.*
AU  - Cucca, F.*
AU  - Czene, K.*
AU  - Smith, G.D.*
AU  - de Geus, E.J.C.N.*
AU  - de Mutsert, R.*
AU  - de Vivo, I.*
AU  - Demerath, E.W.*
AU  - Dennis, J.*
AU  - Dunning, A.M.*
AU  - Dwek, M.*
AU  - Eriksson, M.*
AU  - Esko, T.*
AU  - Fasching, P.A.*
AU  - Faul, J.D.*
AU  - Ferrucci, L.*
AU  - Franceschini, N.*
AU  - Frayling, T.M.*
AU  - Gago-Dominguez, M.*
AU  - Mezzavilla, M.*
AU  - Garcia-Closas, M.*
AU  - Gieger, C.
AU  - Giles, G.G.*
AU  - Grallert, H.
AU  - Gudbjartsson, D.F.*
AU  - Gudnason, V.*
AU  - Guénel, P.*
AU  - Haiman, C.A.*
AU  - Håkansson, N.*
AU  - Hall, P.*
AU  - Hayward, C.*
AU  - He, C.*
AU  - He, W.*
AU  - Heiss, G.*
AU  - Høffding, M.K.*
AU  - Hopper, J.L.*
AU  - Hottenga, J.J.*
AU  - Hu, F.*
AU  - Ikram, M.A.*
AU  - Jackson, R.D.*
AU  - Joaquim, M.D.R.*
AU  - John, E.M.*
AU  - Joshi, P.K.*
AU  - Karasik, D.*
AU  - Kardia, S.L.R.*
AU  - Kartsonaki, C.*
AU  - Karlsson, R.*
AU  - Kitahara, C.M.*
AU  - Kolcic, I.*
AU  - Kooperberg, C.*
AU  - Kraft, P.*
AU  - Kurian, A.W.*
AU  - Kutalik, Z.*
AU  - La Bianca, M.*
AU  - Lachance, G.*
AU  - Langenberg, C.*
AU  - Launer, L.J.*
AU  - Laven, J.S.E.*
AU  - Lawlor, D.A.*
AU  - Le Marchand, L.*
AU  - Li, J.*
AU  - Lindblom, A.*
AU  - Lindström, S.*
AU  - Lindstrom, T.*
AU  - Linet, M.*
AU  - Liu, Y.*
AU  - Liu, S.*
AU  - Luan, J.*
AU  - Mägi, R.*
AU  - Magnusson, P.K.E.*
AU  - Mangino, M.*
AU  - Mannermaa, A.*
AU  - Marco, B.*
AU  - Marten, J.*
AU  - Martin, N.G.*
AU  - Mbarek, H.*
AU  - McKnight, B.*
AU  - Medland, S.E.*
AU  - Meisinger, C.
AU  - Meitinger, T.
AU  - Menni, C.*
AU  - Metspalu, A.*
AU  - Milani, L.*
AU  - Milne, R.L.*
AU  - Montgomery, G.W.*
AU  - Mook-Kanamori, D.O.*
AU  - Mulas, A.*
AU  - Mulligan, A.M.*
AU  - Murray, A.*
AU  - Nalls, M.A.*
AU  - Newman, A.*
AU  - Noordam, R.*
AU  - Nutile, T.*
AU  - Nyholt, D.R.*
AU  - Olshan, A.F.*
AU  - Olsson, H.*
AU  - Painter, J.N.*
AU  - Patel, A.V.*
AU  - Pedersen, N.L.*
AU  - Perjakova, N.*
AU  - Peters, A.
AU  - Peters, U.*
AU  - Pharoah, P.D.P.*
AU  - Polasek, O.*
AU  - Porcu, E.*
AU  - Psaty, B.M.*
AU  - Rahman, I.*
AU  - Rennert, G.*
AU  - Rennert, H.S.*
AU  - Ridker, P.M.*
AU  - Ring, S.M.*
AU  - Robino, A.*
AU  - Rose, L.M.*
AU  - Rosendaal, F.R.*
AU  - Rossouw, J.*
AU  - Rudan, I.*
AU  - Rueedi, R.*
AU  - Ruggiero, D.*
AU  - Sala, C.F.*
AU  - Saloustros, E.*
AU  - Sandler, D.P.*
AU  - Sanna, S.*
AU  - Sawyer, E.J.*
AU  - Sarnowski, C.*
AU  - Schlessinger, D.*
AU  - Schmidt, M.K.*
AU  - Schoemaker, M.J.*
AU  - Schraut, K.E.*
AU  - Scott, C.E.*
AU  - Shekari, S.*
AU  - Shrikhande, A.*
AU  - Smith, A.V.*
AU  - Smith, B.H.*
AU  - Smith, J.A.*
AU  - Sorice, R.*
AU  - Southey, M.C.*
AU  - Spector, T.D.*
AU  - Spinelli, J.J.*
AU  - Stampfer, M.*
AU  - Stöckl, D.
AU  - van Meurs, J.B.J.*
AU  - Strauch, K.
AU  - Styrkarsdottir, U.*
AU  - Swerdlow, A.J.*
AU  - Tanaka, T.*
AU  - Teras, L.R.*
AU  - Teumer, A.*
AU  - Þorsteinsdottir, U.*
AU  - Timpson, N.J.*
AU  - Toniolo, D.*
AU  - Traglia, M.*
AU  - Troester, M.A.*
AU  - Truong, T.*
AU  - Tyrrell, J.*
AU  - Uitterlinden, A.G.*
AU  - Ulivi, S.*
AU  - Vachon, C.M.*
AU  - Vitart, V.*
AU  - Völker, U.*
AU  - Vollenweider, P.*
AU  - Völzke, H.*
AU  - Wang, Q.*
AU  - Wareham, N.J.*
AU  - Weinberg, C.R.*
AU  - Weir, D.R.*
AU  - Wilcox, A.N.*
AU  - van Dijk, K.W.*
AU  - Willemsen, G.*
AU  - Wilson, J.F.*
AU  - Wolffenbuttel, B.H.R.*
AU  - Wolk, A.*
AU  - Wood, A.R.*
AU  - Zhao, W.*
AU  - Zygmunt, M.*
AU  - Biobank-based Integrative Omics Study (BIOS) Consortium*
AU  - eQTLGen Consortium*
AU  - Biobank Japan Project*
AU  - China Kadoorie Biobank Collaborative Group*
AU  - kConFab Investigators*
AU  - Lifelines Cohort Study*
AU  - InterAct consortium*
AU  - 23andMe Research Team*
AU  - Chen, Z.*
AU  - Li, L.*
AU  - Franke, L.*
AU  - Burgess, S.*
AU  - Deelen, P.*
AU  - Pers, T.H.*
AU  - Grøndahl, M.L.*
AU  - Andersen, C.Y.*
AU  - Pujol, A.*
AU  - Lopez-Contreras, A.J.*
AU  - Daniel, J.A.*
AU  - Stefansson, K.*
AU  - Chang-Claude, J.*
AU  - van der Schouw, Y.T.*
AU  - Lunetta, K.L.*
AU  - Chasman, D.I.*
AU  - Easton, D.F.*
AU  - Visser, J.A.*
AU  - Ozanne, S.E.*
AU  - Namekawa, S.H.*
AU  - Solc, P.*
AU  - Murabito, J.M.*
AU  - Ong, K.K.*
AU  - Hoffmann, E.R.*
AU  - Roig, I.*
AU  - Perry, J.R.B.*
C1  - 62758
C2  - 51047
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 393-397
TI  - Genetic insights into biological mechanisms governing human ovarian ageing.
JO  - Nature
VL  - 596
IS  - 7872
PB  - Nature Portfolio
PY  - 2021
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - The genetic make-up of an individual contributes to the susceptibility 
      and response to viral infection. Although environmental, clinical and 
      social factors have a role in the chance of exposure to SARS-CoV-2 and 
      the severity of COVID-191,2, host genetics may also be 
      important. Identifying host-specific genetic factors may reveal 
      biological mechanisms of therapeutic relevance and clarify causal 
      relationships of modifiable environmental risk factors for SARS-CoV-2 
      infection and outcomes. We formed a global network of researchers to 
      investigate the role of human genetics in SARS-CoV-2 infection and 
      COVID-19 severity. Here we describe the results of three genome-wide 
      association meta-analyses that consist of up to 49,562 patients with 
      COVID-19 from 46 studies across 19 countries. We report 13 genome-wide 
      significant loci that are associated with SARS-CoV-2 infection or severe
       manifestations of COVID-19. Several of these loci correspond to 
      previously documented associations to lung or autoimmune and 
      inflammatory diseases3-7. They also represent potentially 
      actionable mechanisms in response to infection. Mendelian randomization 
      analyses support a causal role for smoking and body-mass index for 
      severe COVID-19 although not for type II diabetes. The identification of
       novel host genetic factors associated with COVID-19 was made possible 
      by the community of human genetics researchers coming together to 
      prioritize the sharing of data, results, resources and analytical 
      frameworks. This working model of international collaboration 
      underscores what is possible for future genetic discoveries in emerging 
      pandemics, or indeed for any complex human disease.
AU  - COVID-19 Host Genetics Initiative (Schulte, E.C.)
C1  - 63923
C2  - 51722
SP  - 472-477
TI  - Mapping the human genetic architecture of COVID-19.
JO  - Nature
VL  - 600
IS  - 7889
PY  - 2021
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Gastrulation is the fundamental process in all multicellular animals through which the basic body plan is first laid down1–4. It is pivotal in generating cellular diversity coordinated with spatial patterning. In humans, gastrulation occurs in the third week after fertilization. Our understanding of this process in humans is relatively limited and based primarily on historical specimens5–8, experimental models9–12 or, more recently, in vitro cultured samples13–16. Here we characterize in a spatially resolved manner the single-cell transcriptional profile of an entire gastrulating human embryo, staged to be between 16 and 19 days after fertilization. We use these data to analyse the cell types present and to make comparisons with other model systems. In addition to pluripotent epiblast, we identified primordial germ cells, red blood cells and various mesodermal and endodermal cell types. This dataset offers a unique glimpse into a central but inaccessible stage of our development. This characterization provides new context for interpreting experiments in other model systems and represents a valuable resource for guiding directed differentiation of human cells in vitro.
AU  - Tyser, R.C.V.*
AU  - Mahammadov, E.
AU  - Nakanoh, S.*
AU  - Vallier, L.*
AU  - Scialdone, A.
AU  - Srinivas, S.*
C1  - 63577
C2  - 51607
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 285-289
TI  - Single-cell transcriptomic characterization of a gastrulating human embryo.
JO  - Nature
VL  - 600
IS  - 7888
PB  - Nature Portfolio
PY  - 2021
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Fast and reliable detection of patients with severe and heterogeneous illnesses is a major goal of precision medicine . Patients with leukaemia can be identified using machine learning on the basis of their blood transcriptomes . However, there is an increasing divide between what is technically possible and what is allowed, because of privacy legislation . Here, to facilitate the integration of any medical data from any data owner worldwide without violating privacy laws, we introduce Swarm Learning—a decentralized machine-learning approach that unites edge computing, blockchain-based peer-to-peer networking and coordination while maintaining confidentiality without the need for a central coordinator, thereby going beyond federated learning. To illustrate the feasibility of using Swarm Learning to develop disease classifiers using distributed data, we chose four use cases of heterogeneous diseases (COVID-19, tuberculosis, leukaemia and lung pathologies). With more than 16,400 blood transcriptomes derived from 127 clinical studies with non-uniform distributions of cases and controls and substantial study biases, as well as more than 95,000 chest X-ray images, we show that Swarm Learning classifiers outperform those developed at individual sites. In addition, Swarm Learning completely fulfils local confidentiality regulations by design. We believe that this approach will notably accelerate the introduction of precision medicine. 1,2 3 4,5
AU  - Warnat-Herresthal, S.*
AU  - Schultze, H.*
AU  - Shastry, K.L.*
AU  - Manamohan, S.*
AU  - Mukherjee, S.*
AU  - Garg, V.*
AU  - Sarveswara, R.*
AU  - Händler, K.*
AU  - Pickkers, P.*
AU  - Aziz, N.A.*
AU  - Ktena, S.*
AU  - Tran, F.*
AU  - Bitzer, M.*
AU  - Ossowski, S.*
AU  - Casadei, N.*
AU  - Herr, C.*
AU  - Petersheim, D.*
AU  - Behrends, U.*
AU  - Kern, F.*
AU  - Fehlmann, T.*
AU  - Schommers, P.*
AU  - Lehmann, C.*
AU  - Augustin, M.*
AU  - Rybniker, J.*
AU  - Altmüller, J.*
AU  - Mishra, N.*
AU  - Bernardes, J.P.*
AU  - Krämer, B.F.*
AU  - Bonaguro, L.*
AU  - Schulte-Schrepping, J.*
AU  - De Domenico, E.*
AU  - Siever, C.*
AU  - Kraut, M.*
AU  - Desai, M.*
AU  - Monnet, B.*
AU  - Saridaki, M.*
AU  - Siegel, C.M.*
AU  - Drews, A.*
AU  - Nuesch-Germano, M.*
AU  - Theis, H.*
AU  - Heyckendorf, J.*
AU  - Schreiber, S.*
AU  - Kim-Hellmuth, S.*
AU  - Nattermann, J.*
AU  - Skowasch, D.*
AU  - Kurth, I.*
AU  - Keller, A.*
AU  - Bals, R.*
AU  - Nürnberg, P.*
AU  - Rieß, O.*
AU  - Rosenstiel, P.*
AU  - Netea, M.G.*
AU  - Theis, F.J.
AU  - Backes, M.*
AU  - Aschenbrenner, A.C.*
AU  - Ulas, T.*
AU  - Deutsche COVID-19 Omics Initiative (DeCOI) (De La Rosa Velázquez, I.A.)
AU  - Breteler, M.M.B.*
AU  - Giamarellos-Bourboulis, E.J.*
AU  - Kox, M.*
AU  - Beck, M.*
AU  - Cheran, S.*
AU  - Woodacre, M.S.*
AU  - Lim Goh, E.*
AU  - Schultze, J.L.*
C1  - 62154
C2  - 50684
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Swarm Learning for decentralized and confidential clinical machine learning.
JO  - Nature
PB  - Nature Research
PY  - 2021
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Understanding cellular architecture is essential for understanding biology. Electron microscopy (EM) uniquely visualizes cellular structures with nanometre resolution. However, traditional methods, such as thin-section EM or EM tomography, have limitations in that they visualize only a single slice or a relatively small volume of the cell, respectively. Focused ion beam-scanning electron microscopy (FIB-SEM) has demonstrated the ability to image small volumes of cellular samples with 4-nm isotropic voxels1. Owing to advances in the precision and stability of FIB milling, together with enhanced signal detection and faster SEM scanning, we have increased the volume that can be imaged with 4-nm voxels by two orders of magnitude. Here we present a volume EM atlas at such resolution comprising ten three-dimensional datasets for whole cells and tissues, including cancer cells, immune cells, mouse pancreatic islets and Drosophila neural tissues. These open access data (via OpenOrganelle2) represent the foundation of a field of high-resolution whole-cell volume EM and subsequent analyses, and we invite researchers to explore this atlas and pose questions.
AU  - Xu, C.S.*
AU  - Pang, S.*
AU  - Shtengel, G.*
AU  - Müller, A.
AU  - Ritter, A.T.*
AU  - Hoffman, H.K.*
AU  - Takemura, S.y.*
AU  - Lu, Z.*
AU  - Pasolli, H.A.*
AU  - Iyer, N.*
AU  - Chung, J.*
AU  - Bennett, D.*
AU  - Weigel, A.V.*
AU  - Freeman, M.*
AU  - van Engelenburg, S.B.*
AU  - Walther, T.C.*
AU  - Farese, R.V.*
AU  - Lippincott-Schwartz, J.*
AU  - Mellman, I.*
AU  - Solimena, M.
AU  - Hess, H.F.*
C1  - 63250
C2  - 51357
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 147-151
TI  - An open-access volume electron microscopy atlas of whole cells and tissues.
JO  - Nature
VL  - 599
IS  - 7883
PB  - Nature Portfolio
PY  - 2021
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - In the version of this Article initially published, there were processing errors in the Supplementary and Extended Data. Specifically, for Supplementary Video 2, the file was damaged and would not render. For Extended Data Fig. 2, the “x–z, y–z, x–y” labels in the lower left of each panel were divergent to the format of similar panels in main text Fig. 2. The changes have been corrected in the online version of the Article.
AU  - Xu, C.S.*
AU  - Pang, S.*
AU  - Shtengel, G.*
AU  - Müller, A.
AU  - Ritter, A.T.*
AU  - Hoffman, H.K.*
AU  - Takemura, S.Y.*
AU  - Lu, Z.*
AU  - Pasolli, H.A.*
AU  - Iyer, N.*
AU  - Chung, J.*
AU  - Bennett, D.*
AU  - Weigel, A.V.*
AU  - Freeman, M.*
AU  - van Engelenburg, S.B.*
AU  - Walther, T.C.*
AU  - Farese, R.V.*
AU  - Lippincott-Schwartz, J.*
AU  - Mellman, I.*
AU  - Solimena, M.
AU  - Hess, H.F.*
C1  - 63414
C2  - 51358
TI  - Publisher Correction: An open-access volume electron microscopy atlas of whole cells and tissues.
JO  - Nature
VL  - 599
PY  - 2021
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - The N6-methyladenosine (m6A) is an abundant internal RNA modification1,2 catalysed predominantly by the METTL3-METTL14 methyltransferase complex3,4. The m6A writer METTL3 has been linked to the initiation and maintenance of acute myeloid leukaemia (AML), but its true therapeutic importance is still unknown5-7. Here we present the identification and characterization of a highly potent and selective first-in-class catalytic inhibitor of METTL3 (STM2457) and its co-crystal structure bound to METTL3/METTL14. Treatment with STM2457 leads to reduced AML growth, and an increase in differentiation and apoptosis. These cellular effects are accompanied by selective reduction of m6A levels on known leukaemogenic mRNAs and a decrease in their expression consistent with a translational defect. We demonstrate that pharmacological inhibition of METTL3 in vivo leads to impaired engraftment and prolonged survival in various AML mouse models, specifically targeting key stem-cell subpopulations of AML. Collectively, these results reveal the inhibition of METTL3 as a potential therapeutic strategy against AML, and provide proof of concept that the targeting of RNA modifying enzymes represents a promising new avenue for anti-cancer therapy.
AU  - Yankova, E.*
AU  - Blackaby, W.*
AU  - Albertella, M.*
AU  - Rak, J.*
AU  - De Braekeleer, E.*
AU  - Tsagkogeorga, G.*
AU  - Pilka, E.S.*
AU  - Aspris, D.*
AU  - Leggate, D.*
AU  - Hendrick, A.G.*
AU  - Webster, N.A.*
AU  - Andrews, B.*
AU  - Fosbeary, R.*
AU  - Guest, P.*
AU  - Irigoyen, N.*
AU  - Eleftheriou, M.*
AU  - Gozdecka, M.*
AU  - Dias, J.M.L.*
AU  - Bannister, A.J.*
AU  - Vick, B.
AU  - Jeremias, I.
AU  - Vassiliou, G.S.*
AU  - Rausch, O.*
AU  - Tzelepis, K.*
AU  - Kouzarides, T.*
C1  - 61877
C2  - 50495
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 597-601
TI  - Small molecule inhibition of METTL3 as a strategy against myeloid leukaemia.
JO  - Nature
VL  - 593
IS  - 7860
PB  - Nature Research
PY  - 2021
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Plant hormones coordinate responses to environmental cues with developmental programs(1), and are fundamental for stress resilience and agronomic yield(2). The core signalling pathways underlying the effects of phytohormones have been elucidated by genetic screens and hypothesis-driven approaches, and extended by interactome studies of select pathways(3). However, fundamental questions remain about how information from different pathways is integrated. Genetically, most phenotypes seem to be regulated by several hormones, but transcriptional profiling suggests that hormones trigger largely exclusive transcriptional programs(4). We hypothesized that protein-protein interactions have an important role in phytohormone signal integration. Here, we experimentally generated a systems-level map of the Arabidopsis phytohormone signalling network, consisting of more than 2,000 binary protein-protein interactions. In the highly interconnected network, we identify pathway communities and hundreds of previously unknown pathway contacts that represent potential points of crosstalk. Functional validation of candidates in seven hormone pathways reveals new functions for 74% of tested proteins in 84% of candidate interactions, and indicates that a large majority of signalling proteins function pleiotropically in several pathways. Moreover, we identify several hundred largely small-molecule-dependent interactions of hormone receptors. Comparison with previous reports suggests that noncanonical and nontranscription-mediated receptor signalling is more common than hitherto appreciated.
AU  - Altmann, M.
AU  - Altmann, S.
AU  - Rodriguez, P.A.
AU  - Weller, B.
AU  - Elorduy Vergara, L.
AU  - Palme, J.
AU  - Marin De La Rosa, N.A.
AU  - Sauer, M.
AU  - Wenig, M.
AU  - Villaécija-Aguilar, J.A.*
AU  - Sales, J.
AU  - Lin, C.-W.
AU  - Pandiarajan, R.
AU  - Young, V.
AU  - Strobel, A.
AU  - Gross, L.*
AU  - Carbonnel, S.*
AU  - Kugler, K.G.
AU  - Garcia-Molina
AU  - Bassel, G.W.*
AU  - Falter, C.
AU  - Mayer, K.F.X.
AU  - Gutjahr, C.*
AU  - Vlot, A.C.
AU  - Grill, E.*
AU  - Falter-Braun, P.
C1  - 59577
C2  - 48853
CY  - Macmillan Building, 4 Crinan St, London N1 9xw, England
SP  - 271-276
TI  - Extensive signal integration by the phytohormone protein network.
JO  - Nature
VL  - 583
IS  - 7815
PB  - Nature Publishing Group
PY  - 2020
SN  - 0028-0836
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  - Altmann, M.
AU  - Altmann, S.
AU  - Rodriguez, P.A.
AU  - Weller, B.
AU  - Elorduy Vergara, L.
AU  - Palme, J.
AU  - Marin De La Rosa, N.A.
AU  - Sauer, M.
AU  - Wenig, M.
AU  - Villaécija-Aguilar, J.A.*
AU  - Sales, J.
AU  - Lin, C.-W.
AU  - Pandiarajan, R.
AU  - Young, V.
AU  - Strobel, A.
AU  - Gross, L.*
AU  - Carbonnel, S.*
AU  - Kugler, K.G.
AU  - Garcia-Molina
AU  - Bassel, G.W.*
AU  - Falter, C.
AU  - Mayer, K.F.X.
AU  - Gutjahr, C.*
AU  - Vlot, A.C.
AU  - Grill, E.*
AU  - Falter-Braun, P.
C1  - 59802
C2  - 48994
TI  - Publisher Correction: Extensive signal integration by the phytohormone protein network (Nature, (2020), 583, 7815, (271-276), 10.1038/s41586-020-2460-0).
JO  - Nature
VL  - 584
PY  - 2020
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - The serum metabolome contains a plethora of biomarkers and causative agents of various diseases, some of which are endogenously produced and some that have been taken up from the environment(1). The origins of specific compounds are known, including metabolites that are highly heritable(2,3), or those that are influenced by the gut microbiome(4), by lifestyle choices such as smoking(5), or by diet(6). However, the key determinants of most metabolites are still poorly understood. Here we measured the levels of 1,251 metabolites in serum samples from a unique and deeply phenotyped healthy human cohort of 491 individuals. We applied machine-learning algorithms to predict metabolite levels in held-out individuals on the basis of host genetics, gut microbiome, clinical parameters, diet, lifestyle and anthropometric measurements, and obtained statistically significant predictions for more than 76% of the profiled metabolites. Diet and microbiome had the strongest predictive power, and each explained hundreds of metabolites-in some cases, explaining more than 50% of the observed variance. We further validated microbiome-related predictions by showing a high replication rate in two geographically independent cohorts(7,8) that were not available to us when we trained the algorithms. We used feature attribution analysis(9) to reveal specific dietary and bacterial interactions. We further demonstrate that some of these interactions might be causal, as some metabolites that we predicted to be positively associated with bread were found to increase after a randomized clinical trial of bread intervention. Overall, our results reveal potential determinants of more than 800 metabolites, paving the way towards a mechanistic understanding of alterations in metabolites under different conditions and to designing interventions for manipulating the levels of circulating metabolites.The levels of 1,251 metabolites are measured in 475 phenotyped individuals, and machine-learning algorithms reveal that diet and the microbiome are the determinants with the strongest predictive power for the levels of these metabolites.
AU  - Bar, N.*
AU  - Korem, T.*
AU  - Weissbrod, O.*
AU  - Zeevi, D.*
AU  - Rothschild, D.*
AU  - Leviatan, S.*
AU  - Kosower, N.*
AU  - Lotan-Pompan, M.*
AU  - Weinberger, A.*
AU  - Le Roy, C.I.*
AU  - Menni, C.*
AU  - Visconti, A.*
AU  - Falchi, M.*
AU  - Spector, T.D.*
AU  - Adamski, J.
AU  - Franks, P.W.*
AU  - Pedersen, O.*
AU  - Segal, E.*
AU  - IMI DIRECT Consortium (Thorand, B.
AU  - Troll, M.
AU  - Grallert, H.
AU  - Adam, J.
AU  - Sharma, S.
AU  - Haid, M.)
C1  - 60538
C2  - 49365
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 135–140
TI  - A reference map of potential determinants for the human serum metabolome.
JO  - Nature
VL  - 588
PB  - Nature Research
PY  - 2020
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Blockade of lymphotoxin beta-receptor (LT beta R) signalling restores WNT signalling and epithelial repair in a model of chronic obstructive pulmonary disease.Lymphotoxin beta-receptor (LT beta R) signalling promotes lymphoid neogenesis and the development of tertiary lymphoid structures(1,2), which are associated with severe chronic inflammatory diseases that span several organ systems(3-6). How LT beta R signalling drives chronic tissue damage particularly in the lung, the mechanism(s) that regulate this process, and whether LT beta R blockade might be of therapeutic value have remained unclear. Here we demonstrate increased expression of LT beta R ligands in adaptive and innate immune cells, enhanced non-canonical NF-kappa B signalling, and enriched LT beta R target gene expression in lung epithelial cells from patients with smoking-associated chronic obstructive pulmonary disease (COPD) and from mice chronically exposed to cigarette smoke. Therapeutic inhibition of LT beta R signalling in young and aged mice disrupted smoking-related inducible bronchus-associated lymphoid tissue, induced regeneration of lung tissue, and reverted airway fibrosis and systemic muscle wasting. Mechanistically, blockade of LT beta R signalling dampened epithelial non-canonical activation of NF-kappa B, reduced TGF beta signalling in airways, and induced regeneration by preventing epithelial cell death and activating WNT/beta-catenin signalling in alveolar epithelial progenitor cells. These findings suggest that inhibition of LT beta R signalling represents a viable therapeutic option that combines prevention of tertiary lymphoid structures(1) and inhibition of apoptosis with tissue-regenerative strategies.
AU  - Conlon, T.M.
AU  - John-Schuster, G.
AU  - Heide, D.*
AU  - Pfister, D.*
AU  - Lehmann, M.
AU  - Hu, Y.*
AU  - Ertüz, Z.
AU  - López, M.A.*
AU  - Ansari, M.
AU  - Strunz, M.
AU  - Mayr, C.
AU  - Ciminieri, C.*
AU  - Costa, R.
AU  - Kohlhepp, M.S.*
AU  - Guillot, A.*
AU  - Güneş, G.
AU  - Jeridi, A.
AU  - Funk, M.C.*
AU  - Beroshvili, G.
AU  - Prokosch, S.*
AU  - Hetzer, J.*
AU  - Verleden, S.E.*
AU  - Alsafadi, H.N.
AU  - Lindner, M.
AU  - Burgstaller, G.
AU  - Becker, L.
AU  - Irmler, M.
AU  - Dudek, M.*
AU  - Janzen, J.*
AU  - Goffin, E.*
AU  - Gosens, R.*
AU  - Knolle, P.*
AU  - Pirotte, B.*
AU  - Stöger, T.
AU  - Beckers, J.
AU  - Wagner, D.E.
AU  - Singh, I.*
AU  - Theis, F.J.
AU  - Hrabě de Angelis, M.
AU  - O’Connor, T.*
AU  - Tacke, F.*
AU  - Boutros, M.*
AU  - Dejardin, E.*
AU  - Eickelberg, O.*
AU  - Schiller, H. B.
AU  - Königshoff, M.
AU  - Heikenwalder, M.*
AU  - Yildirim, A.Ö.
C1  - 60479
C2  - 49338
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 151–156
TI  - Inhibition of LTβR signalling activates WNT-induced regeneration in lung.
JO  - Nature
VL  - 588
PB  - Nature Research
PY  - 2020
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - High blood cholesterol is typically considered a feature of wealthy western countries(1,2). However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world(3) and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health(4,5). However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol-which is a marker of cardiovascular riskchanged from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95% credible interval 3.7 million-4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and personal interventions to improve nutrition and enhance access to treatment throughout the world.
AU  - NCD Risk Factors Collaboration (Döring, A.
AU  - Meisinger, C.
AU  - Müller-Nurasyid, M.
AU  - Peters, A.
AU  - Stöckl, D.
AU  - Stieber, J.)
C1  - 59346
C2  - 48777
CY  - Macmillan Building, 4 Crinan St, London N1 9xw, England
SP  - 73-77
TI  - Repositioning of the global epicentre of non-optimal cholesterol.
JO  - Nature
VL  - 582
IS  - 7810
PB  - Nature Publishing Group
PY  - 2020
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Haploid genetic screening of cells under different types of mitochondrial perturbation shows that a pathway involving OMA1, DELE1 and the eIF2 alpha kinase HRI communicates mitochondrial stress to the cytosol to trigger the integrated stress response.Mitochondrial fidelity is tightly linked to overall cellular homeostasis and is compromised in ageing and various pathologies(1-3). Mitochondrial malfunction needs to be relayed to the cytosol, where an integrated stress response is triggered by the phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2 alpha) in mammalian cells(4,5). eIF2 alpha phosphorylation is mediated by the four eIF2 alpha kinases GCN2, HRI, PERK and PKR, which are activated by diverse types of cellular stress(6). However, the machinery that communicates mitochondrial perturbation to the cytosol to trigger the integrated stress response remains unknown(1,2,7). Here we combine genome engineering and haploid genetics to unbiasedly identify genes that affect the induction of C/EBP homologous protein (CHOP), a key factor in the integrated stress response. We show that the mitochondrial protease OMA1 and the poorly characterized protein DELE1, together with HRI, constitute the missing pathway that is triggered by mitochondrial stress. Mechanistically, stress-induced activation of OMA1 causes DELE1 to be cleaved into a short form that accumulates in the cytosol, where it binds to and activates HRI via its C-terminal portion. Obstruction of this pathway can be beneficial or adverse depending on the type of mitochondrial perturbation. In addition to the core pathway components, our comparative genetic screening strategy identifies a suite of additional regulators. Together, these findings could be used to inform future strategies to modulate the cellular response to mitochondrial dysfunction in the context of human disease.
AU  - Fessler, E.*
AU  - Eckl, E.M.*
AU  - Schmitt, S.*
AU  - Mancilla, I.A.*
AU  - Meyer-Bender, M.F.*
AU  - Hanf, M.*
AU  - Philippou-Massier, J.*
AU  - Krebs, S.*
AU  - Zischka, H.
AU  - Jae, L.T.*
C1  - 58522
C2  - 48246
CY  - Macmillan Building, 4 Crinan St, London N1 9xw, England
SP  - 433-437
TI  - A pathway coordinated by DELE1 relays mitochondrial stress to the cytosol.
JO  - Nature
VL  - 579
IS  - 7799
PB  - Nature Publishing Group
PY  - 2020
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Genetic diversity is key to crop improvement. Owing to pervasive genomic structural variation, a single reference genome assembly cannot capture the full complement of sequence diversity of a crop species (known as the ‘pan-genome’1). Multiple high-quality sequence assemblies are an indispensable component of a pan-genome infrastructure. Barley (Hordeum vulgare L.) is an important cereal crop with a long history of cultivation that is adapted to a wide range of agro-climatic conditions2. Here we report the construction of chromosome-scale sequence assemblies for the genotypes of 20 varieties of barley—comprising landraces, cultivars and a wild barley—that were selected as representatives of global barley diversity. We catalogued genomic presence/absence variants and explored the use of structural variants for quantitative genetic analysis through whole-genome shotgun sequencing of 300 gene bank accessions. We discovered abundant large inversion polymorphisms and analysed in detail two inversions that are frequently found in current elite barley germplasm; one is probably the product of mutation breeding and the other is tightly linked to a locus that is involved in the expansion of geographical range. This first-generation barley pan-genome makes previously hidden genetic variation accessible to genetic studies and breeding.
AU  - Jayakodi, M.*
AU  - Padmarasu, S.*
AU  - Haberer, G.
AU  - Bonthala, V.
AU  - Gundlach, H.
AU  - Monat, C.*
AU  - Lux, T.
AU  - Kamal, N.
AU  - Lang, D.
AU  - Himmelbach, A.*
AU  - Ens, J.*
AU  - Zhang, X.Q.*
AU  - Angessa, T.T.*
AU  - Zhou, G.*
AU  - Tan, C.*
AU  - Hill, C.*
AU  - Wang, P.*
AU  - Schreiber, M.*
AU  - Boston, L.B.*
AU  - Plott, C.*
AU  - Jenkins, J.*
AU  - Guo, Y.*
AU  - Fiebig, A.*
AU  - Budak, H.*
AU  - Xu, D.*
AU  - Zhang, J.*
AU  - Wang, C.*
AU  - Grimwood, J.*
AU  - Schmutz, J.*
AU  - Guo, G.*
AU  - Zhang, G.*
AU  - Mochida, K.*
AU  - Hirayama, T.*
AU  - Sato, K.*
AU  - Chalmers, K.J.*
AU  - Langridge, P.*
AU  - Waugh, R.*
AU  - Pozniak, C.J.*
AU  - Scholz, U.*
AU  - Mayer, K.F.X.
AU  - Spannagl, M.
AU  - Li, C.*
AU  - Mascher, M.*
AU  - Stein, N.*
C1  - 60616
C2  - 49533
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 284-289
TI  - The barley pan-genome reveals the hidden legacy of mutation breeding.
JO  - Nature
VL  - 588
IS  - 7837
PB  - Nature Research
PY  - 2020
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Cardiovascular disease is the leading cause of death worldwide. Advanced insights into disease mechanisms and therapeutic strategies require a deeper understanding of the molecular processes involved in the healthy heart. Knowledge of the full repertoire of cardiac cells and their gene expression profiles is a fundamental first step in this endeavour. Here, using state-of-the-art analyses of large-scale single-cell and single-nucleus transcriptomes, we characterize six anatomical adult heart regions. Our results highlight the cellular heterogeneity of cardiomyocytes, pericytes and fibroblasts, and reveal distinct atrial and ventricular subsets of cells with diverse developmental origins and specialized properties. We define the complexity of the cardiac vasculature and its changes along the arterio-venous axis. In the immune compartment, we identify cardiac-resident macrophages with inflammatory and protective transcriptional signatures. Furthermore, analyses of cell-to-cell interactions highlight different networks of macrophages, fibroblasts and cardiomyocytes between atria and ventricles that are distinct from those of skeletal muscle. Our human cardiac cell atlas improves our understanding of the human heart and provides a valuable reference for future studies.
AU  - Litviňuková, M.*
AU  - Talavera-López, C.*
AU  - Maatz, H.*
AU  - Reichart, D.*
AU  - Worth, C.L.*
AU  - Lindberg, E.L.*
AU  - Kanda, M.*
AU  - Polanski, K.*
AU  - Heinig, M.
AU  - Lee, M.*
AU  - Nadelmann, E.R.*
AU  - Roberts, K.*
AU  - Tuck, L.*
AU  - Fasouli, E.S.*
AU  - DeLaughter, D.M.*
AU  - McDonough, B.*
AU  - Wakimoto, H.*
AU  - Gorham, J.M.*
AU  - Samari, S.*
AU  - Mahbubani, K.T.*
AU  - Saeb-Parsy, K.*
AU  - Patone, G.*
AU  - Boyle, J.J.*
AU  - Zhang, H.*
AU  - Viveiros, A.*
AU  - Oudit, G.Y.*
AU  - Bayraktar, O.A.*
AU  - Seidman, J.G.*
AU  - Seidman, C.E.*
AU  - Noseda, M.*
AU  - Hubner, N.*
AU  - Teichmann, S.A.*
C1  - 60669
C2  - 49581
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 466-472
TI  - Cells of the adult human heart.
JO  - Nature
VL  - 588
IS  - 7838
PB  - Nature Research
PY  - 2020
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - An historic breakthrough that altered our understanding of cell fate.A method for directly converting connective-tissue cells into neurons opened up a new branch of research into cell-based therapies and called into question long-held beliefs about how development affects a cell's identity.
AU  - Masserdotti, G.
AU  - Götz, M.
C1  - 58700
C2  - 48254
CY  - Macmillan Building, 4 Crinan St, London N1 9xw, England
SP  - 522-524
TI  - Turning connective tissue into neurons for 10 years.
JO  - Nature
VL  - 578
IS  - 7796
PB  - Nature Publishing Group
PY  - 2020
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Plants are essential for life and are extremely diverse organisms with unique molecular capabilities(1). Here we present a quantitative atlas of the transcriptomes, proteomes and phosphoproteomes of 30 tissues of the model plant Arabidopsis thaliana. Our analysis provides initial answers to how many genes exist as proteins (more than 18,000), where they are expressed, in which approximate quantities (a dynamic range of more than six orders of magnitude) and to what extent they are phosphorylated (over 43,000 sites). We present examples of how the data may be used, such as to discover proteins that are translated from short open-reading frames, to uncover sequence motifs that are involved in the regulation of protein production, and to identify tissue-specific protein complexes or phosphorylation-mediated signalling events. Interactive access to this resource for the plant community is provided by the ProteomicsDB and ATHENA databases, which include powerful bioinformatics tools to explore and characterize Arabidopsis proteins, their modifications and interactions.A quantitative atlas of the transcriptomes, proteomes and phosphoproteomes of 30 tissues of the model plant Arabidopsis thaliana provides a valuable resource for plant research.
AU  - Mergner, J.*
AU  - Frejno, M.*
AU  - List, M.*
AU  - Papacek, M.*
AU  - Chen, X.*
AU  - Chaudhary, A.*
AU  - Samaras, P.*
AU  - Richter, S.*
AU  - Shikata, H.*
AU  - Messerer, M.
AU  - Lang, D.
AU  - Altmann, S.
AU  - Cyprys, P.*
AU  - Zolg, D.P.*
AU  - Mathieson, T.*
AU  - Bantscheff, M.*
AU  - Hazarika, R.R.*
AU  - Schmidt, T.*
AU  - Dawid, C.*
AU  - Dunkel, A.*
AU  - Hofmann, T.*
AU  - Sprunck, S.*
AU  - Falter-Braun, P.
AU  - Johannes, F.*
AU  - Mayer, K.F.X.
AU  - Jürgens, G.*
AU  - Wilhelm, M.*
AU  - Baumbach, J.*
AU  - Grill, E.*
AU  - Schneitz, K.*
AU  - Schwechheimer, C.*
AU  - Kuster, B.*
C1  - 58639
C2  - 48244
CY  - Macmillan Building, 4 Crinan St, London N1 9xw, England
SP  - 409-414
TI  - Mass-spectrometry-based draft of the Arabidopsis proteome.
JO  - Nature
VL  - 579
IS  - 7799
PB  - Nature Publishing Group
PY  - 2020
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Proteins carry out the vast majority of functions in all biological domains, but for technological reasons their large-scale investigation has lagged behind the study of genomes. Since the first essentially complete eukaryotic proteome was reported(1), advances in mass-spectrometry-based proteomics(2)have enabled increasingly comprehensive identification and quantification of the human proteome(3-6). However, there have been few comparisons across species(7,8), in stark contrast with genomics initiatives(9). Here we use an advanced proteomics workflow-in which the peptide separation step is performed by a microstructured and extremely reproducible chromatographic system-for the in-depth study of 100 taxonomically diverse organisms. With two million peptide and 340,000 stringent protein identifications obtained in a standardized manner, we double the number of proteins with solid experimental evidence known to the scientific community. The data also provide a large-scale case study for sequence-based machine learning, as we demonstrate by experimentally confirming the predicted properties of peptides fromBacteroides uniformis. Our results offer a comparative view of the functional organization of organisms across the entire evolutionary range. A remarkably high fraction of the total proteome mass in all kingdoms is dedicated to protein homeostasis and folding, highlighting the biological challenge of maintaining protein structure in all branches of life. Likewise, a universally high fraction is involved in supplying energy resources, although these pathways range from photosynthesis through iron sulfur metabolism to carbohydrate metabolism. Generally, however, proteins and proteomes are remarkably diverse between organisms, and they can readily be explored and functionally compared at www.proteomesoflife.org.
AU  - Müller, J.B.*
AU  - Geyer, P.E.*
AU  - Colaço, A.R.*
AU  - Treit, P.V.*
AU  - Strauss, M.T.*
AU  - Oroshi, M.*
AU  - Doll, S.*
AU  - Virreira Winter, S.*
AU  - Bader, J.M.*
AU  - Koehler, N.
AU  - Theis, F.J.
AU  - Santos, A.*
AU  - Mann, M.*
C1  - 59422
C2  - 48809
CY  - Macmillan Building, 4 Crinan St, London N1 9xw, England
SP  - 592–596
TI  - The proteome landscape of the kingdoms of life.
JO  - Nature
VL  - 582
PB  - Nature Publishing Group
PY  - 2020
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Here we describe the LifeTime Initiative, which aims to track, understand and target human cells during the onset and progression of complex diseases, and to analyse their response to therapy at single-cell resolution. This mission will be implemented through the development, integration and application of single-cell multi-omics and imaging, artificial intelligence and patient-derived experimental disease models during the progression from health to disease. The analysis of large molecular and clinical datasets will identify molecular mechanisms, create predictive computational models of disease progression, and reveal new drug targets and therapies. The timely detection and interception of disease embedded in an ethical and patient-centred vision will be achieved through interactions across academia, hospitals, patient associations, health data management systems and industry. The application of this strategy to key medical challenges in cancer, neurological and neuropsychiatric disorders, and infectious, chronic inflammatory and cardiovascular diseases at the single-cell level will usher in cell-based interceptive medicine in Europe over the next decade.The LifeTime initiative is an ambitious, multidisciplinary programme that aims to improve healthcare by tracking individual human cells during disease processes and responses to treatment in order to develop and implement cell-based interceptive medicine in Europe.
AU  - Rajewsky, N.*
AU  - Almouzni, G.*
AU  - Gorski, S.A.*
AU  - Aerts, S.*
AU  - Amit, I.*
AU  - Bertero, M.G.*
AU  - Bock, C.*
AU  - Bredenoord, A.L.*
AU  - Cavalli, G.*
AU  - Chiocca, S.*
AU  - Clevers, H.*
AU  - de Strooper, B.*
AU  - Eggert, A.*
AU  - Ellenberg, J.*
AU  - Fernández, X.M.*
AU  - Figlerowicz, M.*
AU  - Gasser, S.M.*
AU  - Hubner, N.*
AU  - Kjems, J.*
AU  - Knoblich, J.A.*
AU  - Krabbe, G.*
AU  - Lichter, P.*
AU  - Linnarsson, S.*
AU  - Marine, J.C.*
AU  - Marioni, J.*
AU  - Marti-Renom, M.A.*
AU  - Netea, M.G.*
AU  - Nickel, D.*
AU  - Nollmann, M.*
AU  - Novak, H.R.*
AU  - Parkinson, H.*
AU  - Piccolo, S.*
AU  - Pinheiro, I.*
AU  - Pombo, A.*
AU  - Popp, C.*
AU  - Reik, W.*
AU  - Roman-Roman, S.*
AU  - Rosenstiel, P.*
AU  - Schultze, J.L.*
AU  - Stegle, O.*
AU  - Tanay, A.*
AU  - Testa, G.*
AU  - Thanos, D.*
AU  - Theis, F.J.
AU  - Torres-Padilla, M.E.
AU  - Valencia, A.*
AU  - Vallot, C.*
AU  - van Oudenaarden, A.*
AU  - Vidal, M.*
AU  - Voet, T.*
AU  - LifeTime Community (Schiller, H. B.)
AU  - LifeTime Community (Ziegler, A.-G.)
C1  - 60040
C2  - 49185
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 377–386
TI  - LifeTime and improving European healthcare through cell-based interceptive medicine.
JO  - Nature
VL  - 587
PB  - Nature Research
PY  - 2020
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - The widely available silicon-on-insulator technology is used to develop a miniaturized ultrasound detector, which is 200 times smaller than the wavelengths of sound that it can detect.Ultrasound detectors use high-frequency sound waves to image objects and measure distances, but the resolution of these readings is limited by the physical dimensions of the detecting element. Point-like broadband ultrasound detection can greatly increase the resolution of ultrasonography and optoacoustic (photoacoustic) imaging(1,2), but current ultrasound detectors, such as those used for medical imaging, cannot be miniaturized sufficiently. Piezoelectric transducers lose sensitivity quadratically with size reduction(3), and optical microring resonators(4)and Fabry-Perot etalons(5)cannot adequately confine light to dimensions smaller than about 50 micrometres. Micromachining methods have been used to generate arrays of capacitive(6)and piezoelectric(7)transducers, but with bandwidths of only a few megahertz and dimensions exceeding 70 micrometres. Here we use the widely available silicon-on-insulator technology to develop a miniaturized ultrasound detector, with a sensing area of only 220 nanometres by 500 nanometres. The silicon-on-insulator-based optical resonator design provides per-area sensitivity that is 1,000 times higher than that of microring resonators and 100,000,000 times better than that of piezoelectric detectors. Our design also enables an ultrawide detection bandwidth, reaching 230 megahertz at -6 decibels. In addition to making the detectors suitable for manufacture in very dense arrays, we show that the submicrometre sensing area enables super-resolution detection and imaging performance. We demonstrate imaging of features 50 times smaller than the wavelength of ultrasound detected. Our detector enables ultra-miniaturization of ultrasound readings, enabling ultrasound imaging at a resolution comparable to that achieved with optical microscopy, and potentially enabling the development of very dense ultrasound arrays on a silicon chip.
AU  - Shnaiderman, R.
AU  - Wissmeyer, G.
AU  - Ülgen, O.
AU  - Mustafa, Q.
AU  - Chmyrov, A.
AU  - Ntziachristos, V.
C1  - 60094
C2  - 49239
CY  - Macmillan Building, 4 Crinan St, London N1 9xw, England
SP  - 372-378
TI  - A submicrometre silicon-on-insulator resonator for ultrasound detection.
JO  - Nature
VL  - 585
IS  - 7825
PB  - Nature Publishing Group
PY  - 2020
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Microbiome community typing analyses have recently identified the Bacteroides2 (Bact2) enterotype, an intestinal microbiota configuration that is associated with systemic inflammation and has a high prevalence in loose stools in humans1,2. Bact2 is characterized by a high proportion of Bacteroides, a low proportion of Faecalibacterium and low microbial cell densities1,2, and its prevalence varies from 13% in a general population cohort to as high as 78% in patients with inflammatory bowel disease2. Reported changes in stool consistency3 and inflammation status4 during the progression towards obesity and metabolic comorbidities led us to propose that these developments might similarly correlate with an increased prevalence of the potentially dysbiotic Bact2 enterotype. Here, by exploring obesity-associated microbiota alterations in the quantitative faecal metagenomes of the cross-sectional MetaCardis Body Mass Index Spectrum cohort (n = 888), we identify statin therapy as a key covariate of microbiome diversification. By focusing on a subcohort of participants that are not medicated with statins, we find that the prevalence of Bact2 correlates with body mass index, increasing from 3.90% in lean or overweight participants to 17.73% in obese participants. Systemic inflammation levels in Bact2-enterotyped individuals are higher than predicted on the basis of their obesity status, indicative of Bact2 as a dysbiotic microbiome constellation. We also observe that obesity-associated microbiota dysbiosis is negatively associated with statin treatment, resulting in a lower Bact2 prevalence of 5.88% in statin-medicated obese participants. This finding is validated in both the accompanying MetaCardis cardiovascular disease dataset (n = 282) and the independent Flemish Gut Flora Project population cohort (n = 2,345). The potential benefits of statins in this context will require further evaluation in a prospective clinical trial to ascertain whether the effect is reproducible in a randomized population and before considering their application as microbiota-modulating therapeutics.
AU  - Vieira-Silva, S.*
AU  - Falony, G.*
AU  - Belda, E.*
AU  - Nielsen, T.*
AU  - Aron-Wisnewsky, J.*
AU  - Chakaroun, R.*
AU  - Forslund, S.K.*
AU  - Assmann, K.*
AU  - Valles-Colomer, M.*
AU  - Nguyen, T.T.D.*
AU  - Proost, S.*
AU  - Prifti, E.*
AU  - Tremaroli, V.*
AU  - Pons, N.*
AU  - Le Chatelier, E.*
AU  - Andreelli, F.*
AU  - Bastard, J.P.*
AU  - Coelho, L.P.*
AU  - Galleron, N.*
AU  - Hansen, T.H.*
AU  - Hulot, J.S.*
AU  - Lewinter, C.*
AU  - Pedersen, H.K.*
AU  - Quinquis, B.*
AU  - Rouault, C.*
AU  - Roume, H.*
AU  - Salem, J.E.*
AU  - Søndertoft, N.B.*
AU  - Touch, S.*
AU  - Dumas, M.E.*
AU  - Ehrlich, S.D.*
AU  - Galan, P.*
AU  - Gøtze, J.P.*
AU  - Hansen, T.*
AU  - Holst, J.J.*
AU  - Køber, L.*
AU  - Letunic, I.*
AU  - Nielsen, J.*
AU  - Oppert, J.M.*
AU  - Stumvoll, M.
AU  - Vestergaard, H.*
AU  - Zucker, J.D.*
AU  - Bork, P.*
AU  - Pedersen, O.*
AU  - Bäckhed, F.*
AU  - Clément, K.*
AU  - Raes, J.*
C1  - 59168
C2  - 48650
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 310-315
TI  - Statin therapy is associated with lower prevalence of gut microbiota dysbiosis.
JO  - Nature
VL  - 581
IS  - 7808
PB  - Nature Research
PY  - 2020
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Advances in genomics have expedited the improvement of several agriculturally important crops but similar efforts in wheat (Triticum spp.) have been more challenging. This is largely owing to the size and complexity of the wheat genome1, and the lack of genome-assembly data for multiple wheat lines2,3. Here we generated ten chromosome pseudomolecule and five scaffold assemblies of hexaploid wheat to explore the genomic diversity among wheat lines from global breeding programs. Comparative analysis revealed extensive structural rearrangements, introgressions from wild relatives and differences in gene content resulting from complex breeding histories aimed at improving adaptation to diverse environments, grain yield and quality, and resistance to stresses4,5. We provide examples outlining the utility of these genomes, including a detailed multi-genome-derived nucleotide-binding leucine-rich repeat protein repertoire involved in disease resistance and the characterization of Sm16, a gene associated with insect resistance. These genome assemblies will provide a basis for functional gene discovery and breeding to deliver the next generation of modern wheat cultivars.
AU  - Walkowiak, S.*
AU  - Gao, L.*
AU  - Monat, C.*
AU  - Haberer, G.
AU  - Kassa, M.T.*
AU  - Brinton, J.*
AU  - Ramirez-Gonzalez, R.H.*
AU  - Kolodziej, M.C.*
AU  - Delorean, E.*
AU  - Thambugala, D.*
AU  - Klymiuk, V.*
AU  - Byrns, B.*
AU  - Gundlach, H.*
AU  - Bandi, V.*
AU  - Siri, J.N.*
AU  - Nilsen, K.*
AU  - Aquino, C.*
AU  - Himmelbach, A.*
AU  - Copetti, D.*
AU  - Ban, T.*
AU  - Venturini, L.*
AU  - Bevan, M.*
AU  - Clavijo, B.J.*
AU  - Koo, D.H.*
AU  - Ens, J.*
AU  - Wiebe, K.*
AU  - N'Diaye, A.*
AU  - Fritz, A.K.*
AU  - Gutwin, C.*
AU  - Fiebig, A.*
AU  - Fosker, C.*
AU  - Fu, B.X.*
AU  - Accinelli, G.G.*
AU  - Gardner, K.A.*
AU  - Fradgley, N.*
AU  - Gutierrez-Gonzalez, J.*
AU  - Halstead-Nussloch, G.*
AU  - Hatakeyama, M.*
AU  - Koh, C.S.*
AU  - Deek, J.*
AU  - Costamagna, A.C.*
AU  - Fobert, P.*
AU  - Heavens, D.*
AU  - Kanamori, H.*
AU  - Kawaura, K.*
AU  - Kobayashi, F.*
AU  - Krasileva, K.*
AU  - Kuo, T.*
AU  - McKenzie, N.*
AU  - Murata, K.*
AU  - Nabeka, Y.*
AU  - Paape, T.*
AU  - Padmarasu, S.*
AU  - Percival-Alwyn, L.*
AU  - Kagale, S.*
AU  - Scholz, U.*
AU  - Sese, J.*
AU  - Juliana, P.*
AU  - Singh, R.*
AU  - Shimizu-Inatsugi, R.*
AU  - Swarbreck, D.*
AU  - Cockram, J.*
AU  - Budak, H.*
AU  - Tameshige, T.*
AU  - Tanaka, T.*
AU  - Tsuji, H.*
AU  - Wright, J.*
AU  - Wu, J.*
AU  - Steuernagel, B.*
AU  - Small, I.*
AU  - Cloutier, S.*
AU  - Keeble-Gagnère, G.*
AU  - Muehlbauer, G.*
AU  - Tibbets, J.*
AU  - Nasuda, S.*
AU  - Melonek, J.*
AU  - Hucl, P.J.*
AU  - Sharpe, A.G.*
AU  - Clark, M.*
AU  - Legg, E.*
AU  - Bharti, A.*
AU  - Langridge, P.*
AU  - Hall, A.*
AU  - Uauy, C.*
AU  - Mascher, M.*
AU  - Krattinger, S.G.*
AU  - Handa, H.*
AU  - Shimizu, K.K.*
AU  - Distelfeld, A.*
AU  - Chalmers, K.*
AU  - Keller, B.*
AU  - Mayer, K.F.X.
AU  - Poland, J.*
AU  - Stein, N.*
AU  - McCartney, C.A.*
AU  - Spannagl, M.
AU  - Wicker, T.*
AU  - Pozniak, C.J.*
C1  - 60636
C2  - 49521
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 277-283
TI  - Multiple wheat genomes reveal global variation in modern breeding.
JO  - Nature
VL  - 588
IS  - 7837
PB  - Nature Research
PY  - 2020
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Formation of the three primary germ layers during gastrulation is an essential step in the establishment of the vertebrate body plan and is associated with major transcriptional changes(1-5). Global epigenetic reprogramming accompanies these changes(6-8), but the role of the epigenome in regulating early cell-fate choice remains unresolved, and the coordination between different molecular layers is unclear. Here we describe a single-cell multi-omics map of chromatin accessibility, DNA methylation and RNA expression during the onset of gastrulation in mouse embryos. The initial exit from pluripotency coincides with the establishment of a global repressive epigenetic landscape, followed by the emergence of lineage-specific epigenetic patterns during gastrulation. Notably, cells committed to mesoderm and endoderm undergo widespread coordinated epigenetic rearrangements at enhancer marks, driven by ten-eleven translocation (TET)-mediated demethylation and a concomitant increase of accessibility. By contrast, the methylation and accessibility landscape of ectodermal cells is already established in the early epiblast. Hence, regulatory elements associated with each germ layer are either epigenetically primed or remodelled before cell-fate decisions, providing the molecular framework for a hierarchical emergence of the primary germ layers.
AU  - Argelaguet, R.*
AU  - Clark, S.J.*
AU  - Mohammed, H.*
AU  - Stapel, L.C.*
AU  - Krueger, C.*
AU  - Kapourani, C.A.*
AU  - Imaz-Rosshandler, I.*
AU  - Lohoff, T.*
AU  - Xiang, Y.*
AU  - Hanna, C.W.*
AU  - Smallwood, S.*
AU  - Ibarra-Soria, X.*
AU  - Buettner, F.
AU  - Sanguinetti, G.*
AU  - Xie, W.*
AU  - Krueger, F.*
AU  - Göttgens, B.*
AU  - Rugg-Gunn, P.J.*
AU  - Kelsey, G.*
AU  - Dean, W.*
AU  - Nichols, J.*
AU  - Stegle, O.*
AU  - Marioni, J.C.*
AU  - Reik, W.*
C1  - 57713
C2  - 47945
CY  - Macmillan Building, 4 Crinan St, London N1 9xw, England
SP  - 487-491
TI  - Multi-omics profiling of mouse gastrulation at single-cell resolution.
JO  - Nature
VL  - 576
IS  - 7787
PB  - Nature Publishing Group
PY  - 2019
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities(.)(1,2) This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity(3-6). Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017-and more than 80% in some low- and middle-income regions-was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing-and in some countries reversal-of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories.
AU  - Bixby, H.*
AU  - Bentham, J.*
AU  - Zhou, B.*
AU  - di Cesare, M.*
AU  - Paciorek, C.J.*
AU  - Bennett, J.E.*
AU  - Taddei, C.*
AU  - Stevens, G.A.*
AU  - Rodriguez-Martinez, A.*
AU  - Carrillo-Larco, R.M.*
AU  - Khang, Y.H.*
AU  - Sorić, M.*
AU  - Gregg, E.W.*
AU  - Miranda, J.J.*
AU  - Bhutta, Z.A.*
AU  - Savin, S.*
AU  - Sophiea, M.K.*
AU  - Iurilli, M.L.C.*
AU  - Solomon, B.D.*
AU  - Cowan, M.J.*
AU  - Riley, L.M.*
AU  - Danaei, G.*
AU  - Bovet, P.*
AU  - Chirita-Emandi, A.*
AU  - Hambleton, I.R.*
AU  - Hayes, A.J.*
AU  - Ikeda, N.*
AU  - Kengne, A.P.*
AU  - Laxmaiah, A.*
AU  - Li, Y.*
AU  - McGarvey, S.T.*
AU  - Mostafa, A.*
AU  - Neovius, M.*
AU  - Starc, G.*
AU  - Zainuddin, A.A.*
AU  - Abarca-Gómez, L.*
AU  - Abdeen, Z.A.*
AU  - Abdrakhmanova, S.*
AU  - Abdul Ghaffar, S.*
AU  - Abdul Hamid, Z.*
AU  - Abubakar Garba, J.*
AU  - Abu-Rmeileh, N.M.*
AU  - Acosta-Cazares, B.*
AU  - Adams, R.J.*
AU  - Aekplakorn, W.*
AU  - Afsana, K.*
AU  - Agdeppa, I.A.*
AU  - Aguilar-Salinas, C.A.*
AU  - Agyemang, C.*
AU  - Ahmad, M.H.*
AU  - Ahmad, N.A.*
AU  - Ahmadi, N.*
AU  - Ahmadvand, A.*
AU  - Ahrens, W.*
AU  - Ajlouni, K.*
AU  - AlBuhairan, F.*
AU  - AlDhukair, S.*
AU  - Al-Hazzaa, H.M.*
AU  - Ali, M.M.*
AU  - Ali, O.*
AU  - AlKerwi, A.*
AU  - Al-Othman, A.R.*
AU  - Al-Raddadi, R.*
AU  - Alvarez-Pedrerol, M.*
AU  - Aly, E.*
AU  - Amarapurkar, D.N.*
AU  - Amouyel, P.*
AU  - Amuzu, A.*
AU  - Andersen, L.B.*
AU  - Anderssen, S.A.*
AU  - Ängquist, L.H.*
AU  - Anjana, R.M.*
AU  - Ansari-Moghaddam, A.*
AU  - Aounallah-Skhiri, H.*
AU  - Araújo, J.*
AU  - Ariansen, I.*
AU  - Aris, T.*
AU  - Arku, R.E.*
AU  - Arlappa, N.*
AU  - Aryal, K.K.*
AU  - Aspelund, T.*
AU  - Assah, F.K.*
AU  - Assunção, M.C.F.*
AU  - Aung, M.S.*
AU  - Auvinen, J.*
AU  - Avdicová, M.*
AU  - Azevedo, A.*
AU  - Azizi, F.*
AU  - Azmin, M.*
AU  - Babu, B.V.*
AU  - Baharudin, A.*
AU  - Bahijri, S.*
AU  - Baker, J.L.*
AU  - Balakrishna, N.*
AU  - Bamoshmoosh, M.*
AU  - Banach, M.*
AU  - Bandosz, P.*
AU  - Banegas, J.R.*
AU  - Barbagallo, C.M.*
AU  - Barceló, A.*
AU  - NCD Risk Factors Collaboration (Döring, A.
AU  - Meisinger, C.
AU  - Müller-Nurasyid, M.
AU  - Peters, A.
AU  - Stöckl, D.)
C1  - 56102
C2  - 46821
CY  - Macmillan Building, 4 Crinan St, London N1 9xw, England
SP  - 260-264
TI  - Rising rural body-mass index is the main driver of the global obesity epidemic in adults.
JO  - Nature
VL  - 569
IS  - 7755
PB  - Nature Publishing Group
PY  - 2019
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - In mammals, the emergence of totipotency after fertilization involves extensive rearrangements of the spatial positioning of the genome(1,2). However, the contribution of spatial genome organization to the regulation of developmental programs is unclear(3). Here we generate high-resolution maps of genomic interactions with the nuclear lamina (a filamentous meshwork that lines the inner nuclear membrane) in mouse pre-implantation embryos. We reveal that nuclear organization is not inherited from the maternal germline but is instead established de novo shortly after fertilization. The two parental genomes establish lamina-associated domains (LADs)(4) with different features that converge after the 8-cell stage. We find that the mechanism of LAD establishment is unrelated to DNA replication. Instead, we show that paternal LAD formation in zygotes is prevented by ectopic expression of Kdm5b, which suggests that LAD establishment may be dependent on remodelling of H3K4 methylation. Our data suggest a step-wise assembly model whereby early LAD formation precedes consolidation of topologically associating domains.
AU  - Borsos, M.
AU  - Perricone, S.M.*
AU  - Schauer, T.*
AU  - Pontabry, J.
AU  - de Luca, K.L.*
AU  - de Vries, S.S.*
AU  - Ruiz-Morales, E.R.
AU  - Torres-Padilla, M.E.
AU  - Kind, J.*
C1  - 56136
C2  - 46843
CY  - Macmillan Building, 4 Crinan St, London N1 9xw, England
SP  - 729-733
TI  - Genome-lamina interactions are established de novo in the early mouse embryo.
JO  - Nature
VL  - 569
IS  - 7758
PB  - Nature Publishing Group
PY  - 2019
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - The expansion of brain size is accompanied by a relative enlargement of the subventricular zone during development. Epithelial-like neural stem cells divide in the ventricular zone at the ventricles of the embryonic brain, self-renew and generate basal progenitors(1) that delaminate and settle in the subventricular zone in enlarged brain regions(2). The length of time that cells stay in the subventricular zone is essential for controlling further amplification and fate determination. Here we show that the interphase centrosome protein AKNA has a key role in this process. AKNA localizes at the subdistal appendages of the mother centriole in specific subtypes of neural stem cells, and in almost all basal progenitors. This protein is necessary and sufficient to organize centrosomal microtubules, and promote their nucleation and growth. These features of AKNA are important for mediating the delamination process in the formation of the subventricular zone. Moreover, AKNA regulates the exit from the subventricular zone, which reveals the pivotal role of centrosomal microtubule organization in enabling cells to both enter and remain in the subventricular zone. The epithelial-to-mesenchymal transition is also regulated by AKNA in other epithelial cells, demonstrating its general importance for the control of cell delamination.
AU  - Camargo Ortega, G.
AU  - Falk, S.
AU  - Johansson, P.A.
AU  - Peyre, E.*
AU  - Broix, L.*
AU  - Sahu, S.K.*
AU  - Hirst, W.*
AU  - Schlichthaerle, T.*
AU  - de Juan Romero, C.*
AU  - Draganova, K.
AU  - Vinopal, S.*
AU  - Chinnappa, K.
AU  - Gavranovic, A.
AU  - Karakaya, T.
AU  - Steininger, T.
AU  - Merl-Pham, J.
AU  - Feederle, R.
AU  - Shao, W.*
AU  - Shi, S.H.*
AU  - Hauck, S.M.
AU  - Jungmann, R.*
AU  - Bradke, F.*
AU  - Borrell, V.*
AU  - Geerlof, A.
AU  - Reber, S.*
AU  - Tiwari, V.K.*
AU  - Huttner, W.B.*
AU  - Wilsch-Bräuninger, M.*
AU  - Nguyen, L.A.*
AU  - Götz, M.
C1  - 55563
C2  - 46391
CY  - Macmillan Building, 4 Crinan St, London N1 9xw, England
SP  - 113-117
TI  - The centrosome protein AKNA regulates neurogenesis via microtubule organization.
JO  - Nature
VL  - 567
IS  - 7746
PB  - Nature Publishing Group
PY  - 2019
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Mammals form scars to quickly seal wounds and ensure survival by an incompletely understood mechanism(1-5). Here we show that skin scars originate from prefabricated matrix in the subcutaneous fascia. Fate mapping and live imaging revealed that fascia fibroblasts rise to the skin surface after wounding, dragging their surrounding extracellular jelly-like matrix, including embedded blood vessels, macrophages and peripheral nerves, to form the provisional matrix. Genetic ablation of fascia fibroblasts prevented matrix from homing into wounds and resulted in defective scars, whereas placing an impermeable film beneath the skin-preventing fascia fibroblasts from migrating upwards-led to chronic open wounds. Thus, fascia contains a specialized prefabricated kit of sentry fibroblasts, embedded within a movable sealant, that preassemble together diverse cell types and matrix components needed to heal wounds. Our findings suggest that chronic and excessive skin wounds may be attributed to the mobility of the fascia matrix.
AU  - Correa-Gallegos, D.
AU  - Jiang, D.
AU  - Christ, S.
AU  - Ramesh, P.
AU  - Ye, H.
AU  - Wannemacher, J.
AU  - Kalgudde Gopal, S.
AU  - Yu, Q.
AU  - Aichler, M.
AU  - Walch, A.K.
AU  - Mirastschijski, U.*
AU  - Volz, T.*
AU  - Rinkevich, Y.
C1  - 57449
C2  - 47800
CY  - Macmillan Building, 4 Crinan St, London N1 9xw, England
SP  - 287-292
TI  - Patch repair of deep wounds by mobilized fascia.
JO  - Nature
VL  - 576
IS  - 7786
PB  - Nature Publishing Group
PY  - 2019
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Ferroptosis is an iron-dependent form of necrotic cell death marked by oxidative damage to phospholipids(1,2). To date, ferroptosis has been thought to be controlled only by the phospholipid hydroperoxide-reducing enzyme glutathione peroxidase 4 (GPX4)(3,4) and radical-trapping antioxidants(5,6). However, elucidation of the factors that underlie the sensitivity of a given cell type to ferroptosis(7) is crucial to understand the pathophysiological role of ferroptosis and how it may be exploited for the treatment of cancer. Although metabolic constraints(8) and phospholipid composition(9,10) contribute to ferroptosis sensitivity, no cell-autonomous mechanisms have been identified that account for the resistance of cells to ferroptosis. Here we used an expression cloning approach to identify genes in human cancer cells that are able to complement the loss of GPX4. We found that the flavoprotein apoptosis-inducing factor mitochondria-associated 2 (AIFM2) is a previously unrecognized anti-ferroptotic gene. AIFM2, which we renamed ferroptosis suppressor protein 1 (FSP1) and which was initially described as a pro-apoptotic gene(11), confers protection against ferroptosis elicited by GPX4 deletion. We further demonstrate that the suppression of ferroptosis by FSP1 is mediated by ubiquinone (also known as coenzyme Q(10), CoQ(10)): the reduced form, ubiquinol, traps lipid peroxyl radicals that mediate lipid peroxidation, whereas FSP1 catalyses the regeneration of CoQ(10) using NAD(P)H. Pharmacological targeting of FSP1 strongly synergizes with GPX4 inhibitors to trigger ferroptosis in a number of cancer entities. In conclusion, the FSP1-CoQ(10)-NAD(P)H pathway exists as a stand-alone parallel system, which co-operates with GPX4 and glutathione to suppress phospholipid peroxidation and ferroptosis.
AU  - Doll, S.
AU  - Freitas, F.P.*
AU  - Shah, R.*
AU  - Aldrovandi, M.
AU  - da Silva, M.C.
AU  - Ingold, I.
AU  - Grocin, A.G.*
AU  - Xavier da Silva, T.N.*
AU  - Panzilius, E.
AU  - Scheel, C.
AU  - Mourao, A.
AU  - Buday, K.
AU  - Sato, M.
AU  - Wanninger, J.
AU  - Vignane, T.
AU  - Mohana, V.
AU  - Rehberg, M.
AU  - Flatley, A.
AU  - Schepers, A.
AU  - Kurz, A.*
AU  - White, D.*
AU  - Sauer, M.*
AU  - Sattler, M.
AU  - Tate, E.W.*
AU  - Schmitz, W.*
AU  - Schulze, A.*
AU  - O’Donnell, V.*
AU  - Proneth, B.
AU  - Popowicz, G.M.
AU  - Pratt, D.A.*
AU  - Angeli, J.P.F.*
AU  - Conrad, M.
C1  - 57388
C2  - 47775
CY  - Macmillan Building, 4 Crinan St, London N1 9xw, England
SP  - 693-698
TI  - FSP1 is a glutathione-independent ferroptosis suppressor.
JO  - Nature
VL  - 575
IS  - 7784
PB  - Nature Publishing Group
PY  - 2019
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Single-cell RNA sequencing (scRNA-seq) has highlighted the important role of intercellular heterogeneity in phenotype variability in both health and disease(1). However, current scRNA-seq approaches provide only a snapshot of gene expression and convey little information on the true temporal dynamics and stochastic nature of transcription. A further key limitation of scRNA-seq analysis is that the RNA profile of each individual cell can be analysed only once. Here we introduce single-cell, thiol-(SH)-linked alkylation of RNA for metabolic labelling sequencing (scSLAM-seq), which integrates metabolic RNA labelling(2), biochemical nucleoside conversion(3) and scRNA-seq to record transcriptional activity directly by differentiating between new and old RNA for thousands of genes per single cell. We use scSLAM-seq to study the onset of infection with lytic cytomegalovirus in single mouse fibroblasts. The cell-cycle state and dose of infection deduced from old RNA enable dose-response analysis based on new RNA. scSLAM-seq thereby both visualizes and explains differences in transcriptional activity at the single-cell level. Furthermore, it depicts 'on-off' switches and transcriptional burst kinetics in host gene expression with extensive gene-specific differences that correlate with promoter-intrinsic features (TBP-TATA-box interactions and DNA methylation). Thus, gene-specific, and not cell-specific, features explain the heterogeneity in transcriptomes between individual cells and the transcriptional response to perturbations.
AU  - Erhard, F.*
AU  - Baptista, M.A.P.*
AU  - Krammer, T.*
AU  - Hennig, T.*
AU  - Lange, M.
AU  - Arampatzi, P.*
AU  - Jürges, C.S.*
AU  - Theis, F.J.
AU  - Saliba, A.-E.*
AU  - Dölken, L.*
C1  - 56537
C2  - 47093
CY  - Macmillan Building, 4 Crinan St, London N1 9xw, England
SP  - 419-423
TI  - scSLAM-seq reveals core features of transcription dynamics in single cells.
JO  - Nature
VL  - 571
IS  - 7765
PB  - Nature Publishing Group
PY  - 2019
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 x 10(-3)) and candidate genes from knockout mice (P = 5.2 x 10(-3)). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.
AU  - Flannick, J.*
AU  - Mercader, J.M.*
AU  - Fuchsberger, C.*
AU  - Udler, M.S.*
AU  - Mahajan, A.*
AU  - Wessel, J.*
AU  - Teslovich, T.M.*
AU  - Caulkins, L.*
AU  - Koesterer, R.*
AU  - Barajas-Olmos, F.*
AU  - Blackwell, T.W.*
AU  - Boerwinkle, E.*
AU  - Brody, J.A.*
AU  - Centeno-Cruz, F.*
AU  - Chen, L.*
AU  - Chen, S.*
AU  - Contreras-Cubas, C.*
AU  - Córdova, E.*
AU  - Correa, A.*
AU  - Cortes, M.*
AU  - DeFronzo, R.A.*
AU  - Dolan, L.*
AU  - Drews, K.L.*
AU  - Elliott, A.*
AU  - Floyd, J.S.*
AU  - Gabriel, S.*
AU  - Garay-Sevilla, M.E.*
AU  - García-Ortiz, H.*
AU  - Gross, M.*
AU  - Han, S.*
AU  - Heard-Costa, N.L.*
AU  - Jackson, A.U.*
AU  - Jørgensen, M.E.*
AU  - Kang, H.M.*
AU  - Kelsey, M.*
AU  - Kim, B.J.*
AU  - Koistinen, H.A.*
AU  - Kuusisto, J.*
AU  - Leader, J.B.*
AU  - Linneberg, A.*
AU  - Liu, C.T.*
AU  - Liu, J.*
AU  - Lyssenko, V.*
AU  - Manning, A.K.*
AU  - Marcketta, A.*
AU  - Malacara-Hernandez, J.M.*
AU  - Martínez-Hernández, A.*
AU  - Matsuo, K.*
AU  - Mayer-Davis, E.*
AU  - Mendoza-Caamal, E.*
AU  - Mohlke, K.L.*
AU  - Morrison, A.C.*
AU  - Ndungu, A.*
AU  - Ng, M.C.Y.*
AU  - O'Dushlaine, C.*
AU  - Payne, A.J.*
AU  - Pihoker, C.*
AU  - Post, W.S.*
AU  - Preuss, M.*
AU  - Psaty, B.M.*
AU  - Vasan, R.S.*
AU  - Rayner, N.W.*
AU  - Reiner, A.P.*
AU  - Revilla-Monsalve, C.*
AU  - Robertson, N.R.*
AU  - Santoro, N.*
AU  - Schurmann, C.*
AU  - So, W.Y.*
AU  - Soberón, X.*
AU  - Stringham, H.M.*
AU  - Strom, T.M.
AU  - Tam, C.H.T.*
AU  - Thameem, F.*
AU  - Tomlinson, B.*
AU  - Torres, J.M.*
AU  - Tracy, R.P.*
AU  - van Dam, R.M.*
AU  - Vujkovic, M.R.*
AU  - Wang, S.*
AU  - Welch, R.P.*
AU  - Witte, D.R.*
AU  - Wong, T.Y.*
AU  - Atzmon, G.*
AU  - Barzilai, N.*
AU  - Blangero, J.*
AU  - Bonnycastle, L.L.*
AU  - Bowden, D.W.*
AU  - Chambers, J.C.*
AU  - Chan, E.*
AU  - Cheng, C.Y.*
AU  - Cho, Y.S.*
AU  - Collins, F.S.*
AU  - de Vries, P.S.*
AU  - Duggirala, R.*
AU  - Glaser, B.*
AU  - Gonzalez, C.*
AU  - Gonzalez, M.E.*
AU  - Groop, L.*
AU  - Kooner, J.S.*
AU  - Kwak, S.H.*
AU  - Laakso, M.*
AU  - Lehman, D.M.*
AU  - Nilsson, P.*
AU  - Spector, T.D.*
AU  - Tai, E.S.*
AU  - Tuomi, T.*
AU  - Tuomilehto, J.*
AU  - Wilson, J.G.*
AU  - Aguilar-Salinas, C.A.*
AU  - Bottinger, E.B.*
AU  - Burke, B.*
AU  - Carey, D.J.*
AU  - Chan, J.C.N.*
AU  - Dupuis, J.*
AU  - Frossard, P.*
AU  - Heckbert, S.R.*
AU  - Hwang, M.Y.*
AU  - Kim, Y.J.*
AU  - Kirchner, H.L.*
AU  - Lee, J.Y.*
AU  - Lee, J.*
AU  - Loos, R.J.F.*
AU  - Ma, R.C.W.*
AU  - Morris, A.D.*
AU  - O'Donnell, C.J.*
AU  - Palmer, C.N.A.*
AU  - Pankow, J.*
AU  - Park, K.S.*
AU  - Rasheed, A.*
AU  - Saleheen, D.*
AU  - Sim, X.*
AU  - Small, K.S.*
AU  - Teo, Y.Y.*
AU  - Haiman, C.*
AU  - Hanis, C.L.*
AU  - Henderson, B.E.*
AU  - Orozco, L.*
AU  - Tusié-Luna, T.*
AU  - Dewey, F.E.*
AU  - Baras, A.*
AU  - Gieger, C.
AU  - Meitinger, T.
AU  - Strauch, K.
AU  - Lange, L.A.*
AU  - Grarup, N.*
AU  - Hansen, T.*
AU  - Pedersen, O.*
AU  - Zeitler, P.*
AU  - Dabelea, D.*
AU  - Abecasis, G.*
AU  - Bell, G.I.*
AU  - Cox, N.J.*
AU  - Seielstad, M.*
AU  - Sladek, R.*
AU  - Meigs, J.B.*
AU  - Rich, S.S.*
AU  - Rotter, J.I.*
AU  - Altshuler, D.*
AU  - Burtt, N.P.*
AU  - Scott, L.J.*
AU  - Morris, A.P.*
AU  - Florez, J.C.*
AU  - McCarthy, M.I.*
AU  - Boehnke, M.*
C1  - 56135
C2  - 46848
CY  - Macmillan Building, 4 Crinan St, London N1 9xw, England
SP  - 71-76
TI  - Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls.
JO  - Nature
VL  - 570
IS  - 7759
PB  - Nature Publishing Group
PY  - 2019
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Zoonotic influenza A viruses of avian origin can cause severe disease in individuals, or even global pandemics, and thus pose a threat to human populations. Waterfowl and shorebirds are believed to be the reservoir for all influenza A viruses, but this has recently been challenged by the identification of novel influenza A viruses in bats(1,2). The major bat influenza A virus envelope glycoprotein, haemagglutinin, does not bind the canonical influenza A virus receptor, sialic acid or any other glycan(1,3,4), despite its high sequence and structural homology with conventional haemagglutinins. This functionally uncharacterized plasticity of the bat influenza A virus haemagglutinin means the tropism and zoonotic potential of these viruses has not been fully determined. Here we show, using transcriptomic profiling of susceptible versus non-susceptible cells in combination with genome-wide CRISPR-Cas9 screening, that the major histocompatibility complex class II (MHC-II) human leukocyte antigen DR isotype (HLA-DR) is an essential entry determinant for bat influenza A viruses. Genetic ablation of the HLA-DR alpha a-chain rendered cells resistant to infection by bat influenza A virus, whereas ectopic expression of the HLA-DR complex in non-susceptible cells conferred susceptibility. Expression of MHC-II from different bat species, pigs, mice or chickens also conferred susceptibility to infection. Notably, the infection of mice with bat influenza A virus resulted in robust virus replication in the upper respiratory tract, whereas mice deficient for MHC-II were resistant. Collectively, our data identify MHC-II as a crucial entry mediator for bat influenza A viruses in multiple species, which permits a broad vertebrate tropism.
AU  - Karakus, U.*
AU  - Thamamongood, T.*
AU  - Ciminski, K.*
AU  - Ran, W.*
AU  - Günther, S.C.*
AU  - Pohl, M.O.*
AU  - Eletto, D.*
AU  - Jeney, C.*
AU  - Hoffmann, D.*
AU  - Reiche, S.*
AU  - Schinköthe, J.*
AU  - Ulrich, R.*
AU  - Wiener, J.
AU  - Hayes, M.G.B.*
AU  - Chang, M.W.*
AU  - Hunziker, A.*
AU  - Yángüez, E.*
AU  - Aydillo, T.*
AU  - Krammer, F.*
AU  - Oderbolz, J.*
AU  - Meier, M.
AU  - Oxenius, A.*
AU  - Halenius, A.*
AU  - Zimmer, G.*
AU  - Benner, C.*
AU  - Hale, B.G.*
AU  - García-Sastre, A.*
AU  - Beer, M.*
AU  - Schwemmle, M.*
AU  - Stertz, S.*
C1  - 55564
C2  - 46392
CY  - Macmillan Building, 4 Crinan St, London N1 9xw, England
SP  - 109-112
TI  - MHC class II proteins mediate cross-species entry of bat influenza viruses.
JO  - Nature
VL  - 567
IS  - 7746
PB  - Nature Publishing Group
PY  - 2019
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - The nuclear exosome and its essential co-factor, the RNA helicase MTR4, play crucial roles in several RNA degradation pathways. Besides unwinding RNA substrates for exosome-mediated degradation, MTR4 associates with RNA-binding proteins that function as adaptors in different RNA processing and decay pathways. Here, we identify and characterize the interactions of human MTR4 with a ribosome processing adaptor, NVL, and with ZCCHC8, an adaptor involved in the decay of small nuclear RNAs. We show that the unstructured regions of NVL and ZCCHC8 contain short linear motifs that bind the MTR4 arch domain in a mutually exclusive manner. These short sequences diverged from the arch-interacting motif (AIM) of yeast rRNA processing factors. Our results suggest that nuclear exosome adaptors have evolved canonical and non-canonical AIM sequences to target human MTR4 and demonstrate the versatility and specificity with which the MTR4 arch domain can recruit a repertoire of different RNA-binding proteins.
AU  - Lingaraju, M.*
AU  - Johnsen, D.*
AU  - Schlundt, A.
AU  - Langer, L.M.*
AU  - Basquin, J.*
AU  - Sattler, M.
AU  - Jensen, T.H.*
AU  - Falk, S.*
AU  - Conti, E.*
C1  - 56667
C2  - 47142
CY  - Macmillan Building, 4 Crinan St, London N1 9xw, England
TI  - The MTR4 helicase recruits nuclear adaptors of the human RNA exosome using distinct arch-interacting motifs.
JO  - Nature
VL  - 10
IS  - 1
PB  - Nature Publishing Group
PY  - 2019
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Haematopoietic stem cells self-renew and differentiate into all blood lineages throughout life, and can repair damaged blood systems upon transplantation. Asymmetric cell division has previously been suspected to be a regulator of haematopoietic-stem-cell fate, but its existence has not directly been shown(1). In asymmetric cell division, asymmetric fates of future daughter cells are prospectively determined by a mechanism that is linked to mitosis. This can be mediated by asymmetric inheritance of cell-extrinsic niche signals by, for example, orienting the divisional plane, or by the asymmetric inheritance of cell-intrinsic fate determinants. Observations of asymmetric inheritance or of asymmetric daughter-cell fates alone are not sufficient to demonstrate asymmetric cell division(2). In both cases, sister-cell fates could be controlled by mechanisms that are independent of division. Here we demonstrate that the cellular degradative machinery-including lysosomes, autophagosomes, mitophagosomes and the protein NUMB-can be asymmetrically inherited into haematopoietic-stem-cell daughter cells. This asymmetric inheritance predicts the asymmetric future metabolic and translational activation and fates of haematopoietic-stem-cell daughter cells and their offspring. Therefore, our studies provide evidence for the existence of asymmetric cell division in haematopoietic stem cells.
AU  - Loeffler, D.
AU  - Wehling, A.*
AU  - Schneiter, F.*
AU  - Zhang, Y.*
AU  - Müller-Bötticher, N.*
AU  - Hoppe, P.S.
AU  - Hilsenbeck, O.
AU  - Kokkaliaris, K.D.
AU  - Endele, M.
AU  - Schroeder, T.
C1  - 56853
C2  - 47358
CY  - Macmillan Building, 4 Crinan St, London N1 9xw, England
SP  - 426-429
TI  - Asymmetric lysosome inheritance predicts activation of haematopoietic stem cells.
JO  - Nature
VL  - 573
IS  - 7774
PB  - Nature Publishing Group
PY  - 2019
SN  - 0028-0836
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  - Loeffler, D.
AU  - Wehling, A.*
AU  - Schneiter, F.*
AU  - Zhang, Y.*
AU  - Müller-Bötticher, N.*
AU  - Hoppe, P.S.
AU  - Hilsenbeck, O.
AU  - Kokkaliaris, K.D.
AU  - Endele, M.
AU  - Schroeder, T.
C1  - 56900
C2  - 47359
SP  - E5
TI  - Erratum: Publisher Correction: Asymmetric lysosome inheritance predicts activation of haematopoietic stem cells (Nature (2019) 573 7774 (426-429)).
JO  - Nature
VL  - 573
IS  - 7775
PY  - 2019
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - The use of stem-cell-derived beta-cells to replace those destroyed in pancreatic islets has the potential to cure diabetes. A new analysis provides a deep mechanistic understanding of islet-cell differentiation from stem cells. SEE ARTICLE P. 368
AU  - Theis, F.J.
AU  - Lickert, H.
C1  - 56187
C2  - 46876
CY  - Macmillan Building, 4 Crinan St, London N1 9xw, England
SP  - 342-343
TI  - A map of beta-cell differentiation.
JO  - Nature
VL  - 569
IS  - 7756
PB  - Nature Publishing Group
PY  - 2019
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - The ability to repair or promote regeneration within the adult human brain has been envisioned for decades. Until recently, such efforts mainly involved delivery of growth factors and cell transplants designed to rescue or replace a specific population of neurons, and the results have largely been disappointing. New approaches using stem-cell-derived cell products and direct cell reprogramming have opened up the possibility of reconstructing neural circuits and achieving better repair. In this Review we briefly summarize the history of neural repair and then discuss these new therapeutic approaches, especially with respect to chronic neurodegenerative disorders.
AU  - Barker, R.A.*
AU  - Götz, M.
AU  - Parmar, M.*
C1  - 53563
C2  - 44636
SP  - 329-334
TI  - New approaches for brain repair-from rescue to reprogramming.
JO  - Nature
VL  - 557
IS  - 7705
PY  - 2018
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - The pancreas originates from two epithelial evaginations of the foregut, which consist of multipotent epithelial progenitors that organize into a complex tubular epithelial network. The trunk domain of each epithelial branch consists of bipotent pancreatic progenitors (bi-PPs) that give rise to both duct and endocrine lineages, whereas the tips give rise to acinar cells(1). Here we identify the extrinsic and intrinsic signalling mechanisms that coordinate the fate-determining transcriptional events underlying these lineage decisions(1,2). Single-cell analysis of pancreatic bipotent pancreatic progenitors derived from human embryonic stem cells reveal that cell confinement is a prerequisite for endocrine specification, whereas spreading drives the progenitors towards a ductal fate. Mechanistic studies identify the interaction of extracellular matrix (ECM) with integrin alpha 5 as the extracellular cue that cell-autonomously, via the F-actin-YAP1-Notch mechanosignalling axis, controls the fate of bipotent pancreatic progenitors. Whereas ECM-integrin alpha 5 signalling promotes differentiation towards the duct lineage, endocrinogenesis is stimulated when this signalling cascade is disrupted. This cascade can be disrupted pharmacologically or genetically to convert bipotent pancreatic progenitors derived from human embryonic stem cells to hormone-producing islet cells. Our findings identify the cell-extrinsic and intrinsic mechanotransduction pathway that acts as gatekeeper in the fate decisions of bipotent pancreatic progenitors in the developing pancreas.
AU  - Mamidi, A.*
AU  - Prawiro, C.*
AU  - Seymour, P.A.*
AU  - de Lichtenberg, K.H.*
AU  - Jackson, A.*
AU  - Serup, P.*
AU  - Semb, H.
C1  - 54966
C2  - 46046
CY  - Macmillan Building, 4 Crinan St, London N1 9xw, England
SP  - 114-118
TI  - Mechanosignalling via integrins directs fate decisions of pancreatic progenitors.
JO  - Nature
VL  - 564
IS  - 7734
PB  - Nature Publishing Group
PY  - 2018
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - The poor correlation of mutational landscapes with phenotypes limits our understanding of the pathogenesis and metastasis of pancreatic ductal adenocarcinoma (PDAC). Here we show that oncogenic dosage-variation has a critical role in PDAC biology and phenotypic diversification. We find an increase in gene dosage of mutant KRAS in human PDAC precursors, which drives both early tumorigenesis and metastasis and thus rationalizes early PDAC dissemination. To overcome the limitations posed to gene dosage studies by the stromal richness of PDAC, we have developed large cell culture resources of metastatic mouse PDAC. Integration of cell culture genomes, transcriptomes and tumour phenotypes with functional studies and human data reveals additional widespread effects of oncogenic dosage variation on cell morphology and plasticity, histopathology and clinical outcome, with the highest Kras MUT levels underlying aggressive undifferentiated phenotypes. We also identify alternative oncogenic gains (Myc, Yap1 or Nfkb2), which collaborate with heterozygous Kras MUT in driving tumorigenesis, but have lower metastatic potential. Mechanistically, different oncogenic gains and dosages evolve along distinct evolutionary routes, licensed by defined allelic states and/or combinations of hallmark tumour suppressor alterations (Cdkn2a, Trp53, Tgfβ-pathway). Thus, evolutionary constraints and contingencies direct oncogenic dosage gain and variation along defined routes to drive the early progression of PDAC and shape its downstream biology. Our study uncovers universal principles of Ras-driven oncogenesis that have potential relevance beyond pancreatic cancer.
AU  - Mueller, S.*
AU  - Engleitner, T.*
AU  - Maresch, R.*
AU  - Zukowska, M.*
AU  - Lange, S.*
AU  - Kaltenbacher, T.*
AU  - Konukiewitz, B.*
AU  - Öllinger, R.*
AU  - Zwiebel, M.*
AU  - Strong, A.*
AU  - Yen, H.Y.*
AU  - Banerjee, R.*
AU  - Louzada, S.*
AU  - Fu, B.*
AU  - Seidler, B.*
AU  - Götzfried, J.*
AU  - Schuck, K.*
AU  - Hassan, Z.*
AU  - Arbeiter, A.*
AU  - Schönhuber, N.*
AU  - Klein, S.*
AU  - Veltkamp, C.*
AU  - Friedrich, M.*
AU  - Rad, L.*
AU  - Barenboim, M.*
AU  - Ziegenhain, C.*
AU  - Hess J.
AU  - Dovey, O.M.*
AU  - Eser, S.*
AU  - Parekh, S.*
AU  - Constantino-Casas, F.*
AU  - de la Rosa, J.*
AU  - Sierra, M.I.*
AU  - Fraga, M.*
AU  - Mayerle, J.*
AU  - Klöppel, G.*
AU  - Cadiñanos, J.*
AU  - Liu, P.*
AU  - Vassiliou, G.S.*
AU  - Weichert, W.*
AU  - Steiger, K.*
AU  - Enard, W.*
AU  - Schmid, R.M.*
AU  - Yang, F.*
AU  - Unger, K.
AU  - Schneider, G.*
AU  - Varela, I.*
AU  - Bradley, A.*
AU  - Saur, D.*
AU  - Rad, R.*
C1  - 52794
C2  - 44435
SP  - 62-68
TI  - Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes.
JO  - Nature
VL  - 554
IS  - 7690
PY  - 2018
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Zika virus (ZIKV) has recently emerged as a global health concern owing to its widespread diffusion and its association with severe neurological symptoms and microcephaly in newborns(1). However, the molecular mechanisms that are responsible for the pathogenicity of ZIKV remain largely unknown. Here we use human neural progenitor cells and the neuronal cell line SK-N-BE2 in an integrated proteomics approach to characterize the cellular responses to viral infection at the proteome and phosphoproteome level, and use affinity proteomics to identify cellular targets of ZIKV proteins. Using this approach, we identify 386 ZIKV-interacting proteins, ZIKV-specific and pan-flaviviral activities as well as host factors with known functions in neuronal development, retinal defects and infertility. Moreover, our analysis identified 1,216 phosphorylation sites that are specifically up-or downregulated after ZIKV infection, indicating profound modulation of fundamental signalling pathways such as AKT, MAPK-ERK and ATM-ATR and thereby providing mechanistic insights into the proliferation arrest elicited by ZIKV infection. Functionally, our integrative study identifies ZIKV host-dependency factors and provides a comprehensive framework for a system-level understanding of ZIKV-induced perturbations at the levels of proteins and cellular pathways.
AU  - Scaturro, P.*
AU  - Stukalov, A.*
AU  - Haas, D.A.*
AU  - Cortese, M.*
AU  - Draganova, K.
AU  - Płaszczyca, A.*
AU  - Bartenschlager, R.*
AU  - Götz, M.
AU  - Pichlmair, A.*
C1  - 54327
C2  - 45508
CY  - Macmillan Building, 4 Crinan St, London N1 9xw, England
SP  - 253-257
TI  - An orthogonal proteomic survey uncovers novel Zika virus host factors.
JO  - Nature
VL  - 561
IS  - 7722
PB  - Nature Publishing Group
PY  - 2018
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - The development of the microbiome from infancy to childhood is dependent on a range of factors, with microbial-immune crosstalk during this time thought to be involved in the pathobiology of later life diseases(1-9) such as persistent islet autoimmunity and type 1 diabetes(10-12). However, to our knowledge, no studies have performed extensive characterization of the microbiome in early life in a large, multi-centre population. Here we analyse longitudinal stool samples from 903 children between 3 and 46 months of age by 16S rRNA gene sequencing (n = 12,005) and metagenomic sequencing (n = 10,867), as part of the The Environmental Determinants of Diabetes in the Young (TEDDY) study. We show that the developing gut microbiome undergoes three distinct phases of microbiome progression: a developmental phase (months 3-14), a transitional phase (months 15-30), and a stable phase (months 31-46). Receipt of breast milk, either exclusive or partial, was the most significant factor associated with the microbiome structure. Breastfeeding was associated with higher levels of Bifidobacterium species (B. breve and B. bifidum), and the cessation of breast milk resulted in faster maturation of the gut microbiome, as marked by the phylum Firmicutes. Birth mode was also significantly associated with the microbiome during the developmental phase, driven by higher levels of Bacteroides species (particularly B. fragilis) in infants delivered vaginally. Bacteroides was also associated with increased gut diversity and faster maturation, regardless of the birth mode. Environmental factors including geographical location and household exposures (such as siblings and furry pets) also represented important covariates. A nested case-control analysis revealed subtle associations between microbial taxonomy and the development of islet autoimmunity or type 1 diabetes. These data determine the structural and functional assembly of the microbiome in early life and provide a foundation for targeted mechanistic investigation into the consequences of microbial-immune crosstalk for long-term health.
AU  - Stewart, C.J.*
AU  - Ajami, N.J.*
AU  - O’Brien, J.L.*
AU  - Hutchinson, D.S.*
AU  - Smith, D.P.*
AU  - Wong, M.C.*
AU  - Ross, M.C.*
AU  - Lloyd, R.E.*
AU  - Doddapaneni, H.V.*
AU  - Metcalf, G.A.*
AU  - Muzny, D.*
AU  - Gibbs, R.A.*
AU  - Vatanen, T.*
AU  - Huttenhower, C.*
AU  - Xavier, R.J.*
AU  - Rewers, M.*
AU  - Hagopian, W.*
AU  - Toppari, J.*
AU  - Ziegler, A.-G.
AU  - She, J.X.*
AU  - Akolkar, B.*
AU  - Lernmark, A.*
AU  - Hyoty, H.*
AU  - Vehik, K.*
AU  - Krischer, J.P.*
AU  - Petrosino, J.F.*
C1  - 54647
C2  - 45718
CY  - Macmillan Building, 4 Crinan St, London N1 9xw, England
SP  - 583-588
TI  - Temporal development of the gut microbiome in early childhood from the TEDDY study.
JO  - Nature
VL  - 562
IS  - 7728
PB  - Nature Publishing Group
PY  - 2018
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Type 1 diabetes (T1D) is an autoimmune disease that targets pancreatic islet beta cells and incorporates genetic and environmental factors(1), including complex genetic elements(2), patient exposures(3) and the gut microbiome(4). Viral infections(5) and broader gut dysbioses(6) have been identified as potential causes or contributing factors; however, human studies have not yet identified microbial compositional or functional triggers that are predictive of islet autoimmunity or T1D. Here we analyse 10,913 metagenomes in stool samples from 783 mostly white, non-Hispanic children. The samples were collected monthly from three months of age until the clinical end point (islet autoimmunity or T1D) in the The Environmental Determinants of Diabetes in the Young (TEDDY) study, to characterize the natural history of the early gut microbiome in connection to islet autoimmunity, T1D diagnosis, and other common early life events such as antibiotic treatments and probiotics. The microbiomes of control children contained more genes that were related to fermentation and the biosynthesis of short-chain fatty acids, but these were not consistently associated with particular taxa across geographically diverse clinical centres, suggesting that microbial factors associated with T1D are taxonomically diffuse but functionally more coherent. When we investigated the broader establishment and development of the infant microbiome, both taxonomic and functional profiles were dynamic and highly individualized, and dominated in the first year of life by one of three largely exclusive Bifidobacterium species (B. bifidum, B. breve or B. longum) or by the phylum Proteobacteria. In particular, the strain-specific carriage of genes for the utilization of human milk oligosaccharide within a subset of B. longum was present specifically in breast-fed infants. These analyses of TEDDY gut metagenomes provide, to our knowledge, the largest and most detailed longitudinal functional profile of the developing gut microbiome in relation to islet autoimmunity, T1D and other early childhood events. Together with existing evidence from human cohorts(7,8) and a T1D mouse model(9), these data support the protective effects of short-chain fatty acids in early-onset human T1D.
AU  - Vatanen, T.*
AU  - Franzosa, E.A.*
AU  - Schwager, R.*
AU  - Tripathi, S.*
AU  - Arthur, T.D.*
AU  - Vehik, K.*
AU  - Lernmark, Å.*
AU  - Hagopian, W.A.*
AU  - Rewers, M.J.*
AU  - She, J.X.*
AU  - Toppari, J.*
AU  - Ziegler, A.-G.
AU  - Akolkar, B.*
AU  - Krischer, J.P.*
AU  - Stewart, C.J.*
AU  - Ajami, N.J.*
AU  - Petrosino, J.F.*
AU  - Gevers, D.*
AU  - Lähdesmäki, H.*
AU  - Vlamakis, H.*
AU  - Huttenhower, C.*
AU  - Xavier, R.J.*
C1  - 54646
C2  - 45717
CY  - Macmillan Building, 4 Crinan St, London N1 9xw, England
SP  - 589-594
TI  - The human gut microbiome in early-onset type 1 diabetes from the TEDDY study.
JO  - Nature
VL  - 562
IS  - 7728
PB  - Nature Publishing Group
PY  - 2018
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Cell fate perturbations underlie many human diseases, including breast cancer(1,2). Unfortunately, the mechanisms by which breast cell fate are regulated are largely unknown. The mammary gland epithelium consists of differentiated luminal epithelial and basal myoepithelial cells, as well as undifferentiated stem cells and more restricted progenitors(3,4). Breast cancer originates from this epithelium, but the molecular mechanisms that underlie breast epithelial hierarchy remain ill-defined. Here, we use a high-content confocal image-based short hairpin RNA screen to identify tumour suppressors that regulate breast cell fate in primary human breast epithelial cells. We show that ablation of the large tumour suppressor kinases (LATS) 1 and 2 (refs 5, 6), which are part of the Hippo pathway, promotes the luminal phenotype and increases the number of bipotent and luminal progenitors, the proposed cells-of-origin of most human breast cancers. Mechanistically, we have identified a direct interaction between Hippo and oestrogen receptor-alpha (ER alpha) signalling. In the presence of LATS, ERa was targeted for ubiquitination and Ddb1-cullin4-associated-factor 1 (DCAF1)-dependent proteasomal degradation. Absence of LATS stabilized ERa and the Hippo effectors YAP and TAZ (hereafter YAP/TAZ), which together control breast cell fate through intrinsic and paracrine mechanisms. Our findings reveal a non-canonical (that is, YAP/TAZ-independent) effect of LATS in the regulation of human breast cell fate.
AU  - Britschgi, A.*
AU  - Duss, S.*
AU  - Kim, S.*
AU  - Couto, J.P.*
AU  - Brinkhaus, H.*
AU  - Koren, S.*
AU  - de Silva, D.*
AU  - Mertz, K.D.*
AU  - Kaup, D.*
AU  - Varga, Z.*
AU  - Voshol, H.*
AU  - Vissieres, A.*
AU  - Leroy, C.*
AU  - Roloff, T.*
AU  - Stadler, M.B.*
AU  - Scheel, C.
AU  - Miraglia, L.J.*
AU  - Orth, A.P.*
AU  - Bonamy, G.M.C.*
AU  - Reddy, V.A.*
AU  - Bentires-Alj, M.*
C1  - 50772
C2  - 42850
CY  - London
SP  - 541-545
TI  - The Hippo kinases LATS1 and 2 control human breast cell fate via crosstalk with ERα.
JO  - Nature
VL  - 541
IS  - 7638
PB  - Nature Publishing Group
PY  - 2017
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - This corrects the article DOI: 10.1038/nature19356.
AU  - Dickinson, M.E.*
AU  - Flenniken, A.M.*
AU  - Ji, X.*
AU  - Teboul, L.*
AU  - Wong, M.D.*
AU  - White, J.K.*
AU  - Meehan, T.F.*
AU  - Weninger, W.J.*
AU  - Westerberg, H.*
AU  - Adissu, H.A.*
AU  - Baker, C.N.*
AU  - Bower, L.*
AU  - Brown, J.M.*
AU  - Caddle, L.B.*
AU  - Chiani, F.*
AU  - Clary, D.*
AU  - Cleak, J.*
AU  - Daly, M.J.*
AU  - Denegre, J.M.*
AU  - Doe, B.*
AU  - Dolan, M.E.*
AU  - Edie, S.M.*
AU  - Fuchs, H.
AU  - Gailus-Durner, V.
AU  - Galli, A.*
AU  - Gambadoro, A.*
AU  - Gallegos, J.*
AU  - Guo, S.*
AU  - Horner, N.R.*
AU  - Hsu, C.-W.*
AU  - Johnson, S.J.*
AU  - Kalaga, S.*
AU  - Keith, L.C.*
AU  - Lanoue, L.*
AU  - Lawson, T.N.*
AU  - Lek, M.*
AU  - Mark, M.*
AU  - Marschall, S.
AU  - Mason, J.*
AU  - McElwee, M.L.*
AU  - Newbigging, S.*
AU  - Nutter, L.M.J.*
AU  - Peterson, K.A.*
AU  - Ramirez-Solis, R.*
AU  - Rowland, D.J.*
AU  - Ryder, E.*
AU  - Samocha, K.E.*
AU  - Seavitt, J.R.*
AU  - Selloum, M.*
AU  - Szoke-Kovacs, Z.*
AU  - Tamura, M.*
AU  - Trainor, A.G.*
AU  - Tudose, I.*
AU  - Wakana, S.*
AU  - Warren, J.*
AU  - Wendling, O.*
AU  - West, D.B.*
AU  - Wong, L.*
AU  - Yoshiki, A.*
AU  - Wurst, W.
AU  - MacArthur, D.G.*
AU  - Tocchini-Valentini, G.P.*
AU  - Gao, X.*
AU  - Flicek, P.*
AU  - Bradley, A.*
AU  - Skarnes, W.C.*
AU  - Justice, M.J.*
AU  - Parkinson, H.E.*
AU  - Moore, M.*
AU  - Wells, S.*
AU  - Braun, R.E.*
AU  - Svenson, K.L.*
AU  - Hrabě de Angelis, M.
AU  - Herault, Y.*
AU  - Mohun, T.*
AU  - Mallon, A.M.*
AU  - Henkelman, R.M.*
AU  - Brown, S.D.M.*
AU  - Adams, D.J.*
AU  - Lloyd, K.C.K.*
AU  - McKerlie, C.*
AU  - Beaudet, A.L.*
AU  - Bućan, M.*
AU  - Murray, S.A.*
C1  - 52826
C2  - 44173
SP  - 398
TI  - Corrigendum: High-throughput discovery of novel developmental phenotypes.
JO  - Nature
VL  - 551
IS  - 7680
PY  - 2017
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Aegilops tauschii is the diploid progenitor of the D genome of hexaploid wheat (Triticum aestivum, genomes AABBDD) and an important genetic resource for wheat. The large size and highly repetitive nature of the Ae. tauschii genome has until now precluded the development of a reference-quality genome sequence. Here we use an array of advanced technologies, including ordered-clone genome sequencing, whole-genome shotgun sequencing, and BioNano optical genome mapping, to generate a reference-quality genome sequence for Ae. tauschii ssp. strangulata accession AL8/78, which is closely related to the wheat D genome. We show that compared to other sequenced plant genomes, including a much larger conifer genome, the Ae. tauschii genome contains unprecedented amounts of very similar repeated sequences. Our genome comparisons reveal that the Ae. tauschii genome has a greater number of dispersed duplicated genes than other sequenced genomes and its chromosomes have been structurally evolving an order of magnitude faster than those of other grass genomes. The decay of colinearity with other grass genomes correlates with recombination rates along chromosomes. We propose that the vast amounts of very similar repeated sequences cause frequent errors in recombination and lead to gene duplications and structural chromosome changes that drive fast genome evolution.
AU  - Luo, M.C.*
AU  - Gu, Y.Q.*
AU  - Puiu, D.*
AU  - Wang, H.*
AU  - Twardziok, S.O.
AU  - Deal, K.R.*
AU  - Huo, N.*
AU  - Zhu, T.*
AU  - Wang, L.*
AU  - Wang, Y.*
AU  - McGuire, P.E.*
AU  - Liu, S.*
AU  - Long, H.*
AU  - Ramasamy, R.K.*
AU  - Rodriguez, J.C.*
AU  - Van, S.L.*
AU  - Yuan, L.Y.*
AU  - Wang, Z.*
AU  - Xia, Z.L.*
AU  - Xiao, L.*
AU  - Anderson, O.D.*
AU  - Ouyang, S.*
AU  - Liang, Y.*
AU  - Zimin, A.V.*
AU  - Pertea, G.*
AU  - Qi, P.*
AU  - Bennetzen, J.L.*
AU  - Dai, X.*
AU  - Dawson, M.W.*
AU  - Müller, H.G.*
AU  - Kugler, K.G.
AU  - Rivarola-Duarte, L.
AU  - Spannagl, M.
AU  - Mayer, K.F.X.
AU  - Lu, F.H.*
AU  - Bevan, M.W.*
AU  - Leroy, P.*
AU  - Li, P.*
AU  - You, F.M.*
AU  - Sun, Q.*
AU  - Liu, Z.*
AU  - Lyons, E.*
AU  - Wicker, T.*
AU  - Salzberg, S.L.*
AU  - Devos, K.M.*
AU  - Dvořák, J.*
C1  - 52355
C2  - 43910
CY  - London
SP  - 498-502
TI  - Genome sequence of the progenitor of the wheat D genome Aegilops tauschii.
JO  - Nature
VL  - 551
IS  - 7681
PB  - Nature Publishing Group
PY  - 2017
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
AU  - Marouli, E.*
AU  - Graff, M.*
AU  - Medina-Gomez, C.*
AU  - Lo, K.S.*
AU  - Wood, A.R.*
AU  - Kjaer, T.R.*
AU  - Fine, R.S.*
AU  - Lu, Y.*
AU  - Schurmann, C.*
AU  - Highland, H.M.*
AU  - Rüeger, S.*
AU  - Thorleifsson, G.*
AU  - Justice, A.E.*
AU  - Lamparter, D.*
AU  - Stirrups, K.E.*
AU  - Turcot, V.*
AU  - Young, K.L.*
AU  - Winkler, T.W.*
AU  - Esko, T.*
AU  - Karaderi, T.*
AU  - Locke, A.E.*
AU  - Masca, N.G.D.*
AU  - Ng, M.C.Y.*
AU  - Mudgal, P.*
AU  - Rivas, M.A.*
AU  - Vedantam, S.*
AU  - Mahajan, A.*
AU  - Guo, X.*
AU  - Abecasis, G.*
AU  - Aben, K.K.*
AU  - Adair, L.S.*
AU  - Alam, D.S.*
AU  - Albrecht, E.
AU  - Allin, K.H.*
AU  - Allison, M.A.*
AU  - Amouyel, P.*
AU  - Appel, E.V.*
AU  - Arveiler, D.*
AU  - Asselbergs, F.W.*
AU  - Auer, P.L.*
AU  - Balkau, B.*
AU  - Heid, I.M.
AU  - Kriebel, J.
AU  - Müller-Nurasyid, M.
AU  - Bergmann, S.*
AU  - Bielak, L.F.*
AU  - Blüher, M.*
AU  - Boeing, H.*
AU  - Boerwinkle, E.*
AU  - Böger, C.A.*
AU  - Bonnycastle, L.L.*
AU  - Bork-Jensen, J.*
AU  - Bots, M.L.*
AU  - Bottinger, E.P.*
AU  - Bowden, D.W.*
AU  - Brandslund, I.*
AU  - Breen, G.*
AU  - Brilliant, M.H.*
AU  - Broer, L.*
AU  - Burt, A.A.*
AU  - Butterworth, A.S.*
AU  - Carey, D.J.*
AU  - Caulfield, M.J.*
AU  - Chambers, J.C.*
AU  - Chasman, D.I.*
C1  - 50549
C2  - 42354
CY  - London
SP  - 186-190
TI  - Rare and low-frequency coding variants alter human adult height.
JO  - Nature
VL  - 542
IS  - 7640
PB  - Nature Publishing Group
PY  - 2017
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Cereal grasses of the Triticeae tribe have been the major food source in temperate regions since the dawn of agriculture. Their large genomes are characterized by a high content of repetitive elements and large pericentromeric regions that are virtually devoid of meiotic recombination. Here we present a high-quality reference genome assembly for barley (Hordeum vulgare L.). We use chromosome conformation capture mapping to derive the linear order of sequences across the pericentromeric space and to investigate the spatial organization of chromatin in the nucleus at megabase resolution. The composition of genes and repetitive elements differs between distal and proximal regions. Gene family analyses reveal lineage-specific duplications of genes involved in the transport of nutrients to developing seeds and the mobilization of carbohydrates in grains. We demonstrate the importance of the barley reference sequence for breeding by inspecting the genomic partitioning of sequence variation in modern elite germplasm, highlighting regions vulnerable to genetic erosion.
AU  - Mascher, M.*
AU  - Gundlach, H.
AU  - Himmelbach, A.*
AU  - Beier, S.*
AU  - Twardziok, S.O.
AU  - Wicker, T.*
AU  - Radchuk, V.*
AU  - Dockter, C.*
AU  - Hedley, P.E.*
AU  - Russell, J.A.*
AU  - Bayer, M.*
AU  - Ramsay, L.*
AU  - Liu, H.*
AU  - Haberer, G.
AU  - Zhang, X.Q.*
AU  - Zhang, Q.*
AU  - Barrero, R.A.*
AU  - Li, L.*
AU  - Taudien, S.*
AU  - Groth, M.*
AU  - Felder, M.*
AU  - Hastie, A.*
AU  - Šimková, H.*
AU  - Staňková, H.*
AU  - Vrána, J.*
AU  - Chan, S.W.*
AU  - Muñoz-Amatriaín, M.*
AU  - Ounit, R.*
AU  - Wanamaker, S.*
AU  - Bolser, D.*
AU  - Colmsee, C.*
AU  - Schmutzer, T.*
AU  - Aliyeva-Schnorr, L.*
AU  - Grasso, S.*
AU  - Tanskanen, J.*
AU  - Chailyan, A.*
AU  - Sampath, D.*
AU  - Heavens, D.*
AU  - Clissold, L.*
AU  - Cao, S.*
AU  - Chapman, B.*
AU  - Dai, F.*
AU  - Han, Y.*
AU  - Li, H.*
AU  - Li, X.*
AU  - Lin, C.*
AU  - McCooke, J.K.*
AU  - Tan, C.S.*
AU  - Wang, P.*
AU  - Wang, S.*
AU  - Yin, S.*
AU  - Zhou, G.*
AU  - Poland, J.A.*
AU  - Bellgard, M.I.*
AU  - Borisjuk, L.*
AU  - Houben, A.*
AU  - Doležel, J.*
AU  - Ayling, S.*
AU  - Lonardi, S.*
AU  - Kersey, P.*
AU  - Langridge, P.*
AU  - Muehlbauer, G.J.*
AU  - Clark, M.D.*
AU  - Caccamo, M.*
AU  - Schulman, A.H.*
AU  - Mayer, K.F.X.*
AU  - Platzer, M.*
AU  - Close, T.J.*
AU  - Scholz, U.*
AU  - Hansson, M.*
AU  - Zhang, G.*
AU  - Braumann, I.*
AU  - Spannagl, M.
AU  - Li, C.*
AU  - Waugh, R.*
AU  - Stein, N.*
C1  - 51009
C2  - 43033
CY  - London
SP  - 427-433
TI  - A chromosome conformation capture ordered sequence of the barley genome.
JO  - Nature
VL  - 544
IS  - 7651
PB  - Nature Publishing Group
PY  - 2017
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - The foundations of mammalian development lie in a cluster of embryonic epiblast stem cells. In response to extracellular matrix signalling, these cells undergo epithelialization and create an apical surface in contact with a cavity, a fundamental event for all subsequent development. Concomitantly, epiblast cells transit through distinct pluripotent states, before lineage commitment at gastrulation. These pluripotent states have been characterized at the molecular level, but their biological importance remains unclear. Here we show that exit from an unrestricted naive pluripotent state is required for epiblast epithelialization and generation of the pro-amniotic cavity in mouse embryos. Embryonic stem cells locked in the naive state are able to initiate polarization but fail to undergo lumenogenesis. Mechanistically, exit from naive pluripotency activates an Oct4-governed transcriptional program that results in expression of glycosylated sialomucin proteins and the vesicle tethering and fusion events of lumenogenesis. Similarly, exit of epiblasts from naive pluripotency in cultured human post-implantation embryos triggers amniotic cavity formation and developmental progression. Our results add tissue-level architecture as a new criterion for the characterization of different pluripotent states, and show the relevance of transitions between these states during development of the mammalian embryo.
AU  - Shahbazi, M.N.*
AU  - Scialdone, A.
AU  - Skorupska, N.*
AU  - Weberling, A.*
AU  - Recher, G.*
AU  - Zhu, M.*
AU  - Jedrusik, A.*
AU  - Devito, L.G.*
AU  - Noli, L.*
AU  - Macaulay, I.C.*
AU  - Buecker, C.*
AU  - Khalaf, Y.*
AU  - Ilic, D.*
AU  - Voet, T.*
AU  - Marioni, J.C.*
AU  - Zernicka-Goetz, M.*
C1  - 52589
C2  - 44102
CY  - London
SP  - 239-243
TI  - Pluripotent state transitions coordinate morphogenesis in mouse and human embryos.
JO  - Nature
VL  - 552
IS  - 7684
PB  - Nature Publishing Group
PY  - 2017
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type 2 diabetes, cardiovascular disease and related metabolic and inflammatory disturbances1, 2. Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation3, 4, 5, 6, a key regulator of gene expression and molecular phenotype7. Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with P < 1 × 10−7, range P = 9.2 × 10−8 to 6.0 × 10−46; n = 10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues (P < 0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P < 9.0 × 10−6, range P = 5.5 × 10−6 to 6.1 × 10−35, n = 1,785 samples). The methylation loci identify genes involved in lipid and lipoprotein metabolism, substrate transport and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future development of type 2 diabetes (relative risk per 1 standard deviation increase in methylation risk score: 2.3 (2.07–2.56); P = 1.1 × 10−54). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type 2 diabetes and other adverse clinical consequences of obesity.
AU  - Wahl, S.
AU  - Drong, A.*
AU  - Lehne, B.*
AU  - Loh, M.*
AU  - Scott, W.R.*
AU  - Kunze, S.
AU  - Tsai, P.C.*
AU  - Ried, J.S.
AU  - Zhang, W.*
AU  - Yang, Y.*
AU  - Tan, S.*
AU  - Fiorito, G.*
AU  - Franke, L.*
AU  - Guarrera, S.*
AU  - Kasela, S.*
AU  - Kriebel, J.
AU  - Richmond, R.C.*
AU  - Adamo, M.*
AU  - Afzal, U.*
AU  - Ala-Korpela, M.*
AU  - Albetti, B.*
AU  - Ammerpohl, O.*
AU  - Apperley, J.*
AU  - Beekman, M.*
AU  - Bertazzi, P.A.*
AU  - Black, S.L.*
AU  - Blancher, C.*
AU  - Bonder, M.J.*
AU  - Brosch, M.*
AU  - Carstensen-Kirberg, M.*
AU  - de Craen, A.J.M.*
AU  - de Lusignan, S.*
AU  - Dehghan, A.*
AU  - Elkalaawy, M.*
AU  - Fischer, K.*
AU  - Franco, O.H.*
AU  - Gaunt, T.R.*
AU  - Hampe, J.*
AU  - Hashemi, M*
AU  - Isaacs, A.*
AU  - Jenkinson, A.*
AU  - Jha, S.*
AU  - Kato, N.*
AU  - Krogh, V.*
AU  - Laffan, M.*
AU  - Meisinger, C.
AU  - Meitinger, T.
AU  - Mok, Z.Y.*
AU  - Motta, V.*
AU  - Ng, H.K.*
AU  - Nikolakopoulou, Z.*
AU  - Nteliopoulos, G.*
AU  - Panico, S.*
AU  - Pervjakova, N.*
AU  - Prokisch, H.
AU  - Rathmann, W.*
AU  - Roden, M.*
AU  - Rota, F.*
AU  - Rozario, M.A.*
AU  - Sandling, J.K.*
AU  - Schafmayer, C.*
AU  - Schramm, K.
AU  - Siebert, R.*
AU  - Slagboom, P.E.*
AU  - Soininen, P.*
AU  - Stolk, L.*
AU  - Strauch, K.
AU  - Tai, E.S.*
AU  - Tarantini, L.*
AU  - Thorand, B.
AU  - Tigchelaar, E.F.*
AU  - Tumino, R.*
AU  - Uitterlinden, A.G.*
AU  - van Duijn, C.M.*
AU  - van Meurs, J.B.J.*
AU  - Vineis, P.*
AU  - Wichremasinghe, A.R.*
AU  - Wijmenga, C*
AU  - Yang, T.P.*
AU  - Yuan, W.*
AU  - Zhernakova, A.*
AU  - Batterham, R.*
AU  - Smith, G.D.*
AU  - Deloukas, P.*
AU  - Heijman, B.T.*
AU  - Herder, C.*
AU  - Hofman, A.*
AU  - Lindgren, C.M.*
AU  - Milani, L.*
AU  - van der Harst, P.*
AU  - Peters, A.
AU  - Illig, T.
AU  - Relton, C.L.*
AU  - Waldenberger, M.
AU  - Järvelin, M.-R.*
AU  - Bollati, V.*
AU  - Soong, R.*
AU  - Spector, T.D.*
AU  - Scott, J.*
AU  - McCarthy, M.I.*
AU  - Elliott, P.*
AU  - Bell, J.T.*
AU  - Matullo, G.*
AU  - Gieger, C.
AU  - Kooner, J.S.*
AU  - Grallert, H.
AU  - Chambers, J.C.*
C1  - 50519
C2  - 42309
CY  - London
SP  - 81-86
TI  - Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity.
JO  - Nature
VL  - 541
IS  - 7635
PB  - Nature Publishing Group
PY  - 2017
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Insulin-dependent diabetes is a complex multifactorial disorder characterized by loss or dysfunction of β-cells. Pancreatic β-cells differ in size, glucose responsiveness, insulin secretion and precursor cell potential; understanding the mechanisms that underlie this functional heterogeneity might make it possible to develop new regenerative approaches. Here we show that Fltp (also known as Flattop and Cfap126), a Wnt/planar cell polarity (PCP) effector and reporter gene, acts as a marker gene that subdivides endocrine cells into two subpopulations and distinguishes proliferation-competent from mature β-cells with distinct molecular, physiological and ultrastructural features. Genetic lineage tracing revealed that endocrine subpopulations from Fltp-negative and -positive lineages react differently to physiological and pathological changes. The expression of Fltp increases when endocrine cells cluster together to form polarized and mature 3D islet mini-organs. We show that 3D architecture and Wnt/PCP ligands are sufficient to trigger β-cell maturation. By contrast, the Wnt/PCP effector Fltp is not necessary for β-cell development, proliferation or maturation. We conclude that 3D architecture and Wnt/PCP signalling underlie functional β-cell heterogeneity and induce β-cell maturation. The identification of Fltp as a marker for endocrine subpopulations sheds light on the molecular underpinnings of islet cell heterogeneity and plasticity and might enable targeting of endocrine subpopulations for the regeneration of functional β-cell mass in diabetic patients.
AU  - Bader, E.
AU  - Migliorini, A.
AU  - Gegg, M.
AU  - Moruzzi, N.
AU  - Gerdes, J.M.
AU  - Roscioni, S.
AU  - Bakhti, M.
AU  - Brandl, E.
AU  - Irmler, M.
AU  - Beckers, J.
AU  - Aichler, M.
AU  - Feuchtinger, A.
AU  - Leitzinger, C.
AU  - Zischka, H.
AU  - Wang-Sattler, R.
AU  - Jastroch, M.
AU  - Tschöp, M.H.
AU  - Machicao, F.
AU  - Staiger, H.
AU  - Häring, H.-U.
AU  - Chmelova, H.
AU  - Chouinard, J.A.*
AU  - Oskolkov, N.*
AU  - Korsgren, O.*
AU  - Speier, S.
AU  - Lickert, H.
C1  - 49052
C2  - 41603
CY  - London
SP  - 430-434
TI  - Identification of proliferative and mature β-cells in the islets of Langerhans.
JO  - Nature
VL  - 535
IS  - 7612
PB  - Nature Publishing Group
PY  - 2016
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Approximately one-third of all mammalian genes are essential for life. Phenotypes resulting from knockouts of these genes in mice have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5,000 knockout mouse lines, here we identify 410 lethal genes during the production of the first 1,751 unique gene knockouts. Using a standardized phenotyping platform that incorporates high-resolution 3D imaging, we identify phenotypes at multiple time points for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. Unexpectedly, our analysis reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background. In addition, we show that human disease genes are enriched for essential genes, thus providing a dataset that facilitates the prioritization and validation of mutations identified in clinical sequencing efforts.
AU  - Dickinson, M.E.*
AU  - Flenniken, A.M.*
AU  - Ji, X.*
AU  - Teboul, L.*
AU  - Wong, M.D.*
AU  - White, J.K.*
AU  - Meehan, T.F.*
AU  - Weninger, W.J.*
AU  - Westerberg, H.*
AU  - Adissu, H.A.*
AU  - Baker, C.N.*
AU  - Bower, L.*
AU  - Brown, J.M.*
AU  - Caddle, L.B.*
AU  - Chiani, F.*
AU  - Clary, D.*
AU  - Cleak, J.*
AU  - Daly, M.J.*
AU  - Denegre, J.M.*
AU  - Doe, B.*
AU  - Dolan, M.E.*
AU  - Edie, S.M.*
AU  - Fuchs, H.
AU  - Gailus-Durner, V.
AU  - Galli, A.*
AU  - Gambadoro, A.*
AU  - Gallegos, J.*
AU  - Guo, S.*
AU  - Horner, N.R.*
AU  - Hsu, C.W.*
AU  - Johnson, S.J.*
AU  - Kalaga, S.*
AU  - Keith, L.C.*
AU  - Lanoue, L.*
AU  - Lawson, T.N.*
AU  - Lek, M.*
AU  - Mark, M.*
AU  - Marschall, S.
AU  - Mason, J.*
AU  - McElwee, M.L.*
AU  - Newbigging, S.*
AU  - Nutter, L.M.*
AU  - Peterson, K.A.*
AU  - Ramirez-Solis, R.*
AU  - Rowland, D.J.*
AU  - Ryder, E.*
AU  - Samocha, K.E.*
AU  - Seavitt, J.R.*
AU  - Selloum, M.*
AU  - Szoke-Kovacs, Z.*
AU  - Tamura, M.*
AU  - Trainor, A.G.*
AU  - Tudose, I.*
AU  - Wakana, S.*
AU  - Warren, J.*
AU  - Wendling, O.*
AU  - West, D.B.*
AU  - Wong, L.J.*
AU  - Yoshiki, A.*
AU  - MacArthur, D.G.*
AU  - Tocchini-Valentini, G.P.*
AU  - Gao, X.*
AU  - Flicek, P.*
AU  - Bradley, A.*
AU  - Skarnes, W.C.*
AU  - Justice, M.J.*
AU  - Parkinson, H.E.*
AU  - Moore, M.*
AU  - Wells, S.*
AU  - Braun, R.E.*
AU  - Svenson, K.L.*
AU  - Hrabě de Angelis, M.
AU  - Herault, Y.*
AU  - Mohun, T.*
AU  - Mallon, A.M.*
AU  - Henkelman, R.M.*
AU  - Brown, S.D.*
AU  - Adams, D.J.*
AU  - Lloyd, K.C.K.*
AU  - McKerlie, C.*
AU  - Beaudet, A.L.*
AU  - Bucan, M.*
AU  - Murray, S.A.*
C1  - 49486
C2  - 30057
CY  - London
SP  - 508-514
TI  - High-throughput discovery of novel developmental phenotypes.
JO  - Nature
VL  - 537
IS  - 7621
PB  - Nature Publishing Group
PY  - 2016
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - The ability of the adult mammalian brain to compensate for neuronal loss caused by injury or disease is very limited. Transplantation aims to replace lost neurons, but the extent to which new neurons can integrate into existing circuits is unknown. Here, using chronic in vivo two-photon imaging, we show that embryonic neurons transplanted into the visual cortex of adult mice mature into bona fide pyramidal cells with selective pruning of basal dendrites, achieving adult-like densities of dendritic spines and axonal boutons within 4–8 weeks. Monosynaptic tracing experiments reveal that grafted neurons receive area-specific, afferent inputs matching those of pyramidal neurons in the normal visual cortex, including topographically organized geniculo-cortical connections. Furthermore, stimulus-selective responses refine over the course of many weeks and finally become indistinguishable from those of host neurons. Thus, grafted neurons can integrate with great specificity into neocortical circuits that normally never incorporate new neurons in the adult brain.
AU  - Falkner, S.*
AU  - Grade, S.
AU  - Dimou, L.
AU  - Conzelmann, K.-H.*
AU  - Bonhoeffner, T.*
AU  - Götz, M.
AU  - Hübener, M.*
C1  - 50129
C2  - 42025
SP  - 248-253
TI  - Transplanted embryonic neurons integrate into adult neocortical circuits.
JO  - Nature
VL  - 539
PY  - 2016
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.
AU  - Fuchsberger, C.*
AU  - Flannick, J.*
AU  - Teslovich, T.M.*
AU  - Mahajan, A.*
AU  - Agarwala, V.*
AU  - Gaulton, K.J.*
AU  - Ma, C.*
AU  - Fontanillas, P.*
AU  - Moutsianas, L.*
AU  - McCarthy, D.J.*
AU  - Rivas, M.A.*
AU  - Perry, J.R.*
AU  - Sim, X.*
AU  - Blackwell, T.W.*
AU  - Robertson, N.R.*
AU  - Rayner, N.W.*
AU  - Cingolani, P.*
AU  - Locke, A.E.*
AU  - Tajes, J.F.*
AU  - Highland, H.M.*
AU  - Dupuis, J.*
AU  - Chines, P.S.*
AU  - Lindgren, C.M.*
AU  - Hartl, C.*
AU  - Jackson, A.U.*
AU  - Chen, H.*
AU  - Huyghe, J.R.*
AU  - van de Bunt, M.*
AU  - Pearson, R.D.*
AU  - Kumar, A.*
AU  - Müller-Nurasyid, M.
AU  - Grarup, N.*
AU  - Stringham, H.M.*
AU  - Gamazon, E.R.*
AU  - Lee, J.*
AU  - Chen, Y.*
AU  - Scott, R.A.*
AU  - Below, J.E.*
AU  - Chen, P.*
AU  - Huang, J.*
AU  - Go, M.J.*
AU  - Stitzel, M.L.*
AU  - Pasko, D.*
AU  - Parker, S.C.*
AU  - Varga, T.V.*
AU  - Green, T.*
AU  - Beer, N.L.*
AU  - Day-Williams, A.G.*
AU  - Ferreira, T.*
AU  - Fingerlin, T.E.*
AU  - Horikoshi, M.*
AU  - Hu, C.*
AU  - Huh, I.*
AU  - Ikram, M.K.*
AU  - Kim, B.J.*
AU  - Kim, Y.*
AU  - Kim, Y.J.*
AU  - Kwon, M.S.*
AU  - Lee, S.*
AU  - Lin, K.H.*
AU  - Maxwell, T.J.*
AU  - Nagai, Y.*
AU  - Wang, X.*
AU  - Welch, R.P.*
AU  - Yoon, J.*
AU  - Zhang, W.*
AU  - Barzilai, N.*
AU  - Voight, B.F.*
AU  - Han, B.G.*
AU  - Jenkinson, C.P.*
AU  - Kuulasmaa, T.*
AU  - Kuusisto, J.*
AU  - Manning, A.*
AU  - Ng, M.C.*
AU  - Palmer, N.D.*
AU  - Balkau, B.*
AU  - Stancáková, A.*
AU  - Abboud, H.E.*
AU  - Boeing, H.*
AU  - Giedraitis, V.*
AU  - Prabhakaran, D.*
AU  - Gottesman, O.*
AU  - Scott, J.*
AU  - Carey, J.*
AU  - Kwan, P.*
AU  - Grant, G.B.*
AU  - Smith, J.D.*
AU  - Neale, B.M.*
AU  - Purcell, S.*
AU  - Butterworth, A.S.*
AU  - Howson, J.M.M.*
AU  - Lee, H.M.*
AU  - Lu, Y.*
AU  - Kwak, S.H.*
AU  - Zhao, W.*
AU  - Danesh, J.*
AU  - Lam, V.K.*
AU  - Park, K.S.*
AU  - Saleheen, D.*
AU  - So, W.Y.*
AU  - Tam, C.H.*
AU  - Afzal, U.*
AU  - Aguilar, D.*
AU  - Arya, R.*
AU  - Aung, T.*
AU  - Chan, E.*
AU  - Navarro, C.*
AU  - Cheng, C.Y.*
AU  - Palli, D.*
AU  - Correa, A.*
AU  - Curran, J.E.*
AU  - Rybin, D.*
AU  - Farook, V.S.*
AU  - Fowler, S.P.*
AU  - Freedman, B.I.*
AU  - Griswold, M.E.*
AU  - Hale, D.E.*
AU  - Hicks, P.J.*
AU  - Khor, C.C.*
AU  - Kumar, S.*
AU  - Lehne, B.*
AU  - Thuillier, D.*
AU  - Lim, W.Y.*
AU  - Liu, J.*
AU  - van der Schouw, Y.T.*
AU  - Loh, M.*
AU  - Musani, S.K.*
AU  - Puppala, S.*
AU  - Scott, W.R.*
AU  - Yengo, L.*
AU  - Tan, S.T.*
AU  - Taylor, H.A.*
AU  - Thameem, F.*
AU  - Wilson, G.*
AU  - Wong, T.Y.*
AU  - Njølstad, P.R.*
AU  - Levy, J.C.*
AU  - Mangino, M.*
AU  - Bonnycastle, L.L.*
AU  - Schwarzmayr, T.
AU  - Fadista, J.*
AU  - Surdulescu, G.L.*
AU  - Herder, C.*
AU  - Groves, C.J.*
AU  - Wieland, T.
AU  - Bork-Jensen, J.*
AU  - Brandslund, I.*
AU  - Christensen, C.*
AU  - Koistinen, H.A.*
AU  - Doney, A.S.*
AU  - Kinnunen, L.*
AU  - Esko, T.*
AU  - Farmer, A.J.*
AU  - Hakaste, L.*
AU  - Hodgkiss, D.*
AU  - Kravic, J.*
AU  - Lyssenko, V.*
AU  - Hollensted, M.*
AU  - Jørgensen, M.E.*
AU  - Jørgensen, T.*
AU  - Ladenvall, C.*
AU  - Justesen, J.M.*
AU  - Käräjämäki, A.*
AU  - Kriebel, J.
AU  - Rathmann, W.*
AU  - Lannfelt, L.*
AU  - Lauritzen, T.*
AU  - Narisu, N.*
AU  - Linneberg, A.*
AU  - Melander, O.*
AU  - Milani, L.*
AU  - Neville, M.*
AU  - Orho-Melander, M.*
AU  - Qi, L.*
AU  - Qi, Q.*
AU  - Roden, M.*
AU  - Rolandsson, O.*
AU  - Swift, A.*
AU  - Rosengren, A.H.*
AU  - Stirrups, K.*
AU  - Wood, A.R.*
AU  - Mihailov, E.*
AU  - Blancher, C.*
AU  - Carneiro, M.O.*
AU  - Maguire, J.*
AU  - Poplin, R.*
AU  - Shakir, K.*
AU  - Fennell, T.*
AU  - DePristo, M.*
AU  - Hrabě de Angelis, M.
AU  - Deloukas, P.*
AU  - Gjesing, A.P.*
AU  - Jun, G.*
AU  - Nilsson, P.*
AU  - Murphy, J.*
AU  - Onofrio, R.*
AU  - Thorand, B.
AU  - Hansen, T.*
AU  - Meisinger, C.
AU  - Hu, F.B.*
AU  - Isomaa, B.*
AU  - Karpe, F.*
AU  - Liang, L.*
AU  - Peters, A.
AU  - Huth, C.
AU  - O'Rahilly, S.P.
AU  - Palmer, C.N.*
AU  - Pedersen, O.*
AU  - Rauramaa, R.*
AU  - Tuomilehto, J.*
AU  - Salomaa, V.*
AU  - Watanabe, R.M.*
AU  - Syvanen, A.C.*
AU  - Bergman, R.N.*
AU  - Bharadwaj, D.*
AU  - Bottinger, E.P.*
AU  - Cho, Y.S.*
AU  - Chandak, G.R.*
AU  - Chan, J.C.*
AU  - Chia, K.S.*
AU  - Daly, M.J.*
AU  - Ebrahim, S.B.*
AU  - Langenberg, C.*
AU  - Elliott, P.*
AU  - Jablonski, K.A.*
AU  - Lehman, D.M.*
AU  - Jia, W.*
AU  - Ma, R.C.
AU  - Pollin, T.I.*
AU  - Sandhu, M.*
AU  - Tandon, N.*
AU  - Froguel, P.*
AU  - Barroso, I.*
AU  - Teo, Y.Y.*
AU  - Zeggini, E.*
AU  - Loos, R.J.*
AU  - Small, K.S.*
AU  - Ried, J.S.
AU  - DeFronzo, R.A.*
AU  - Grallert, H.
AU  - Glaser, B.*
AU  - Metspalu, A.*
AU  - Wareham, N.J.*
AU  - Walker, M.*
AU  - Banks, E.*
AU  - Gieger, C.
AU  - Ingelsson, E.*
AU  - Im, H.K.*
AU  - Illig, T.
AU  - Franks, P.W.*
AU  - Buck, G.*
AU  - Trakalo, J.*
AU  - Buck, D.*
AU  - Prokopenko, I.*
AU  - Mägi, R.*
AU  - Lind, L.*
AU  - Farjoun, Y.*
AU  - Owen, K.R.*
AU  - Gloyn, A.L.*
AU  - Strauch, K.
AU  - Tuomi, T.*
AU  - Kooner, J.S.*
AU  - Lee, J.Y.*
AU  - Park, T.*
AU  - Donnelly, P.*
AU  - Morris, A.D.*
AU  - Hattersley, A.T.*
AU  - Bowden, D.W.*
AU  - Collins, F.S.*
AU  - Atzmon, G.*
AU  - Chambers, J.C.*
AU  - Spector, T.D.*
AU  - Laakso, M.*
AU  - Strom, T.M.
AU  - Bell, G.I.*
AU  - Blangero, J.*
AU  - Duggirala, R.*
AU  - Tai, E.S.*
AU  - McVean, G.*
AU  - Hanis, C.L.*
AU  - Wilson, J.G.*
AU  - Seielstad, M.*
AU  - Frayling, T.M.*
AU  - Meigs, J.B.*
AU  - Cox, N.J.*
AU  - Sladek, R.*
AU  - Lander, E.S.*
AU  - Gabriel, S.*
AU  - Burtt, N.P.*
AU  - Mohlke, K.L.*
AU  - Meitinger, T.
AU  - Groop, L.*
AU  - Abecasis, G.*
AU  - Florez, J.C*
AU  - Scott, L.J.*
AU  - Morris, A.P.*
AU  - Kang, H.M.*
AU  - Boehnke, M.*
AU  - Altshuler, D.*
AU  - McCarthy, M.I.*
C1  - 49051
C2  - 41593
CY  - London
SP  - 41-47
TI  - The genetic architecture of type 2 diabetes.
JO  - Nature
VL  - 536
IS  - 7614
PB  - Nature Publishing Group
PY  - 2016
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - The mechanisms underlying haematopoietic lineage decisions remain disputed. Lineage-affiliated transcription factors with the capacity for lineage reprogramming, positive auto-regulation and mutual inhibition have been described as being expressed in uncommitted cell populations. This led to the assumption that lineage choice is cell-intrinsically initiated and determined by stochastic switches of randomly fluctuating cross-antagonistic transcription factors. However, this hypothesis was developed on the basis of RNA expression data from snapshot and/or population-averaged analyses. Alternative models of lineage choice therefore cannot be excluded. Here we use novel reporter mouse lines and live imaging for continuous single-cell long-term quantification of the transcription factors GATA1 and PU.1 (also known as SPI1). We analyse individual haematopoietic stem cells throughout differentiation into megakaryocytic-erythroid and granulocytic-monocytic lineages. The observed expression dynamics are incompatible with the assumption that stochastic switching between PU.1 and GATA1 precedes and initiates megakaryocytic-erythroid versus granulocytic-monocytic lineage decision-making. Rather, our findings suggest that these transcription factors are only executing and reinforcing lineage choice once made. These results challenge the current prevailing model of early myeloid lineage choice.
AU  - Hoppe, P.S.
AU  - Schwarzfischer, M.
AU  - Loeffler, D.
AU  - Kokkaliaris, K.D.
AU  - Hilsenbeck, O.
AU  - Moritz, N.
AU  - Endele, M.
AU  - Filipczyk, A.
AU  - Gambardella, A.*
AU  - Ahmed, N.*
AU  - Etzrodt, M.*
AU  - Coutu, D.L.*
AU  - Rieger, M.A.
AU  - Marr, C.
AU  - Strasser, M.
AU  - Schauberger, B.
AU  - Burtscher, I.
AU  - Ermakova, O.*
AU  - Bürger, A.
AU  - Lickert, H.
AU  - Nerlov, C.*
AU  - Theis, F.J.
AU  - Schroeder, T.
C1  - 49087
C2  - 41583
CY  - London
SP  - 299-302
TI  - Early myeloid lineage choice is not initiated by random PU.1 to GATA1 protein ratios.
JO  - Nature
VL  - 535
IS  - 7611
PB  - Nature Publishing Group
PY  - 2016
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P < 5 × 10(-8)). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (Rg = -0.22, P = 5.5 × 10(-13)), T2D (Rg = -0.27, P = 1.1 × 10(-6)) and coronary artery disease (Rg = -0.30, P = 6.5 × 10(-9)). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P = 1.9 × 10(-4)). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.
AU  - Horikoshi, M.*
AU  - Beaumont, R.N.*
AU  - Day, F.R.*
AU  - Warrington, N.M.*
AU  - Kooijman, M.N.*
AU  - Fernandez-Tajes, J.*
AU  - Feenstra, B.*
AU  - van Zuydam, N.R.*
AU  - Gaulton, K.J.*
AU  - Grarup, N.*
AU  - Bradfield, J.P.*
AU  - Strachan, D.P.*
AU  - Li-Gao, R.*
AU  - Ahluwalia, T.S.*
AU  - Kreiner, E.*
AU  - Rueedi, R.*
AU  - Lyytikäinen, L.-P.*
AU  - Cousminer, D.L.*
AU  - Wu, Y.*
AU  - Thiering, E.
AU  - Wang, C.A.*
AU  - Have, C.T.*
AU  - Hottenga, J.J.*
AU  - Vilor-Tejedor, N.*
AU  - Joshi, P.K.*
AU  - Boh, E.T.*
AU  - Ntalla, I.*
AU  - Pitkänen, N.*
AU  - Mahajan, A.*
AU  - van Leeuwen, E.M.*
AU  - Joro, R.*
AU  - Lagou, V.*
AU  - Nodzenski, M.*
AU  - Diver, L.A.*
AU  - Zondervan, K.T.*
AU  - Bustamante, M.*
AU  - Marques-Vidal, P.*
AU  - Mercader, J.M.*
AU  - Bennett, A.J.*
AU  - Rahmioglu, N.*
AU  - Nyholt, D.R.*
AU  - Ma, R.C.*
AU  - Tam, C.H.*
AU  - Tam, W.H.*
AU  - Ganesh, S.K.*
AU  - van Rooij, F.J.*
AU  - Jones, S.E.*
AU  - Loh, P.R.*
AU  - Ruth, K.S.*
AU  - Tuke, M.A.*
AU  - Tyrrell, J.*
AU  - Wood, A.R.*
AU  - Yaghootkar, H.*
AU  - Scholtens, D.M.*
AU  - Paternoster, L.*
AU  - Prokopenko, I.*
AU  - Kovacs, P.*
AU  - Atalay, M.*
AU  - Willems, S.M.*
AU  - Panoutsopoulou, K.*
AU  - Wang, X.*
AU  - Carstensen, L.*
AU  - Geller, F.*
AU  - Schraut, K.E.*
AU  - Murcia, M.*
AU  - van Beijsterveldt, C.E.*
AU  - Willemsen, G.*
AU  - Appel, E.V.*
AU  - Fonvig, C.E.*
AU  - Trier, C.*
AU  - Tiesler, C.M.
AU  - Standl, M.
AU  - Kutalik, Z.*
AU  - Bonàs-Guarch, S.*
AU  - Hougaard, D.M.*
AU  - Sánchez, F.*
AU  - Torrents, D.*
AU  - Waage, J.*
AU  - Hollegaard, M.V.*
AU  - de Haan, H.G.*
AU  - Rosendaal, F.R.*
AU  - Medina-Gomez, C.*
AU  - Ring, S.M.*
AU  - Hemani, G.*
AU  - McMahon, G.*
AU  - Robertson, N.R.*
AU  - Groves, C.J.*
AU  - Langenberg, C.*
AU  - Luan, J.*
AU  - Scott, R.A.*
AU  - Zhao, J.H.*
AU  - Mentch, F.D.*
AU  - MacKenzie, S.M.*
AU  - Reynolds, R.M.*
AU  - Lowe, W.L.*
AU  - Tönjes, A.*
AU  - Stumvoll, M.*
AU  - Lindi, V.*
AU  - Lakka, T.A.*
AU  - van Duijn, C.M.*
AU  - Kiess, W.*
AU  - Körner, A.*
AU  - Sørensen, T.I.*
AU  - Niinikoski, H.*
AU  - Pahkala, K.*
AU  - Raitakari, O.T.*
AU  - Zeggini, E.*
AU  - Dedoussis, G.V.*
AU  - Teo, Y.Y.*
AU  - Saw, S.M.*
AU  - Melbye, M.*
AU  - Campbell, H.*
AU  - Wilson, J.F.*
AU  - Vrijheid, M.*
AU  - de Geus, E.J.*
AU  - Boomsma, D.I.*
AU  - Kadarmideen, H.N.*
AU  - Holm, J.C.*
AU  - Hansen, T.*
AU  - Sebert, S.*
AU  - Hattersley, A.T.*
AU  - Beilin, L.J.*
AU  - Newnham, J.P.*
AU  - Pennell, C.E.*
AU  - Heinrich, J.
AU  - Adair, L.S.*
AU  - Borja, J.B.*
AU  - Mohlke, K.L.*
AU  - Eriksson, J.G.*
AU  - Widen, E.*
AU  - Kähönen, M.*
AU  - Viikari, J.S.*
AU  - Lehtimäki, T.*
AU  - Vollenweider, P.*
AU  - Bønnelykke, K.*
AU  - Bisgaard, H.*
AU  - Mook-Kanamori, D.O.*
AU  - Hofman, A.*
AU  - Rivadeneira, F.*
AU  - Uitterlinden, A.G.*
AU  - Pisinger, C.*
AU  - Pedersen, O.*
AU  - Power, C.*
AU  - Hyppönen, E.*
AU  - Wareham, N.J.*
AU  - Hakonarson, H.*
AU  - Davies, E.*
AU  - Walker, B.R.*
AU  - Jaddoe, V.W.*
AU  - Jarvelin, M.R.*
AU  - Grant, S.F.*
AU  - Vaag, A.A.*
AU  - Lawlor, D.A.*
AU  - Frayling, T.M.*
AU  - Smith, G.D.*
AU  - Morris, A.P.*
AU  - Ong, K.K.*
AU  - Felix, J.F.*
AU  - Timpson, N.J.*
AU  - Perry, J.R.*
AU  - Evans, D.M*
AU  - McCarthy, M.I.*
AU  - Freathy, R.M.*
C1  - 49576
C2  - 40844
CY  - London
SP  - 248-252
TI  - Genome-wide associations for birth weight and correlations with adult disease.
JO  - Nature
VL  - 538
IS  - 7624
PB  - Nature Publishing Group
PY  - 2016
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death. Non-alcoholic fatty liver disease (NAFLD) affects a large proportion of the US population and is considered to be a metabolic predisposition to liver cancer. However, the role of adaptive immune responses in NAFLD-promoted HCC is largely unknown. Here we show, in mouse models and human samples, that dysregulation of lipid metabolism in NAFLD causes a selective loss of intrahepatic CD4(+) but not CD8(+) T lymphocytes, leading to accelerated hepatocarcinogenesis. We also demonstrate that CD4(+) T lymphocytes have greater mitochondrial mass than CD8(+) T lymphocytes and generate higher levels of mitochondrially derived reactive oxygen species (ROS). Disruption of mitochondrial function by linoleic acid, a fatty acid accumulated in NAFLD, causes more oxidative damage than other free fatty acids such as palmitic acid, and mediates selective loss of intrahepatic CD4(+) T lymphocytes. In vivo blockade of ROS reversed NAFLD-induced hepatic CD4(+) T lymphocyte decrease and delayed NAFLD-promoted HCC. Our results provide an unexpected link between lipid dysregulation and impaired anti-tumour surveillance.
AU  - Ma, C.*
AU  - Kesarwala, A.H.*
AU  - Eggert, T.*
AU  - Medina-Echeverz, J.*
AU  - Kleiner, D.E.*
AU  - Jin, P.*
AU  - Stroncek, D.F.*
AU  - Terabe, M.*
AU  - Kapoor, V.*
AU  - ElGindi, M.*
AU  - Han, M.*
AU  - Thornton, A.M.*
AU  - Zhang, H.*
AU  - Egger, M.*
AU  - Luo, J.*
AU  - Felsher, D.W.*
AU  - McVicar, D.W.*
AU  - Weber, A.*
AU  - Heikenwälder, M.
AU  - Greten, T.F.*
C1  - 48046
C2  - 39874
CY  - London
SP  - 253-257
TI  - NAFLD causes selective CD4+ T lymphocyte loss and promotes hepatocarcinogenesis.
JO  - Nature
VL  - 531
IS  - 7593
PB  - Nature Publishing Group
PY  - 2016
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.
AU  - Okbay, A.*
AU  - Beauchamp, J.P.*
AU  - Fontana, M.A.*
AU  - Lee, J.J.*
AU  - Pers, T.H.*
AU  - Rietveld, C.A.*
AU  - Turley, P.*
AU  - Chen, G.B.*
AU  - Emilsson, V.*
AU  - Meddens, S.F.*
AU  - Oskarsson, S.*
AU  - Pickrell, J.K.*
AU  - Thom, K.*
AU  - Timshel, P.*
AU  - de Vlaming, R.*
AU  - Abdellaoui, A.*
AU  - Ahluwalia, T.S.*
AU  - Bacelis, J.*
AU  - Baumbach, C.
AU  - Bjornsdottir, G.*
AU  - Brandsma, J.H.*
AU  - Concas, M.P.*
AU  - Derringer, J.*
AU  - Furlotte, N.A.*
AU  - Galesloot, T.E.*
AU  - Girotto, G.*
AU  - Gupta, R.*
AU  - Hall, L.M.*
AU  - Harris, S.E.*
AU  - Hofer, E.*
AU  - Horikoshi, M.*
AU  - Huffman, J.E.*
AU  - Kaasik, K.*
AU  - Kalafati, I.P.*
AU  - Karlsson, R.*
AU  - Kong, A.*
AU  - Lahti, J.*
AU  - van der Lee, S.J.*
AU  - de Leeuw, C.*
AU  - Lind, P.A.*
AU  - Lindgren, K.O.*
AU  - Liu, T.*
AU  - Mangino, M.*
AU  - Marten, J.*
AU  - Mihailov, E.*
AU  - Miller, M.B.*
AU  - van der Most, P.J.*
AU  - Oldmeadow, C.*
AU  - Payton, A.*
AU  - Pervjakova, N.*
AU  - Peyrot, W.J.*
AU  - Qian, Y.*
AU  - Raitakari, O.*
AU  - Rueedi, R.*
AU  - Salvi, E.*
AU  - Schmidt, B.*
AU  - Schraut, K.E.*
AU  - Shi, J.*
AU  - Smith, A.V.*
AU  - Poot, R.A.*
AU  - St Pourcain, B.*
AU  - Teumer, A.*
AU  - Thorleifsson, G.*
AU  - Verweij, N.*
AU  - Vuckovic, D.*
AU  - Wellmann, J.*
AU  - Westra, H.J.*
AU  - Yang, J.*
AU  - Zhao, W.*
AU  - Zhu, Z.*
AU  - Alizadeh, B.Z.*
AU  - Amin, N.*
AU  - Bakshi, A.*
AU  - Baumeister, S.E.*
AU  - Biino, G.*
AU  - Bønnelykke, K.*
AU  - Boyle, P.A.*
AU  - Campbell, H.*
AU  - Cappuccio, F.P.*
AU  - Davies, G.*
AU  - de Neve, J.E.*
AU  - Deloukas, P.*
AU  - Demuth, I.*
AU  - Ding, J.*
AU  - Eibich, P.*
AU  - Eisele, L.*
AU  - Eklund, N.*
AU  - Evans, D.M*
AU  - Faul, J.D.*
AU  - Feitosa, M.F.*
AU  - Forstner, A.J.*
AU  - Gandin, I.*
AU  - Gunnarsson, B.*
AU  - Halldorsson, B.V.*
AU  - Harris, T.B.*
AU  - Heath, A.C.*
AU  - Hocking, L.J.*
AU  - Holliday, E.G.*
AU  - Homuth, G.*
AU  - Horan, M.A.*
AU  - Hottenga, J.J.*
AU  - de Jager, P.L.*
AU  - Joshi, P.K.*
AU  - Jugessur, A.*
AU  - Kaakinen, M.A.*
AU  - Kähönen, M.*
AU  - Kanoni, S.*
AU  - Keltigangas-Järvinen, L.*
AU  - Kiemeney, L.A.*
AU  - Kolcic, I.*
AU  - Koskinen, S.*
AU  - Kraja, A.T.*
AU  - Kroh, M.*
AU  - Kutalik, Z.*
AU  - Latvala, A.*
AU  - Launer, L.J.*
AU  - Lebreton, M.P.*
AU  - Levinson, D.F.*
AU  - Lichtenstein, P.*
AU  - Lichtner, P.
AU  - Liewald, D.C.*
AU  - Loukola, A.*
AU  - Madden, P.A.*
AU  - Mägi, R.*
AU  - Mäki-Opas, T.*
AU  - Marioni, R.E.*
AU  - Marques-Vidal, P.*
AU  - Meddens, G.A.*
AU  - McMahon, G.*
AU  - Meisinger, C.
AU  - Meitinger, T.
AU  - Milaneschi, Y.*
AU  - Milani, L.*
AU  - Montgomery, G.W.*
AU  - Myhre, R.
AU  - Nelson, C.P.*
AU  - Nyholt, D.R.*
AU  - Ollier, W.E.*
AU  - Palotie, A.*
AU  - Paternoster, L.*
AU  - Pedersen, N.L.*
AU  - Petrovic, K.E.*
AU  - Porteous, D.J.*
AU  - Räikkönen, K.*
AU  - Ring, S.M.*
AU  - Robino, A.*
AU  - Rostapshova, O.*
AU  - Rudan, I.*
AU  - Rustichini, A.*
AU  - Salomaa, V.*
AU  - Sanders, A.R.*
AU  - Sarin, A.P.*
AU  - Schmidt, H.*
AU  - Scott, R.J.*
AU  - Smith, B.H.*
AU  - Smith, J.A.*
AU  - Staessen, J.A.*
AU  - Steinhagen-Thiessen, E.*
AU  - Strauch, K.
AU  - Terracciano, A.*
AU  - Tobin, M.D.*
AU  - Ulivi, S.*
AU  - Vaccargiu, S.*
AU  - Quaye, L.*
AU  - van Rooij, F.J.*
AU  - Venturini, C.*
AU  - Vinkhuyzen, A.A.*
AU  - Völker, U.*
AU  - Völzke, H.*
AU  - Vonk, J.M.*
AU  - Vozzi, D.*
AU  - Waage, J.*
AU  - Ware, E.B.*
AU  - Willemsen, G.*
AU  - Attia, J.R.*
AU  - Bennett, D.A.*
AU  - Berger, K.*
AU  - Bertram, L.*
AU  - Bisgaard, H.*
AU  - Boomsma, D.I.*
AU  - Borecki, I.B.*
AU  - Bültmann, U.*
AU  - Chabris, C.F.*
AU  - Cucca, F.*
AU  - Cusi, D.*
AU  - Deary, I.J.*
AU  - Dedoussis, G.V.*
AU  - van Duijn, C.M.*
AU  - Eriksson, J.G.*
AU  - Franke, B.*
AU  - Franke, L.*
AU  - Gasparini, P.*
AU  - Gejman, P.V.*
AU  - Gieger, C.
AU  - Grabe, H.J.*
AU  - Gratten, J.*
AU  - Groenen, P.J.*
AU  - Gudnason, V.*
AU  - van der Harst, P.*
AU  - Hayward, C.*
AU  - Hinds, D.A.*
AU  - Hoffmann, W.*
AU  - Hyppönen, E.*
AU  - Iacono, W.G.*
AU  - Jacobsson, B.*
AU  - Jarvelin, M.R.*
AU  - Jöckel, K.-H.*
AU  - Kaprio, J.*
AU  - Kardia, S.L.*
AU  - Lehtimäki, T.*
AU  - Lehrer, S.F.*
AU  - Magnusson, P.K.*
AU  - Martin, N.G.*
AU  - McGue, M.*
AU  - Metspalu, A.*
AU  - Pendleton, N.*
AU  - Penninx, B.W.*
AU  - Perola, M.*
AU  - Pirastu, N.*
AU  - Pirastu, M.
AU  - Polasek, O.*
AU  - Posthuma, D.*
AU  - Power, C.*
AU  - Province, M.A.*
AU  - Samani, N.J.*
AU  - Schlessinger, D.*
AU  - Schmidt, R.*
AU  - Sørensen, T.I.*
AU  - Spector, T.D.*
AU  - Stefansson, K.*
AU  - Thorsteinsdottir, U.*
AU  - Thurik, A.R.*
AU  - Timpson, N.J.*
AU  - Tiemeier, H.*
AU  - Tung, J.Y.*
AU  - Uitterlinden, A.G.*
AU  - Vitart, V.*
AU  - Vollenweider, P.*
AU  - Weir, D.R.*
AU  - Wilson, J.F.*
AU  - Wright, A.F.*
AU  - Conley, D.C.*
AU  - Krueger, R.F.*
AU  - Davey Smith, G.*
AU  - Hofman, A.*
AU  - Laibson, D.I.*
AU  - Medland, S.E.*
AU  - Meyer, M.N.*
AU  - Johannesson, M.*
AU  - Visscher, P.M.*
AU  - Esko, T.*
AU  - Koellinger, P.D.*
AU  - Cesarini, D.*
AU  - Benjamin, D.J.*
C1  - 48693
C2  - 41258
CY  - London
SP  - 539-542
TI  - Genome-wide association study identifies 74 loci associated with educational attainment.
JO  - Nature
VL  - 533
IS  - 7604
PB  - Nature Publishing Group
PY  - 2016
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Many experiments have shown that loss of biodiversity reduces the capacity of ecosystems to provide the multiple services on which humans depend. However, experiments necessarily simplify the complexity of natural ecosystems and will normally control for other important drivers of ecosystem functioning, such as the environment or land use. In addition, existing studies typically focus on the diversity of single trophic groups, neglecting the fact that biodiversity loss occurs across many taxa and that the functional effects of any trophic group may depend on the abundance and diversity of others. Here we report analysis of the relationships between the species richness and abundance of nine trophic groups, including 4,600 above- and below-ground taxa, and 14 ecosystem services and functions and with their simultaneous provision (or multifunctionality) in 150 grasslands. We show that high species richness in multiple trophic groups (multitrophic richness) had stronger positive effects on ecosystem services than richness in any individual trophic group; this includes plant species richness, the most widely used measure of biodiversity. On average, three trophic groups influenced each ecosystem service, with each trophic group influencing at least one service. Multitrophic richness was particularly beneficial for 'regulating' and 'cultural' services, and for multifunctionality, whereas a change in the total abundance of species or biomass in multiple trophic groups (the multitrophic abundance) positively affected supporting services. Multitrophic richness and abundance drove ecosystem functioning as strongly as abiotic conditions and land-use intensity, extending previous experimental results to real-world ecosystems. Primary producers, herbivorous insects and microbial decomposers seem to be particularly important drivers of ecosystem functioning, as shown by the strong and frequent positive associations of their richness or abundance with multiple ecosystem services. Our results show that multitrophic richness and abundance support ecosystem functioning, and demonstrate that a focus on single groups has led to researchers to greatly underestimate the functional importance of biodiversity.
AU  - Soliveres, S.*
AU  - van der Plas, F.*
AU  - Manning, P.*
AU  - Prati, D.*
AU  - Gossner, M.M.*
AU  - Renner, S.C.*
AU  - Alt, F.*
AU  - Arndt, H.*
AU  - Baumgartner, V.*
AU  - Binkenstein, J.*
AU  - Birkhofer, K.*
AU  - Blaser, S.*
AU  - Blüthgen, N.*
AU  - Boch, S.*
AU  - Böhm, S.*
AU  - Börschig, C.*
AU  - Buscot, F.*
AU  - Diekötter, T.*
AU  - Heinze, J.*
AU  - Hölzel, N.*
AU  - Jung, K.*
AU  - Klaus, V.H.*
AU  - Kleinebecker, T.*
AU  - Klemmer, S.*
AU  - Krauss, J.*
AU  - Lange, M.*
AU  - Morris, E.K.*
AU  - Müller, J.*
AU  - Oelmann, Y.*
AU  - Overmann, J.*
AU  - Pašalić, E.*
AU  - Rillig, M.C.*
AU  - Schaefer, H.M.*
AU  - Schloter, M.
AU  - Schmitt, B.*
AU  - Schöning, I.*
AU  - Schrumpf, M.*
AU  - Sikorski, J.*
AU  - Socher, S.A.*
AU  - Solly, E.F.*
AU  - Sonnemann, I.*
AU  - Sorkau, E.*
AU  - Steckel, J.*
AU  - Steffan-Dewenter, I.*
AU  - Stempfhuber, B.
AU  - Tschapka, M.*
AU  - Türke, M.*
AU  - Venter, P.C.*
AU  - Weiner, C.N.*
AU  - Weisser, W.W.*
AU  - Werner, M.*
AU  - Westphal, C.*
AU  - Wilcke, W.*
AU  - Wolters, V.*
AU  - Wubet, T.*
AU  - Wurst, S.*
AU  - Fischer, M.*
AU  - Allan, E.*
C1  - 49277
C2  - 41731
CY  - London
SP  - 456-459
TI  - Biodiversity at multiple trophic levels is needed for ecosystem multifunctionality.
JO  - Nature
VL  - 536
IS  - 7617
PB  - Nature Publishing Group
PY  - 2016
SN  - 0028-0836
ER  - 

TY  - JOUR
AU  - Vaquerizas, J.M.*
AU  - Torres-Padilla, M.E.
C1  - 49487
C2  - 40699
SP  - 494-496
TI  - Developmental biology: Panoramic views of the early epigenome.
JO  - Nature
VL  - 537
PY  - 2016
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
AU  - Joshi, P.K.*
AU  - Esko, T.*
AU  - Mattsson, H.*
AU  - Eklund, N.*
AU  - Gandin, I.*
AU  - Nutile, T.*
AU  - Jackson, A.U.*
AU  - Schurmann, C.*
AU  - Smith, A.V.*
AU  - Zhang, W.*
AU  - Okada, Y.*
AU  - Stancáková, A.*
AU  - Faul, J.D.*
AU  - Zhao, W.*
AU  - Bartz, T.M.*
AU  - Concas, M.P.*
AU  - Franceschini, N.*
AU  - Enroth, S.*
AU  - Vitart, V.*
AU  - Trompet, S.*
AU  - Guo, X.*
AU  - Chasman, D.I.*
AU  - O'Connel, J.R.*
AU  - Corre, T.*
AU  - Nongmaithem, S.S.*
AU  - Chen, Y.*
AU  - Mangino, M.*
AU  - Ruggiero, D.*
AU  - Traglia, M.*
AU  - Farmaki, A.-E.*
AU  - Kacprowski, T.*
AU  - Bjonnes, A.*
AU  - van der Spek, A.*
AU  - Wu, Y.*
AU  - Giri, A.K.*
AU  - Yanek, L.R.*
AU  - Wang, L.*
AU  - Hofer, E.*
AU  - Rietveld, C.A.*
AU  - McLeod, O.*
AU  - Cornelis, M.C.*
AU  - Pattaro, C.*
AU  - Verweij, N.*
AU  - Baumbach, C.
AU  - Abdellaoui, A.*
AU  - Warren, H.R.*
AU  - Vuckovic, D.*
AU  - Mei, H.*
AU  - Bouchard, C.*
AU  - Perry, J.R.*
AU  - Cappellani, S.*
AU  - Mirza, S.S.*
AU  - Benton, M.C.*
AU  - Broeckel, U.*
AU  - Medland, S.E.*
AU  - Lind, P.A.*
AU  - Malerba, G.*
AU  - Drong, A.*
AU  - Yengo, L.*
AU  - Bielak, L.F.*
AU  - Zhi, D.*
AU  - van der Most, P.J.*
AU  - Shriner, D.*
AU  - Mägi, R.*
AU  - Hemani, G.*
AU  - Karaderi, T.*
AU  - Wang, Z.*
AU  - Liu, T.*
AU  - Demuth, I.*
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C1  - 45671
C2  - 37415
CY  - London
SP  - 459-462
TI  - Directional dominance on stature and cognition in diverse human populations.
JO  - Nature
VL  - 523
IS  - 7561
PB  - Nature Publishing Group
PY  - 2015
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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AU  - Chambers, J.C.*
AU  - Chanock, S.J.*
AU  - Cooper, R.S.*
AU  - de Bakker, P.I.*
AU  - Dedoussis, G.*
AU  - Ferrucci, L.*
AU  - Franks, P.W.*
AU  - Froguel, P.*
AU  - Groop, L.C.*
AU  - Haiman, C.A.*
AU  - Hamsten, A.*
AU  - Hui, J.*
AU  - Hunter, D.J.*
AU  - Hveem, K.*
AU  - Kaplan, R.C.*
AU  - Kivimaki, M.*
AU  - Kuh, D.*
AU  - Laakso, M.*
AU  - Liu, Y.*
AU  - Martin, N.G.*
AU  - Marz, W.*
AU  - Melbye, M.*
AU  - Metspalu, A.*
AU  - Moebus, S.*
AU  - Munroe, P.B.*
AU  - Njølstad, I.*
AU  - Oostra, B.A.*
AU  - Palmer, C.N.*
AU  - Pedersen, N.L.*
AU  - Perola, M.*
AU  - Perusse, L.*
AU  - Peters, U.*
AU  - Power, C.*
AU  - Quertermous, T.*
AU  - Rauramaa, R.*
AU  - Rivadeneira, F.*
AU  - Saaristo, T.E.*
AU  - Saleheen, D.*
AU  - Sattar, N.*
AU  - Schadt, E.E.*
AU  - Schlessinger, D.*
AU  - Slagboom, P.E.*
AU  - Snieder, H.*
AU  - Spector, T.D.*
AU  - Thorsteinsdottir, U.*
AU  - Stumvoll, M.*
AU  - Tuomilehto, J.*
AU  - Uitterlinden, A.G.*
AU  - Uusitupa, M.*
AU  - van der Harst, P.*
AU  - Walker, M.*
AU  - Wallaschofski, H.*
AU  - Wareham, N.J.*
AU  - Watkins, H.*
AU  - Weir, D.R.*
AU  - Wichmann, H.-E.
AU  - Wilson, J.F.*
AU  - Zanen, P.*
AU  - Borecki, I.B.*
AU  - Deloukas, P.*
AU  - Fox, C.S.*
AU  - Heid, I.M.
AU  - O'Connell, J.R.*
AU  - Strachan, D.P.*
AU  - Stefansson, K.*
AU  - van Duijn, C.M.*
AU  - Abecasis, G.R.*
AU  - Franke, L.*
AU  - Frayling, T.M.*
AU  - McCarthy, M.I.*
AU  - Visscher, P.M.*
AU  - Scherag, A.*
AU  - Willer, C.J.*
AU  - Boehnke, M.*
AU  - Mohlke, K.L.*
AU  - Lindgren, C.M.*
AU  - Beckmann, J.S.*
AU  - Barroso, I.*
AU  - North, K.E.*
AU  - Ingelsson, E.*
AU  - Hirschhorn, J.N.*
AU  - Loos, R.J.*
AU  - Speliotes, E.K.*
C1  - 43280
C2  - 36378
CY  - London
SP  - 197-206
TI  - Genetic studies of body mass index yield new insights for obesity biology.
JO  - Nature
VL  - 518
IS  - 7538
PB  - Nature Publishing Group
PY  - 2015
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
AU  - Shungin, D.*
AU  - Winkler, T.W.*
AU  - Croteau-Chonka, D.C.*
AU  - Ferreira, T.*
AU  - Locke, A.E.*
AU  - Mägi, R.*
AU  - Strawbridge, R.J.*
AU  - Pers, T.H.*
AU  - Fischer, K.*
AU  - Justice, A.E.*
AU  - Workalemahu, T.*
AU  - Wu, J.M.*
AU  - Buchkovich, M.L.*
AU  - Heard-Costa, N.L.*
AU  - Roman, T.S.*
AU  - Drong, A.W.*
AU  - Song, C.*
AU  - Gustafsson, S.*
AU  - Day, F.R.*
AU  - Esko, T.*
AU  - Fall, T.*
AU  - Kutalik, Z.*
AU  - Luan, J.*
AU  - Randall, J.C.*
AU  - Scherag, A.*
AU  - Vedantam, S.*
AU  - Wood, A.R.*
AU  - Chen, J.*
AU  - Fehrmann, R.S.N.*
AU  - Karjalainen, J.*
AU  - Kahali, B.*
AU  - Liu, C.-T.*
AU  - Schmidt, E.M.*
AU  - Absher, D.*
AU  - Amin, N.*
AU  - Anderson, D.*
AU  - Beekman, M.*
AU  - Bragg-Gresham, J.L.*
AU  - Buyske, S.*
AU  - Demirkan, A.*
AU  - Ehret, G.B.*
AU  - Feitosa, M.F.*
AU  - Goel, A.*
AU  - Jackson, A.U.*
AU  - Johnson, T.*
AU  - Kleber, M.E.*
AU  - Kristiansson, K.*
AU  - Mangino, M.*
AU  - Mateo Leach, I.*
AU  - Medina-Gomez, C.*
AU  - Palmer, C.D.*
AU  - Pasko, D.*
AU  - Pechlivanis, S.*
AU  - Peters, M.J.*
AU  - Prokopenko, I.*
AU  - Stancáková, A.*
AU  - Ju Sung, Y.*
AU  - Tanaka, T.*
AU  - Teumer, A.*
AU  - van Vliet-Ostaptchouk, J.V.*
AU  - Yengo, L.*
AU  - Zhang, W.*
AU  - Albrecht, E.
AU  - Ärnlöv, J.*
AU  - Arscott, G.M.*
AU  - Bandinelli, S.*
AU  - Barrett, A.*
AU  - Bellis, C.*
AU  - Bennett, A.J.*
AU  - Berne, C.*
AU  - Blüher, M.*
AU  - Böhringer, S.*
AU  - Bonnet, F.*
AU  - Böttcher, Y.*
AU  - Bruinenberg, M.*
AU  - Carba, D.B.*
AU  - Caspersen, I.H.*
AU  - Clarke, R.*
AU  - Daw, E.W.*
AU  - Deelen, J.*
AU  - Deelman, E.*
AU  - Delgado, G.*
AU  - Doney, A.S.*
AU  - Eklund, N.*
AU  - Erdos, M.R.*
AU  - Estrada, K.*
AU  - Eury, E.*
AU  - Friedrich, N.*
AU  - Garcia, M.E.*
AU  - Giedraitis, V.*
AU  - Gigante, B.*
AU  - Go, A.S.*
AU  - Golay, A.*
AU  - Grallert, H.
AU  - Grammer, T.B.*
AU  - Gräßler, J.*
AU  - Grewal, J.*
AU  - Groves, C.J.*
AU  - Haller, T.*
AU  - Hallmans, G.*
AU  - Hartman, C.A.*
AU  - Hassinen, M.*
AU  - Hayward, C.*
AU  - Heikkilä, K.*
AU  - Herzig, K.H.*
AU  - Helmer, Q.*
AU  - Hillege, H.L.*
AU  - Holmen, O.L.*
AU  - Hunt, S.C.*
AU  - Isaacs, A.*
AU  - Ittermann, T.*
AU  - James, A.L.*
AU  - Johansson, I.*
AU  - Juliusdottir, T.*
AU  - Kalafati, I.P.*
AU  - Kinnunen, L.*
AU  - Koenig, W.*
AU  - Kooner, I.K.*
AU  - Kratzer, W.*
AU  - Lamina, C.*
AU  - Leander, K.*
AU  - Lee, N.R.*
AU  - Lichtner, P.
AU  - Lind, L.*
AU  - Lindstrom, J.*
AU  - Lobbens, S.*
AU  - Lorentzon, M.*
AU  - Mach, F.*
AU  - Magnusson, P.K.*
AU  - Mahajan, A.*
AU  - McArdle, W.L.*
AU  - Menni, C.*
AU  - Merger, S.*
AU  - Mihailov, E.*
AU  - Milani, L.*
AU  - Mills, R.*
AU  - Moayyeri, A.*
AU  - Monda, K.L.*
AU  - Mooijaart, S.P.*
AU  - Mühleisen, T.W.*
AU  - Mulas, A.*
AU  - Müller, G.*
AU  - Müller-Nurasyid, M.
AU  - Nagaraja, R.*
AU  - Nalls, M.A.*
AU  - Narisu, N.*
AU  - Glorioso, N.*
AU  - Nolte, I.M.*
AU  - Olden, M.*
AU  - Rayner, N.W.*
AU  - Renström, F.*
AU  - Ried, J.S.
AU  - Robertson, N.R.*
AU  - Rose, L.M.*
AU  - Sanna, S.*
AU  - Scharnagl, H.*
AU  - Scholtens, S.*
AU  - Sennblad, B.*
AU  - Seufferlein, T.*
AU  - Sitlani, C.M.*
AU  - Smith, A.V.*
AU  - Stirrups, K.*
AU  - Stringham, H.M.*
AU  - Sundström, J.*
AU  - Swertz, M.A.*
AU  - Swift, A.J.*
AU  - Syvanen, A.C.*
AU  - Tayo, B.O.*
AU  - Thorand, B.
AU  - Thorleifsson, G.*
AU  - Tomaschitz, A.*
AU  - Troffa, C.*
AU  - van Oort, F.V.*
AU  - Verweij, N.*
AU  - Vonk, J.M.*
AU  - Waite, L.L.*
AU  - Wennauer, R.*
AU  - Wilsgaard, T.*
AU  - Wojczynski, M.K.*
AU  - Wong, A.*
AU  - Zhang, Q.*
AU  - Hua Zhao, J.*
AU  - Brennan, E.P.*
AU  - Choi, M.*
AU  - Eriksson, P.*
AU  - Folkersen, L.*
AU  - Franco-Cereceda, A.*
AU  - Gharavi, A.G.*
AU  - Hedman, A.K.*
AU  - Hivert, M.F.*
AU  - Huang, J.*
AU  - Kanoni, S.*
AU  - Karpe, F.*
AU  - Keildson, S.*
AU  - Kiryluk, K.*
AU  - Liang, L.*
AU  - Lifton, R.P.*
AU  - Ma, B.*
AU  - McKnight, A.J.*
AU  - McPherson, R.*
AU  - Metspalu, A.*
AU  - Min, J.L.*
AU  - Moffatt, M.F.*
AU  - Montgomery, G.W.*
AU  - Murabito, J.M.*
AU  - Nicholson, G.*
AU  - Nyholt, D.R.*
AU  - Olsson, C.*
AU  - Perry, J.R.*
AU  - Reinmaa, E.*
AU  - Salem, R.M.*
AU  - Sandholm, N.*
AU  - Schadt, E.E.*
AU  - Scott, R.A.*
AU  - Stolk, L.*
AU  - Vallejo, E.E.*
AU  - Westra, H.J.*
AU  - Zondervan, K.T.*
AU  - Amouyel, P.*
AU  - Arveiler, D.*
AU  - Bakker, S.J.*
AU  - Beilby, J.*
AU  - Bergman, R.N.*
AU  - Blangero, J.*
AU  - Brown, M.J.*
AU  - Burnier, M.*
AU  - Campbell, H.*
AU  - Chakravarti, A.*
AU  - Chines, P.S.*
AU  - Claudi-Boehm, S.*
AU  - Collins, F.S.*
AU  - Crawford, D.C.*
AU  - Danesh, J.*
AU  - de Faire, U.*
AU  - de Geus, E.J.*
AU  - Dörr, M.*
AU  - Erbel, R.*
AU  - Eriksson, J.G.*
AU  - Farrall, M.*
AU  - Ferrannini, E.*
AU  - Ferrieres, J.*
AU  - Forouhi, N.G.*
AU  - Forrester, T.*
AU  - Franco, O.H.*
AU  - Gansevoort, R.T.*
AU  - Gieger, C.
AU  - Gudnason, V.*
AU  - Haiman, C.A.*
AU  - Harris, T.B.*
AU  - Hattersley, A.T.*
AU  - Heliövaara, M.*
AU  - Hicks, A.A.*
AU  - Hingorani, A.D.*
AU  - Hoffmann, W.*
AU  - Hofman, A.*
AU  - Homuth, G.*
AU  - Humphries, S.E.*
AU  - Hyppönen, E.*
AU  - Illig, T.
AU  - Jarvelin, M.R.*
AU  - Johansen, B.*
AU  - Jousilahti, P.*
AU  - Jula, A.M.*
AU  - Kaprio, J.*
AU  - Kee, F.*
AU  - Keinanen-Kiukaanniemi, S.M.*
AU  - Kooner, J.S.*
AU  - Kooperberg, C.*
AU  - Kovacs, P.*
AU  - Kraja, A.T.*
AU  - Kumari, M.*
AU  - Kuulasmaa, K.*
AU  - Kuusisto, J.*
AU  - Lakka, T.A.*
AU  - Langenberg, C.*
AU  - Le Marchand, L.*
AU  - Lehtimäki, T.*
AU  - Lyssenko, V.*
AU  - Männistö, S.*
AU  - Marette, A.*
AU  - Matise, T.C.*
AU  - McKenzie, C.A.*
AU  - McKnight, B.*
AU  - Musk, A.W.*
AU  - Möhlenkamp, S.*
AU  - Morris, A.D.*
AU  - Nelis, M.*
AU  - Ohlsson, C.*
AU  - Oldehinkel, A.J.*
AU  - Ong, K.K.*
AU  - Palmer, L.J.*
AU  - Penninx, B.W.*
AU  - Peters, A.
AU  - Pramstaller, P.P.*
AU  - Raitakari, O.T.*
AU  - Rankinen, T.*
AU  - Rao, D.C.*
AU  - Rice, T.K.*
AU  - Ridker, P.M.*
AU  - Ritchie, M.D.*
AU  - Rudan, I.*
AU  - Salomaa, V.*
AU  - Samani, N.J.*
AU  - Saramies, J.*
AU  - Sarzynski, M.A.*
AU  - Schwarz, P.E.*
AU  - Shuldiner, A.R.*
AU  - Staessen, J.A.*
AU  - Steinthorsdottir, V.*
AU  - Stolk, R.P.*
AU  - Strauch, K.
AU  - Tönjes, A.*
AU  - Tremblay, A.*
AU  - Tremoli, E.*
AU  - Vohl, M.C.*
AU  - Völker, U.*
AU  - Vollenweider, P.*
AU  - Wilson, J.F.*
AU  - Witteman, J.C.*
AU  - Adair, L.S.*
AU  - Bochud, M.*
AU  - Boehm, B.O.*
AU  - Bornstein, S.R.*
AU  - Bouchard, C.*
AU  - Cauchi, S.*
AU  - Caulfield, M.J.*
AU  - Chambers, J.C.*
AU  - Chasman, D.I.*
AU  - Cooper, R.S.*
AU  - Dedoussis, G.*
AU  - Ferrucci, L.*
AU  - Froguel, P.*
AU  - Grabe, H.J.*
AU  - Hamsten, A.*
AU  - Hui, J.*
AU  - Hveem, K.*
AU  - Jöckel, K.-H.*
AU  - Kivimaki, M.*
AU  - Kuh, D.*
AU  - Laakso, M.*
AU  - Liu, Y.*
AU  - Marz, W.*
AU  - Munroe, P.B.*
AU  - Njølstad, I.*
AU  - Oostra, B.A.*
AU  - Palmer, C.N.*
AU  - Pedersen, N.L.*
AU  - Perola, M.*
AU  - Perusse, L.*
AU  - Peters, U.*
AU  - Power, C.*
AU  - Quertermous, T.*
AU  - Rauramaa, R.*
AU  - Rivadeneira, F.*
AU  - Saaristo, T.E.*
AU  - Saleheen, D.*
AU  - Sinisalo, J.*
AU  - Slagboom, P.E.*
AU  - Snieder, H.*
AU  - Spector, T.D.*
AU  - Thorsteinsdottir, U.*
AU  - Stumvoll, M.*
AU  - Tuomilehto, J.*
AU  - Uitterlinden, A.G.*
AU  - Uusitupa, M.*
AU  - van der Harst, P.*
AU  - Veronesi, G.*
AU  - Walker, M.*
AU  - Wareham, N.J.*
AU  - Watkins, H.*
AU  - Wichmann, H.-E.
AU  - Abecasis, G.R.*
AU  - Assimes, T.L.*
AU  - Berndt, S.I.*
AU  - Boehnke, M.*
AU  - Borecki, I.B.*
AU  - Deloukas, P.*
AU  - Franke, L.*
AU  - Frayling, T.M.*
AU  - Groop, L.C.*
AU  - Hunter, D.J.*
AU  - Kaplan, R.C.*
AU  - O'Connell, J.R.*
AU  - Qi, L.*
AU  - Schlessinger, D.*
AU  - Strachan, D.P.*
AU  - Stefansson, K.*
AU  - van Duijn, C.M.*
AU  - Willer, C.J.*
AU  - Visscher, P.M.*
AU  - Yang, J.*
AU  - Hirschhorn, J.N.*
AU  - Zillikens, M.C.*
AU  - McCarthy, M.I.*
AU  - Speliotes, E.K.*
AU  - North, K.E.*
AU  - Fox, C.S.*
AU  - Barroso, I.*
AU  - Franks, P.W.*
AU  - Ingelsson, E.*
AU  - Heid, I.M.
AU  - Loos, R.J.*
AU  - Cupples, L.A.*
AU  - Morris, A.P.*
AU  - Lindgren, C.M.*
AU  - Mohlke, K.L.*
C1  - 43281
C2  - 36533
CY  - London
SP  - 187-196
TI  - New genetic loci link adipose and insulin biology to body fat distribution.
JO  - Nature
VL  - 518
IS  - 7538
PB  - Nature Publishing Group
PY  - 2015
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - It is generally believed that splicing removes introns as single units from precursor messenger RNA transcripts. However, some long Drosophila melanogaster introns contain a cryptic site, known as a recursive splice site (RS-site), that enables a multi-step process of intron removal termed recursive splicing. The extent to which recursive splicing occurs in other species and its mechanistic basis have not been examined. Here we identify highly conserved RS-sites in genes expressed in the mammalian brain that encode proteins functioning in neuronal development. Moreover, the RS-sites are found in some of the longest introns across vertebrates. We find that vertebrate recursive splicing requires initial definition of an 'RS-exon' that follows the RS-site. The RS-exon is then excluded from the dominant mRNA isoform owing to competition with a reconstituted 5' splice site formed at the RS-site after the first splicing step. Conversely, the RS-exon is included when preceded by cryptic promoters or exons that fail to reconstitute an efficient 5' splice site. Most RS-exons contain a premature stop codon such that their inclusion can decrease mRNA stability. Thus, by establishing a binary splicing switch, RS-sites demarcate different mRNA isoforms emerging from long genes by coupling cryptic elements with inclusion of RS-exons.
AU  - Sibley, C.R.*
AU  - Emmett, W.*
AU  - Blazquez, L.*
AU  - Faro, A.*
AU  - Haberman, N.*
AU  - Briese, M.*
AU  - Trabzuni, D.*
AU  - Ryten, M.*
AU  - Weale, M.E.*
AU  - Hardy, J.*
AU  - Modic, M.
AU  - Curk, T.*
AU  - Wilson, S.W.*
AU  - Plagnol, V.*
AU  - Ule, J.*
C1  - 44866
C2  - 37181
CY  - London
SP  - 371-375
TI  - Recursive splicing in long vertebrate genes.
JO  - Nature
VL  - 521
IS  - 7552
PB  - Nature Publishing Group
PY  - 2015
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Alzheimer disease (AD) is characterized by the accumulation of amyloid plaques, which are predominantly composed of amyloid-β peptide. Two principal physiological pathways either prevent or promote amyloid-β generation from its precursor, β-amyloid precursor protein (APP), in a competitive manner. Although APP processing has been studied in great detail, unknown proteolytic events seem to hinder stoichiometric analyses of APP metabolism in vivo. Here we describe a new physiological APP processing pathway, which generates proteolytic fragments capable of inhibiting neuronal activity within the hippocampus. We identify higher molecular mass carboxy-terminal fragments (CTFs) of APP, termed CTF-η, in addition to the long-known CTF-α and CTF-β fragments generated by the α- and β-secretases ADAM10 (a disintegrin and metalloproteinase 10) and BACE1 (β-site APP cleaving enzyme 1), respectively. CTF-η generation is mediated in part by membrane-bound matrix metalloproteinases such as MT5-MMP, referred to as η-secretase activity. η-Secretase cleavage occurs primarily at amino acids 504-505 of APP695, releasing a truncated ectodomain. After shedding of this ectodomain, CTF-η is further processed by ADAM10 and BACE1 to release long and short Aη peptides (termed Aη-α and Aη-β). CTFs produced by η-secretase are enriched in dystrophic neurites in an AD mouse model and in human AD brains. Genetic and pharmacological inhibition of BACE1 activity results in robust accumulation of CTF-η and Aη-α. In mice treated with a potent BACE1 inhibitor, hippocampal long-term potentiation was reduced. Notably, when recombinant or synthetic Aη-α was applied on hippocampal slices ex vivo, long-term potentiation was lowered. Furthermore, in vivo single-cell two-photon calcium imaging showed that hippocampal neuronal activity was attenuated by Aη-α. These findings not only demonstrate a major functionally relevant APP processing pathway, but may also indicate potential translational relevance for therapeutic strategies targeting APP processing.
AU  - Willem, M.*
AU  - Tahirovic, S.*
AU  - Busche, M.A.*
AU  - Ovsepian, S.V.*
AU  - Chafai, M.*
AU  - Kootar, S.*
AU  - Hornburg, D.*
AU  - Evans, L.D.*
AU  - Moore, S.*
AU  - Daria, A.*
AU  - Hampel, H.*
AU  - Müller, V.*
AU  - Giudici, C.*
AU  - Nuscher, B.*
AU  - Wenninger-Weinzierl, A.*
AU  - Kremmer, E.
AU  - Heneka, M.T.*
AU  - Thal, D.R.*
AU  - Giedraitis, V.*
AU  - Lannfelt, L.*
AU  - Müller, U.*
AU  - Livesey, F.J.*
AU  - Meissner, F.*
AU  - Herms, J.*
AU  - Konnerth, A.*
AU  - Marie, H.*
AU  - Haass, C.*
C1  - 46784
C2  - 37799
SP  - 443-447
TI  - η-secretase processing of APP inhibits neuronal activity in the hippocampus.
JO  - Nature
VL  - 526
IS  - 7573
PY  - 2015
SN  - 0028-0836
ER  - 

TY  - JOUR
AU  - Wittmaack, K.
C1  - 45189
C2  - 37253
SP  - 156
TI  - The joys of research in retirement.
JO  - Nature
VL  - 522
IS  - 7555
PY  - 2015
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Microbes and their viruses drive myriad processes across ecosystems ranging from oceans and soils to bioreactors and humans. Despite this importance, microbial diversity is only now being mapped at scales relevant to nature, while the viral diversity associated with any particular host remains little researched. Here we quantify host-associated viral diversity using viral-tagged metagenomics, which links viruses to specific host cells for high-throughput screening and sequencing. In a single experiment, we screened 10(7) Pacific Ocean viruses against a single strain of Synechococcus and found that naturally occurring cyanophage genome sequence space is statistically clustered into discrete populations. These population-based, host-linked viral ecological data suggest that, for this single host and seawater sample alone, there are at least 26 double-stranded DNA viral populations with estimated relative abundances ranging from 0.06 to 18.2%. These populations include previously cultivated cyanophage and new viral types missed by decades of isolate-based studies. Nucleotide identities of homologous genes mostly varied by less than 1% within populations, even in hypervariable genome regions, and by 42-71% between populations, which provides benchmarks for viral metagenomics and genome-based viral species definitions. Together these findings showcase a new approach to viral ecology that quantitatively links objectively defined environmental viral populations, and their genomes, to their hosts.
AU  - Deng, L.
AU  - Ignacio-Espinoza, J.C.*
AU  - Gregory, A.C.*
AU  - Poulos, B.T.*
AU  - Weitz, J.S.*
AU  - Hugenholtz, P.*
AU  - Sullivan, M.B.*
C1  - 32184
C2  - 34978
SP  - 242-245
TI  - Viral tagging reveals discrete populations in Synechococcus viral genome sequence space.
JO  - Nature
VL  - 513
IS  - 7517
PY  - 2014
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Genetic equality between males and females is established by chromosome-wide dosage-compensation mechanisms. In the fruitfly Drosophila melanogaster, the dosage-compensation complex promotes twofold hypertranscription of the single male X-chromosome and is silenced in females by inhibition of the translation of msl2, which codes for the limiting component of the dosage-compensation complex. The female-specific protein Sex-lethal (Sxl) recruits Upstream-of-N-ras (Unr) to the 3' untranslated region of msl2 messenger RNA, preventing the engagement of the small ribosomal subunit. Here we report the 2.8 Å crystal structure, NMR and small-angle X-ray and neutron scattering data of the ternary Sxl-Unr-msl2 ribonucleoprotein complex featuring unprecedented intertwined interactions of two Sxl RNA recognition motifs, a Unr cold-shock domain and RNA. Cooperative complex formation is associated with a 1,000-fold increase of RNA binding affinity for the Unr cold-shock domain and involves novel ternary interactions, as well as non-canonical RNA contacts by the α1 helix of Sxl RNA recognition motif 1. Our results suggest that repression of dosage compensation, necessary for female viability, is triggered by specific, cooperative molecular interactions that lock a ribonucleoprotein switch to regulate translation. The structure serves as a paradigm for how a combination of general and widespread RNA binding domains expands the code for specific single-stranded RNA recognition in the regulation of gene expression.
AU  - Hennig, J.
AU  - Militti, C.*
AU  - Popowicz, G.M.
AU  - Wang, I.
AU  - Sonntag, M.
AU  - Geerlof, A.
AU  - Gabel, F.*
AU  - Gebauer, F.*
AU  - Sattler, M.
C1  - 32170
C2  - 34966
SP  - 287-290
TI  - Structural basis for the assembly of the Sxl-Unr translation regulatory complex.
JO  - Nature
VL  - 515
IS  - 7526
PY  - 2014
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Rapid industrialization and urbanization in developing countries has led to an increase in air pollution, along a similar trajectory to that previously experienced by the developed nations. In China, particulate pollution is a serious environmental problem that is influencing air quality, regional and global climates, and human health. In response to the extremely severe and persistent haze pollution experienced by about 800 million people during the first quarter of 2013 (refs 4, 5), the Chinese State Council announced its aim to reduce concentrations of PM2.5 (particulate matter with an aerodynamic diameter less than 2.5 micrometres) by up to 25 per cent relative to 2012 levels by 2017 (ref. 6). Such efforts however require elucidation of the factors governing the abundance and composition of PM2.5, which remain poorly constrained in China. Here we combine a comprehensive set of novel and state-of-the-art offline analytical approaches and statistical techniques to investigate the chemical nature and sources of particulate matter at urban locations in Beijing, Shanghai, Guangzhou and Xi'an during January 2013. We find that the severe haze pollution event was driven to a large extent by secondary aerosol formation, which contributed 30-77 per cent and 44-71 per cent (average for all four cities) of PM2.5 and of organic aerosol, respectively. On average, the contribution of secondary organic aerosol (SOA) and secondary inorganic aerosol (SIA) are found to be of similar importance (SOA/SIA ratios range from 0.6 to 1.4). Our results suggest that, in addition to mitigating primary particulate emissions, reducing the emissions of secondary aerosol precursors from, for example, fossil fuel combustion and biomass burning is likely to be important for controlling China's PM2.5 levels and for reducing the environmental, economic and health impacts resulting from particulate pollution.
AU  - Huang, R.J.*
AU  - Zhang, Y.*
AU  - Bozzetti, C.*
AU  - Ho, K.F.*
AU  - Cao, J.J.*
AU  - Han, Y.*
AU  - Daellenbach, K.R.*
AU  - Slowik, J.G.*
AU  - Platt, S.M.*
AU  - Canonaco, F.*
AU  - Zotter, P.*
AU  - Wolf, R.*
AU  - Pieber, S.M.*
AU  - Bruns, E.A.*
AU  - Crippa, M.*
AU  - Ciarelli, G.*
AU  - Piazzalunga, A.*
AU  - Schwikowski, M.*
AU  - Abbaszade, G.
AU  - Schnelle-Kreis, J.
AU  - Zimmermann, R.
AU  - An, Z.*
AU  - Szidat, S.*
AU  - Baltensperger, U.*
AU  - Haddad, I.E.*
AU  - Prevot, A.S.H.*
C1  - 32264
C2  - 34998
CY  - London
SP  - 218-222
TI  - High secondary aerosol contribution to particulate pollution during haze events in China.
JO  - Nature
VL  - 514
IS  - 7521
PB  - Nature Publishing Group
PY  - 2014
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10−8) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.
AU  - Perry, J.R.B.*
AU  - Day, F.*
AU  - Elks, C.E.*
AU  - Sulem, P.*
AU  - Thompson, D.J.*
AU  - Ferreira, T.*
AU  - He, C.*
AU  - Chasman, D.I.*
AU  - Esko, T.*
AU  - Thorleifsson, G.*
AU  - Albrecht, E.
AU  - Ang, W.Q.*
AU  - Corre, T.*
AU  - Cousminer, D.L.*
AU  - Feenstra, B.*
AU  - Franceschini, N.*
AU  - Ganna, A.*
AU  - Johnson, A.D.*
AU  - Kjellqvist, S.*
AU  - Lunetta, K.L.*
AU  - McMahon, G.*
AU  - Nolte, I.M.*
AU  - Paternoster, L.*
AU  - Porcu, E.*
AU  - Smith, A.V.*
AU  - Stolk, L.*
AU  - Teumer, A.*
AU  - Tsernikova, N.*
AU  - Tikkanen, E.*
AU  - Ulivi, S.*
AU  - Wagner, E.K.*
AU  - Amin, N.*
AU  - Bierut, L.J.*
AU  - Byrne, E.M.*
AU  - Hottenga, J.-J.*
AU  - Koller, D.L.*
AU  - Mangino, M.*
AU  - Pers, T.H.*
AU  - Yerges-Armstrong, L.M.*
AU  - Zhao, J.H.*
AU  - Andrulis, I.L.*
AU  - Anton-Culver, H.*
AU  - Atsma, F.*
AU  - Bandinelli, S.*
AU  - Beckmann, M.W.*
AU  - Benítez, J.*
AU  - Blomqvist, C.*
AU  - Bojesen, S.E.*
AU  - Bolla, M.K.*
AU  - Bonanni, B.*
AU  - Brauch, H.*
AU  - Brenner, H.*
AU  - Buring, J.E.*
AU  - Chang-Claude, J.*
AU  - Chanock, S.*
AU  - Chen, J.*
AU  - Chenevix-Trench, G.*
AU  - Collee, J.M.*
AU  - Couch, F.J.*
AU  - Couper, D.*
AU  - Coviello, A.D.*
AU  - Cox, A.*
AU  - Czene, K.*
AU  - D’adamo, A.P.*
AU  - Smith, G.D.*
AU  - de Vivo, I.*
AU  - Demerath, E.W.*
AU  - Dennis, J.*
AU  - Devilee, P.*
AU  - Dieffenbach, A.K.*
AU  - Dunning, A.M.*
AU  - Eiriksdottir, G.*
AU  - Eriksson, J.G.*
AU  - Fasching, P.A.*
AU  - Ferrucci, L.*
AU  - Flesch-Janys, D.*
AU  - Flyger, H.*
AU  - Foroud, T.*
AU  - Franke, L.*
AU  - Garcia, M.E.*
AU  - Garcia-Closas, M.*
AU  - Geller, F.*
AU  - de Geus, E.J.*
AU  - Giles, G.G.*
AU  - Gudbjartsson, D.F.*
AU  - Gudnason, V.*
AU  - Guénel, P.*
AU  - Guo, S.*
AU  - Hall, P.*
AU  - Hamann, U.*
AU  - Haring, R.*
AU  - Hartman, C.A.*
AU  - Heath, A.C.*
AU  - Hofman, A.*
AU  - Hooning, M.J.*
AU  - Hopper, J.L.*
AU  - Hu, F.B.*
AU  - Hunter, D.J.*
AU  - Karasik, D.*
AU  - Kiel, D.P.*
AU  - Knight, J.A.*
AU  - Kosma, V.M.*
AU  - Kutalik, Z.*
AU  - Lai, S.*
AU  - Lambrechts, D.*
AU  - Lindblom, A.*
AU  - Mägi, R.*
AU  - Magnusson, P.K.*
AU  - Mannermaa, A.*
AU  - Martin, N.G.*
AU  - Masson, G.*
AU  - McArdle, P.F.*
AU  - McArdle, W.L.*
AU  - Melbye, M.*
AU  - Michailidou, K.*
AU  - Mihailov, E.*
AU  - Milani, L.*
AU  - Milne, R.L.*
AU  - Nevanlinna, H.*
AU  - Neven, P.*
AU  - Nohr, E.A.*
AU  - Oldehinkel, A.J.*
AU  - Oostra, B.A.*
AU  - Palotie, A.*
AU  - Peacock, M.*
AU  - Pedersen, N.L.*
AU  - Peterlongo, P.*
AU  - Peto, J.*
AU  - Pharoah, P.D.P.*
AU  - Postma, D.S.*
AU  - Pouta, A.*
AU  - Pylkäs, K.*
AU  - Radice, P.*
AU  - Ring, S.*
AU  - Rivadeneira, F.*
AU  - Robino, A.*
AU  - Rose, L.M.*
AU  - Rudolph, A.*
AU  - Salomaa, V.*
AU  - Sanna, S.*
AU  - Schlessinger, D.*
AU  - Schmidt, M.K.*
AU  - Southey, M.C.*
AU  - Sovio, U.*
AU  - Stampfer, M.*
AU  - Stöckl, D.
AU  - Storniolo, A.*
AU  - Timpson, N.J.*
AU  - Tyrer, J.*
AU  - Visser, J.A.*
AU  - Vollenweider, P.*
AU  - Völzke, H.*
AU  - Waeber, G.*
AU  - Waldenberger, M.
AU  - Wallaschofski, H.*
AU  - Wang, Q.*
AU  - Willemsen, G.*
AU  - Winqvist, R.*
AU  - Wolffenbuttel, B.H.R.*
AU  - Wright, M.J.*
AU  - Boomsma, D.I.*
AU  - Econs, M.J.*
AU  - Khaw, K.-T.*
AU  - Loos, R.J.F.*
AU  - McCarthy, M.I.*
AU  - Montgomery, G.W.*
AU  - Rice, J.P.*
AU  - Streeten, E.A.*
AU  - Thorsteinsdottir, U.*
AU  - van Duijn, C.M.*
AU  - Alizadeh, B.Z.*
AU  - Bergmann, S.*
AU  - Boerwinkle, E.*
AU  - Boyd, H.A.*
AU  - Crisponi, L.*
AU  - Gasparini, P.*
AU  - Gieger, C.
AU  - Harris, T.B.*
AU  - Ingelsson, E.*
AU  - Järvelin, M.-R.*
AU  - Kraft, P.*
AU  - Lawlor, D.*
AU  - Metspalu, A.*
AU  - Pennell, C.E.*
AU  - Ridker, P.M.*
AU  - Snieder, H.*
AU  - Sørensen, T.I.*
AU  - Spector, T.D.*
AU  - Strachan, D.P.*
AU  - Uitterlinden, A.G.*
AU  - Wareham, N.J.*
AU  - Widen, E.*
AU  - Zygmunt, M.*
AU  - Murray, A.*
AU  - Easton, D.F.*
AU  - Stefansson, K.*
AU  - Murabito, J.M.*
AU  - Ong, K.K.*
C1  - 31901
C2  - 34857
CY  - London
SP  - 92-97
TI  - Parent-of-origin specific allelic associations among 106 genomic1 loci for age at menarche.
JO  - Nature
VL  - 514
IS  - 7520
PB  - Nature Publishing Group
PY  - 2014
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Protein synthesis in all cells is carried out by macromolecular machines called ribosomes. Although the structures of prokaryotic, yeast and protist ribosomes have been determined, the more complex molecular architecture of metazoan 80S ribosomes has so far remained elusive. Here we present structures of Drosophila melanogaster and Homo sapiens 80S ribosomes in complex with the translation factor eEF2, E-site transfer RNA and Stm1-like proteins, based on high-resolution cryo-electron-microscopy density maps. These structures not only illustrate the co-evolution of metazoan-specific ribosomal RNA with ribosomal proteins but also reveal the presence of two additional structural layers in metazoan ribosomes, a well-ordered inner layer covered by a flexible RNA outer layer. The human and Drosophila ribosome structures will provide the basis for more detailed structural, biochemical and genetic experiments.
AU  - Anger, A.M.*
AU  - Armache, J.P.*
AU  - Berninghausen, O.*
AU  - Habeck, M.*
AU  - Subklewe, M.
AU  - Wilson, D.N.*
AU  - Beckmann, R.*
C1  - 28402
C2  - 33365
SP  - 80-85
TI  - Structures of the human and Drosophila 80S ribosome.
JO  - Nature
VL  - 497
IS  - 7447
PB  - Nature Publishing
PY  - 2013
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Cancer control by adaptive immunity involves a number of defined death and clearance mechanisms. However, efficient inhibition of exponential cancer growth by T cells and interferon-γ (IFN-γ) requires additional undefined mechanisms that arrest cancer cell proliferation. Here we show that the combined action of the T-helper-1-cell cytokines IFN-γ and tumour necrosis factor (TNF) directly induces permanent growth arrest in cancers. To safely separate senescence induced by tumour immunity from oncogene-induced senescence, we used a mouse model in which the Simian virus 40 large T antigen (Tag) expressed under the control of the rat insulin promoter creates tumours by attenuating p53- and Rb-mediated cell cycle control. When combined, IFN-γ and TNF drive Tag-expressing cancers into senescence by inducing permanent growth arrest in G1/G0, activation of p16INK4a (also known as CDKN2A), and downstream Rb hypophosphorylation at serine 795. This cytokine-induced senescence strictly requires STAT1 and TNFR1 (also known as TNFRSF1A) signalling in addition to p16INK4a. In vivo, Tag-specific T-helper 1 cells permanently arrest Tag-expressing cancers by inducing IFN-γ- and TNFR1-dependent senescence. Conversely, Tnfr1(-/- )Tag-expressing cancers resist cytokine-induced senescence and grow aggressively, even in TNFR1-expressing hosts. Finally, as IFN-γ and TNF induce senescence in numerous murine and human cancers, this may be a general mechanism for arresting cancer progression.
AU  - Braumüller, H.*
AU  - Wieder, T.*
AU  - Brenner, E.*
AU  - Aßmann, S.*
AU  - Hahn, M.*
AU  - Alkhaled, M.*
AU  - Schilbach, K.*
AU  - Essmann, F.*
AU  - Kneilling, M.*
AU  - Griessinger, C.*
AU  - Ranta, F.*
AU  - Ullrich, S.*
AU  - Mocikat, R.
AU  - Braungart, K.*
AU  - Mehra, T.*
AU  - Fehrenbacher, B.*
AU  - Berdel, J.*
AU  - Niessner, H.*
AU  - Meier, F.*
AU  - van den Broek, M.*
AU  - Häring, H.-U.*
AU  - Handgretinger, R.*
AU  - Quintanilla-Martinez, L.*
AU  - Fend, F.*
AU  - Pesic, M.*
AU  - Bauer, J.*
AU  - Zender, L.*
AU  - Schaller, M.*
AU  - Schulze-Osthoff, K.*
AU  - Röcken, M.*
C1  - 22527
C2  - 30896
SP  - 361-365
TI  - T-helper-1-cell cytokines drive cancer into senescence.
JO  - Nature
VL  - 494
IS  - 7437
PB  - Nature Publishing
PY  - 2013
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Myocardial infarction, a leading cause of death in the Western world, usually occurs when the fibrous cap overlying an atherosclerotic plaque in a coronary artery ruptures. The resulting exposure of blood to the atherosclerotic material then triggers thrombus formation, which occludes the artery. The importance of genetic predisposition to coronary artery disease and myocardial infarction is best documented by the predictive value of a positive family history. Next-generation sequencing in families with several affected individuals has revolutionized mutation identification. Here we report the segregation of two private, heterozygous mutations in two functionally related genes, GUCY1A3 (p.Leu163Phefs*24) and CCT7 (p.Ser525Leu), in an extended myocardial infarction family. GUCY1A3 encodes the α1 subunit of soluble guanylyl cyclase (α1-sGC), and CCT7 encodes CCTη, a member of the tailless complex polypeptide 1 ring complex, which, among other functions, stabilizes soluble guanylyl cyclase. After stimulation with nitric oxide, soluble guanylyl cyclase generates cGMP, which induces vasodilation and inhibits platelet activation. We demonstrate in vitro that mutations in both GUCY1A3 and CCT7 severely reduce α1-sGC as well as β1-sGC protein content, and impair soluble guanylyl cyclase activity. Moreover, platelets from digenic mutation carriers contained less soluble guanylyl cyclase protein and consequently displayed reduced nitric-oxide-induced cGMP formation. Mice deficient in α1-sGC protein displayed accelerated thrombus formation in the microcirculation after local trauma. Starting with a severely affected family, we have identified a link between impaired soluble-guanylyl-cyclase-dependent nitric oxide signalling and myocardial infarction risk, possibly through accelerated thrombus formation. Reversing this defect may provide a new therapeutic target for reducing the risk of myocardial infarction.
AU  - Erdmann, J.*
AU  - Stark, K.*
AU  - Esslinger, U.B.*
AU  - Rumpf, P.M.*
AU  - Koesling, D.*
AU  - de Wit, C.*
AU  - Kaiser, F.J.*
AU  - Braunholz, D.*
AU  - Medack, A.*
AU  - Fischer, M.*
AU  - Zimmermann, M.E.*
AU  - Tennstedt, S.*
AU  - Graf, E.
AU  - Eck, S.
AU  - Aherrahrou, Z*
AU  - Nahrstaedt, J.*
AU  - Willenborg, C.*
AU  - Bruse, P.*
AU  - Brænne, I.*
AU  - Nöthen, M.M.*
AU  - Hofmann, P.*
AU  - Braund, P.S.*
AU  - Mergia, E.*
AU  - Reinhard, W.*
AU  - Burgdorf, C.*
AU  - Schreiber, S.*
AU  - Balmforth, A.J.*
AU  - Hall, A.S.*
AU  - Bertram, L.*
AU  - Steinhagen-Thiessen, E.*
AU  - Li, S.C.*
AU  - Marz, W.*
AU  - Reilly, M.*
AU  - Kathiresan, S.*
AU  - McPherson, R.*
AU  - Walter, U.*
AU  - CARDIoGRAM Consortium (Wichmann, H.-E.
AU  - Döring, A.
AU  - Illig, T.
AU  - Klopp, N.
AU  - Meisinger, C.
AU  - Peters, A.)
AU  - Ott, J.*
AU  - Samani, N.J.*
AU  - Strom, T.M.
AU  - Meitinger, T.
AU  - Hengstenberg, C.*
AU  - Schunkert, H.*
C1  - 28178
C2  - 32991
SP  - 432-436
TI  - Dysfunctional nitric oxide signalling increases risk of myocardial infarction.
JO  - Nature
VL  - 504
IS  - 7480
PB  - Nature Publishing
PY  - 2013
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - About 8,000 years ago in the Fertile Crescent, a spontaneous hybridization of the wild diploid grass Aegilops tauschii (2n = 14; DD) with the cultivated tetraploid wheat Triticum turgidum (2n = 4x = 28; AABB) resulted in hexaploid wheat (T. aestivum; 2n = 6x = 42; AABBDD). Wheat has since become a primary staple crop worldwide as a result of its enhanced adaptability to a wide range of climates and improved grain quality for the production of baker's flour. Here we describe sequencing the Ae. tauschii genome and obtaining a roughly 90-fold depth of short reads from libraries with various insert sizes, to gain a better understanding of this genetically complex plant. The assembled scaffolds represented 83.4% of the genome, of which 65.9% comprised transposable elements. We generated comprehensive RNA-Seq data and used it to identify 43,150 protein-coding genes, of which 30,697 (71.1%) were uniquely anchored to chromosomes with an integrated high-density genetic map. Whole-genome analysis revealed gene family expansion in Ae. tauschii of agronomically relevant gene families that were associated with disease resistance, abiotic stress tolerance and grain quality. This draft genome sequence provides insight into the environmental adaptation of bread wheat and can aid in defining the large and complicated genomes of wheat species.
AU  - Jia, J.*
AU  - Zhao, S.*
AU  - Kong, X.*
AU  - Li, Y.*
AU  - Zhao, G.*
AU  - He, W.*
AU  - Appels, R.*
AU  - Pfeifer, M.
AU  - Tao, Y.*
AU  - Zhang, X.*
AU  - Jing, R.*
AU  - Zhang, C.*
AU  - Ma, Y.*
AU  - Gao, L.*
AU  - Gao, C.*
AU  - Spannagl, M.
AU  - Mayer, K.F.X.
AU  - Li, D.*
AU  - Pan, S.*
AU  - Zheng, F.*
AU  - Hu, Q.*
AU  - Xia, X.*
AU  - Li, J.*
AU  - Liang, Q.*
AU  - Chen, J.*
AU  - Wicker, T.*
AU  - Gou, C.*
AU  - Kuang, H.*
AU  - He, G.*
AU  - Luo, Y.*
AU  - Keller, B.*
AU  - Xia, Q.*
AU  - Lu, P.*
AU  - Wang, J.*
AU  - Zou, H.*
AU  - Zhang, R.*
AU  - Xu, J.*
AU  - Gao, J.*
AU  - Middleton, C.*
AU  - Quan, Z.*
AU  - Liu, G.*
AU  - International Wheat Genome Sequencing Consortium (*)
AU  - Yang, H.*
AU  - Liu, X.*
AU  - He, Z.*
AU  - Mao, L.*
C1  - 23811
C2  - 31292
SP  - 91-95
TI  - Aegilops tauschii draft genome sequence reveals a gene repertoire for wheat adaptation.
JO  - Nature
VL  - 496
IS  - 7443
PB  - Nature Publishing
PY  - 2013
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Genome sequencing projects are discovering millions of genetic variants in humans, and interpretation of their functional effects is essential for understanding the genetic basis of variation in human traits. Here we report sequencing and deep analysis of messenger RNA and microRNA from lymphoblastoid cell lines of 462 individuals from the 1000 Genomes Project-the first uniformly processed high-throughput RNA-sequencing data from multiple human populations with high-quality genome sequences. We discover extremely widespread genetic variation affecting the regulation of most genes, with transcript structure and expression level variation being equally common but genetically largely independent. Our characterization of causal regulatory variation sheds light on the cellular mechanisms of regulatory and loss-of-function variation, and allows us to infer putative causal variants for dozens of disease-associated loci. Altogether, this study provides a deep understanding of the cellular mechanisms of transcriptome variation and of the landscape of functional variants in the human genome.
AU  - Lappalainen, T.*
AU  - Sammeth, M.*
AU  - Friedländer, M.R.*
AU  - 't Hoen, P.A.*
AU  - Monlong, J.*
AU  - Rivas, M.A.*
AU  - Gonzàlez-Porta, M.*
AU  - Kurbatova, N.*
AU  - Griebel, T.*
AU  - Ferreira, P.G.*
AU  - Barann, M.*
AU  - Wieland, T.
AU  - Greger, L.*
AU  - van Iterson, M.*
AU  - Almlöf, J.*
AU  - Ribeca, P.*
AU  - Pulyakhina, I.*
AU  - Esser, D.*
AU  - Giger, T.*
AU  - Tikhonov, A.*
AU  - Sultan, M.*
AU  - Bertier, G.*
AU  - MacArthur, D.G.*
AU  - Lek, M.*
AU  - Lizano, E.*
AU  - Buermans, H.P.*
AU  - Padioleau, I.*
AU  - Schwarzmayr, T.
AU  - Karlberg, O.*
AU  - Ongen, H.*
AU  - Kilpinen, H.*
AU  - Beltran, S.*
AU  - Gut, M.*
AU  - Kahlem, K.*
AU  - Amstislavskiy, V.*
AU  - Stegle, O.*
AU  - Pirinen, M.*
AU  - Montgomery, S.B.*
AU  - Donnelly, P.*
AU  - McCarthy, M.I.*
AU  - Flicek, P.*
AU  - Strom, T.M.
AU  - Geuvadis Consortium (*)
AU  - Lehrach, H.*
AU  - Schreiber, S.*
AU  - Sudbrak, R.*
AU  - Carracedo, A.*
AU  - Antonarakis, S.E.*
AU  - Häsler, R.*
AU  - Syvanen, A.C.*
AU  - van Ommen, G.J.*
AU  - Brazma, A.*
AU  - Meitinger, T.
AU  - Rosenstiel, P.*
AU  - Guigo, R.*
AU  - Gut, I.G.*
AU  - Estivill, X.*
AU  - Dermitzakis, E.T.*
C1  - 27517
C2  - 32709
SP  - 506-511
TI  - Transcriptome and genome sequencing uncovers functional variation in humans.
JO  - Nature
VL  - 501
IS  - 7468
PB  - Nature Publishing
PY  - 2013
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - The generation of induced pluripotent stem (iPS) cells presents a challenge to normal developmental processes. The low efficiency and heterogeneity of most methods have hindered understanding of the precise molecular mechanisms promoting, and roadblocks preventing, efficient reprogramming. Although several intermediate populations have been described, it has proved difficult to characterize the rare, asynchronous transition from these intermediate stages to iPS cells. The rapid expansion of minor reprogrammed cells in the heterogeneous population can also obscure investigation of relevant transition processes. Understanding the biological mechanisms essential for successful iPS cell generation requires both accurate capture of cells undergoing the reprogramming process and identification of the associated global gene expression changes. Here we demonstrate that in mouse embryonic fibroblasts, reprogramming follows an orderly sequence of stage transitions, marked by changes in the cell-surface markers CD44 and ICAM1, and a Nanog-enhanced green fluorescent protein (Nanog-eGFP) reporter. RNA-sequencing analysis of these populations demonstrates two waves of pluripotency gene upregulation, and unexpectedly, transient upregulation of several epidermis-related genes, demonstrating that reprogramming is not simply the reversal of the normal developmental processes. This novel high-resolution analysis enables the construction of a detailed reprogramming route map, and the improved understanding of the reprogramming process will lead to new reprogramming strategies.
AU  - O'Malley, J.*
AU  - Skylaki, S.
AU  - Iwabuchi, K.A.*
AU  - Chantzoura, E.*
AU  - Ruetz, T.*
AU  - Johnsson, A.*
AU  - Tomlinson, S.R.*
AU  - Linnarsson, S.*
AU  - Kaji, K.*
C1  - 26200
C2  - 32119
SP  - 88-91
TI  - High-resolution analysis with novel cell-surface markers identifies routes to iPS cells.
JO  - Nature
VL  - 499
IS  - 7456
PB  - Nature Publishing
PY  - 2013
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Although a prominent role for the brain in glucose homeostasis was proposed by scientists in the nineteenth century, research throughout most of the twentieth century focused on evidence that the function of pancreatic islets is both necessary and sufficient to explain glucose homeostasis, and that diabetes results from defects of insulin secretion, action or both. However, insulin-independent mechanisms, referred to as ‘glucose effectiveness’, account for roughly 50% of overall glucose disposal, and reduced glucose effectiveness also contributes importantly to diabetes pathogenesis. Although mechanisms underlying glucose effectiveness are poorly understood, growing evidence suggests that the brain can dynamically regulate this process in ways that improve or even normalize glycaemia in rodent models of diabetes. Here we present evidence of a brain-centred glucoregulatory system (BCGS) that can lower blood glucose levels via both insulin-dependent and -independent mechanisms, and propose a model in which complex and highly coordinated interactions between the BCGS and pancreatic islets promote normal glucose homeostasis. Because activation of either regulatory system can compensate for failure of the other, defects in both may be required for diabetes to develop. Consequently, therapies that target the BCGS in addition to conventional approaches based on enhancing insulin effects may have the potential to induce diabetes remission, whereas targeting just one typically does not.
AU  - Schwartz, M.W.*
AU  - Seeley, R.J.*
AU  - Tschöp, M.H.
AU  - Woods, S.C.*
AU  - Morton, G.J.*
AU  - Myers, M.G.*
AU  - D'Allesio, D.*
C1  - 28146
C2  - 32962
SP  - 59-66
TI  - Cooperation between brain and islet in glucose homeostasis and diabetes.
JO  - Nature
VL  - 503
IS  - 7474
PB  - Nature Publishing
PY  - 2013
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Bread wheat (Triticum aestivum) is a globally important crop, accounting for 20 per cent of the calories consumed by humans. Major efforts are underway worldwide to increase wheat production by extending genetic diversity and analysing key traits, and genomic resources can accelerate progress. But so far the very large size and polyploid complexity of the bread wheat genome have been substantial barriers to genome analysis. Here we report the sequencing of its large, 17-gigabase-pair, hexaploid genome using 454 pyrosequencing, and comparison of this with the sequences of diploid ancestral and progenitor genomes. We identified between 94,000 and 96,000 genes, and assigned two-thirds to the three component genomes (A, B and D) of hexaploid wheat. High-resolution synteny maps identified many small disruptions to conserved gene order. We show that the hexaploid genome is highly dynamic, with significant loss of gene family members on polyploidization and domestication, and an abundance of gene fragments. Several classes of genes involved in energy harvesting, metabolism and growth are among expanded gene families that could be associated with crop productivity. Our analyses, coupled with the identification of extensive genetic variation, provide a resource for accelerating gene discovery and improving this major crop.
AU  - Brenchley, R.*
AU  - Spannagl, M.
AU  - Pfeifer, M.
AU  - Barker, G.L.A.*
AU  - D'Amore, R.*
AU  - Allen, A.M.*
AU  - McKenzie, N.*
AU  - Kramer, M.*
AU  - Kerhornou, A.*
AU  - Bolser, D.*
AU  - Kay, S.*
AU  - Waite, D.*
AU  - Trick, M.*
AU  - Bancroft, I.*
AU  - Gu, Y.*
AU  - Huo, N.*
AU  - Luo, M.C.*
AU  - Sehgal, S.*
AU  - Gill, B.*
AU  - Kianian, S.*
AU  - Anderson, O.*
AU  - Kersey, P.*
AU  - Dvorak, J.*
AU  - McCombie, W.R.*
AU  - Hall, A.*
AU  - Mayer, K.F.X.
AU  - Edwards, K.J.*
AU  - Bevan, M.W.*
AU  - Hall, N.*
C1  - 11440
C2  - 30672
SP  - 705-710
TI  - Analysis of the breadwheat genome using whole-genome shotgun sequencing.
JO  - Nature
VL  - 491
IS  - 7426
PB  - Nature Publishing Group
PY  - 2012
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.
AU  - Jostins, L.*
AU  - Ripke, S.*
AU  - Weersma, R.K.*
AU  - Duerr, R.H.*
AU  - McGovern, D.P.*
AU  - Hui, K.Y.*
AU  - Lee, J.C.*
AU  - Schumm, L.P.*
AU  - Sharma, Y.*
AU  - Anderson, C.A.*
AU  - Essers, J.*
AU  - Mitrovic, M.*
AU  - Ning, K.*
AU  - Cleynen, I.*
AU  - Theatre, E.*
AU  - Spain, S.L.*
AU  - Raychaudhuri, S.*
AU  - Goyette, P.*
AU  - Wei, Z.*
AU  - Abraham, C.*
AU  - Achkar, J.P.*
AU  - Ahmad, T.*
AU  - Amininejad, L.*
AU  - Ananthakrishnan, A.N.*
AU  - Andersen, V.*
AU  - Andrews, J.M.*
AU  - Baidoo, L.*
AU  - Balschun, T.*
AU  - Bampton, P.A.*
AU  - Bitton, A.*
AU  - Boucher, G.*
AU  - Brand, S.*
AU  - Büning, C.*
AU  - Cohain, A.*
AU  - Cichon, S.*
AU  - D'Amato, M.*
AU  - de Jong, D.*
AU  - Devaney, K.L.*
AU  - Dubinsky, M.*
AU  - Edwards, C.*
AU  - Ellinghaus, D.*
AU  - Ferguson, L.R.*
AU  - Franchimont, D.*
AU  - Fransen, K.*
AU  - Gearry, R.*
AU  - Georges, M.*
AU  - Gieger, C.
AU  - Glas, J.*
AU  - Haritunians, T.*
AU  - Hart, A.*
AU  - Hawkey, C.*
AU  - Hedl, M.*
AU  - Hu, X.*
AU  - Karlsen, T.H.*
AU  - Kupcinskas, L.*
AU  - Kugathasan, S.*
AU  - Latiano, A.*
AU  - Laukens, D.*
AU  - Lawrance, I.C.*
AU  - Lees, C.W.*
AU  - Louis, E.*
AU  - Mahy, G.*
AU  - Mansfield, J.*
AU  - Morgan, A.R.*
AU  - Mowat, C.*
AU  - Newman, W.*
AU  - Palmieri, O.*
AU  - Ponsioen, C.Y.*
AU  - Potocnik, U.*
AU  - Prescott, N.J.*
AU  - Regueiro, M.*
AU  - Rotter, J.I.*
AU  - Russell, R.K.*
AU  - Sanderson, J.D.*
AU  - Sans, M.*
AU  - Satsangi, J.*
AU  - Schreiber, S.*
AU  - Simms, L.A.*
AU  - Sventoraityte, J.*
AU  - Targan, S.R.*
AU  - Taylor, K.D.*
AU  - Tremelling, M.*
AU  - Verspaget, H.W.*
AU  - de Vos, M.*
AU  - Wijmenga, C.*
AU  - Wilson, D.C.*
AU  - Winkelmann, J.*
AU  - Xavier, R.J.*
AU  - Zeissig, S.*
AU  - Zhang, B.*
AU  - Zhang, C.K.*
AU  - Zhao, H.*
AU  - Silverberg, M.S.*
AU  - Annese, V.*
AU  - Hakornarson, H.*
AU  - Brant, S.R.*
AU  - Radford-Smith, G.*
AU  - Mathew, C.G.*
AU  - Rioux, J.D.*
AU  - Schadt, E.E.*
AU  - Daly, M.J.*
AU  - Franke, A.*
AU  - Parkes, M.*
AU  - Vermeire, S.*
AU  - Barrett, J.C.*
AU  - Cho, J.H.*
AU  - International IBD Genetics Consortium (IIBDGC) (*)
C1  - 22457
C2  - 30868
SP  - 119-124
TI  - Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.
JO  - Nature
VL  - 491
IS  - 7422
PB  - Nature Publishing
PY  - 2012
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Barley (Hordeum vulgare L.) is among the world's earliest domesticated and most important crop plants. It is diploid with a large haploid genome of 5.1 gigabases (Gb). Here we present an integrated and ordered physical, genetic and functional sequence resource that describes the barley gene-space in a structured whole-genome context. We developed a physical map of 4.98 Gb, with more than 3.90 Gb anchored to a high-resolution genetic map. Projecting a deep whole-genome shotgun assembly, complementary DNA and deep RNA sequence data onto this framework supports 79,379 transcript clusters, including 26,159 'high-confidence' genes with homology support from other plant genomes. Abundant alternative splicing, premature termination codons and novel transcriptionally active regions suggest that post-transcriptional processing forms an important regulatory layer. Survey sequences from diverse accessions reveal a landscape of extensive single-nucleotide variation. Our data provide a platform for both genome-assisted research and enabling contemporary crop improvement.
AU  - Mayer, K.F.X.
AU  - Waugh, R.*
AU  - Langridge, P.*
AU  - Close, T.J.*
AU  - Wise, R.P.*
AU  - Graner, A.*
AU  - Matsumoto, T.*
AU  - Sato, K.*
AU  - Schulman, A.*
AU  - Muehlbauer, G.J.*
AU  - Stein, N.*
AU  - Ariyadasa, R.*
AU  - Schulte, D.*
AU  - Poursarebani, N.*
AU  - Zhou, R.N.*
AU  - Steuernagel, B.*
AU  - Mascher, M.*
AU  - Scholz, U.*
AU  - Shi, B.J.*
AU  - Madishetty, K.*
AU  - Svensson, J.T.*
AU  - Bhat, P.*
AU  - Moscou, M.*
AU  - Resnik, J.*
AU  - Hedley, P.*
AU  - Liu, H.*
AU  - Morris, J.*
AU  - Frenkel, Z.*
AU  - Korol, A.*
AU  - Bergès, H.*
AU  - Taudien, S.*
AU  - Groth, M.*
AU  - Felder, M.*
AU  - Platzer, M.*
AU  - Brown, J.W.S.*
AU  - Fincher, G.B.*
AU  - Sampath, D.*
AU  - Swarbreck, D.*
AU  - Scalabrin, S.*
AU  - Zuccolo, A.*
AU  - Vendramin, V.*
AU  - Morgante, M.*
C1  - 11439
C2  - 30673
SP  - 711-716
TI  - A physical, genetic and functional sequence assembly of the barley genome.
JO  - Nature
VL  - 491
IS  - 7426
PB  - Nature Publishing Group
PY  - 2012
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - The blood-brain barrier (BBB) and the environment of the central nervous system (CNS) guard the nervous tissue from peripheral immune cells. In the autoimmune disease multiple sclerosis, myelin-reactive T-cell blasts are thought to transgress the BBB1,2 and create a pro-inflammatory environment in the CNS, thereby making possible a second autoimmune attack that starts from the leptomeningeal vessels and progresses into the parenchyma(3-6). Using a Lewis rat model of experimental autoimmune encephalomyelitis, we show here that contrary to the expectations of this concept, T-cell blasts do not efficiently enter the CNS and are not required to prepare the BBB for immune-cell recruitment. Instead, intravenously transferred T-cell blasts gain the capacity to enter the CNS after residing transiently within the lung tissues. Inside the lung tissues, they move along and within the airways to bronchus-associated lymphoid tissues and lung-draining mediastinal lymph nodes before they enter the blood circulation from where they reach the CNS. Effector T cells transferred directly into the airways showed a similar migratory pattern and retained their full pathogenicity. On their way the T cells fundamentally reprogrammed their gene-expression profile, characterized by downregulation of their activation program and upregulation of cellular locomotion molecules together with chemokine and adhesion receptors. The adhesion receptors include ninjurin 1, which participates in T-cell intravascular crawling on cerebral blood vessels. We detected that the lung constitutes a niche not only for activated T cells but also for resting myelin-reactive memory T cells. After local stimulation in the lung, these cells strongly proliferate and, after assuming migratory properties, enter the CNS and induce paralytic disease. The lung could therefore contribute to the activation of potentially autoaggressive T cells and their transition to a migratory mode as a prerequisite to entering their target tissues and inducing autoimmune disease.
AU  - Odoardi, F.*
AU  - Sie, C.*
AU  - Streyl, K.*
AU  - Ulaganathan, V.K.*
AU  - Schläger, C.*
AU  - Lodygin, D.*
AU  - Heckelsmiller, K.*
AU  - Nietfeld, W.*
AU  - Ellwart, J.
AU  - Klinkert, W.E.F.*
AU  - Lottaz, C.*
AU  - Nosov, M.*
AU  - Brinkmann, V.*
AU  - Spang, R.*
AU  - Lehrach, H.*
AU  - Vingron, M.*
AU  - Wekerle, H.*
AU  - Flügel-Koch, C.*
AU  - Flügel, A.*
C1  - 8532
C2  - 30176
SP  - 675-679
TI  - T cells become licensed in the lung to enter the central nervous system.
JO  - Nature
VL  - 488
IS  - 7413
PB  - Nature Publishing Group
PY  - 2012
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Polyploidy often confers emergent properties, such as the higher fibre productivity and quality of tetraploid cottons than diploid cottons bred for the same environments(1). Here we show that an abrupt five-to sixfold ploidy increase approximately 60 million years (Myr) ago, and allopolyploidy reuniting divergent Gossypium genomes approximately 1-2 Myr ago(2), conferred about 30-36-fold duplication of ancestral angiosperm (flowering plant) genes in elite cottons (Gossypium hirsutum and Gossypium barbadense), genetic complexity equalled only by Brassica(3) among sequenced angiosperms. Nascent fibre evolution, before allopolyploidy, is elucidated by comparison of spinnable-fibred Gossypium herbaceum A and non-spinnable Gossypium longicalyx F genomes to one another and the outgroup D genome of non-spinnable Gossypium raimondii. The sequence of a G. hirsutum A(t)D(t) (in which 't' indicates tetraploid) cultivar reveals many non-reciprocal DNA exchanges between subgenomes that may have contributed to phenotypic innovation and/or other emergent properties such as ecological adaptation by polyploids. Most DNA-level novelty in G. hirsutum recombines alleles from the D-genome progenitor native to its New World habitat and the Old World A-genome progenitor in which spinnable fibre evolved. Coordinated expression changes in proximal groups of functionally distinct genes, including a nuclear mitochondrial DNA block, may account for clusters of cotton-fibre quantitative trait loci affecting diverse traits. Opportunities abound for dissecting emergent properties of other polyploids, particularly angiosperms, by comparison to diploid progenitors and outgroups.
AU  - Paterson, A.H.*
AU  - Wendel, J.F.*
AU  - Gundlach, H.
AU  - Guo, H.*
AU  - Jenkins, J.*
AU  - Jin, D.C.*
AU  - Llewellyn, D.*
AU  - Showmaker, K.C.*
AU  - Shu, S.Q.*
AU  - Udall, J.*
AU  - Yoo, M.J.*
AU  - Byers, R.*
AU  - Chen, W.*
AU  - Doron-Faigenboim, A.*
AU  - Duke, M.V.*
AU  - Gong, L.*
AU  - Grimwood, J.*
AU  - Grover, C.*
AU  - Grupp, K.*
AU  - Hu, G.J.*
AU  - Lee, T.H.*
AU  - Li, J.P.*
AU  - Lin, L.F.*
AU  - Liu, T.*
AU  - Marler, B.S.*
AU  - Page, J.T.*
AU  - Roberts, A.W.*
AU  - Romanel, E.*
AU  - Sanders, W.S.*
AU  - Szadkowski, E.*
AU  - Tan, X.*
AU  - Tang, H.B.*
AU  - Xu, C.M.*
AU  - Wang, J.P.*
AU  - Wang, Z.N.*
AU  - Zhang, D.*
AU  - Zhang, L.*
AU  - Ashrafi, H.*
AU  - Bedon, F.*
AU  - Bowers, J.E.*
AU  - Brubaker, C.L.*
AU  - Chee, P.W.*
AU  - Das, S.*
AU  - Gingle, A.R.*
AU  - Haigler, C.H.*
AU  - Harker, D.*
AU  - Hoffmann, L.V.*
AU  - Hovav, R.*
AU  - Jones, D.C.*
AU  - Lemke, C.*
AU  - Mansoor, S.*
AU  - Rahman, M.U.*
AU  - Rainville, L.N.*
AU  - Rambani, A.*
AU  - Reddy, U.K.*
AU  - Rong, J.K.*
AU  - Saranga, Y.*
AU  - Scheffler, B.E.*
AU  - Scheffler, J.A.*
AU  - Stelly, D.M.*
AU  - Triplett, B.A.*
AU  - van Deynze, A.*
AU  - Vaslin, M.F.S.*
AU  - Waghmare, V.N.*
AU  - Walford, S.A.*
AU  - Wright, R.J.*
AU  - Zaki, E.A.*
AU  - Zhang, T.Z.*
AU  - Dennis, E.S.*
AU  - Mayer, K.F.X.
AU  - Peterson, D.G.*
AU  - Rokhsar, D.S.*
AU  - Wang, X.Y.*
AU  - Schmutz, J.*
C1  - 11633
C2  - 30738
SP  - 423-437
TI  - Repeated polyploidization of Gossypium genomes and the evolution of spinnable cotton fibres.
JO  - Nature
VL  - 492
IS  - 7429
PB  - Nature Publishing Group
PY  - 2012
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Tomato (Solanum lycopersicum) is a major crop plant and a model system for fruit development. Solanum is one of the largest angiosperm genera(1) and includes annual and perennial plants from diverse habitats. Here we present a high-quality genome sequence of domesticated tomato, a draft sequence of its closest wild relative, Solanum pimpinellifolium(2), and compare them to each other and to the potato genome (Solanum tuberosum). The two tomato genomes show only 0.6% nucleotide divergence and signs of recent admixture, but show more than 8% divergence from potato, with nine large and several smaller inversions. In contrast to Arabidopsis, but similar to soybean, tomato and potato small RNAs map predominantly to gene-rich chromosomal regions, including gene promoters. The Solanum lineage has experienced two consecutive genome triplications: one that is ancient and shared with rosids, and a more recent one. These triplications set the stage for the neofunctionalization of genes controlling fruit characteristics, such as colour and fleshiness.
AU  - Sato, S.*
AU  - Tabata, S.*
AU  - Hirakawa, H.*
AU  - Asamizu, E.*
AU  - Shirasawa, K.*
AU  - Isobe, S.*
AU  - Kaneko, T.*
AU  - Nakamura, Y.*
AU  - Shibata, D.*
AU  - Aoki, K.*
AU  - Egholm, M.*
AU  - Knight, J.*
AU  - Bogden, R.*
AU  - Li, C.B.*
AU  - Shuang, Y.*
AU  - Xu, X.*
AU  - Pan, S.K.*
AU  - Cheng, S.F.*
AU  - Liu, X.*
AU  - Ren, Y.Y.*
AU  - Wang, J.*
AU  - Albiero, A.*
AU  - Dal Pero, F.*
AU  - Todesco, S.*
AU  - van Eck, J.*
AU  - Buels, R.M.*
AU  - Bombarely, A.*
AU  - Gosselin, J.R.*
AU  - Huang, M.Y.*
AU  - Leto, J.A.*
AU  - Menda, N.*
AU  - Strickler, S.*
AU  - Mao, L.Y.*
AU  - Gao, S.*
AU  - Tecle, I.Y.*
AU  - York, T.*
AU  - Zheng, Y.*
AU  - Vrebalov, J.T.*
AU  - Lee, J.*
AU  - Zhong, S.L.*
AU  - Mueller, L.A.*
AU  - Stiekema, W.J.*
AU  - Ribeca, P.*
AU  - Alioto, T.*
AU  - Yang, W.C.*
AU  - Huang, S.W.*
AU  - Du, Y.C.*
AU  - Zhang, Z.H.*
AU  - Gao, J.C.*
AU  - Guo, Y.M.*
AU  - Wang, X.X.*
AU  - Li, Y.*
AU  - He, J.*
AU  - Li, C.Y.*
AU  - Cheng, Z.K.*
AU  - Zuo, J.R.*
AU  - Ren, J.F.*
AU  - Zhao, J.H.*
AU  - Yan, L.H.*
AU  - Jiang, H.L.*
AU  - Wang, B.*
AU  - Li, H.S.*
AU  - Li, Z.J.*
AU  - Fu, F.Y.*
AU  - Chen, B.T.*
AU  - Han, B.*
AU  - Feng, Q.*
AU  - Fan, D.L.*
AU  - Wang, Y.*
AU  - Ling, H.Q.*
AU  - Xue, Y.B.A.*
AU  - Ware, D.*
AU  - McCombie, W.R.*
AU  - Lippman, Z.B.*
AU  - Chia, J.M.*
AU  - Jiang, K.*
AU  - Pasternak, S.*
AU  - Gelley, L.*
AU  - Kramer, M.*
AU  - Anderson, L.K.*
AU  - Chang, S.B.*
AU  - Royer, S.M.*
AU  - Shearer, L.A.*
AU  - Stack, S.M.*
AU  - Rose, J.K.C.*
AU  - Xu, Y.M.*
AU  - Eannetta, N.*
AU  - Matas, A.J.*
AU  - McQuinn, R.*
AU  - Tanksley, S.D.*
AU  - Camara, F.*
AU  - Guigo, R.*
AU  - Rombauts, S.*
AU  - Fawcett, J.*
AU  - van de Peer, Y.*
AU  - Zamir, D.*
AU  - Liang, C.B.*
AU  - Spannagl, M.
AU  - Gundlach, H.
AU  - Bruggmann, R.
AU  - Mayer, K.F.X.
AU  - Jia, Z.Q.*
AU  - Zhang, J.H.*
AU  - Ye, Z.B.A.*
AU  - Bishop, G.J.*
AU  - Butcher, S.*
AU  - Lopez-Cobollo, R.*
AU  - Buchan, D.*
AU  - Filippis, I.*
AU  - Abbott, J.*
AU  - Dixit, R.*
AU  - Singh, M.*
AU  - Singh, A.*
AU  - Pal, J.K.*
AU  - Pandit, A.*
AU  - Singh, P.K.*
AU  - Mahato, A.K.*
AU  - Dogra, V.*
AU  - Gaikwad, K.*
AU  - Sharma, T.R.*
AU  - Mohapatra, T.*
AU  - Singh, N.K.*
AU  - Causse, M.*
AU  - Rothan, C.*
AU  - Schiex, T.*
AU  - Noirot, C.*
AU  - Bellec, A.*
AU  - Klopp, C.*
AU  - Delalande, C.*
AU  - Bergès, H.*
AU  - Mariette, J.*
AU  - Frasse, P.*
AU  - Vautrin, S.*
AU  - Zouine, M.*
AU  - Latche, A.*
AU  - Rousseau, C.*
AU  - Regad, F.*
AU  - Pech, J.C.*
AU  - Philippot, M.*
AU  - Bouzayen, M.*
AU  - Pericard, P.*
AU  - Osorio, S.*
AU  - del Carmen, A.F.*
AU  - Monforte, A.*
AU  - Granell, A.*
AU  - Fernandez-Munoz, R.*
AU  - Conte, M.*
AU  - Lichtenstein, G.*
AU  - Carrari, F.*
AU  - de Bellis, G.*
AU  - Fuligni, F.*
AU  - Peano, C.*
AU  - Grandillo, S.*
AU  - Termolino, P.*
AU  - Pietrella, M.*
AU  - Fantini, E.*
AU  - Falcone, G.*
AU  - Fiore, A.*
AU  - Giuliano, G.*
AU  - Lopez, L.*
AU  - Facella, P.*
AU  - Perrotta, G.*
AU  - Daddiego, L.*
AU  - Bryan, G.*
AU  - Orozco, M.*
AU  - Pastor, X.*
AU  - Torrents, D.*
AU  - van Schriek, K.N.V.M.G.M.*
AU  - Feron, R.M.C.*
AU  - van Oeveren, J.*
AU  - de Heer, P.*
AU  - daPonte, L.*
AU  - Jacobs-Oomen, S.*
AU  - Cariaso, M.*
AU  - Prins, M.*
AU  - van Eijk, M.J.T.*
AU  - Janssen, A.*
AU  - van Haaren, M.J.J.*
AU  - Jo, S.H.*
AU  - Kim, J.*
AU  - Kwon, S.Y.*
AU  - Kim, S.*
AU  - Koo, D.H.*
AU  - Lee, S.*
AU  - Hur, C.G.*
AU  - Clouser, C.*
AU  - Rico, A.*
AU  - Hallab, A.*
AU  - Gebhardt, C.*
AU  - Klee, K.*
AU  - Jöcker, A.*
AU  - Warfsmann, J.*
AU  - Gobel, U.*
AU  - Kawamura, S.*
AU  - Yano, K.*
AU  - Sherman, J.D.*
AU  - Fukuoka, H.*
AU  - Negoro, S.*
AU  - Bhutty, S.*
AU  - Chowdhury, P.*
AU  - Chattopadhyay, D.*
AU  - Datema, E.*
AU  - Smit, S.*
AU  - Schijlen, E.W.M.*
AU  - van de Belt, J.*
AU  - van Haarst, J.C.*
AU  - Peters, S.A.*
AU  - van Staveren, M.J.*
AU  - Henkens, M.H.C.*
AU  - Mooyman, P.J.W.*
AU  - Hesselink, T.*
AU  - van Ham, R.C.H.J.*
AU  - Jiang, G.Y.*
AU  - Droege, M.*
AU  - Choi, D.*
AU  - Kang, B.C.*
AU  - Kim, B.D.*
AU  - Park, M.*
AU  - Yeom, S.I.*
AU  - Lee, Y.H.*
AU  - Choi, Y.D.*
AU  - Li, G.C.*
AU  - Gao, J.W.*
AU  - Liu, Y.S.*
AU  - Huang, S.X.*
AU  - Fernandez-Pedrosa, V.*
AU  - Collado, C.*
AU  - Zuniga, S.*
AU  - Wang, G.P.*
AU  - Cade, R.*
AU  - Dietrich, R.A.*
AU  - Rogers, J.*
AU  - Knapp, S.*
AU  - Fei, Z.J.*
AU  - White, R.A.*
AU  - Thannhauser, T.W.*
AU  - Giovannoni, J.J.*
AU  - Botella, M.A.*
AU  - Gilbert, L.*
AU  - González, R.*
AU  - Goicoechea, J.L.*
AU  - Yu, Y.*
AU  - Kudrna, D.*
AU  - Collura, K.*
AU  - Wissotski, M.*
AU  - Wing, R.*
AU  - Schoof, H.*
AU  - Meyers, B.C.*
AU  - Gurazada, A.B.*
AU  - Green, P.J.*
AU  - Mathur, S.*
AU  - Vyas, S.*
AU  - Solanke, A.U.*
AU  - Kumar, R.*
AU  - Gupta, V.*
AU  - Sharma, A.K.*
AU  - Khurana, P.*
AU  - Khurana, J.P.*
AU  - Tyagi, A.K.*
AU  - Dalmay, T.*
AU  - Mohorianu, I.*
AU  - Walts, B.*
AU  - Chamala, S.*
AU  - Barbazuk, W.B.*
AU  - Li, J.P.*
AU  - Guo, H.*
AU  - Lee, T.H.*
AU  - Wang, Y.P.*
AU  - Zhang, D.*
AU  - Paterson, A.H.*
AU  - Wang, X.Y.*
AU  - Tang, H.B.*
AU  - Barone, A.*
AU  - Chiusano, M.L.*
AU  - Ercolano, M.R.*
AU  - D'Agostino, N.*
AU  - di Filippo, M.*
AU  - Traini, A.*
AU  - Sanseverino, W.*
AU  - Frusciante, L.*
AU  - Seymour, G.B.*
AU  - Elharam, M.*
AU  - Fu, Y.*
AU  - Hua, A.*
AU  - Kenton, S.*
AU  - Lewis, J.*
AU  - Lin, S.P.*
AU  - Najar, F.*
AU  - Lai, H.S.*
AU  - Qin, B.F.*
AU  - Qu, C.M.*
AU  - Shi, R.H.*
AU  - White, D.*
AU  - White, J.*
AU  - Xing, Y.B.*
AU  - Yang, K.Q.*
AU  - Yi, J.*
AU  - Yao, Z.Y.*
AU  - Zhou, L.P.*
AU  - Roe, B.A.*
AU  - Vezzi, A.*
AU  - D'Angelo, M.*
AU  - Zimbello, R.*
AU  - Schiavon, R.*
AU  - Caniato, E.*
AU  - Rigobello, C.*
AU  - Campagna, D.*
AU  - Vitulo, N.*
AU  - Valle, G.*
AU  - Nelson, D.R.*
AU  - de Paoli, E.*
AU  - Szinay, D.*
AU  - de Jong, H.H.*
AU  - Bai, Y.L.*
AU  - Visser, R.G.F.*
AU  - Lankhorst, R.M.K.*
AU  - Beasley, H.*
AU  - McLaren, K.*
AU  - Nicholson, C.*
AU  - Riddle, C.*
AU  - Gianese, G.*
AU  - Tomato Genome Consortium (*)
C1  - 8043
C2  - 29952
SP  - 635-641
TI  - The tomato genome sequence provides insights into fleshy fruit evolution.
JO  - Nature
VL  - 485
IS  - 7400
PB  - Nature Publishing Group
PY  - 2012
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10(-8), which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.
AU  - van der Harst, P.*
AU  - Zhang, W.H.*
AU  - Leach, I.M.*
AU  - Rendon, A.*
AU  - Verweij, N.*
AU  - Sehmi, J.*
AU  - Paul, D.S.*
AU  - Elling, U.*
AU  - Allayee, H.*
AU  - Li, X.Z.*
AU  - Radhakrishnan, A.*
AU  - Tan, S.T.*
AU  - Voss, K.*
AU  - Weichenberger, C.X.*
AU  - Albers, C.A.*
AU  - Al-Hussani, A.*
AU  - Asselbergs, F.W.*
AU  - Ciullo, M.*
AU  - Danjou, F.*
AU  - Dina, C.*
AU  - Esko, T.*
AU  - Evans, D.M*
AU  - Franke, L.*
AU  - Goegele, M.*
AU  - Hartiala, J.*
AU  - Hersch, M.*
AU  - Holm, H.*
AU  - Hottenga, J.J.*
AU  - Kanoni, S.*
AU  - Kleber, M.E.*
AU  - Lagou, V.*
AU  - Langenberg, C.*
AU  - Lopez, L.M.*
AU  - Lyytikäinen, L.-P.*
AU  - Melander, O.*
AU  - Murgia, F.*
AU  - Nolte, I.M.*
AU  - O'Reilly, P.F.*
AU  - Padmanabhan, S.*
AU  - Parsa, A.*
AU  - Pirastu, N.*
AU  - Porcu, E.*
AU  - Portas, L.*
AU  - Prokopenko, I.*
AU  - Ried, J.S.
AU  - Shin, S.Y.*
AU  - Tang, C.S.*
AU  - Teumer, A.*
AU  - Traglia, M.*
AU  - Ulivi, S.*
AU  - Westra, H.J.*
AU  - Yang, J.*
AU  - Zhao, J.H.*
AU  - Anni, F.*
AU  - Abdellaoui, A.*
AU  - Attwood, A.*
AU  - Balkau, B.*
AU  - Bandinelli, S.*
AU  - Bastardot, F.*
AU  - Benyamin, B.*
AU  - Boehm, B.O.*
AU  - Cookson, W.O.*
AU  - Das, D.*
AU  - de Bakker, P.I.W.*
AU  - de Boer, R.A.*
AU  - de Geus, E.J.C.*
AU  - de Moor, M.H.*
AU  - Dimitriou, M.*
AU  - Domingues, F.S.*
AU  - Döring, A.
AU  - Engström, G.*
AU  - Eyjolfsson, G.I.*
AU  - Ferrucci, L.*
AU  - Fischer, K.*
AU  - Galanello, R.*
AU  - Garner, S.F.*
AU  - Genser, B.*
AU  - Gibson, Q.D.*
AU  - Girotto, G.*
AU  - Gudbjartsson, D.F.*
AU  - Harris, S.E.*
AU  - Hartikainen, A.L.*
AU  - Hastie, C.E.*
AU  - Hedblad, B.*
AU  - Illig, T.
AU  - Jolley, J.*
AU  - Kähönen, M.*
AU  - Kema, I.P.*
AU  - Kemp, J.P.*
AU  - Liang, L.M.*
AU  - Lloyd-Jones, H.*
AU  - Loos, R.J.F.*
AU  - Meacham, S.*
AU  - Medland, S.E.*
AU  - Meisinger, C.
AU  - Memari, Y.*
AU  - Mihailov, E.*
AU  - Miller, K.*
AU  - Moffatt, M.F.*
AU  - Nauck, M.*
AU  - Novatchkova, M.*
AU  - Nutile, T.*
AU  - Olafsson, I.*
AU  - Onundarson, P.T.*
AU  - Parracciani, D.*
AU  - Penninx, B.W.*
AU  - Perseu, L.*
AU  - Piga, A.*
AU  - Pistis, G.*
AU  - Pouta, A.*
AU  - Puc, U.*
AU  - Raitakari, O.*
AU  - Ring, S.M.*
AU  - Robino, A.*
AU  - Ruggiero, D.*
AU  - Ruokonen, A.*
AU  - Saint-Pierre, A.*
AU  - Sala, C.*
AU  - Salumets, A.*
AU  - Sambrook, J.*
AU  - Schepers, H.*
AU  - Schmidt, C.O.*
AU  - Sillje, H.H.W.*
AU  - Sladek, R.*
AU  - Smit, J.H.*
AU  - Starr, J.M.*
AU  - Stephens, J.*
AU  - Sulem, P.*
AU  - Tanaka, T.*
AU  - Thorsteinsdottir, U.*
AU  - Tragante, V.*
AU  - van Gilst, W.H.*
AU  - van Pelt, L.J.*
AU  - van Veldhuisen, D.J.*
AU  - Völker, U.*
AU  - Whitfield, J.B.*
AU  - Willemsen, G.*
AU  - Winkelmann, B.R.*
AU  - Wirnsberger, G.*
AU  - Algra, A.*
AU  - Cucca, F.*
AU  - d'Adamo, A.P.*
AU  - Danesh, J.*
AU  - Deary, I.J.*
AU  - Dominiczak, A.F.*
AU  - Elliott, P.*
AU  - Fortina, P.*
AU  - Froguel, P.*
AU  - Gasparini, P.*
AU  - Greinacher, A.*
AU  - Hazen, S.L.*
AU  - Jarvelin, M.R.*
AU  - Khaw, K.T.*
AU  - Lehtimäki, T.*
AU  - Maerz, W.*
AU  - Martin, N.G.*
AU  - Metspalu, A.*
AU  - Mitchell, B.D.*
AU  - Montgomery, G.W.*
AU  - Moore, C.*
AU  - Navis, G.*
AU  - Pirastu, M.*
AU  - Pramstaller, P.P.*
AU  - Ramirez-Solis, R.*
AU  - Schadt, E.*
AU  - Scott, J.*
AU  - Shuldiner, A.R.*
AU  - Smith, G.D.*
AU  - Smith, J.G.*
AU  - Snieder, H.*
AU  - Sorice, R.*
AU  - Spector, T.D.*
AU  - Stefansson, K.*
AU  - Stumvoll, M.*
AU  - Tang, W.H.W.*
AU  - Toniolo, D.*
AU  - Tönjes, A.*
AU  - Visscher, P.M.*
AU  - Vollenweider, P.*
AU  - Wareham, N.J.*
AU  - Wolffenbuttel, B.H.R.*
AU  - Boomsma, D.I.*
AU  - Beckmann, J.S.*
AU  - Dedoussis, G.V.*
AU  - Deloukas, P.*
AU  - Ferreira, M.A.*
AU  - Sanna, S.*
AU  - Uda, M.*
AU  - Hicks, A.A.*
AU  - Penninger, J.M.*
AU  - Gieger, C.
AU  - Kooner, J.S.*
AU  - Ouwehand, W.H.*
AU  - Soranzo, N.*
AU  - Chambers, J.C.*
C1  - 11634
C2  - 30737
SP  - 369-375
TI  - Seventy-five genetic loci influencing the human red blood cell.
JO  - Nature
VL  - 492
IS  - 7429
PB  - Nature Publishing Group
PY  - 2012
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - There is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ∼170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ∼0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.
AU  - Yang, J.*
AU  - Loos, R.J.*
AU  - Powell, J.E.*
AU  - Medland, S.E.*
AU  - Speliotes, E.K.*
AU  - Chasman, D.I.*
AU  - Rose, L.M.*
AU  - Thorleifsson, G.*
AU  - Steinthorsdottir, V.*
AU  - Mägi, R.*
AU  - Waite, L.*
AU  - Smith, A.V.*
AU  - Yerges-Armstrong, L.M.*
AU  - Monda, K.L.*
AU  - Hadley, D.*
AU  - Mahajan, A.*
AU  - Li, G.*
AU  - Kapur, K.*
AU  - Vitart, V.*
AU  - Huffman, J.E.*
AU  - Wang, S.R.*
AU  - Palmer, C.*
AU  - Esko, T.*
AU  - Fischer, K.*
AU  - Zhao, J.H.*
AU  - Demirkan, A.*
AU  - Isaacs, A.*
AU  - Feitosa, M.F.*
AU  - Luan, J.*
AU  - Heard-Costa, N.L.*
AU  - White, C.*
AU  - Jackson, A.U.*
AU  - Preuss, M.*
AU  - Ziegler, A.*
AU  - Eriksson, J.*
AU  - Kutalik, Z.*
AU  - Frau, F.*
AU  - Nolte, I.M.*
AU  - van Vliet-Ostaptchouk, J.V.*
AU  - Hottenga, J.J.*
AU  - Jacobs, K.B.*
AU  - Verweij, N.*
AU  - Goel, A.*
AU  - Medina-Gomez, C.*
AU  - Estrada, K.*
AU  - Bragg-Gresham, J.L.*
AU  - Sanna, S.*
AU  - Sidore, C.*
AU  - Tyrer, J.*
AU  - Teumer, A.*
AU  - Prokopenko, I.*
AU  - Mangino, M.*
AU  - Lindgren, C.M.*
AU  - Assimes, T.L.*
AU  - Shuldiner, A.R.*
AU  - Hui, J.*
AU  - Beilby, J.P.*
AU  - McArdle, W.L.*
AU  - Hall, P.*
AU  - Haritunians, T.*
AU  - Zgaga, L.*
AU  - Kolcic, I.*
AU  - Polasek, O.*
AU  - Zemunik, T.*
AU  - Oostra, B.A.*
AU  - Junttila, M.J.*
AU  - Grönberg, H.*
AU  - Schreiber, S.*
AU  - Peters, A.
AU  - Hicks, A.A.*
AU  - Stephens, J.*
AU  - Foad, N.S.*
AU  - Laitinen, J.*
AU  - Pouta, A.*
AU  - Kaakinen, M.*
AU  - Willemsen, G.*
AU  - Vink, J.M.*
AU  - Wild, S.H.*
AU  - Navis, G.*
AU  - Asselbergs, F.W.*
AU  - Homuth, G.*
AU  - John, U.*
AU  - Iribarren, C.*
AU  - Harris, T.*
AU  - Launer, L.*
AU  - Gudnason, V.*
AU  - O'Connell, J.R.*
AU  - Boerwinkle, E.*
AU  - Cadby, G.*
AU  - Palmer, L.J.*
AU  - James, A.L.*
AU  - Musk, A.W.*
AU  - Ingelsson, E.*
AU  - Psaty, B.M.*
AU  - Beckmann, J.S.*
AU  - Waeber, G.*
AU  - Vollenweider, P.*
AU  - Hayward, C.*
AU  - Wright, A.F.*
AU  - Rudan, I.*
AU  - Groop, L.C.*
AU  - Metspalu, A.*
AU  - Khaw, K.T.*
AU  - van Duijn, C.M.*
AU  - Borecki, I.B.*
AU  - Province, M.A.*
AU  - Wareham, N.J.*
AU  - Tardif, J.-C.*
AU  - Huikuri, H.V.*
AU  - Cupples, L.A.*
AU  - Atwood, L.D.*
AU  - Fox, C.S.*
AU  - Boehnke, M.
AU  - Collins, F.S.*
AU  - Mohlke, K.L.*
AU  - Erdmann, J.*
AU  - Schunkert, H.*
AU  - Hengstenberg, C.*
AU  - Stark, K.*
AU  - Lorentzon, M.*
AU  - Ohlsson, C.*
AU  - Cusi, D.*
AU  - Staessen, J.A.*
AU  - van der Klauw, M.M.*
AU  - Pramstaller, P.P.*
AU  - Kathiresan, S.*
AU  - Jolley, J.D.*
AU  - Ripatti, S.*
AU  - Jarvelin, M.R.*
AU  - de Geus, E.J.*
AU  - Boomsma, D.I.*
AU  - Penninx, B.*
AU  - Wilson, J.F.*
AU  - Campbell, H.*
AU  - Chanock, S.J.*
AU  - van der Harst, P.*
AU  - Hamsten, A.*
AU  - Watkins, H.*
AU  - Hofman, A.*
AU  - Witteman, J.C.*
AU  - Zillikens, M.C.*
AU  - Uitterlinden, A.G.*
AU  - Rivadeneira, F.*
AU  - Kiemeney, L.A.*
AU  - Vermeulen, S.H.*
AU  - Abecasis, G.R.*
AU  - Schlessinger, D.*
AU  - Schipf, S.*
AU  - Stumvoll, M.*
AU  - Tönjes, A.*
AU  - Spector, T.D.*
AU  - North, K.E.*
AU  - Lettre, G.*
AU  - McCarthy, M.I.*
AU  - Berndt, S.I.*
AU  - Heath, A.C.*
AU  - Madden, P.A.*
AU  - Nyholt, D.R.*
AU  - Montgomery, G.W.*
AU  - Martin, N.G.*
AU  - McKnight, B.*
AU  - Strachan, D.P.*
AU  - Hill, W.G.*
AU  - Snieder, H.*
AU  - Ridker, P.M.*
AU  - Thorsteinsdottir, U.*
AU  - Stefansson, K.*
AU  - Frayling, T.M.*
AU  - Hirschhorn, J.N.*
AU  - Goddard, M.E.*
AU  - Visscher, P.M.*
C1  - 11570
C2  - 30693
SP  - 267-272
TI  - FTO genotype is associated with phenotypic variability of body mass index.
JO  - Nature
VL  - 490
IS  - 7419
PB  - Nature Publishing Group
PY  - 2012
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function.
AU  - Gieger, C.
AU  - Radhakrishnan, A.*
AU  - Cvejic, A.*
AU  - Tang, W.*
AU  - Porcu, E.*
AU  - Pistis, G.*
AU  - Serbanovic-Canic, J.*
AU  - Elling, U.*
AU  - Goodall, A.H.*
AU  - Labrune, Y.*
AU  - Lopez, LM.*
AU  - Mägi, R.*
AU  - Meacham, S.*
AU  - Okada, Y.*
AU  - Pirastu, N.*
AU  - Sorice, R.*
AU  - Teumer, A.*
AU  - Voss, K.*
AU  - Zhang, W.*
AU  - Ramirez-Solis, R.*
AU  - Bis, J.C.*
AU  - Ellinghaus, D.*
AU  - Gögele, M.*
AU  - Hottenga, J.J.*
AU  - Langenberg, C.*
AU  - Kovacs, P.*
AU  - O'Reilly, P.F.*
AU  - Shin, S.Y.*
AU  - Esko, T.*
AU  - Hartiala, J.*
AU  - Kanoni, S.*
AU  - Murgia, F.*
AU  - Parsa, A.*
AU  - Stephens, J.*
AU  - van der Harst, P.*
AU  - van der Schoot, C.E.*
AU  - Allayee, H.*
AU  - Attwood, A.*
AU  - Balkau, B.*
AU  - Bastardot, F.*
AU  - Basu, S.*
AU  - Baumeister, S.E.*
AU  - Biino, G.*
AU  - Bomba, L.*
AU  - Bonnefond, A.*
AU  - Cambien, F.*
AU  - Chambers, J.C.*
AU  - Cucca, F.*
AU  - D'Adamo, P.*
AU  - Davies, G.*
AU  - de Boer, R.A.*
AU  - de Geus, E.J.*
AU  - Döring, A.
AU  - Elliott, P.*
AU  - Erdmann, J.*
AU  - Evans, D.M*
AU  - Falchi, M.*
AU  - Feng, W.*
AU  - Folsom, A.R.*
AU  - Frazer, I.H.*
AU  - Gibson, Q.D.*
AU  - Glazer, N.L.*
AU  - Hammond, C.*
AU  - Hartikainen, A.L.*
AU  - Heckbert, S.R.*
AU  - Hengstenberg, C.*
AU  - Hersch, M.*
AU  - Illig, T.
AU  - Loos, R.J.*
AU  - Jolley, J.*
AU  - Tee, Khaw, K.*
AU  - Kühnel, B.*
AU  - Kyrtsonis, M.C.*
AU  - Lagou, V.*
AU  - Lloyd-Jones, H.*
AU  - Lumley, T.*
AU  - Mangino, M.*
AU  - Maschio, A.*
AU  - Mateo, Leach, I.*
AU  - McKnight, B.*
AU  - Memari, Y.*
AU  - Mitchell, B.D.*
AU  - Montgomery, G.W.*
AU  - Nakamura, Y.*
AU  - Nauck, M.*
AU  - Navis, G.*
AU  - Nöthlings, U.*
AU  - Nolte, I.M.*
AU  - Porteous, D.J.*
AU  - Pouta, A.*
AU  - Pramstaller, P.P.*
AU  - Pullat, J.*
AU  - Ring, S.M.*
AU  - Rotter, J.I.*
AU  - Ruggiero, D.*
AU  - Ruokonen, A.*
AU  - Sala, C.*
AU  - Samani, N.J.*
AU  - Sambrook, J.*
AU  - Schlessinger, D.*
AU  - Schreiber, S.*
AU  - Schunkert, H.*
AU  - Scott, J.*
AU  - Smith, N.L.*
AU  - Snieder, H.*
AU  - Starr, J.M.*
AU  - Stumvoll, M.*
AU  - Takahashi, A.*
AU  - Tang, W.H.*
AU  - Taylor, K.*
AU  - Tenesa, A.*
AU  - Lay, Thein, S.*
AU  - Tönjes, A.*
AU  - Uda, M.*
AU  - Ulivi, S.*
AU  - van Veldhuisen, DJ.*
AU  - Visscher, P.M.*
AU  - Völker, U.*
AU  - Wichmann, H.-E.
AU  - Wiggins, K.L.*
AU  - Willemsen, G.*
AU  - Yang, T.P.*
AU  - Hua, Zhao, J.*
AU  - Zitting, P.*
AU  - Bradley, J.R.*
AU  - Dedoussis, G.V.*
AU  - Gasparini, P.*
AU  - Hazen, S.L.*
AU  - Metspalu, A.*
AU  - Pirastu, M.*
AU  - Shuldiner, A.R.*
AU  - van Pelt, L.J.*
AU  - Zwaginga, J.J.*
AU  - Boomsma, D.I.*
AU  - Deary, I.J.*
AU  - Franke, A.*
AU  - Froguel, P.*
AU  - Ganesh, S.K.*
AU  - Jarvelin, M.R.*
AU  - Martin, N.G.*
AU  - Meisinger, C.*
AU  - Psaty, B.M.*
AU  - Spector, T.D.*
AU  - Wareham, N.J.*
AU  - Akkerman, JW.*
AU  - Ciullo, M.*
AU  - Deloukas, P.*
AU  - Greinacher, A.*
AU  - Jupe, S.*
AU  - Kamatani, N.*
AU  - Khadake, J.*
AU  - Kooner, J.S.*
AU  - Penninger, J.*
AU  - Prokopenko, I.*
AU  - Stemple, D.*
AU  - Toniolo, D.*
AU  - Wernisch, L.*
AU  - Sanna, S.*
AU  - Hicks, A.A.*
AU  - Rendon, A.*
AU  - Ferreira, M.A.*
AU  - Ouwehand, W.H.*
AU  - Soranzo, N.*
C1  - 3966
C2  - 29397
SP  - 201-208
TI  - New gene functions in megakaryopoiesis and platelet formation.
JO  - Nature
VL  - 480
IS  - 7376
PB  - Nature Publishing Group
PY  - 2011
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index (BMI) ≤ 18.5 kg per m(2) in adults and ≤ -2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive, feeding and eating disorder and/or anorexia nervosa. In contrast to obesity, few genetic variants underlying these clinical conditions have been reported. We previously showed that hemizygosity of a ∼600-kilobase (kb) region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities. Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers (including 132 novel cases and 108 unrelated carriers) from individuals clinically referred for developmental or intellectual disabilities (DD/ID) or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance.
AU  - Jacquemont, S.*
AU  - Reymond, A.*
AU  - Zufferey, F.*
AU  - Harewood, L.*
AU  - Walters, R.G.*
AU  - Kutalik, Z.*
AU  - Martinet, D.*
AU  - Shen, Y.*
AU  - Valsesia, A.*
AU  - Beckmann, N.D.*
AU  - Thorleifsson, G.*
AU  - Belfiore, M.*
AU  - Bouquillon, S.*
AU  - Campion, D.*
AU  - de Leeuw, N.*
AU  - de Vries, B.B.*
AU  - Esko, T.*
AU  - Fernandez, B.A.*
AU  - Fernández-Aranda, F.*
AU  - Fernández-Real, J.M.*
AU  - Gratacòs, M.*
AU  - Guilmatre, A.*
AU  - Hoyer, J.*
AU  - Jarvelin, M.R.*
AU  - Kooy, R.F.*
AU  - Kurg, A.*
AU  - Le Caignec, C.*
AU  - Männik, K.*
AU  - Platt, O.S.*
AU  - Sanlaville, D.*
AU  - van Haelst, M.M.*
AU  - Villatoro Gomez, S.*
AU  - Walha, F.*
AU  - Wu, B.L.*
AU  - Yu, Y.*
AU  - Aboura, A.*
AU  - Addor, M.C.*
AU  - Alembik, Y.*
AU  - Antonarakis, S.E.*
AU  - Arveiler, B.*
AU  - Barth, M.*
AU  - Bednarek, N.*
AU  - Béna, F.*
AU  - Bergmann, S.*
AU  - Beri, M.*
AU  - Bernardini, L.*
AU  - Blaumeiser, B.*
AU  - Bonneau, D.*
AU  - Bottani, A.*
AU  - Boute, O.*
AU  - Brunner, H.G.*
AU  - Cailley, D.*
AU  - Callier, P.*
AU  - Chiesa, J.*
AU  - Chrast, J.*
AU  - Coin, L.*
AU  - Coutton, C.*
AU  - Cuisset, J.M.*
AU  - Cuvellier, J.C.*
AU  - David, A.*
AU  - de Freminville, B.*
AU  - Delobel, B.*
AU  - Delrue, M.A.*
AU  - Demeer, B.*
AU  - Descamps, D.*
AU  - Didelot, G.*
AU  - Dieterich, K.*
AU  - Disciglio, V.*
AU  - Doco-Fenzy, M.*
AU  - Drunat, S.*
AU  - Duban-Bedu, B.*
AU  - Dubourg, C.*
AU  - El-Sayed Moustafa, J.S.*
AU  - Elliott, P.*
AU  - Faas, B.H.*
AU  - Faivre, L.*
AU  - Faudet, A.*
AU  - Fellmann, F.*
AU  - Ferrarini, A.*
AU  - Fisher, R.*
AU  - Flori, E.*
AU  - Forer, L.*
AU  - Gaillard, D.*
AU  - Gerard, M.*
AU  - Gieger, C.
AU  - Gimelli, S.*
AU  - Gimelli, G.*
AU  - Grabe, H.J.*
AU  - Guichet, A.*
AU  - Guillin, O.*
AU  - Hartikainen, A.L.*
AU  - Heron, D.*
AU  - Hippolyte, L.*
AU  - Holder, M.*
AU  - Homuth, G.*
AU  - Isidor, B.*
AU  - Jaillard, S.*
AU  - Jaros, Z.*
AU  - Jiménez-Murcia, S.*
AU  - Helas, G.J.*
AU  - Jonveaux, P.*
AU  - Kaksonen, S.*
AU  - Keren, B.*
AU  - Kloss-Brandstätter, A.*
AU  - Knoers, N.V.*
AU  - Koolen, D.A.*
AU  - Kroisel, P.M.*
AU  - Kronenberg, F.*
AU  - Labalme, A.*
AU  - Landais, E.*
AU  - Lapi, E.*
AU  - Layet, V.*
AU  - Legallic, S.*
AU  - Leheup, B.*
AU  - Leube, B.*
AU  - Lewis, S.*
AU  - Lucas, J.*
AU  - MacDermot, K.D.*
AU  - Magnusson, P.*
AU  - Marshall, C.*
AU  - Mathieu-Dramard, M.*
AU  - McCarthy, M.I.*
AU  - Meitinger, T.
AU  - Mencarelli, M.A.*
AU  - Merla, G.*
AU  - Moerman, A.*
AU  - Mooser, V.*
AU  - Morice-Picard, F.*
AU  - Mucciolo, M.*
AU  - Nauck, M.*
AU  - Ndiaye, N.C.*
AU  - Nordgren, A.*
AU  - Pasquier, L.*
AU  - Petit, F.*
AU  - Pfundt, R.*
AU  - Plessis, G.*
AU  - Rajcan-Separovic, E.*
AU  - Ramelli, G.P.*
AU  - Rauch, A.*
AU  - Ravazzolo, R.*
AU  - Reis, A.*
AU  - Renieri, A.*
AU  - Richart, C.*
AU  - Ried, J.S.
AU  - Rieubland, C.*
AU  - Roberts, W.*
AU  - Roetzer, K.M.*
AU  - Rooryck, C.*
AU  - Rossi, M.*
AU  - Saemundsen, E.*
AU  - Satre, V.*
AU  - Schurmann, C.*
AU  - Sigurdsson, E.*
AU  - Stavropoulos, D.J.*
AU  - Stefansson, H.*
AU  - Tengström, C.*
AU  - Thorsteinsdottir, U.*
AU  - Tinahones, F.J.*
AU  - Touraine, R.*
AU  - Vallée, L.*
AU  - van Binsbergen, E.*
AU  - van der Aa, N.*
AU  - Vincent-Delorme, C.*
AU  - Visvikis-Siest, S.*
AU  - Vollenweider, P.*
AU  - Völzke, H.*
AU  - Vulto-van Silfhout, A.T.*
AU  - Waeber, G.*
AU  - Wallgren-Pettersson, C.*
AU  - Witwicki, R.M.*
AU  - Zwolinksi, S.*
AU  - Andrieux, J.*
AU  - Estivill, X.*
AU  - Gusella, J.F.*
AU  - Gustafsson, O.*
AU  - Metspalu, A.*
AU  - Scherer, S.W.*
AU  - Stefansson, K.*
AU  - Blakemore, A.I.*
AU  - Beckmann, J.S.*
AU  - Froguel, P.*
C1  - 6264
C2  - 29108
SP  - 97-102
TI  - Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus.
JO  - Nature
VL  - 478
IS  - 7367
PB  - Nature Publishing Group
PY  - 2011
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Upon the aberrant activation of oncogenes, normal cells can enter the cellular senescence program, a state of stable cell-cycle arrest, which represents an important barrier against tumour development in vivo. Senescent cells communicate with their environment by secreting various cytokines and growth factors, and it was reported that this 'secretory phenotype' can have pro- as well as anti-tumorigenic effects. Here we show that oncogene-induced senescence occurs in otherwise normal murine hepatocytes in vivo. Pre-malignant senescent hepatocytes secrete chemo- and cytokines and are subject to immune-mediated clearance (designated as 'senescence surveillance'), which depends on an intact CD4(+) T-cell-mediated adaptive immune response. Impaired immune surveillance of pre-malignant senescent hepatocytes results in the development of murine hepatocellular carcinomas (HCCs), thus showing that senescence surveillance is important for tumour suppression in vivo. In accordance with these observations, ras-specific Th1 lymphocytes could be detected in mice, in which oncogene-induced senescence had been triggered by hepatic expression of Nras(G12V). We also found that CD4(+) T cells require monocytes/macrophages to execute the clearance of senescent hepatocytes. Our study indicates that senescence surveillance represents an important extrinsic component of the senescence anti-tumour barrier, and illustrates how the cellular senescence program is involved in tumour immune surveillance by mounting specific immune responses against antigens expressed in pre-malignant senescent cells.
AU  - Kang, T.W.*
AU  - Yevsa, T.*
AU  - Woller, N.*
AU  - Hoenicke, L.*
AU  - Wuestefeld, T.*
AU  - Dauch, D.*
AU  - Hohmeyer, A.*
AU  - Gereke, M.*
AU  - Rudalska, R.*
AU  - Potapova, A.*
AU  - Iken, M.*
AU  - Vucur, M.*
AU  - Weiss, S.*
AU  - Heikenwälder, M.
AU  - Khan, S.*
AU  - Gil, J.*
AU  - Bruder, D.*
AU  - Manns, M.*
AU  - Schirmacher, P.*
AU  - Tacke, F.*
AU  - Ott, M.*
AU  - Luedde, T.*
AU  - Longerich, T.*
AU  - Kubicka, S.*
AU  - Zender, L.*
C1  - 6816
C2  - 29311
SP  - 547-551
TI  - Senescence surveillance of pre-malignant hepatocytes limits liver cancer development.
JO  - Nature
VL  - 479
IS  - 7374
PB  - Nature Publishing Group
PY  - 2011
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
AU  - International Multiple Sclerosis Genetics Consortium (Klopp, N.
AU  - Rückert, I.-M.
AU  - Wichmann, H.-E.
AU  - Winkelmann, J.)
AU  - Wellcome Trust Case Control Consortium 2 (WTCCC2) (*)
C1  - 6493
C2  - 28797
SP  - 214-219
TI  - Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.
JO  - Nature
VL  - 476
IS  - 7359
PB  - Nature Publ. Group
PY  - 2011
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Many cellular functions involve multi-domain proteins, which are composed of structurally independent modules connected by flexible linkers. Although it is often well understood how a given domain recognizes a cognate oligonucleotide or peptide motif, the dynamic interaction of multiple domains in the recognition of these ligands remains to be characterized. Here we have studied the molecular mechanisms of the recognition of the 3'-splice-site-associated polypyrimidine tract RNA by the large subunit of the human U2 snRNP auxiliary factor (U2AF65) as a key early step in pre-mRNA splicing. We show that the tandem RNA recognition motif domains of U2AF65 adopt two remarkably distinct domain arrangements in the absence or presence of a strong (that is, high affinity) polypyrimidine tract. Recognition of sequence variations in the polypyrimidine tract RNA involves a population shift between these closed and open conformations. The equilibrium between the two conformations functions as a molecular rheostat that quantitatively correlates the natural variations in polypyrimidine tract nucleotide composition, length and functional strength to the efficiency to recruit U2 snRNP to the intron during spliceosome assembly. Mutations that shift the conformational equilibrium without directly affecting RNA binding modulate splicing activity accordingly. Similar mechanisms of cooperative multi-domain conformational selection may operate more generally in the recognition of degenerate nucleotide or amino acid motifs by multi-domain proteins.
AU  - Mackereth, C.D.
AU  - Madl, T.
AU  - Bonnal, S.*
AU  - Simon, B.*
AU  - Zanier, K.*
AU  - Gasch, A.*
AU  - Rybin, V.*
AU  - Valcárcel, J.*
AU  - Sattler, M.
C1  - 6267
C2  - 29111
SP  - 408-411
TI  - Multi-domain conformational selection underlies pre-mRNA splicing regulation by U2AF.
JO  - Nature
VL  - 475
IS  - 7356
PB  - Nature Publishing Group
PY  - 2011
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.
AU  - ICBP Consortium (Meitinger, T.
AU  - Wichmann, H.-E.
AU  - Gieger, C.)
C1  - 6266
C2  - 29110
SP  - 103-109
TI  - Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.
JO  - Nature
VL  - 478
IS  - 7367
PB  - Nature Publishing Group
PY  - 2011
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Genome-wide association studies (GWAS) have identified many risk loci for complex diseases, but effect sizes are typically small and information on the underlying biological processes is often lacking. Associations with metabolic traits as functional intermediates can overcome these problems and potentially inform individualized therapy. Here we report a comprehensive analysis of genotype-dependent metabolic phenotypes using a GWAS with non-targeted metabolomics. We identified 37 genetic loci associated with blood metabolite concentrations, of which 25 show effect sizes that are unusually high for GWAS and account for 10-60% differences in metabolite levels per allele copy. Our associations provide new functional insights for many disease-related associations that have been reported in previous studies, including those for cardiovascular and kidney disorders, type 2 diabetes, cancer, gout, venous thromboembolism and Crohn's disease. The study advances our knowledge of the genetic basis of metabolic individuality in humans and generates many new hypotheses for biomedical and pharmaceutical research.
AU  - Suhre, K.
AU  - Shin, S.Y.*
AU  - Petersen, A.-K.
AU  - Mohney, R.P.*
AU  - Meredith, D.*
AU  - Wägele, B.
AU  - Altmaier, E.
AU  - CARDIoGRAM Consortium (Lichtner, P.
AU  - Eckstein, G.N.
AU  - Fischer, G.
AU  - Strom, T.M.
AU  - Peters, A.
AU  - Holle, R.
AU  - John, J.)
AU  - Deloukas, P.*
AU  - Erdmann, J.*
AU  - Grundberg, E.*
AU  - Hammond, C.J.*
AU  - Hrabě de Angelis, M.
AU  - Kastenmüller, G.
AU  - Köttgen, A.*
AU  - Kronenberg, F.*
AU  - Mangino, M.*
AU  - Meisinger, C.
AU  - Meitinger, T.
AU  - Mewes, H.-W.
AU  - Milburn, M.V.*
AU  - Prehn, C.
AU  - Raffler, J.
AU  - Ried, J.S.
AU  - Römisch-Margl, W.
AU  - Samani, N.J.*
AU  - Small, K.S.*
AU  - Wichmann, H.-E.
AU  - Zhai, G.*
AU  - Illig, T.
AU  - Spector, T.D.*
AU  - Adamski, J.
AU  - Soranzo, N.*
AU  - Gieger, C.
C1  - 6516
C2  - 28841
SP  - 54-60
TI  - Human metabolic individuality in biomedical and pharmaceutical research.
JO  - Nature
VL  - 477
IS  - 7362
PB  - Nature Publ. Group
PY  - 2011
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Legumes (Fabaceae or Leguminosae) are unique among cultivated plants for their ability to carry out endosymbiotic nitrogen fixation with rhizobial bacteria, a process that takes place in a specialized structure known as the nodule. Legumes belong to one of the two main groups of eurosids, the Fabidae, which includes most species capable of endosymbiotic nitrogen fixation. Legumes comprise several evolutionary lineages derived from a common ancestor 60 million years ago (Myr ago). Papilionoids are the largest clade, dating nearly to the origin of legumes and containing most cultivated species. Medicago truncatula is a long-established model for the study of legume biology. Here we describe the draft sequence of the M. truncatula euchromatin based on a recently completed BAC assembly supplemented with Illumina shotgun sequence, together capturing ∼94% of all M. truncatula genes. A whole-genome duplication (WGD) approximately 58 Myr ago had a major role in shaping the M. truncatula genome and thereby contributed to the evolution of endosymbiotic nitrogen fixation. Subsequent to the WGD, the M. truncatula genome experienced higher levels of rearrangement than two other sequenced legumes, Glycine max and Lotus japonicus. M. truncatula is a close relative of alfalfa (Medicago sativa), a widely cultivated crop with limited genomics tools and complex autotetraploid genetics. As such, the M. truncatula genome sequence provides significant opportunities to expand alfalfa's genomic toolbox.
AU  - Young, N.D.*
AU  - Debellé, F.*
AU  - Oldroyd, G.E.*
AU  - Geurts, R.*
AU  - Cannon, S.B.*
AU  - Udvardi, M.K.*
AU  - Benedito, V.A.*
AU  - Mayer, K.F.X.
AU  - Gouzy, J.*
AU  - Schoof, H.*
AU  - van de Peer, Y.*
AU  - Proost, S.*
AU  - Cook, D.R.*
AU  - Meyers, B.C.*
AU  - Spannagl, M.*
AU  - Cheung, F.*
AU  - de Mita, S.*
AU  - Krishnakumar, V.*
AU  - Gundlach, H.
AU  - Zhou, S.*
AU  - Mudge, J.*
AU  - Bharti, A.K.*
AU  - Murray, J.D.*
AU  - Naoumkina, M.A.*
AU  - Rosen, B.*
AU  - Silverstein, K.A.*
AU  - Tang, H.*
AU  - Rombauts, S.*
AU  - Zhao, P.X.*
AU  - Zhou, P.*
AU  - Barbe, V.*
AU  - Bardou, P.*
AU  - Bechner, M.*
AU  - Bellec, A.*
AU  - Berger, A.*
AU  - Bergès, H.*
AU  - Bidwell, S.*
AU  - Bisseling, T.*
AU  - Choisne, N.*
AU  - Couloux, A.*
AU  - Denny, R.*
AU  - Deshpande, S.*
AU  - Dai, X.*
AU  - Doyle, J.J.*
AU  - Dudez, A.M.*
AU  - Farmer, A.D.*
AU  - Fouteau, S.*
AU  - Franken, C.*
AU  - Gibelin, C.*
AU  - Gish, J.*
AU  - Goldstein, S.*
AU  - González, A.J.*
AU  - Green, P.J.*
AU  - Hallab, A.*
AU  - Hartog, M.*
AU  - Hua, A.*
AU  - Humphray, S.J.*
AU  - Jeong, D.H.*
AU  - Jing, Y.*
AU  - Jöcker, A.*
AU  - Kenton, S.M.*
AU  - Kim, D.J.*
AU  - Klee, K.*
AU  - Lai, H.*
AU  - Lang, C.*
AU  - Lin, S.*
AU  - Macmil, S.L.*
AU  - Magdelenat, G.*
AU  - Matthews, L.*
AU  - McCorrison, J.*
AU  - Monaghan, E.L.*
AU  - Mun, J.-H.*
AU  - Najar, F.Z.*
AU  - Nicholson, C.*
AU  - Noirot, C.*
AU  - O'Bleness, M.*
AU  - Paule, C.R.*
AU  - Poulain, J.*
AU  - Prion, F.*
AU  - Qin, B.*
AU  - Qu, C.*
AU  - Retzel, E.F.*
AU  - Riddle, C.*
AU  - Sallet, E.*
AU  - Samain, S.*
AU  - Samson, N.*
AU  - Sanders, I.*
AU  - Saurat, O.*
AU  - Scarpelli, C.*
AU  - Schiex, T.*
AU  - Segurens, B.*
AU  - Severin, A.J.*
AU  - Sherrier, D.J.*
AU  - Shi, R.*
AU  - Sims, S.*
AU  - Singer, S.R.*
AU  - Sinharoy, S.*
AU  - Sterck, L.*
AU  - Viollet, A.*
AU  - Wang, B.B.*
AU  - Wang, K.*
AU  - Wang, M.*
AU  - Wang, X.*
AU  - Warfsmann, J.*
AU  - Weissenbach, J.*
AU  - White, D.D.*
AU  - White, J.D.*
AU  - Wiley, G.B.*
AU  - Wincker, P.*
AU  - Xing, Y.*
AU  - Yang, L.*
AU  - Yao, Z.*
AU  - Ying, F.*
AU  - Zhai, J.*
AU  - Zhou, L.*
AU  - Zuber, A.*
AU  - Dénarié, J.*
AU  - Dixon, R.A.*
AU  - May, G.D.*
AU  - Schwartz, D.C.*
AU  - Rogers, J.*
AU  - Quétier, F.*
AU  - Town, C.D.*
AU  - Roe, B.A.*
C1  - 6263
C2  - 29107
SP  - 520-524
TI  - The Medicago genome provides insight into the evolution of rhizobial symbioses.
JO  - Nature
VL  - 480
IS  - 7378
PB  - Nature Publishing Group
PY  - 2011
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
AU  - Allen, H.L.*
AU  - Estrada, K.*
AU  - Lettre, G.*
AU  - Berndt, S.I.*
AU  - Weedon, M.N.*
AU  - Rivadeneira, F.*
AU  - Willer, C.J.*
AU  - Jackson, A.U.*
AU  - Vedantam, S.*
AU  - Raychaudhuri, S.*
AU  - Ferreira, T.*
AU  - Wood, A.R.*
AU  - Weyant, R.J.*
AU  - Segrè, A.V.*
AU  - Speliotes, E.K.*
AU  - Wheeler, E.*
AU  - Soranzo, N.*
AU  - Park, J.H.*
AU  - Yang, J.*
AU  - Gudbjartsson, D.*
AU  - Heard-Costa, N.L.*
AU  - Randall, J.C.*
AU  - Qi, L.*
AU  - Smith, A.V.*
AU  - Mägi, R.*
AU  - Pastinen, T.*
AU  - Liang, L.*
AU  - Heid, I.M.
AU  - Luan, J.*
AU  - Thorleifsson, G.*
AU  - Winkler, T.W.*
AU  - Goddard, M.E.*
AU  - Lo, K.S.*
AU  - Palmer, C.*
AU  - Workalemahu, T.*
AU  - Aulchenko, Y.S.*
AU  - Johansson, A.*
AU  - Zillikens, M.C.*
AU  - Feitosa, M.F.*
AU  - Esko, T.*
AU  - Johnson, T.*
AU  - Ketkar, S.*
AU  - Kraft, P.*
AU  - Mangino, M.*
AU  - Prokopenko, I.*
AU  - Absher, D.*
AU  - Albrecht, E.
AU  - Ernst, F.*
AU  - Glazer, N.L.*
AU  - Hayward, C.*
AU  - Hottenga, J.J.*
AU  - Jacobs, K.B.*
AU  - Knowles, J.W.*
AU  - Kutalik, Z.*
AU  - Monda, K.L.*
AU  - Polasek, O.*
AU  - Preuss, M.*
AU  - Rayner, N.W.*
AU  - Robertson, N.R.*
AU  - Steinthorsdottir, V.*
AU  - Tyrer, J.P.*
AU  - Voight, B.F.*
AU  - Wiklund, F.*
AU  - Xu, J.F.*
AU  - Zhao, J.H.*
AU  - Nyholt, D.R.*
AU  - Pellikka, N.*
AU  - Perola, M.*
AU  - Perry, J.R.B.*
AU  - Surakka, I.*
AU  - Tammesoo, M.L.*
AU  - Altmaier, E.L.*
AU  - Amin, N.*
AU  - Aspelund, T.*
AU  - Bhangale, T.*
AU  - Boucher, G.*
AU  - Chasman, D.I.*
AU  - Chen, C.*
AU  - Coin, L.*
AU  - Cooper, M.N.*
AU  - Dixon, A.L.
AU  - Gibson, Q.*
AU  - Grundberg, E.*
AU  - Hao, K.*
AU  - Junttila, M.J.*
AU  - Kaplan, L.M.*
AU  - Kettunen, J.*
AU  - König, I.R.*
AU  - Kwan, T.*
AU  - Lawrence, R.W.*
AU  - Levinson, D.F.*
AU  - Lorentzon, M.
AU  - McKnight, B.*
AU  - Morris, A.P.*
AU  - Müller, M.
AU  - Ngwa, J.S.*
AU  - Purcell, S.*
AU  - Rafelt, S.*
AU  - Salem, R.M.*
AU  - Salvi, E.*
AU  - Sanna, S.*
AU  - Shi, J.X.*
AU  - Sovio, U.*
AU  - Thompson, J.R.*
AU  - Turchin, M.C.*
AU  - Vandenput, L.*
AU  - Verlaan, D.J.*
AU  - Vitart, V.*
AU  - White, C.C.*
AU  - Ziegler, A.*
AU  - Almgren, P.*
AU  - Balmforth, A.J.*
AU  - Campbell, H.*
AU  - Citterio, L.*
AU  - de Grandi, A.*
AU  - Dominiczak, A.*
AU  - Duan, J.*
AU  - Elliott, P.*
AU  - Elosua, R.*
AU  - Eriksson, J.G.*
AU  - Freimer, N.B.*
AU  - Geus, E.J.C.*
AU  - Glorioso, N.*
AU  - Haiqing, S.*
AU  - Hartikainen, A.L.*
AU  - Havulinna, A.S.*
AU  - Hicks, A.A.*
AU  - Hui, J.N.*
AU  - Igl, W.*
AU  - Illig, T.
AU  - Jula, A.*
AU  - Kajantie, E.*
AU  - Kilpeläeinen, T.O.*
AU  - Koiranen, M.*
AU  - Kolcic, I.*
AU  - Koskinen, S.*
AU  - Kovacs, P.*
AU  - Laitinen, J.*
AU  - Liu, J.J.*
AU  - Lokki, M.L.*
AU  - Marusic, A.*
AU  - Maschio, A.*
AU  - Meitinger, T.
AU  - Mulas, A.*
AU  - Paré, G.*
AU  - Parker, A.N.*
AU  - Peden, J.F.*
AU  - Petersmann, A.*
AU  - Pichler, I.*
AU  - Pietiläinen, K.H.*
AU  - Pouta, A.*
AU  - Riddertrale, M.*
AU  - Rotter, J.I.*
AU  - Sambrook, J.G.*
AU  - Sanders, A.R.*
AU  - Schmidt, C.O.*
AU  - Sinisalo, J.*
AU  - Smit, J.H.*
AU  - Stringham, H.M.*
AU  - Walters, G.B.*
AU  - Widen, E.*
AU  - Wild, S.H.*
AU  - Willemsen, G.*
AU  - Zagato, L.*
AU  - Zgaga, L.*
AU  - Zitting, P.*
AU  - Alavere, H.*
AU  - Farrall, M.*
AU  - McArdle, W.L.*
AU  - Nelis, M.*
AU  - Peters, M.J.*
AU  - Ripatti, S.*
AU  - Meurs, J.B.J.*
AU  - Aben, K.K.*
AU  - Ardlie, K.G.*
AU  - Beckmann, J.S.*
AU  - Beilby, J.P.*
AU  - Bergman, R.N.*
AU  - Bergmann, S.*
AU  - Collins, F.S.*
AU  - Cusi, D.*
AU  - den Heijer, M.*
AU  - Eiriksdottir, G.*
AU  - Gejman, P.V.*
AU  - Hall, A.S.*
AU  - Hamsten, A.*
AU  - Huikuri, H.V.*
AU  - Iribarren, C.*
AU  - Kähönen, M.*
AU  - Kaprio, J.*
AU  - Kathiresan, S.*
AU  - Kiemeney, L.*
AU  - Kocher, T.*
AU  - Launer, L.J.*
AU  - Lehtimäki, T.*
AU  - Melander, O.*
AU  - Mosley, T.H.*
AU  - Musk, A.W.*
AU  - Nieminen, M.S.*
AU  - O'Donnell, C.J.*
AU  - Ohlsson, C.*
AU  - Oostra, B.*
AU  - Palmer, L.J.*
AU  - Raitakari, O.*
AU  - Ridker, P.M.*
AU  - Rioux, J.D.*
AU  - Rissanen, A.*
AU  - Rivolta, C.*
AU  - Schunkert, H.*
AU  - Shuldiner, A.R.*
AU  - Siscovick, D.S.*
AU  - Stumvoll, M.*
AU  - Tönjes, A.*
AU  - Tuomilehto, J.*
AU  - van Ommen, G.J.*
AU  - Viikari, J.*
AU  - Heath, A.C.*
AU  - Martin, N.G.*
AU  - Montgomery, G.W.*
AU  - Province, M.A.*
AU  - Kayser, M.*
AU  - Arnold, A.M.*
AU  - Atwood, L.D.*
AU  - Boerwinkle, E.*
AU  - Chanock, S.J.*
AU  - Deloukas, P.*
AU  - Gieger, C.
AU  - Grönberg, H.*
AU  - Hall, P.*
AU  - Hattersley, A.T.*
AU  - Hengstenberg, C.*
AU  - Hoffman, W.*
AU  - Lathrop, G.M.*
AU  - Salomaa, V.*
AU  - Schreiber, S.*
AU  - Uda, M.*
AU  - Waterworth, D.*
AU  - Wright, A.F.*
AU  - Assimes, T.L.*
AU  - Barroso, I.*
AU  - Hofman, A.*
AU  - Mohlke, K.L.*
AU  - Boomsma, D.I.*
AU  - Caulfield, M.J.*
AU  - Cupples, L.A.*
AU  - Erdmann, J.*
AU  - Fox, C.S.*
AU  - Gudnason, V.*
AU  - Gyllensten, U.*
AU  - Harris, T.B.*
AU  - Hayes, R.B.*
AU  - Jarvelin, M.R.*
AU  - Mooser, V.*
AU  - Munroe, P.B.*
AU  - Ouwehand, W.H.*
AU  - Penninx, B.W.*
AU  - Pramstaller, P.P.*
AU  - Quertermous, T.*
AU  - Rudan, I.*
AU  - Samani, N.J.*
AU  - Spector, T.D.*
AU  - Völzke, H.*
AU  - Watkins, H.*
AU  - Wilson, J.F.*
AU  - Groop, L.C.*
AU  - Haritunians, T.*
AU  - Hu, F.B.*
AU  - Kaplan, R.C.*
AU  - Metspalu, A.*
AU  - North, K.E.*
AU  - Schlessinger, D.*
AU  - Wareham, N.J.*
AU  - Hunter, D.J.*
AU  - O'Connell, J.R.*
AU  - Strachan, D.P.*
AU  - Schadt, H.E.*
AU  - Thorsteinsdottir, U.*
AU  - Peltonen, L.*
AU  - Uitterlinden, A.G.*
AU  - Visscher, P.M.*
AU  - Chatterjee, N.*
AU  - Loos, R.J.F.*
AU  - Boehnke, M.*
AU  - McCarthy, M.I.*
AU  - Ingelsson, E.*
AU  - Lindgren, C.M.*
AU  - Abecasis, G.R.*
AU  - Stefansson, K.*
AU  - Frayling, T.M.*
AU  - Hirschhorn, J.N.*
C1  - 5989
C2  - 27757
SP  - 832-838
TI  - Hundreds of variants clustered in genomic loci and biological pathways affect human height.
JO  - Nature
VL  - 467
IS  - 7317
PB  - Nature Publ. Group
PY  - 2010
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Neurons of the peripheral nervous system have long been known to require survival factors to prevent their death during development. But why they selectively become dependent on secretory molecules has remained a mystery, as is the observation that in the central nervous system, most neurons do not show this dependency. Using engineered embryonic stem cells, we show here that the neurotrophin receptors TrkA and TrkC (tropomyosin receptor kinase A and C, also known as Ntrk1 and Ntrk3, respectively) instruct developing neurons to die, both in vitro and in vivo. By contrast, TrkB (also known as Ntrk2), a closely related receptor primarily expressed in the central nervous system, does not. These results indicate that TrkA and TrkC behave as dependence receptors, explaining why developing sympathetic and sensory neurons become trophic-factor-dependent for survival. We suggest that the expansion of the Trk gene family that accompanied the segregation of the peripheral from the central nervous system generated a novel mechanism of cell number control.
AU  - Nikoletopoulou, V.*
AU  - Lickert, H.
AU  - Frade, J.M.*
AU  - Rencurel, C.*
AU  - Giallonardo, P.
AU  - Zhang, L.X.*
AU  - Bibel, M.*
AU  - Barde, Y.A.*
C1  - 2251
C2  - 27708
SP  - 59-63
TI  - Neurotrophin receptors TrkA and TrkC cause neuronal death whereas TrkB does not.
JO  - Nature
VL  - 467
IS  - 7311
PB  - Nature Publ. Group
PY  - 2010
SN  - 0028-0836
ER  - 

TY  - JOUR
AU  - Schofield, P.N.*
AU  - Tapio, S.
AU  - Grosche, B.*
C1  - 6100
C2  - 28083
SP  - 634
TI  - Comment 'Archiving lessons from radiobiology'.
JO  - Nature
VL  - 468
IS  - 7324
PB  - Nature Publ. Group
PY  - 2010
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
AU  - Teslovich, T.M.*
AU  - Musunuru, K.*
AU  - Smith, A.V.*
AU  - Edmondson, A.C.*
AU  - Stylianou, I.M.*
AU  - Koseki, M.*
AU  - Pirruccello, J.P.*
AU  - Ripatti, S.*
AU  - Chasman, D.I.*
AU  - Willer, C.J.*
AU  - Johansen, C.T.*
AU  - Fouchier, S.W.*
AU  - Isaacs, A.*
AU  - Peloso, G.M.*
AU  - Barbalic, M.*
AU  - Ricketts, S.L.*
AU  - Bis, J.C.*
AU  - Aulchenko, Y.S.*
AU  - Thorleifsson, G.*
AU  - Feitosa, M.F.*
AU  - Chambers, J.*
AU  - Orho-Melander, M.*
AU  - Melander, O.*
AU  - Johnson, T.*
AU  - Li, X.H.*
AU  - Guo, X.Q.*
AU  - Li, M.Y*
AU  - Cho, Y.S.*
AU  - Go, M.J.*
AU  - Kim, Y.J.*
AU  - Lee, J.Y.*
AU  - Park, T.*
AU  - Kim, K.*
AU  - Sim, X.*
AU  - Ong, R.T.H.*
AU  - Croteau-Chonka, D.C.*
AU  - Lange, L.A.*
AU  - Smith, J.D.*
AU  - Song, K.*
AU  - Zhao, J.H.*
AU  - Yuan, X.*
AU  - Luan, J.A.*
AU  - Lamina, C.*
AU  - Ziegler, A.*
AU  - Zhang, W.*
AU  - Zee, R.Y.L.*
AU  - Wright, A.F.*
AU  - Witteman, J.C.M.*
AU  - Wilson, J.F.*
AU  - Willemsen, G.*
AU  - Wichmann, H.-E.
AU  - Whitfield, J.B.*
AU  - Waterworth, D.M.*
AU  - Wareham, N.J.*
AU  - Waeber, G.*
AU  - Vollenweider, P.*
AU  - Voight, B.F.*
AU  - Vitart, V.*
AU  - Uitterlinden, A.G.*
AU  - Uda, M.*
AU  - Tuomilehto, J.*
AU  - Thompson, J.R.*
AU  - Tanaka, T.*
AU  - Surakka, I.*
AU  - Stringham, H.M.*
AU  - Spector, T.D.*
AU  - Soranzo, N.*
AU  - Smit, J.H.*
AU  - Sinisalo, J.*
AU  - Silander, K.*
AU  - Sijbrands, E.J.G.*
AU  - Scuteri, A.*
AU  - Scott, J.*
AU  - Schlessinger, D.*
AU  - Sanna, S.*
AU  - Salomaa, V.*
AU  - Saharinen, J.*
AU  - Sabatti, C.*
AU  - Ruokonen, A.*
AU  - Rudan, I.*
AU  - Rose, L.M.*
AU  - Roberts, R.*
AU  - Rieder, M.*
AU  - Psaty, B.M.*
AU  - Pramstaller, P.P.*
AU  - Pichler, I.*
AU  - Perola, M.*
AU  - Penninx, B.W.J.H.*
AU  - Pedersen, N.L.*
AU  - Pattaro, C.*
AU  - Parker, A.N.*
AU  - Paré, G.*
AU  - Oostra, B.A.*
AU  - O'Donnell, C.J.*
AU  - Nieminen, M.S.*
AU  - Nickerson, D.A.*
AU  - Montgomery, G.W.*
AU  - Meitinger, T.*
AU  - McPherson, R.*
AU  - McCarthy, M.I.*
AU  - McArdle, W.*
AU  - Masson, D.*
AU  - Martin, N.G.*
AU  - Marroni, F.*
AU  - Mangino, M.*
AU  - Magnusson, P.K.E.*
AU  - Lucas, G.*
AU  - Luben, R.*
AU  - Loos, R.J.F.*
AU  - Lokki, M.L.*
AU  - Lettre, G.*
AU  - Langenberg, C.*
AU  - Launer, L.J.*
AU  - Lakatta, E.G.*
AU  - Laaksonen, R.*
AU  - Kyvik, K.O.*
AU  - Kronenberg, F.*
AU  - König, I.R.*
AU  - Khaw, K.T.*
AU  - Kaprio, J.*
AU  - Kaplan, L.M.*
AU  - Johansson, A.*
AU  - Jarvelin, M.R.*
AU  - Janssens, A.C.J.W.*
AU  - Ingelsson, E.*
AU  - Igi, W.*
AU  - Hovingh, G.K.*
AU  - Hottenga, J.J.*
AU  - Hofman, A.*
AU  - Hicks, A.A.*
AU  - Hengstenberg, C.*
AU  - Heid, I.M.
AU  - Hayward, C.*
AU  - Havulinna, A.S.*
AU  - Hastie, N.D.*
AU  - Harris, T.B.*
AU  - Haritunians, T.*
AU  - Hall, A.S.*
AU  - Gyllensten, U.*
AU  - Guiducci, C.*
AU  - Groop, L.C.*
AU  - Gonzalez, E.*
AU  - Gieger, C.
AU  - Freimer, N.B.*
AU  - Ferrucci, L.*
AU  - Erdmann, J.*
AU  - Elliott, P.*
AU  - Ejebe, K.G.*
AU  - Döring, A.
AU  - Dominiczak, A.F.*
AU  - Demissie, S.*
AU  - Deloukas, P.*
AU  - de Geus, E.J.C.*
AU  - de Faire, U.*
AU  - Crawford, G.*
AU  - Collins, F.S.*
AU  - Chen, Y.D.I.*
AU  - Caulfield, M.J.*
AU  - Campbell, H.*
AU  - Burtt, N.P.*
AU  - Bonnycastle, L.L.*
AU  - Boomsma, D.I.*
AU  - Boekholdt, S.M.*
AU  - Bergman, R.N.*
AU  - Barroso, I.*
AU  - Bandinelli, S.*
AU  - Ballantyne, C.M.*
AU  - Assimes, T.L.*
AU  - Quertermous, T.*
AU  - Altshuler, D.*
AU  - Seielstad, M.*
AU  - Wong, T.Y.*
AU  - Tai, E.S.*
AU  - Feranil, A.B.*
AU  - Kuzawa, C.W.*
AU  - Adair, L.S.*
AU  - Taylor, H.A.*
AU  - Borecki, I.B.*
AU  - Gabriel, S.B.*
AU  - Wilson, J.G.*
AU  - Holm, H.*
AU  - Thorsteinsdottir, U.*
AU  - Gudnason, V.*
AU  - Krauss, R.M.*
AU  - Mohlke, K.L.*
AU  - Ordovas, J.M.*
AU  - Munroe, P.B.*
AU  - Kooner, J.S.*
AU  - Tall, A.R.*
AU  - Hegele, R.A.*
AU  - Kastelein, J.J.P.*
AU  - Schadt, E.E.*
AU  - Rotter, J.I.*
AU  - Boerwinkle, E.*
AU  - Strachan, D.P.*
AU  - Mooser, V.*
AU  - Stefansson, K.*
AU  - Reilly, M.P.*
AU  - Samani, N.J.*
AU  - Schunkert, H.*
AU  - Cupples, L.A.*
AU  - Sandhu, M.S.*
AU  - Ridker, P.M.*
AU  - Rader, D.J.*
AU  - van Duijn, C.M.*
AU  - Peltonen, L.*
AU  - Abecasis, G.R.*
AU  - Boehnke, M.*
AU  - Kathiresan, S.*
C1  - 4338
C2  - 27466
SP  - 707-713
TI  - Biological, clinical and population relevance of 95 loci for blood lipids.
JO  - Nature
VL  - 466
IS  - 7307
PB  - Nature Publ. Group
PY  - 2010
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Three subfamilies of grasses, the Ehrhartoideae, Panicoideae and Pooideae, provide the bulk of human nutrition and are poised to become major sources of renewable energy. Here we describe the genome sequence of the wild grass Brachypodium distachyon (Brachypodium), which is, to our knowledge, the first member of the Pooideae subfamily to be sequenced. Comparison of the Brachypodium, rice and sorghum genomes shows a precise history of genome evolution across a broad diversity of the grasses, and establishes a template for analysis of the large genomes of economically important pooid grasses such as wheat. The high-quality genome sequence, coupled with ease of cultivation and transformation, small size and rapid life cycle, will help Brachypodium reach its potential as an important model system for developing new energy and food crops.
AU  - Vogel, J.P.*
AU  - Garvin, D.F.*
AU  - Mockler, T.C.*
AU  - Schmutz, J.*
AU  - Rokhsar, D.*
AU  - Bevan, M.W.*
AU  - Barry, K.*
AU  - Lucas, S.*
AU  - Harmon-Smith, M.*
AU  - Lail, K.*
AU  - Tice, H.*
AU  - Grimwood, J.*
AU  - McKenzie, N.*
AU  - Huo, N.*
AU  - Gu, Y.Q.*
AU  - Lazo, G.R.*
AU  - Anderson, O.D.*
AU  - You, F.M.*
AU  - Luo, M.C.*
AU  - Dvorak, J.*
AU  - Wright, J.*
AU  - Febrer, M.*
AU  - Idziak, D.*
AU  - Hasterok, R.*
AU  - Garvin, DF.*
AU  - Lindquist, E.*
AU  - Wang, M.*
AU  - Fox, SE.*
AU  - Priest, H.D.*
AU  - Filichkin, S.A.*
AU  - Givan, S.A.*
AU  - Bryant, D.W.*
AU  - Chang, J.H.*
AU  - Wu, H.*
AU  - Wu, W.*
AU  - Hsia, A.P.*
AU  - Schnable, P.S.*
AU  - Kalyanaraman, A.*
AU  - Barbazuk, B.*
AU  - Michael, T.P.*
AU  - Hazen, S.P.*
AU  - Bragg, J.N.*
AU  - Laudencia-Chingcuanco, D.*
AU  - Weng, Y.*
AU  - Haberer, G.
AU  - Spannagl, M.
AU  - Mayer, K.F.X.
AU  - Rattei, T.
AU  - Mitros, T.*
AU  - Lee, S.J.*
AU  - Rose, J.K.*
AU  - Mueller, L.A.*
AU  - York, T.L.*
AU  - Wicker, T.*
AU  - Buchmann, J.P.*
AU  - Tanskanen, J.*
AU  - Schulman, A.H.*
AU  - Gundlach, H.*
AU  - Bevan, M.*
AU  - de Oliveira, A.C.*
AU  - Maia, L. da C.*
AU  - Belknap, W.*
AU  - Jiang, N.*
AU  - Lai, J.*
AU  - Zhu, L.*
AU  - Ma, J.*
AU  - Sun, C.*
AU  - Pritham, E.*
AU  - Salse, J.*
AU  - Murat, F.*
AU  - Abrouk, M.*
AU  - Bruggmann, R.*
AU  - Messing, J.*
AU  - Fahlgren, N.*
AU  - Fox, S.E.*
AU  - Sullivan, C.M.*
AU  - Carrington, J.C.*
AU  - Chapman, E.J.*
AU  - May, G.D.*
AU  - Zhai, J.*
AU  - Ganssmann, M.*
AU  - Gurazada, S.G.*
AU  - German, M.*
AU  - Meyers, B.C.*
AU  - Green, P.J.*
AU  - Tyler, L.*
AU  - Wu, J.*
AU  - Gu, YQ.*
AU  - Thomson, J.*
AU  - Chen, S.*
AU  - Scheller, H.V.*
AU  - Harholt, J.*
AU  - Ulvskov, P.*
AU  - Kimbrel, J.A.*
AU  - Bartley, L.E.*
AU  - Cao, P.*
AU  - Jung, K.H.*
AU  - Sharma, M.K.*
AU  - Vega-Sanchez, M.*
AU  - Ronald, P.*
AU  - Dardick, CD.*
AU  - De, Bodt, S.*
AU  - Verelst, W.*
AU  - Inzé, D.*
AU  - Heese, M.*
AU  - Schnittger, A.*
AU  - Yang, X.*
AU  - Kalluri, U.C.*
AU  - Tuskan, G.A.*
AU  - Hua, Z.*
AU  - Vierstra, R.D.*
AU  - Cui, Y.*
AU  - Ouyang, S.*
AU  - Sun, Q.*
AU  - Liu, Z.*
AU  - Yilmaz, A.*
AU  - Grotewold, E.*
AU  - Sibout, R.*
AU  - Hematy, K.*
AU  - Mouille, G.*
AU  - Höfte, H.*
AU  - Michael, T.*
AU  - Pelloux, J.*
AU  - O'Connor, D.*
AU  - Schnable, J.*
AU  - Rowe, S.*
AU  - Harmon, F.*
AU  - Cass, C.L.*
AU  - Sedbrook, J.C.*
AU  - Byrne, M.E.*
AU  - Walsh, S.*
AU  - Higgins, J.*
AU  - Li, P.*
AU  - Brutnell, T.*
AU  - Unver, T.*
AU  - Budak, H.*
AU  - Belcram, H.*
AU  - Charles, M.*
AU  - Chalhoub, B.*
AU  - Baxter, I.*
C1  - 4005
C2  - 27870
SP  - 763-768
TI  - Genome sequencing and analysis of the model grass Brachypodium distachyon.
JO  - Nature
VL  - 463
IS  - 7282
PB  - Nature Publ. Group
PY  - 2010
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - The tissues of the central nervous system are effectively shielded from the blood circulation by specialized vessels that are impermeable not only to cells, but also to most macromolecules circulating in the blood. Despite this seemingly absolute seclusion, central nervous system tissues are subject to immune surveillance and are vulnerable to autoimmune attacks. Using intravital two-photon imaging in a Lewis rat model of experimental autoimmune encephalomyelitis, here we present in real-time the interactive processes between effector T cells and cerebral structures from their first arrival to manifest autoimmune disease. We observed that incoming effector T cells successively scanned three planes. The T cells got arrested to leptomeningeal vessels and immediately monitored the luminal surface, crawling preferentially against the blood flow. After diapedesis, the cells continued their scan on the abluminal vascular surface and the underlying leptomeningeal (pial) membrane. There, the T cells encountered phagocytes that effectively present antigens, foreign as well as myelin proteins. These contacts stimulated the effector T cells to produce pro-inflammatory mediators, and provided a trigger to tissue invasion and the formation of inflammatory infiltrations.
AU  - Bartholomäus, I.*
AU  - Kawakami, N.*
AU  - Odoardi, F.*
AU  - Schläger, C.*
AU  - Miljkovic, D.*
AU  - Ellwart, J.W.
AU  - Klinkert, W.E.*
AU  - Flügel-Koch, C.*
AU  - Issekutz, T.B.*
AU  - Wekerle, H.*
AU  - Flügel, A.*
C1  - 1948
C2  - 26687
CY  - England
SP  - 94-98
TI  - Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions.
JO  - Nature
VL  - 462
IS  - 7269
PB  - Macmillan Publishers
PY  - 2009
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Despite decades of research, the identity of the cells generating the first haematopoietic cells in mammalian embryos is unknown(1). Indeed, whether blood cells arise from mesodermal cells, mesenchymal progenitors, bipotent endothelial - haematopoietic precursors or haemogenic endothelial cells remains controversial(2-9). Proximity of endothelial and blood cells at sites of embryonic haematopoiesis, as well as their similar gene expression, led to the hypothesis of the endothelium generating blood. However, owing to lacking technology(10) it has been impossible to observe blood cell emergence continuously at the single- cell level, and the postulated existence of haemogenic endothelial cells remains disputed(1). Here, using new imaging and cell- tracking methods, we show that embryonic endothelial cells can be haemogenic. By continuous long- term single- cell observation of mouse mesodermal cells generating endothelial cell and blood colonies, it was possible to detect haemogenic endothelial cells giving rise to blood cells. Living endothelial and haematopoietic cells were identified by simultaneous detection of morphology and multiple molecular and functional markers. Detachment of nascent blood cells from endothelium is not directly linked to asymmetric cell division, and haemogenic endothelial cells are specified from cells already expressing endothelial markers. These results improve our understanding of the developmental origin of mammalian blood and the potential generation of haematopoietic stem cells from embryonic stem cells.
AU  - Eilken, H.M.
AU  - Nishikawa, S.-I.*
AU  - Schroeder, T.
C1  - 241
C2  - 26272
SP  - 896-900
TI  - Continuous single-cell imaging of blood generation from haemogenic endothelium.
JO  - Nature
VL  - 457
IS  - 7231
PB  - Nature Publ. Group
PY  - 2009
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Effects of susceptibility variants may depend on from which parent they are inherited. Although many associations between sequence variants and human traits have been discovered through genome-wide associations, the impact of parental origin has largely been ignored. Here we show that for 38,167 Icelanders genotyped using single nucleotide polymorphism (SNP) chips, the parental origin of most alleles can be determined. For this we used a combination of genealogy and long-range phasing. We then focused on SNPs that associate with diseases and are within 500 kilobases of known imprinted genes. Seven independent SNP associations were examined. Five - one with breast cancer, one with basal-cell carcinoma and three with type-2 diabetes - have parental-origin-specific associations. These variants are located in two genomic regions, 11p15 and 7q32, each harbouring a cluster of imprinted genes. Furthermore, we observed a novel association between the SNP rs2334499 at 11p15 and type-2 diabetes. Here the allele that confers risk when paternally inherited is protective when maternally transmitted. We identified a differentially methylated CTCF-binding site at 11p15 and demonstrated correlation of rs2334499 with decreased methylation of that site.
AU  - Kong, A.*
AU  - Steinthorsdottir, V.*
AU  - Masson, G.*
AU  - Thorleifsson, G.*
AU  - Sulem, P.*
AU  - Besenbacher, S.*
AU  - Jonasdottir, A.*
AU  - Sigurdsson, A.*
AU  - Kristinsson, K.T.*
AU  - Frigge, M.L.*
AU  - Gylfason, A. Olason, P.I.*
AU  - Gudjonsson, S.A.*
AU  - Sverrisson, S.*
AU  - Stacey, S.N.*
AU  - Sigurgeirsson, B.*
AU  - Benediktsdottir, K.R.*
AU  - Sigurdsson, H.*
AU  - Jonsson, T.*
AU  - Benediktsson, R.*
AU  - Olafsson, J.H.*
AU  - Johannsson, O.T.*
AU  - Hreidarsson, A.B.*
AU  - Sigurdsson, G.*
AU  - DIAGRAM Consortium (Huth, C.
AU  - Grallert, H.
AU  - Gieger, C.
AU  - Klopp, N.
AU  - Meitinger, T.
AU  - Petersen, A.-K.
AU  - Thorand, B.
AU  - Wichmann, H.-E.
AU  - Illig, T.)
AU  - Ferguson-Smith, A.C.*
AU  - Gudbjartsson, D.F.*
AU  - Thorsteinsdottir, U.*
AU  - Stefansson, K.
C1  - 79
C2  - 26909
SP  - 868-874
TI  - Parental origin of sequence variants associated with complex diseases.
JO  - Nature
VL  - 462
IS  - 7275
PB  - Nature Publ. Group
PY  - 2009
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Sorghum, an African grass related to sugar cane and maize, is grown for food, feed, fibre and fuel. We present an initial analysis of the approximately 730-megabase Sorghum bicolor (L.) Moench genome, placing approximately 98% of genes in their chromosomal context using whole-genome shotgun sequence validated by genetic, physical and syntenic information. Genetic recombination is largely confined to about one-third of the sorghum genome with gene order and density similar to those of rice. Retrotransposon accumulation in recombinationally recalcitrant heterochromatin explains the approximately 75% larger genome size of sorghum compared with rice. Although gene and repetitive DNA distributions have been preserved since palaeopolyploidization approximately 70 million years ago, most duplicated gene sets lost one member before the sorghum-rice divergence. Concerted evolution makes one duplicated chromosomal segment appear to be only a few million years old. About 24% of genes are grass-specific and 7% are sorghum-specific. Recent gene and microRNA duplications may contribute to sorghum's drought tolerance.
AU  - Paterson, A.H.*
AU  - Bowers, J.E.*
AU  - Bruggmann, R.*
AU  - Dubchak, I.*
AU  - Grimwood, J.*
AU  - Gundlach, H.
AU  - Haberer, G.
AU  - Hellsten, U.*
AU  - Mitros, T.*
AU  - Poliakov, A.*
AU  - Schmutz, J.*
AU  - Spannagl, M.
AU  - Tang, H.B.*
AU  - Wang, X.
AU  - Wicker, T.*
AU  - Bharti, A.K.*
AU  - Chapman, J.*
AU  - Feltus, F.A.*
AU  - Gowik, U.*
AU  - Grigoriev, I.V.*
AU  - Lyons, E.*
AU  - Maher, C.A.*
AU  - Martis, M.M.*
AU  - Narechania, A.*
AU  - Otillar, R.P.*
AU  - Penning, B.W.*
AU  - Salamov, A.A.*
AU  - Wang, Y.
AU  - Zhang, L.F.*
AU  - Carpita, N.C.*
AU  - Freeling, M.*
AU  - Gingle, A.R.*
AU  - Hash, C.T.*
AU  - Keller, B.*
AU  - Klein, P.*
AU  - Kresovich, S.*
AU  - McCann, M.C.*
AU  - Ming, R.*
AU  - Peterson, D.G.*
AU  - Mehboob-ur-Rahman
AU  - Ware, D.*
AU  - Westhoff, P.*
AU  - Mayer, K.F.X.
AU  - Messing, J.*
AU  - Rokhsar, D.S.*
C1  - 145
C2  - 25988
SP  - 551-556
TI  - The Sorghum bicolor genome and the diversification of grasses.
JO  - Nature
VL  - 457
IS  - 7229
PB  - Nature Publ. Group
PY  - 2009
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Despite existing guidelines on access to data and bioresources, good practice is not widespread. A meeting of mouse researchers in Rome proposes ways to promote a culture of sharing.
AU  - Schofield, P.N.*
AU  - Bubela, T.*
AU  - Weaver, T.*
AU  - Portilla, L.*
AU  - Brown, S.D.*
AU  - Hancock, J.M.*
AU  - Einhorn, D.*
AU  - Tocchini-Valentini, G.*
AU  - Hrabě de Angelis, M.
AU  - Rosenthal, N.*
AU  - CASIMIR Rome Meeting Participants (*)
C1  - 180
C2  - 26648
SP  - 171-173
TI  - Post-publication sharing of data and tools.
JO  - Nature
VL  - 461
IS  - 7261
PB  - Nature Publ. Group
PY  - 2009
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - The ability to observe biological processes continuously, instead of at discrete time points, holds great promise for the study of tissue regeneration. Ideally, single cells would be followed continuously within large tissue volumes (such as organs) over long periods of time. Technical limitations, however, preclude such studies. But, recently, there have been improvements in imaging technologies and biologically compatible labelling agents. Together with new insights into the molecular characteristics of stem cells, which are ultimately responsible for the regenerative potential of all tissues, researchers are now much closer to applying single-cell imaging approaches to research into regeneration and its clinical applications.
AU  - Schroeder, T.
C1  - 1679
C2  - 25242
SP  - 345-351
TI  - Imaging stem-cell-driven regeneration in mammals.
JO  - Nature
VL  - 453
IS  - 7153
PB  - Nature Publ. Group
PY  - 2008
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Asthma is caused by a combination of poorly understood genetic and environmental factors1, 2. We have systematically mapped the effects of single nucleotide polymorphisms (SNPs) on the presence of childhood onset asthma by genome-wide association. We characterized more than 317,000 SNPs in DNA from 994 patients with childhood onset asthma and 1,243 non-asthmatics, using family and case-referent panels. Here we show multiple markers on chromosome 17q21 to be strongly and reproducibly associated with childhood onset asthma in family and case-referent panels with a combined P value of P < 10-12. In independent replication studies the 17q21 locus showed strong association with diagnosis of childhood asthma in 2,320 subjects from a cohort of German children (P = 0.0003) and in 3,301 subjects from the British 1958 Birth Cohort (P = 0.0005). We systematically evaluated the relationships between markers of the 17q21 locus and transcript levels of genes in Epstein–Barr virus (EBV)-transformed lymphoblastoid cell lines from children in the asthma family panel used in our association study. The SNPs associated with childhood asthma were consistently and strongly associated (P < 10-22) in cis with transcript levels of ORMDL3, a member of a gene family that encodes transmembrane proteins anchored in the endoplasmic reticulum3. The results indicate that genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma.
AU  - Moffatt, M.F.*
AU  - Kabesch, M.*
AU  - Liang, L.*
AU  - Dixon, A.L.*
AU  - Strachan, D.*
AU  - Heath, S.*
AU  - Depner, M.*
AU  - von Berg, A.*
AU  - Bufe, A.*
AU  - Rietschel, E.*
AU  - Heinzmann, A.*
AU  - Simma, B.*
AU  - Frischer, T.*
AU  - Willis-Owen, S.A.*
AU  - Wong, K.C.*
AU  - Illig, T.
AU  - Vogelberg, C.*
AU  - Weiland, S.K.*
AU  - von Mutius, E.*
AU  - Abecasis, G.R.*
AU  - Farrall, M.*
AU  - Gut, I.G.*
AU  - Lathrop, G.M.*
AU  - Cookson, W.O.*
C1  - 5884
C2  - 24580
SP  - 470-474
TI  - Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma.
JO  - Nature
VL  - 448
IS  - 7152
PB  - Nature Publ. Group
PY  - 2007
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Precise knowledge of the phase relationship between climate changes in the two hemispheres is a key for understanding the Earth's climate dynamics. For the last glacial period, ice core studies(1,2) have revealed strong coupling of the largest millennial-scale warm events in Antarctica with the longest Dansgaard - Oeschger events in Greenland(3-5) through the Atlantic meridional overturning circulation(6-8). It has been unclear, however, whether the shorter Dansgaard - Oeschger events have counterparts in the shorter and less prominent Antarctic temperature variations, and whether these events are linked by the same mechanism. Here we present a glacial climate record derived from an ice core from Dronning Maud Land, Antarctica, which represents South Atlantic climate at a resolution comparable with the Greenland ice core records. After methane synchronization with an ice core from North Greenland(9), the oxygen isotope record from the Dronning Maud Land ice core shows a one-to-one coupling between all Antarctic warm events and Greenland Dansgaard - Oeschger events by the bipolar seesaw(6). The amplitude of the Antarctic warm events is found to be linearly dependent on the duration of the concurrent stadial in the North, suggesting that they all result from a similar reduction in the meridional overturning circulation.
AU  - EPIKA Community Members (Graf, W.)
C1  - 5320
C2  - 28279
SP  - 195-198
TI  - One-to-one coupling of glacial climate variability in Greenland and Antarctica.
JO  - Nature
VL  - 444
IS  - 7116
PB  - Nature Publ. Group
PY  - 2006
SN  - 0028-0836
ER  - 

TY  - JOUR
AU  - Hafner, M.*
AU  - Schmitz, A.*
AU  - Grüne, I.*
AU  - Srivatsan, S.G.*
AU  - Paul, B.*
AU  - Kolanus, W.*
AU  - Quast, T.*
AU  - Kremmer, E.
AU  - Bauer, I.*
AU  - Famulok, M.*
C1  - 4971
C2  - 24133
SP  - 941-944
TI  - Inhibition of cytohesins by SecinH3 leads to hepatic insulin resistance.
JO  - Nature
VL  - 444
PY  - 2006
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Ustilago maydis is a ubiquitous pathogen of maize and a well-established model organism for the study of plant-microbe interactions. This basidiomycete fungus does not use aggressive virulence strategies to kill its host. U. maydis belongs to the group of biotrophic parasites (the smuts) that depend on living tissue for proliferation and development. Here we report the genome sequence for a member of this economically important group of biotrophic fungi. The 20.5-million-base U. maydis genome assembly contains 6,902 predicted protein-encoding genes and lacks pathogenicity signatures found in the genomes of aggressive pathogenic fungi, for example a battery of cell-wall-degrading enzymes. However, we detected unexpected genomic features responsible for the pathogenicity of this organism. Specifically, we found 12 clusters of genes encoding small secreted proteins with unknown function. A significant fraction of these genes exists in small gene families. Expression analysis showed that most of the genes contained in these clusters are regulated together and induced in infected tissue. Deletion of individual clusters altered the virulence of U. maydis in five cases, ranging from a complete lack of symptoms to hypervirulence. Despite years of research into the mechanism of pathogenicity in U. maydis, no 'true' virulence factors had been previously identified. Thus, the discovery of the secreted protein gene clusters and the functional demonstration of their decisive role in the infection process illuminate previously unknown mechanisms of pathogenicity operating in biotrophic fungi. Genomic analysis is, similarly, likely to open up new avenues for the discovery of virulence determinants in other pathogens. ©2006 Nature Publishing Group.
AU  - Kämper, J.*
AU  - Kahmann, R.*
AU  - Bölker, M.*
AU  - Ma, L.J.*
AU  - Brefort, T.*
AU  - Saville, B.J.*
AU  - Banuett, F.*
AU  - Kronstad, J.W.*
AU  - Gold, S.E.*
AU  - Müller, O.*
AU  - Perlin, M.H.*
AU  - Wösten, H.A.*
AU  - de Vries, R.*
AU  - Ruiz-Herrera, J.*
AU  - Reynaga-Peña, C.G.*
AU  - Snetselaar, K.*
AU  - McCann, M.*
AU  - Pérez-Martín, J.*
AU  - Feldbrügge, M.*
AU  - Basse, C.W.*
AU  - Steinberg, G.*
AU  - Ibeas, J.I.*
AU  - Holloman, W.*
AU  - Guzman, P.*
AU  - Farman, M.*
AU  - Stajich, J.E.*
AU  - Sentandreu, R.*
AU  - González-Prieto, J.M.*
AU  - Kennell, J.C.*
AU  - Molina, L.*
AU  - Schirawski, J.*
AU  - Mendoza-Mendoza, A.*
AU  - Greilinger, D.*
AU  - Münch, K.*
AU  - Rössel, N.*
AU  - Scherer, M.*
AU  - Vranes, M.*
AU  - Ladendorf, O.*
AU  - Vincon, V.*
AU  - Fuchs, U.*
AU  - Sandrock, B.*
AU  - Meng, S.*
AU  - Ho, E.C.*
AU  - Cahill, M.J.*
AU  - Boyce, K.J.*
AU  - Klose, J.*
AU  - Klosterman, S.J.*
AU  - Deelstra, H.J.*
AU  - Ortiz-Castellanos, L.*
AU  - Li, W.*
AU  - Sanchez-Alonso, P.*
AU  - Schreier, P.H.*
AU  - Häuser-Hahn, I.*
AU  - Vaupel, M.*
AU  - Koopmann, E.*
AU  - Friedrich, G.*
AU  - Voss, H.*
AU  - Schlüter, T.*
AU  - Margolis, J.*
AU  - Platt, D.*
AU  - Swimmer, C.*
AU  - Gnirke, A.*
AU  - Chen, F.*
AU  - Vysotskaia, V.*
AU  - Mannhaupt, G.
AU  - Güldener, U.
AU  - Münsterkötter, M.
AU  - Haase, D.
AU  - Oesterheld, M.
AU  - Mewes, H.-W.
AU  - Mauceli, E.W.*
AU  - Decaprio, D.*
AU  - Wade, C.M.*
AU  - Butler, J.*
AU  - Young, S.*
AU  - Jaffe, D.B.*
AU  - Calvo, S.*
AU  - Nusbaum, C.*
AU  - Galagan, J.*
AU  - Birren, B.W.*
C1  - 5397
C2  - 24098
SP  - 97-101
TI  - Insights from the genome of the biotrophic fungal plant pathogen Ustilago maydis.
JO  - Nature
VL  - 444
IS  - -
PY  - 2006
SN  - 0028-0836
ER  - 

TY  - JOUR
AU  - Leininger, S.*
AU  - Urich, T.*
AU  - Schloter, M.
AU  - Schwark, L.*
AU  - Qi, J.*
AU  - Nicol, G.W.*
AU  - Prosser, J.I.*
AU  - Schuster, S.C.*
AU  - Schleper, C.*
C1  - 2895
C2  - 23722
SP  - 806-809
TI  - Archaea predominate among ammonia-oxidizing prokaryotes in soils.
JO  - Nature
VL  - 442
PY  - 2006
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Anaerobic ammonium oxidation (anammox) has become a main focus in oceanography and wastewater treatment1,2. It is also the nitrogen cycle's major remaining biochemical enigma. Among its features, the occurrence of hydrazine as a free intermediate of catabolism3,4, the biosynthesis of ladderane lipids5,6 and the role of cytoplasm differentiation7 are unique in biology. Here we use environmental genomics8,9 - the reconstruction of genomic data directly from the environment - to assemble the genome of the uncultured anammox bacterium Kuenenia stuttgartiensis10 from a complex bioreactor community. The genome data illuminate the evolutionary history of the Planctomycetes and allow us to expose the genetic blueprint of the organism's special properties. Most significantly, we identified candidate genes responsible for ladderane biosynthesis and biological hydrazine metabolism, and discovered unexpected metabolic versatility. © 2006 Nature Publishing Group.
AU  - Strous, M.*
AU  - Pelletier, E.*
AU  - Mangenot, S.*
AU  - Rattei, T.*
AU  - Lehner, A.*
AU  - Taylor, M.W.*
AU  - Horn, M.*
AU  - Daims, H.*
AU  - Bartol-Mavel, D.*
AU  - Wincker, P.*
AU  - Barbe, V.*
AU  - Fonknechten, N.*
AU  - Vallenet, D.*
AU  - Segurens, B.*
AU  - Schenowitz-Truong, C.*
AU  - Médigue, C.*
AU  - Collingro, A.*
AU  - Snel, B.*
AU  - Dutilh, B.E.*
AU  - Op den Camp, H.J.*
AU  - van der Drift, C.*
AU  - Cirpus, I.*
AU  - van de Pas-Schoonen, K.T.*
AU  - Harhangi, H.R.*
AU  - van Niftrik, L.*
AU  - Schmid, M.*
AU  - Keltjens, J.*
AU  - van de Vossenberg, J.*
AU  - Kartal, B.*
AU  - Meier, H.*
AU  - Frishman, D.*
AU  - Huynen, M.A.*
AU  - Mewes, H.-W.
AU  - Weissenbach, J.*
AU  - Jetten, M.S.*
AU  - Wagner, M.*
AU  - Le, Paslier, D.*
C1  - 5345
C2  - 24104
SP  - 790-794
TI  - Deciphering the evolution and metabolism of an anammox bacterium from a community genome.
JO  - Nature
VL  - 440
PY  - 2006
SN  - 0028-0836
ER  - 

TY  - JOUR
AU  - Lie, D.C.
AU  - Colamarino, S.A.*
AU  - Song, H.-J.*
AU  - Désiré, L.*
AU  - Mira, H.*
AU  - Consiglio, A.*
AU  - Lein, E.S.*
AU  - Jessberger, S.*
AU  - Lansford, H.*
AU  - Dearie, A.R.*
AU  - Gage, F.H.*
C1  - 1281
C2  - 23068
SP  - 1370-1375
TI  - Wnt signalling regulates adult hippocampal neurogenesis.
JO  - Nature
VL  - 437
PY  - 2005
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - The human X chromosome has a unique biology that was shaped by its evolution as the sex chromosome shared by males and females. We have determined 99.3% of the euchromatic sequence of the X chromosome. Our analysis illustrates the autosomal origin of the mammalian sex chromosomes, the stepwise process that led to the progressive loss of recombination between X and Y, and the extent of subsequent degradation of the Y chromosome. LINE1 repeat elements cover one-third of the X chromosome, with a distribution that is consistent with their proposed role as way stations in the process of X-chromosome inactivation. We found 1,098 genes in the sequence, of which 99 encode proteins expressed in testis and in various tumour types. A disproportionately high number of mendelian diseases are documented for the X chromosome. Of this number, 168 have been explained by mutations in 113 X-linked genes, which in many cases were characterized with the aid of the DNA sequence.
AU  - Ross, M.T.*
AU  - Grafham, D.V.*
AU  - Coffey, A.J.*
AU  - Scherer, S.*
AU  - McLay, K.*
AU  - Muzny, D.*
AU  - Platzer, M.*
AU  - Howell, G.R.*
AU  - Burrows, C.*
AU  - Bird, C.P.*
AU  - Frankish, A.*
AU  - Lovell, F.L.*
AU  - Howe, K.L.*
AU  - Ashurst, J.L.*
AU  - Fulton, R.S.*
AU  - Sudbrak, R.*
AU  - Wen, G.*
AU  - Jones, M.C.*
AU  - Hurles, M.E.*
AU  - Andrews, T.D.*
AU  - Scott, C.E.*
AU  - Searle, S.*
AU  - Ramser, J.*
AU  - Whittaker, A.*
AU  - Deadman, R.*
AU  - Carter, N.P.*
AU  - Hunt, S.E.*
AU  - Chen, R.*
AU  - Cree, A.*
AU  - Gunaratne, P.*
AU  - Havlak, P.*
AU  - Hodgson, A.*
AU  - Metzker, M.L.*
AU  - Richards, S.*
AU  - Scott, G.*
AU  - Steffen, D.*
AU  - Sodergren, E.*
AU  - Wheeler, D.A.*
AU  - Worley, K.C.*
AU  - Ainscough, R.*
AU  - Ambrose, K.D.*
AU  - Ansari-Lari, M.A.*
AU  - Aradhya, S.*
AU  - Ashwell, R.I.*
AU  - Babbage, A.K.*
AU  - Bagguley, C.L.*
AU  - Ballabio, A.*
AU  - Banerjee, R.*
AU  - Barker, G.E.*
AU  - Barlow, K.F.*
AU  - Barrett, I.P.*
AU  - Bates, K.N.*
AU  - Beare, D.M.*
AU  - Beasley, H.*
AU  - Beasley, O.*
AU  - Beck, A.*
AU  - Bethel, G.*
AU  - Blechschmidt, K.*
AU  - Brady, N.*
AU  - Bray-Allen, S.*
AU  - Bridgeman, A.M.*
AU  - Brown, A.J.*
AU  - Brown, M.J.*
AU  - Bonnin, D.*
AU  - Bruford, E.A.*
AU  - Buhay, C.*
AU  - Burch, P.*
AU  - Burford, D.*
AU  - Burgess, J.*
AU  - Burrill, W.*
AU  - Burton, J.*
AU  - Bye, J.M.*
AU  - Carder, C.*
AU  - Carrel, L.*
AU  - Chako, J.*
AU  - Chapman, J.C.*
AU  - Chavez, D.*
AU  - Chen, E.*
AU  - Chen, G.*
AU  - Chen, Y.*
AU  - Chen, Z.*
AU  - Chinault, C.*
AU  - Ciccodicola, A.*
AU  - Clark, S.Y.*
AU  - Clarke, G.*
AU  - Clee, C.M.*
AU  - Clegg, S.*
AU  - Clerc-Blankenburg, K.*
AU  - Clifford, K.*
AU  - Cobley, V.*
AU  - Cole, C.G.*
AU  - Conquer, J.S.*
AU  - Corby, N.*
AU  - Connor, R.E.*
AU  - David, R.*
AU  - Davies, J.*
AU  - Davis, C.*
AU  - Davis, J.*
AU  - Delgado, O.*
AU  - Deshazo, D.*
AU  - Dhami, P.*
AU  - Ding, Y.*
AU  - Dinh, H.*
AU  - Dodsworth, S.*
AU  - Draper, H.*
AU  - Dugan-Rocha, S.*
AU  - Dunham, A.*
AU  - Dunn, M.*
AU  - Durbin, K.J.*
AU  - Dutta, I.*
AU  - Eades, T.*
AU  - Ellwood, M.*
AU  - Emery-Cohen, A.*
AU  - Errington, H.*
AU  - Evans, K.L.*
AU  - Faulkner, L.*
AU  - Francis, F.*
AU  - Frankland, J.*
AU  - Fraser, A.E.*
AU  - Galgoczy, P.*
AU  - Gilbert, J.*
AU  - Gill, R.*
AU  - Glöckner, G.*
AU  - Gregory, S.G.*
AU  - Gribble, S.*
AU  - Griffiths, C.*
AU  - Grocock, R.*
AU  - Gu, Y.*
AU  - Gwilliam, R.*
AU  - Hamilton, C.*
AU  - Hart, E.A.*
AU  - Hawes, A.*
AU  - Heath, P.D.*
AU  - Heitmann, K.*
AU  - Hennig, S.*
AU  - Hernandez, J.*
AU  - Hinzmann, B.*
AU  - Ho, S.*
AU  - Hoffs, M.*
AU  - Howden, P.J.*
AU  - Huckle, E.J.*
AU  - Hume, J.*
AU  - Hunt, P.J.*
AU  - Hunt, A.R.*
AU  - Isherwood, J.*
AU  - Jacob, L.*
AU  - Johnson, D.*
AU  - Jones, S.*
AU  - de, Jong, P.J.*
AU  - Joseph, S.S.*
AU  - Keenan, S.*
AU  - Kelly, S.*
AU  - Kershaw, J.K.*
AU  - Khan, Z.*
AU  - Kioschis, P.*
AU  - Klages, S.*
AU  - Knights, A.J.*
AU  - Kosiura, A.*
AU  - Kovar-Smith, C.*
AU  - Laird, G.K.*
AU  - Langford, C.*
AU  - Lawlor, S.*
AU  - Leversha, M.*
AU  - Lewis, L.*
AU  - Liu, W.*
AU  - Lloyd, C.*
AU  - Lloyd, D.M.*
AU  - Loulseged, H.*
AU  - Loveland, J.E.*
AU  - Lovell, J.D.*
AU  - Lozado, R.*
AU  - Lu, J.*
AU  - Lyne, R.*
AU  - Ma, J.*
AU  - Maheshwari, M.*
AU  - Matthews, L.H.*
AU  - McDowall, J.*
AU  - McLaren, S.*
AU  - McMurray, A.*
AU  - Meidl, P.*
AU  - Meitinger, T.
AU  - Milne, S.*
AU  - Miner, G.*
AU  - Mistry, S.L.*
AU  - Morgan, M.*
AU  - Morris, S.*
AU  - Müller, I.*
AU  - Mullikin, J.C.*
AU  - Nguyen, N.*
AU  - Nordsiek, G.*
AU  - Nyakatura, G.*
AU  - O'Dell, C.N.*
AU  - Okwuonu, G.*
AU  - Palmer, S.*
AU  - Pandian, R.*
AU  - Parker, D.*
AU  - Parrish, J.*
AU  - Pasternak, S.*
AU  - Patel, D.*
AU  - Pearce, A.V.*
AU  - Pearson, D.M.*
AU  - Pelan, S.E.*
AU  - Perez, L.*
AU  - Porter, K.M.*
AU  - Ramsey, Y.*
AU  - Reichwald, K.*
AU  - Rhodes, S.*
AU  - Ridler, K.A.*
AU  - Schlessinger, D.*
AU  - Schueler, M.G.*
AU  - Sehra, H.K.*
AU  - Shaw-Smith, C.*
AU  - Shen, H.*
AU  - Sheridan, E.M.*
AU  - Shownkeen, R.*
AU  - Skuce, C.D.*
AU  - Smith, M.L.*
AU  - Sotheran, E.C.*
AU  - Steingruber, H.E.*
AU  - Steward, C.A.*
AU  - Storey, R.*
AU  - Swann, R.M.*
AU  - Swarbreck, D.*
AU  - Tabor, P.E.*
AU  - Taudien, S.*
AU  - Taylor, T.*
AU  - Teague, B.*
AU  - Thomas, K.*
AU  - Thorpe, A.*
AU  - Timms, K.*
AU  - Tracey, A.*
AU  - Trevanion, S.*
AU  - Tromans, A.C.*
AU  - d'Urso, M.*
AU  - Verduzco, D.*
AU  - Villasana, D.*
AU  - Waldron, L.*
AU  - Wall, M.*
AU  - Wang, Q.*
AU  - Warren, J.*
AU  - Warry, G.L.*
AU  - Wei, X.*
AU  - West, A.*
AU  - Whitehead, SL.*
AU  - Whiteley, M.N.*
AU  - Wilkinson, J.E.*
AU  - Willey, D.L.*
AU  - Williams, G.*
AU  - Williams, L.*
AU  - Williamson, A.*
AU  - Williamson, H.*
AU  - Wilming, L.*
AU  - Woodmansey, R.L.*
AU  - Wray, P.W.*
AU  - Yen, J.*
AU  - Zhang, J.*
AU  - Zhou, J.*
AU  - Zoghbi, H.*
AU  - Zorilla, S.*
AU  - Buck, D.*
AU  - Reinhardt, R.*
AU  - Poustka, A.*
AU  - Rosenthal, A.*
AU  - Lehrach, H.*
AU  - Meindl, A.*
AU  - Minx, PJ.*
AU  - Hillier, L.W.*
AU  - Willard, H.F.*
AU  - Wilson, R.*
AU  - Waterston, R.H.*
AU  - Rice, C.M.*
AU  - Vaudin, M.*
AU  - Coulson, A.*
AU  - Nelson, D.L.*
AU  - Weinstock, G.*
AU  - Sulston, J.E.*
AU  - Durbin, R.*
AU  - Hubbard, T.*
AU  - Gibbs, R.A.*
AU  - Beck, S.*
AU  - Rogers, J.*
AU  - Bentley, D.R.*
C1  - 3048
C2  - 22912
SP  - 325-337
TI  - The DNA sequence of the human X chromosome.
JO  - Nature
VL  - 434
IS  - 7031
PY  - 2005
SN  - 0028-0836
ER  - 

TY  - JOUR
AU  - Wittmaack, K.
C1  - 3082
C2  - 23052
SP  - S.24
TI  - Penalties plus high-quality review to fight plagiarism.
JO  - Nature
VL  - 436
PY  - 2005
SN  - 0028-0836
ER  - 

TY  - JOUR
AU  - Wurst, W.
C1  - 1117
C2  - 22743
SP  - S. 13
TI  - Mouse geneticists need European strategy too.
JO  - Nature
VL  - 433
PY  - 2005
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - We present here a draft genome sequence of the red jungle fowl, Gallus gallus. Because the chicken is a modern descendant of the dinosaurs and the first non-mammalian amniote to have its genome sequenced, the draft sequence of its genome-composed of approximately one billion base pairs of sequence and an estimated 20,000-23,000 genes-provides a new perspective on vertebrate genome evolution, while also improving the annotation of mammalian genomes. For example, the evolutionary distance between chicken and human provides high specificity in detecting functional elements, both non-coding and coding. Notably, many conserved non-coding sequences are far from genes and cannot be assigned to defined functional classes. In coding regions the evolutionary dynamics of protein domains and orthologous groups illustrate processes that distinguish the lineages leading to birds and mammals. The distinctive properties of avian microchromosomes, together with the inferred patterns of conserved synteny, provide additional insights into vertebrate chromosome architecture.
AU  - International Chicken Genome Sequencing Consortium
AU  - Hillier, L.W.*
AU  - Miller, W.C.*
AU  - Birney, E.*
AU  - Warren, W.C.*
AU  - Hardison, R.C.*
AU  - Ponting, C.P.*
AU  - Bork, P.*
AU  - Burt, D.W.*
AU  - Groenen, M.A.M.*
AU  - Delany, M.E.*
AU  - Dodgson, J.B.*
AU  - Chinwalla, A.T.*
AU  - Cliften, P.F.*
AU  - Clifton, S.W.*
AU  - Delehaunty, K.D.*
AU  - Fronick, C.C.*
AU  - Fulton, R.S.*
AU  - Graves, T.A.*
AU  - Kremitzki, C.L.*
AU  - Layman, D.*
AU  - Magrini, V.J.*
AU  - McPherson, J.D.*
AU  - Miner Patrick Minx, T.L.*
AU  - Nash, W.E.*
AU  - Nhan, M.*
AU  - Nelson, J.O.*
AU  - Oddy, L.G.*
AU  - Pohl, C.S.*
AU  - Randall-Maher, J.*
AU  - Smith, S.M.*
AU  - Wallis, J.W.*
AU  - Yang, S.*
AU  - Romanov, M.N.*
AU  - Rondelli, C.M.*
AU  - Paton, B.*
AU  - Smith, J.A.M.*
AU  - Morrice, D.R.*
AU  - Daniels, L.M.*
AU  - Tempest, H.G.*
AU  - Robertson, L.*
AU  - Masabanda, J.S.*
AU  - Griffin, D.K.*
AU  - Vignal, A.*
AU  - Fillon, V.*
AU  - Jacobbson, L.*
AU  - Kerje, S.*
AU  - Andersson, L.B.*
AU  - Crooijmans, R.P.M.A.*
AU  - Aerts, J.A.*
AU  - van der Poel, J.J.*
AU  - Ellegren, H.*
AU  - Caldwell, R.B.
AU  - Hubbard, S.J.*
AU  - Grafham, D.V.*
AU  - Kierzek, A.M.*
AU  - McLaren, S.R.*
AU  - Overton, I.M.*
AU  - Arakawa, H.
AU  - Beattie, K.J.*
AU  - Bezzubov, Y.
AU  - Boardman, P.E.*
AU  - Bonfield, J.K.*
AU  - Croning, M.D.R.*
AU  - Davies, R.M.*
AU  - Francis, M.D.*
AU  - Humphray, S.J.*
AU  - Scott, C.E.*
AU  - Taylor, R.G.*
AU  - Tickle, C.A.*
AU  - Brown, W.R.A.*
AU  - Rogers, J.H.*
AU  - Buerstedde, J.M.
AU  - Wilson, S.A.*
AU  - Stubbs, L.J.*
AU  - Ovcharenko, I.*
AU  - Gordon, L.A.*
AU  - Lucas, S.M.*
AU  - Miller, M.M.*
AU  - Inoko, H.*
AU  - Shiina, T.*
AU  - Kaufman, J.F.*
AU  - Salomonsen, J.*
AU  - Skjoedt, K.*
AU  - Wong, G.K.S.*
AU  - Wang, J.*
AU  - Liu, B.*
AU  - Yu, J.*
AU  - Yang, H.*
AU  - Nefedov, M.*
AU  - Koriabine, M.Y.*
AU  - DeJong, P.J.*
AU  - Goodstadt, L.*
AU  - Webber, C.*
AU  - Dickens, N.J.*
AU  - Letunic, I.*
AU  - Suyama, M.*
AU  - Torrents, D.*
AU  - von Mering, C.*
AU  - Zdobnov, E.M.*
AU  - Makova, K.D.*
AU  - Nekrutenko, A.*
AU  - Elnitski, L.L.*
AU  - Eswara, P.*
AU  - King, D.C.*
AU  - Tyekucheva, S.*
AU  - Radakrishnan, A.*
AU  - Harris, R.S.*
AU  - Chiaromonte, F.*
AU  - Taylor, J.R.*
AU  - He, J.*
AU  - Rijnkels, M.*
AU  - Griffiths-Jones, S.*
AU  - Ureta-Vidal, A.*
AU  - Hoffman, M.M.*
AU  - Severin, J.M.*
AU  - Searle, S.M.J.*
AU  - Law, A.S.*
AU  - Speed, D.*
AU  - Waddington, D.W.*
AU  - Cheng, Z.*
AU  - Tüzün, E.*
AU  - Eichler, E.E.*
AU  - Bao, Z.*
AU  - Flicek, P.*
AU  - Shteynberg, D.D.*
AU  - Brent, M.R.*
AU  - Bye, J.M.*
AU  - Huckle, E.J.*
AU  - Chatterji, S.*
AU  - Dewey, C.N.*
AU  - Pachter, L.S.*
AU  - Kouranov, A.Y.*
AU  - Mourelatos, Z.*
AU  - Hatzigeorgiou, A.G.*
AU  - Paterson, A.H.*
AU  - Ivarie, R.*
AU  - Brandström, M.D.*
AU  - Axelsson, E.*
AU  - Backström, N.*
AU  - Berlin, S.*
AU  - Webster, M.T.*
AU  - Pourquie, O.*
AU  - Reymond, A.*
AU  - Ucla, C.*
AU  - Antonarakis, S.E.*
AU  - Long, M.*
AU  - Emerson, J.J.*
AU  - Betrán, E.*
AU  - Dupanloup, I.*
AU  - Kaessmann, H.*
AU  - Hinrichs, A.S.*
AU  - Bejerano, G.*
AU  - Furey, T.S.*
AU  - Harte, R.A.*
AU  - Raney, B.J.*
AU  - Siepel, A.C.*
AU  - James Kent, W.*
AU  - Haussler, D.H.*
AU  - Eyras, E.*
AU  - Castelo, R.*
AU  - Abril, J.F.*
AU  - Castellano, S.*
AU  - Camara, F.*
AU  - Parra, G.*
AU  - Guigo, R.*
AU  - Bourque, G.*
AU  - Tesler, G.*
AU  - Pevzner, P.A.*
AU  - Smit, A.F.A.*
AU  - Fulton, L.A.*
AU  - Mardis, E.*
AU  - Wilson, R.*
C1  - 42967
C2  - 35932
SP  - 695-716
TI  - Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution.
JO  - Nature
VL  - 432
PY  - 2004
SN  - 0028-0836
ER  - 

TY  - JOUR
AU  - Hillier, L.W.*
AU  - Caldwell, R.B.
AU  - Arakawa, H.
AU  - Bezzubov, Y.
AU  - Buerstedde, J.-M.
C1  - 2992
C2  - 22406
SP  - 695-716
TI  - Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution.
JO  - Nature
VL  - 432
PY  - 2004
SN  - 0028-0836
ER  - 

TY  - JOUR
AU  - Rost, S.*
AU  - Fregin, A.*
AU  - Ivaskevicius, V.*
AU  - Conzelmann, E.*
AU  - Hörtnagel, K.
AU  - Pelz, H.-J.*
AU  - Lappegard, K.*
AU  - Seifried, E.*
AU  - Scharrer, I.*
AU  - Tuddenham, E.G.D.*
AU  - Müller, C.R.*
C1  - 1203
C2  - 22084
SP  - 537-541
TI  - Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2.
JO  - Nature
VL  - 427
PY  - 2004
SN  - 0028-0836
ER  - 

TY  - JOUR
AU  - Galagan, J.E.*
AU  - Calvo, S.E.*
AU  - Borkovich, K.A.*
AU  - Selker, E.U.*
AU  - Read, N.D.*
AU  - Jaffe, D.*
AU  - Ma, L.-J.*
AU  - Smirnov, S.*
AU  - Purcell, S.*
AU  - Rehman, B.*
AU  - Elkins, T.*
AU  - Engels, R.*
AU  - Wang, S.*
C1  - 9708
C2  - 21635
SP  - 859-868
TI  - The genome sequence of the filamentous fungus Neurospora crassa. 
JO  - Nature
VL  - 422
PY  - 2003
SN  - 0028-0836
ER  - 

TY  - JOUR
AU  - Marsicano, G.*
AU  - Wotjak, C.T.*
AU  - Azad, S.C.*
AU  - Bisogno, T.*
AU  - Rammes, G.*
AU  - Casclo, M.G.*
AU  - Hermann, H.*
AU  - Tang, J.*
AU  - Hofmann, C.
AU  - Zieglgänsberger, W.*
AU  - di Marzo, V.*
AU  - Lutz, B.*
C1  - 22104
C2  - 20773
SP  - 530-534
TI  - The endogenous cannabinoid system controls extinction of aversive memories.
JO  - Nature
VL  - 418
PY  - 2002
SN  - 0028-0836
ER  - 

TY  - JOUR
AU  - Ries, G.*
AU  - Heller, W.
AU  - Puchta, H.*
AU  - Sandermann, H.
AU  - Seidlitz, H.K.
AU  - Hohn, B.*
C1  - 21807
C2  - 20009
SP  - 98-101
TI  - Elevated UV-B radiation reduces genome stability in plants.
JO  - Nature
VL  - 406
PY  - 2000
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - The homeobox gene Otx2 is expressed in the anterior neural tube with a sharp limit at the midbrain/hindbrain junction (the isthmic organizer). Otx2 inactivation experiments have shown that this gene is essential for the development of its expression domain. Here we investigate whether the caudal limit of Otx2 expression is instrumental in positioning the isthmic organizer and in specifying midbrain versus hindbrain fate, by ectopically expressing Otx2 in the presumptive anterior hindbrain using a knock-in strategy into the En1 locus. Transgenic offspring display a cerebellar ataxia. Morphological and histological studies of adult transgenic brains reveal that most of the anterior cerebellar vermis is missing, whereas the inferior colliculus is complementarily enlarged. During early neural pattern formation expression of the midbrain markers Wnt1 and Ephrin-A5, the isthmic organizer markers Pax2 and Fgf-8 and the hindbrain marker Gbx2 are shifted caudally in the presumptive hindbrain territory. These findings show that the caudal limit of Otx2 expression is sufficient for positioning the isthmic organizer and encoding caudal midbrain fate within the mid/hindbrain domain.
AU  - Broccoli, V.
AU  - Boncinelli, E.*
AU  - Wurst, W.
C1  - 22861
C2  - 31156
SP  - 164-168
TI  - The caudal limit of Otx2 expression positions the isthmic organizer.
JO  - Nature
VL  - 401
IS  - 6749
PB  - Nature Publishing
PY  - 1999
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - During vertebrate limb development, positional information must be specified along three distinct axes. Although much progress has been made in our understanding of the molecular interactions involved in anterior-posterior and proximal-distal limb patterning, less is known about dorsal-ventral patterning. The genes Wnt-7a and Lmx-1, which are expressed in dorsal limb ectoderm and mesoderm, respectively, are thought to be important regulators of dorsal limb differentiation. Whether a complementary set of molecules controls ventral limb development has not been clear. Here we report that Engrailed-1, a homeodomain-containing transcription factor expressed in embryonic ventral limb ectoderm, is essential for ventral limb patterning. Loss of Engrailed-1 function in mice results in dorsal transformations of ventral paw structures, and in subtle alterations along the proximal-distal limb axis. Engrailed-1 seems to act in part by repressing dorsal differentiation induced by Wnt-7a, and is essential for proper formation of the apical ectodermal ridge.
AU  - Loomis, C.A.*
AU  - Harris, E.*
AU  - Michaud, J.*
AU  - Wurst, W.
AU  - Hanks, M.*
AU  - Joyner, A.L.*
C1  - 22874
C2  - 31199
SP  - 360-363
TI  - The mouse Engrailed-1 gene and ventral limb patterning.
JO  - Nature
VL  - 382
IS  - 6589
PB  - Nature Publishing Group
PY  - 1996
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - ENDOGENOUS superantigens are encoded by the open reading frame contained within the mouse mammary tumour virus long terminal repeat (MMTV LTR). Superantigen expression results in T-cell proliferation and, during early ontogeny, T-cell deletion1,2. Here we identify a novel promoter located upstream of the previously described MMTV promoter. Transcripts from this promoter initiate within the U3 region of the MMTV LTR and splice to the acceptor for endogenous superantigen coding region. The novel U3 promoter is active in B lymphocytes, which are cognate antigen-presenting cells for endogenous superantigen, and is able to direct expression of superantigen in the absence of the previously described MMTV promoter.
AU  - Günzburg, W.H.
AU  - Heinemann, F.
AU  - Wintersperger, S.
AU  - Miethke, T.*
AU  - Wagner, H.M.*
AU  - Erfle, V.F.
AU  - Salmons, B.*
C1  - 40453
C2  - 40106
SP  - 154-158
TI  - Endogenous superantigen expression controlled by a novel promoter in the MMTV long terminal repeat.
JO  - Nature
VL  - 364
IS  - 6433
PY  - 1993
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - THE kinase Raf-1 can be activated by treatment of cells with mitogens and by the protein kinase C (PKC) activator 12-O-tetradecanoyl-phorbol-13-acetate (TPA) (reviewed in refs 1, 2). Activated Raf-1 triggers a protein kinase cascade by direct phosphorylation of MAP kinase kinase3-5, resulting in phosphorylation of ternary complex factor6 and Jun7,8 by MAP kinase. Here we investigate the molecular mechanism and biological consequences of PKCα-mediated Raf-1 activation in NIH3T3 fibroblasts. PKCα directly phosphorylates and activates Raf-1 both in vitro and in vivo. PKCα induces Raf-1 phosphorylation at several sites, including a serine residue at position 499. Mutation of serine at this position or at residue 259 does not abrogate Raf-1 stimulation by a combination of Ras plus the src tyrosine kinase Lck, but severely impedes Raf-1 activation by PKCα. Consistent with such a direct interaction is the observation that Raf-1 and PKCα cooperate in the transformation of NIH3T3 cells. The Ser499 phosphorylation site is necessary for this synergism.
AU  - Kolch, W.
AU  - Heldecker, G.*
AU  - Kochs, G.G.*
AU  - Hummel, R.*
AU  - Vahidi, H.*
AU  - Mischak, H.*
AU  - Finkenzeller, G.*
AU  - Marmé, D.*
AU  - Rapp, U.R.*
C1  - 40375
C2  - 40091
SP  - 249-252
TI  - Protein kinase Cα activates RAF-1 by direct phosphorylation.
JO  - Nature
VL  - 364
IS  - 6434
PY  - 1993
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - THE Filchner-Ronne ice shelf, which drains most of the marine-based portions of the West Antarctic ice sheet, is the largest ice shelf on Earth by volume. The origin and properties of the ice that constitutes this shelf are poorly understood, because a strong reflecting interface within the ice and the diffuse nature of the ice-ocean interface make seismic and radio echo sounding data difficult to interpret1,2. Ice in the upper part of the shelf is of meteoric origin, but it has been proposed2,5 that a basal layer of saline ice accumulates from below. Here we present the results of an analysis of the physical and chemical characteristics of an ice core drilled almost to the bottom of the Ronne ice shelf. We observe a change in ice properties at about 150 m depth, which we ascribe to a change from meteoric ice to basal marine ice. The basal ice is very different from sea ice formed at the ocean surface and we propose a formation mechanism in which ice platelets in the water column accrete to the bottom of the ice shelf.
AU  - Oerter, H.*
AU  - Kipfstuhl, J.*
AU  - Determann, J.*
AU  - Miller, H.W.*
AU  - Wagenbach, D.*
AU  - Minikin, A.*
AU  - Graft, W.
C1  - 40526
C2  - 38787
SP  - 399-401
TI  - Evidence for basal marine ice in the Filchner-Ronne ice shelf.
JO  - Nature
VL  - 358
IS  - 6385
PY  - 1992
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Recent analyses of global ozone measurements have confirmed that ozone reductions are not confined to the Antarctic, but now extend to mid-latitudes in both hemispheres1,2. Ozone reductions lead to increases in biologically damaging ultraviolet radiation3, and such increases have been observed in Antarctica1,4 and Australia5. Little is known, however, about hemispheric differences in ultraviolet intensities. Here we use a combination of spectral measurements made in Germany and New Zealand with the same spectroradiometer, together with model calculations, to show that in the New Zealand summer of 1990-1991 biologically weighted ultraviolet irradiances were nearly a factor of two greater than those in the summer at similar northern latitudes in Germany. These differences are larger than expected3,6, and are due mainly to decreased stratospheric ozone over New Zealand and increased levels of tropospheric ozone over Germany.
AU  - Seckmeyer, G.
AU  - McKenzie, R.L.*
C1  - 40502
C2  - 38716
SP  - 135-137
TI  - Increased ultraviolet radiation in New Zealand (45° S) relative to Germany (48° N).
JO  - Nature
VL  - 359
IS  - 6391
PY  - 1992
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - LATE Glacial and Holocene tree-ring chronologies, like deep-sea sediments or polar ice cores, contain information about past environments. Changes in tree-ring growth rates can be related to past climate anomalies and changes in the isotope composition of tree-ring cellulose reflect changes in the composition of the atmosphere and the hydrosphere. We have established a 9,928-year absolutely dated dendrochronological record of Holocene oak (Quercus robur, Quercus petraea) - and a 1,604-year floating Late Glacial and Early Holocene chronology of pine (Pinus sylvestris) from subfossil tree remnants deposited in alluvial terraces of south central European rivers. The pine sequence provides records of dendro-dated 14C, 13C and 2H patterns for the late Younger Dryas and the entire Preboreal (10,100-9,000 yr BP). Through the use of dendrochronology, radiocarbon age calibration and stable isotope analysis, we suggest that the Late Glacial/Holocene transition may be identified and dated by 13C and 2H tree-ring chronologies.
AU  - Becker, B.C.*
AU  - Kromer, B.*
AU  - Trimborn, P.
C1  - 40736
C2  - 40187
SP  - 647-649
TI  - A stable-isotope tree-ring timescale of the Late Glacial/Holocene boundary.
JO  - Nature
VL  - 353
IS  - 6345
PY  - 1991
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Small eye (Sey) in mouse is a semidominant mutation which in the homozygous condition results in the complete lack of eyes and nasal primordia. On the basis of comparative mapping studies and on phenotypic similarities, Sey has been suggested to be homologous to congenital aniridia (lack of iris) in human1,2. A candidate gene for the aniridia (AN) locus at 11p13 has been isolated by positional cloning3 and its sequence and that of the mouse homologue has been established (C.T., manuscript in preparation). This gene belongs to the paired-like class of developmental genes first described in Drosophila which contain two highly conserved motifs, the paired box and the homeobox 4,5. In vertebrates, genes which encode the single paired domain as well as those which express both motifs have been described as the Pax multigene family6-10. A Pax gene recently described as Pax-611,12 is identical to the mouse homologue of the candidate aniridia gene. Here we report the analysis of three independent Sey alleles and show that indeed this gene is mutated and that the mutations would predictably interrupt gene function.
AU  - Hill, R.E.*
AU  - Favor, J.
AU  - Hogan, B.L.M.*
AU  - Ton, C.C.T.*
AU  - Saunders, G.F.*
AU  - Hanson, I.M.*
AU  - Prosser, J.S.*
AU  - Jordan, T.L.*
AU  - Hastie, N.D.*
AU  - van Heyningen, V. *
C1  - 40776
C2  - 12911
SP  - 522-525
TI  - Mouse Small eye results from mutations in a paired-like homeobox-containing gene.
JO  - Nature
VL  - 354
IS  - 6354
PY  - 1991
SN  - 0028-0836
ER  - 

TY  - JOUR
AU  - Müller, W.A.
C1  - 18385
C2  - 11582
SP  - 483-484
TI  - Transmission of Leukaemia.
JO  - Nature
VL  - 345
PY  - 1990
SN  - 0028-0836
ER  - 

TY  - JOUR
AU  - Müller, W.A.
C1  - 42107
C2  - 36440
SP  - 483-484
TI  - Transmission of leukaemia.
JO  - Nature
VL  - 345
IS  - 6275
PY  - 1990
SN  - 0028-0836
ER  - 

TY  - JOUR
AU  - Regulla, D.F.
AU  - Göksu, H.Y.
AU  - Vogenauer, A.
AU  - Wieser, A.
C1  - 18185
C2  - 11395
TI  - Detection of Irradiated Eggs by Electron Spin Resonance.
JO  - Nature
PY  - 1990
SN  - 0028-0836
ER  - 

TY  - JOUR
AU  - Göksu-Ögelman, H.Y.
AU  - Regulla, D.F.
C1  - 41022
C2  - 40349
SP  - 23
TI  - Detection of irradiated food.
JO  - Nature
VL  - 340
IS  - 6228
PY  - 1989
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - It is well established that organic peroxides are formed by OH-radical-induced oxidation of hydrocarbons under atmospheric conditions1. Peroxyacyl nitrates have been known to be constituents of polluted air since the 1950s2,3. In a recent study we have shown that the gas-phase reaction of ozone with a variety of natural and anthropogenic alkenes can contribute to the formation of hydro-philic organic peroxides4. Indications that such peroxides are actually present in the environment have been obtained previously by measurements of the peroxide content of cloudwater and rain. In the absence of a specific analytical method the peroxide content after selective enzymatic destruction of the hydrogen peroxide was taken to be the organic peroxide fraction5-7. In this letter we report the determination by high-performance liquid chroma-tography of methyl (MHP; CH3OOH), hydroxymethyl (HMP; HOCH2OOH) and 1-hydroxyethyl (HEP; CH3CH(OH)OOH) hydroperoxides, in addition to H2O2, and present some preliminary concentration ranges in air and precipitation. The existence of this class of atmospheric trace constituents raises questions about possible adverse biological effects.
AU  - Hellpointner, E.
AU  - Gäb, S.
C1  - 34081
C2  - 36516
SP  - 631-634
TI  - Detection of methyl, hydroxymethyl and hydroxyethyl hydroperoxides in air and precipitation.
JO  - Nature
VL  - 337
IS  - 6208
PY  - 1989
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - There is much concern about the state of West Germany's large forests which are threatened by an unprecedented decline. Research into its causes no longer focuses on acid rain, but on a possible interaction of increased ozone concentrations, acid mist and climatic factors.
AU  - Blank, L.W.
C1  - 40888
C2  - 38516
SP  - 311-314
TI  - A new type of forest decline in Germany.
JO  - Nature
VL  - 314
IS  - 6009
PY  - 1985
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Ozonolysis is one of the main pathways for degradation of alkenes in the atmosphere, where the reaction is associated with smog formation1 and the haze that often occurs over forests2,3. In recent decades, ground-level ozone concentrations have greatly increased4,5. The possibility of significant damage to plants by ozone and its products has consequently been raised in discussions of ‘waldsterben’, the large-scale dying of trees in northern Europe and North America6–9. With particular regard to the formation of peroxides, we have used 13C- nuclear magnetic resonance (NMR) to investigate the water-soluble products of the gas-phase ozonolysis of isoprene and several terpenes, which are emitted into the atmosphere in large quantities (108–109 tonnes yr−1 globally) by trees3,10,11. All these alkenes yield bis(hydroxymethyl)peroxide (BHMP; HOCH2OOCH2OH). The apparent precursor of BHMP is hydroxymethyl hydroperoxide (HMP; HOCH2OOH), which results from addition of water to the ozonolysis intermediate. As both HMP and BHMP have various toxic effects on plant cells and enzymes12–14, we point out here an indirect way by which ozone may adversely affect forests.
AU  - Gäb, S.
AU  - Hellpointner, E.
AU  - Turner, W.V.
AU  - Korte, F.
C1  - 41418
C2  - 38224
SP  - 535-539
TI  - Hydroxymethyl hydroperoxide and bis(hydroxymethyl) peroxide fom gas-phase ozonolysis of naturally occurring alkenes.
JO  - Nature
VL  - 316
IS  - 6028
PY  - 1985
SN  - 0028-0836
ER  - 

TY  - JOUR
AU  - Reineke, W.
AU  - Knackmuß, H.J.
C1  - 33084
C2  - 35284
SP  - 385-386
TI  - Construction of haloaromatics utilising bacteria.
JO  - Nature
VL  - 277
IS  - 5695
PY  - 1979
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Th-1-1 in the rat is the only alloantigen that is confined to stem cells and cells carrying the theta antigen. It is missing not only on B lymphocytes but also, in contradistinction to the mouse, in most peripheral T cells. The Th-1-1 antigen appears very early in the bone marrow of rats and is also demonstrable in haemopoietic stem cells.
AU  - Thierfelder, S.S.
C1  - 41650
C2  - 35688
SP  - 691-693
TI  - Haemopoietic stem cells of rats but not of mice express Th-1.1 alloantigen.
JO  - Nature
VL  - 269
IS  - 5630
PY  - 1977
SN  - 0028-0836
ER  - 

TY  - JOUR
AB  - Deuterium variations in growth rings of a Picea from southern Germany are essentially a function of annual air temperature. Short term isotope variations are partly influenced by changes of relative humidity, but it is the long term annual temperature fluctuations which are mainly responsible for the deuterium variations in the rings. Long term deuterium variations in Picea record climatic changes of the past and also reflect the deuterium content of the annual precipitation.
AU  - Schiegl, W.E.
C1  - 41179
C2  - 38087
SP  - 582-584
TI  - Climatic significance of deuterium abundance in growth rings of Picea.
JO  - Nature
VL  - 251
IS  - 5476
PY  - 1974
SN  - 0028-0836
ER  -