TY  - JOUR
AB  - Brain organoids derived from human pluripotent stem cells (hPSCs) hold immense potential for modeling neurodevelopmental processes and disorders. However, their experimental variability and undefined organoid selection criteria for analysis hinder reproducibility. As part of the Bavarian ForInter consortium, we generated 72 brain organoids from distinct hPSC lines. We conducted a comprehensive analysis of their morphological and cellular characteristics at an early stage of their development. In our assessment, the Feret diameter emerged as a reliable, single parameter that characterizes brain organoid quality. Transcriptomic analysis of our organoid identified the abundance of unintended mesodermal differentiation as a major confounder of unguided brain organoid differentiation, correlating with Feret diameter. High-quality organoids consistently displayed a lower presence of mesenchymal cells. These findings provide a framework for enhancing brain organoid standardization and reproducibility, underscoring the need for morphological quality controls and considering the influence of mesenchymal cells on organoid-based modeling.
AU  - Boerstler, T.*
AU  - Kachkin, D.*
AU  - Gerasimova, E.*
AU  - Zagha, N.*
AU  - Furlanetto, F.*
AU  - Nayebzade, N.*
AU  - Zappia, L.
AU  - Boisvert, M.
AU  - Farrell, M.*
AU  - Ploetz, S.*
AU  - Prots, I.*
AU  - Regensburger, M.*
AU  - Günther, C.*
AU  - Winkler, J.*
AU  - Gupta, P.*
AU  - Theis, F.J.
AU  - Karow, M.*
AU  - Falk, S.*
AU  - Winner, B.*
AU  - Krach, F.*
C1  - 75693
C2  - 58277
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Deciphering brain organoid heterogeneity by identifying key quality determinants.
JO  - Comm. Biol.
VL  - 8
IS  - 1
PB  - Nature Portfolio
PY  - 2025
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - An accurate spatial representation of protein-protein interaction networks is needed to achieve a realistic and biologically relevant representation of interactomes. Here, we leveraged the spatial information included in Proximity-Dependent Biotin Identification (BioID) interactomes of SARS-CoV-2 proteins to calculate weighted distances and model the organization of the SARS-CoV-2-human interactome in three dimensions (3D) within a cell-like volume. Cell regions with viral occupancy were highlighted, along with the coordination of viral proteins exploiting the cellular machinery. Profiling physical intra-virus and virus-host contacts enabled us to demonstrate both the accuracy and the predictive value of our 3D map for direct interactions, meaning that proteins in closer proximity tend to interact physically. Several functionally important virus-host complexes were detected, and robust structural models were obtained, opening the way to structure-directed drug discovery screens. This PPI discovery pipeline approach brings us closer to a realistic spatial representation of interactomes, which, when applied to viruses or other pathogens, can provide significant information for infection. Thus, it represents a promising tool for coping with emerging infectious diseases.
AU  - Dugied, G.*
AU  - Laurent, E.M.*
AU  - Attia, M.*
AU  - Gimeno, J.P.*
AU  - Bachiri, K.*
AU  - Samavarchi-Tehrani, P.*
AU  - Donati, F.*
AU  - Rahou, Y.*
AU  - Munier, S.*
AU  - Amara, F.*
AU  - Dos Santos, M.*
AU  - Soler, N.*
AU  - Volant, S.*
AU  - Pietrosemoli, N.*
AU  - Gingras, A.C.*
AU  - Pavlopoulos, G.A.*
AU  - van der Werf, S.*
AU  - Falter-Braun, P.
AU  - Aloy, P.*
AU  - Jacob, Y.*
AU  - Komarova, A.*
AU  - Sofianatos, Y.*
AU  - Coyaud, E.*
AU  - Demeret, C.*
C1  - 73784
C2  - 57220
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Multimodal SARS-CoV-2 interactome sketches the virus-host spatial organization.
JO  - Comm. Biol.
VL  - 8
IS  - 1
PB  - Nature Portfolio
PY  - 2025
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - Cholinergic modulation of brain reward circuitry appears to play a crucial role in information processing about salience as a key biological mechanism in obesity. However, changes in acetylcholine transmission leading to abnormal eating behavior have not been demonstrated in vivo in human obesity. Using simultaneous positron emission tomography and functional magnetic resonance imaging, we found an increased α4β2* nicotinic acetylcholine receptors (nAChR) availability in response to visually salient food cues in twenty individuals with obesity, particularly in those with high disinhibited eating behavior, whereas there was no change in sixteen volunteers served as normal weight control. This increase was accompanied by a shift from dorsal attention network activation in normal-weight controls to salience network activation in individuals with obesity indicating fundamental differences in sensory cue detection. These data should encourage further investigations into α4β2* nAChR in obesity, particularly with regard to treatment with nicotinic receptor agonists for weight loss targeting hedonic overeating.
AU  - Hesse, S.*
AU  - Rullmann, M.*
AU  - Günnewig, T.*
AU  - Schweickert de Palma, E.*
AU  - Burmeister, L.*
AU  - van Grinsven, M.*
AU  - Zientek, F.*
AU  - Luthardt, J.*
AU  - Hankir, M.K.*
AU  - Meyer, P.M.*
AU  - Becker, G.A.*
AU  - Patt, M.*
AU  - Brust, P.*
AU  - Pleger, B.*
AU  - Stumvoll, M.*
AU  - Hilbert, A.*
AU  - Blüher, M.
AU  - Sabri, O.*
C1  - 75584
C2  - 58227
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Cholinergic network modulation in disinhibited eating behavior.
JO  - Comm. Biol.
VL  - 8
IS  - 1
PB  - Nature Portfolio
PY  - 2025
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - Chromosomal instability (CIN) is a hallmark of cancer that drives metastasis, immune evasion and treatment resistance. CIN may result from chromosome mis-segregation errors and excessive chromatin is frequently packaged in micronuclei (MN), which can be enumerated to quantify CIN. The assessment of CIN remains a predominantly manual and time-consuming task. Here, we present micronuclAI, a pipeline for automated and reliable quantification of MN of varying size and morphology in cells stained only for DNA. micronuclAI can achieve close to human-level performance on various human and murine cancer cell line datasets. The pipeline achieved a Pearson's correlation of 0.9278 on images obtained at 10X magnification. We tested the approach in otherwise isogenic cell lines in which we genetically dialed up or down CIN rates, and on several publicly available image datasets where we achieved a Pearson's correlation of 0.9620. Given the increasing interest in developing therapies for CIN-driven cancers, this method provides an important, scalable, and rapid approach to quantifying CIN on images that are routinely obtained for research purposes. We release a GUI-implementation for easy access and utilization of the pipeline.
AU  - Ibarra-Arellano, M.A.*
AU  - Caprio, L.A.*
AU  - Hada, A.*
AU  - Stotzem, N.
AU  - Cai, L.L.*
AU  - Shah, S.B.*
AU  - Walsh, Z.H.*
AU  - Melms, J.C.*
AU  - Wünneman, F.*
AU  - Bestak, K.*
AU  - Mansaray, I.*
AU  - Izar, B.*
AU  - Schapiro, D.*
C1  - 73589
C2  - 57121
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - micronuclAI enables automated quantification of micronuclei for assessment of chromosomal instability.
JO  - Comm. Biol.
VL  - 8
IS  - 1
PB  - Nature Portfolio
PY  - 2025
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - To better characterize the potential biological mechanisms underlying insulin resistance (IR) and dementia, we derive cross-population and population specific polygenic scores [PSs] for fasting insulin and IR-related partitioned PSs [pPSs]. We conduct a cross-sectional study of the associations of these genetic scores with neurological outcomes in >17k participants (36% men, mean age 55 yrs) from the Trans-Omics for Precision Medicine (TOPMed) program (50% Non-Hispanic White, 23% Black/African American, 21% Hispanic/Latino American, and 4% Asian American). We report significant negative associations (P < 0.002) of the cross-population (P = 1.3 × 10-5) and European (PEA = 3.0 × 10-8) fasting insulin PSs with total cranial volume, and of a metabolic syndrome European PS with general cognitive function (BEA = -0.13, PEA = 0.0002) and lateral ventricular volume (BEA = 0.09, PEA = 0.002). We identify suggestive negative associations (P < 0.007) of metabolic syndrome and obesity pPSs with general cognitive function, and of lipodystrophy pPSs with total cranial volume. A higher genetic predisposition to IR is associated with lower brain size, and a genetic predisposition to specific IR-related type 2 diabetes subtypes, such as metabolic syndrome and mechanisms of IR mediated through obesity and lipodystrophy, is potentially involved in cognitive decline.
AU  - Sarnowski, C.*
AU  - Zhang, Y.*
AU  - Ammous, F.*
AU  - Shade, L.M.P.*
AU  - DiCorpo, D.*
AU  - Jian, X.*
AU  - Arnett, D.K.*
AU  - Austin, T.R.*
AU  - Beiser, A.*
AU  - Bis, J.C.*
AU  - Blangero, J.*
AU  - Boerwinkle, E.*
AU  - Bressler, J.*
AU  - Curran, J.E.*
AU  - DeCarli, C.S.*
AU  - Doddapaneni, H.*
AU  - Dupuis, J.*
AU  - Fardo, D.W.*
AU  - Florez, J.C.*
AU  - Gabriel, S.*
AU  - Gibbs, R.A.*
AU  - Glahn, D.C.*
AU  - Gupta, N.*
AU  - González, H.M.*
AU  - González, K.A.*
AU  - Hatzikotoulas, K.
AU  - Hayden, K.M.*
AU  - Heckbert, S.R.*
AU  - Hidalgo, B.*
AU  - Huerta-Chagoya, A.*
AU  - Hughes, T.M.*
AU  - Kardia, S.L.R.*
AU  - Kooperberg, C.L.*
AU  - Launer, L.J.*
AU  - Longstreth, W.T. Jr.*
AU  - Mandla, R.*
AU  - Mathias, R.A.*
AU  - Morris, A.P.
AU  - Mosley, T.H.*
AU  - Nasrallah, I.M.*
AU  - Nyquist, P.A.*
AU  - Psaty, B.M.*
AU  - Qi, Q.*
AU  - Raffield, L.M.*
AU  - Rayner, N.W.
AU  - Reiner, A.P.*
AU  - Satizabal, C.L.*
AU  - Selvin, E.*
AU  - Sevilla-Gonzalez, M.D.R.*
AU  - Smith, A.V.*
AU  - Smith, J.A.*
AU  - Smith, K.*
AU  - Snively, B.M.*
AU  - Southam, L.
AU  - Sofer, T.*
AU  - Suzuki, K.*
AU  - Taylor, H.J.*
AU  - Udler, M.S.*
AU  - Viaud-Martinez, K.A.*
AU  - Wassertheil-Smoller, S.*
AU  - Wood, A.C.*
AU  - Yanek, L.R.*
AU  - Yin, X.*
AU  - Manning, A.K.*
AU  - Rotter, J.I.*
AU  - Rich, S.S.*
AU  - Meigs, J.B.*
AU  - Fornage, M.*
AU  - Seshadri, S.*
AU  - Morrison, A.C.*
C1  - 75630
C2  - 58171
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Association of genetic scores related to insulin resistance with neurological outcomes in ancestrally diverse cohorts from the Trans-Omics for Precision Medicine (TOPMed) program.
JO  - Comm. Biol.
VL  - 8
IS  - 1
PB  - Nature Portfolio
PY  - 2025
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - Iron homoeostasis is tightly regulated, with hepcidin and soluble transferrin receptor (sTfR) playing significant roles. However, the genetic determinants of these traits and the biomedical consequences of iron homoeostasis variation are unclear. In a meta-analysis of 12 cohorts involving 91,675 participants, we found 43 genomic loci associated with either hepcidin or sTfR concentration, of which 15 previously unreported. Mapping to putative genes indicated involvement in iron-trait expression, erythropoiesis, immune response and cellular trafficking. Mendelian randomisation of 292 disease outcomes in 1,492,717 participants revealed associations of iron-related loci and iron status with selected health outcomes across multiple domains. These associations were largely driven by HFE, which was associated with the largest iron variation. Our findings enhance understanding of iron homoeostasis and its biomedical consequences, suggesting that lifelong exposure to higher iron levels is likely associated with lower risk of anaemia-related disorders and higher risk of genitourinary, musculoskeletal, infectious and neoplastic diseases.
AU  - Allara, E.*
AU  - Bell, S.*
AU  - Smith, R.*
AU  - Keene, S.J.*
AU  - Gill, D.*
AU  - Gaziano, L.*
AU  - Morselli Gysi, D.*
AU  - Wang, F.*
AU  - Tragante, V.*
AU  - Mason, A.*
AU  - Karthikeyan, S.*
AU  - Lumbers, R.T.*
AU  - Bonglack, E.*
AU  - Ouwehand, W.*
AU  - Roberts, D.J.*
AU  - Dowsett, J.*
AU  - Ostrowski, S.R.*
AU  - Larsen, M.H.*
AU  - Ullum, H.*
AU  - Pedersen, O.B.*
AU  - Brunak, S.*
AU  - Banasik, K.*
AU  - Erikstrup, C.*
AU  - Mitchell, J.*
AU  - Fuchsberger, C.*
AU  - Pattaro, C.*
AU  - Pramstaller, P.P.*
AU  - Girelli, D.*
AU  - Arvas, M.*
AU  - Toivonen, J.*
AU  - Molnos, S.
AU  - Peters, A.
AU  - Polasek, O.*
AU  - Rudan, I.*
AU  - Hayward, C.*
AU  - McDonnell, C.*
AU  - Pirastu, N.*
AU  - Wilson, J.F.*
AU  - van den Hurk, K.*
AU  - Quee, F.*
AU  - Ferrucci, L.*
AU  - Bandinelli, S.*
AU  - Tanaka, T.*
AU  - Girotto, G.*
AU  - Concas, M.P.*
AU  - Pecori, A.*
AU  - Verweij, N.*
AU  - van der Harst, P.*
AU  - van de Vegte, Y.J.*
AU  - Kiemeney, L.A.*
AU  - Sweep, F.C.*
AU  - Galesloot, T.E.*
AU  - Sulem, P.*
AU  - Gudbjartsson, D.*
AU  - Ferkingstad, E.*
AU  - Djousse, L.*
AU  - Cho, K.*
AU  - Inouye, M.*
AU  - Burgess, S.*
AU  - Benyamin, B.*
AU  - Oexle, K.
AU  - Swinkels, D.W.*
AU  - Stefansson, K.*
AU  - Magnusson, M.*
AU  - Ganna, A.*
AU  - Gaziano, M.*
AU  - Ivey, K.*
AU  - Danesh, J.*
AU  - Pereira, A.*
AU  - Wood, A.M.*
AU  - Butterworth, A.S.*
AU  - di Angelantonio, E.*
C1  - 72686
C2  - 56700
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Novel loci and biomedical consequences of iron homoeostasis variation.
JO  - Comm. Biol.
VL  - 7
IS  - 1
PB  - Nature Portfolio
PY  - 2024
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - Sexual dimorphism arises because of divergent fitness optima between the sexes. Phenotypic divergence between sexes can range from mild to extreme. Fireflies, bioluminescent beetles, present various degrees of sexual dimorphism, with species showing very mild sexual dimorphism to species presenting female-specific neoteny, posing a unique framework to investigate the evolution of sexually dimorphic traits across species. In this work, we present novel assembled genomes of two firefly species, Lamprohiza splendidula and Luciola italica, species with different degrees of sexual dimorphism. We uncover high synteny conservation of the X-chromosome across ~ 180 Mya and find full X-chromosome dosage compensation in our two fireflies, hinting at common mechanism upregulating the single male X-chromosome. Different degrees of sex-biased expressed genes were found across two body parts showing different proportions of expression conservation between species. Interestingly, we do not find X-chromosome enrichment of sex-biased genes, but retrieve autosomal enrichment of sex-biased genes. We further uncover higher nucleotide diversity in the intronic regions of sex-biased genes, hinting at a maintenance of heterozygosity through sexual selection. We identify different levels of sex-biased gene expression divergence including a set of genes showing conserved sex-biased gene expression between species. Divergent and conserved sex-biased genes are good candidates to test their role in the maintenance of sexually dimorphic traits.
AU  - Catalán, A.*
AU  - Gygax, D.
AU  - Rodríguez-Montes, L.*
AU  - Hinzke, T.*
AU  - Hoff, K.J.*
AU  - Duchen, P.*
C1  - 71316
C2  - 56071
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Two novel genomes of fireflies with different degrees of sexual dimorphism reveal insights into sex-biased gene expression and dosage compensation.
JO  - Comm. Biol.
VL  - 7
IS  - 1
PB  - Nature Portfolio
PY  - 2024
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - Calpains are cysteine proteases that control cell fate transitions whose loss of function causes severe, pleiotropic phenotypes in eukaryotes. Although mainly considered as modulatory proteases, human calpain targets are directed to the N-end rule degradation pathway. Several such targets are transcription factors, hinting at a gene-regulatory role. Here, we analyze the gene-regulatory networks of the moss Physcomitrium patens and characterize the regulons that are misregulated in mutants of the calpain DEFECTIVE KERNEL1 (DEK1). Predicted cleavage patterns of the regulatory hierarchies in five DEK1-controlled subnetworks are consistent with a pleiotropic and regulatory role during cell fate transitions targeting multiple functions. Network structure suggests DEK1-gated sequential transitions between cell fates in 2D-to-3D development. Our method combines comprehensive phenotyping, transcriptomics and data science to dissect phenotypic traits, and our model explains the protease function as a switch gatekeeping cell fate transitions potentially also beyond plant development.
AU  - Demko, V.*
AU  - Belova, T.*
AU  - Messerer, M.
AU  - Hvidsten, T.R.*
AU  - Perroud, P.F.*
AU  - Ako, A.E.*
AU  - Johansen, W.*
AU  - Mayer, K.F.X.
AU  - Olsen, O.A.*
AU  - Lang, D.
C1  - 70084
C2  - 55411
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Regulation of developmental gatekeeping and cell fate transition by the calpain protease DEK1 in Physcomitrium patens.
JO  - Comm. Biol.
VL  - 7
IS  - 1
PB  - Nature Portfolio
PY  - 2024
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - Activating brown adipose tissue (BAT) improves systemic metabolism, making it a promising target for metabolic syndrome. BAT is activated by 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME), which we previously identified to be inversely associated with BMI and which directly improves metabolism in multiple tissues. Here we profile plasma lipidomics from 83 people and test which lipids' association with BMI replicates in a concordant direction using our novel tool ScreenDMT, whose power and validity we demonstrate via mathematical proofs and simulations. We find that the linoleic acid diols 12,13-diHOME and 9,10-diHOME are both replicably inversely associated with BMI and mechanistically activate calcium influx in mouse brown and white adipocytes in vitro, which implicates this signaling pathway and 9,10-diHOME as candidate therapeutic targets. ScreenDMT can be applied to test directional mediation, directional replication, and qualitative interactions, such as identifying biomarkers whose association is shared (replication) or opposite (qualitative interaction) across diverse populations.
AU  - Dreyfuss, J.M.*
AU  - Djordjilović, V.*
AU  - Pan, H.*
AU  - Bussberg, V.*
AU  - MacDonald, A.M.*
AU  - Narain, N.R.*
AU  - Kiebish, M.A.*
AU  - Blüher, M.
AU  - Tseng, Y.H.*
AU  - Lynes, M.D.*
C1  - 71481
C2  - 56208
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - ScreenDMT reveals DiHOMEs are replicably inversely associated with BMI and stimulate adipocyte calcium influx.
JO  - Comm. Biol.
VL  - 7
IS  - 1
PB  - Nature Portfolio
PY  - 2024
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - Microtubule associated proteins (MAPs) are widely expressed in the central nervous system, and have established roles in cell proliferation, myelination, neurite formation, axon specification, outgrowth, dendrite, and synapse formation. We report eleven individuals from seven families harboring predicted pathogenic biallelic, de novo, and heterozygous variants in the NAV3 gene, which encodes the microtubule positive tip protein neuron navigator 3 (NAV3). All affected individuals have intellectual disability (ID), microcephaly, skeletal deformities, ocular anomalies, and behavioral issues. In mouse brain, Nav3 is expressed throughout the nervous system, with more prominent signatures in postmitotic, excitatory, inhibiting, and sensory neurons. When overexpressed in HEK293T and COS7 cells, pathogenic variants impaired NAV3 ability to stabilize microtubules. Further, knocking-down nav3 in zebrafish led to severe morphological defects, microcephaly, impaired neuronal growth, and behavioral impairment, which were rescued with co-injection of WT NAV3 mRNA and not by transcripts encoding the pathogenic variants. Our findings establish the role of NAV3 in neurodevelopmental disorders, and reveal its involvement in neuronal morphogenesis, and neuromuscular responses.
AU  - Ghaffar, A.*
AU  - Akhter, T.*
AU  - Strømme, P.*
AU  - Misceo, D.*
AU  - Khan, A.*
AU  - Frengen, E.*
AU  - Umair, M.*
AU  - Isidor, B.*
AU  - Cogné, B.*
AU  - Khan, A.A.*
AU  - Bruel, A.L.*
AU  - Sorlin, A.*
AU  - Kuentz, P.*
AU  - Chiaverini, C.*
AU  - Innes, A.M.*
AU  - Zech, M.
AU  - Baláž, M.*
AU  - Havránková, P.*
AU  - Jech, R.*
AU  - Ahmed, Z.M.*
AU  - Riazuddin, S.*
C1  - 71071
C2  - 56004
TI  - Variants of NAV3, a neuronal morphogenesis protein, cause intellectual disability, developmental delay, and microcephaly.
JO  - Comm. Biol.
VL  - 7
IS  - 1
PY  - 2024
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - Aggregation of the human islet amyloid polypeptide (hIAPP) contributes to the development and progression of Type 2 Diabetes (T2D). hIAPP aggregates within a few hours at few micromolar concentration in vitro but exists at millimolar concentrations in vivo. Natively occurring inhibitors of hIAPP aggregation might therefore provide a model for drug design against amyloid formation associated with T2D. Here, we describe the combined ability of low pH, zinc, and insulin to inhibit hIAPP fibrillation. Insulin dose-dependently slows hIAPP aggregation near neutral pH but had less effect on the aggregation kinetics at acidic pH. We determine that insulin alters hIAPP aggregation in two manners. First, insulin diverts the aggregation pathway to large nonfibrillar aggregates with ThT-positive molecular structure, rather than to amyloid fibrils. Second, soluble insulin suppresses hIAPP dimer formation, which is an important early aggregation event. Further, we observe that zinc significantly modulates the inhibition of hIAPP aggregation by insulin. We hypothesize that this effect arose from controlling the oligomeric state of insulin and show that hIAPP interacts more strongly with monomeric than oligomeric insulin.
AU  - McCalpin, S.D.*
AU  - Khemtemourian, L.*
AU  - Suladze, S.
AU  - Ivanova, M.I.*
AU  - Reif, B.
AU  - Ramamoorthy, A.*
C1  - 70947
C2  - 55983
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Zinc and pH modulate the ability of insulin to inhibit aggregation of islet amyloid polypeptide.
JO  - Comm. Biol.
VL  - 7
IS  - 1
PB  - Nature Portfolio
PY  - 2024
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - Propofol and midazolam are the current standard of care for prolonged sedation in Intensive Care Units (ICUs). However, the effects and mechanism of these sedatives in brain tissue are unclear. Herein, the development of an ICU patient-on-a-chip platform to elucidate those effects is reported. The humanized neural tissue compartment combines mast cells differentiated from human induced pluripotent stem cells (hiPSCs) with cerebral organoids in a three-dimensional (3D) matrix, which is covered with a membrane populated with human cerebral microvascular endothelial cells (hCMEC/D3) that separates the tissue chamber from the vascular lumen, where sedatives were infused for four days to evaluate neurotoxicity and cell-mediated immune responses. Subsequent to propofol administration, gene expressions of CD40 and TNF-α in mast cells, AIF1 in microglia and GFAP/S100B/OLIG2/MBP in macroglia were elevated, as well as NOS2, CD80, CD40, CD68, IL6 and TNF-α mediated proinflammation is noted in cerebral organoids, which resulted in higher expressions of GJB1, GABA-A and NMDAR1 in the tissue construct of the platform. Besides, midazolam administration stimulated expression of CD40 and CD203c+ reactivated mast cell proliferation and compromised BBB permeability and decreased TEER values with higher barrier disruption, whereas increased populations of CD11b+ microglia, higher expressions of GFAP/DLG4/GJB1 and GABA-A-/NMDAR1- identities, as well as glutamate related neurotoxicity and IL1B, IFNG, IFNA1, IL6 genes mediated proinflammation, resulting in increased apoptotic zones are observed in cerebral organoids. These results suggest that different sedatives cause variations in cell type activation that modulate different pathways related to neuroinflammation and neurotoxicity in the ICU patient-on-chip platform.
AU  - Saglam-Metiner, P.*
AU  - Yanasik, S.*
AU  - Odabasi, Y.C.*
AU  - Modamio Chamarro, J.
AU  - Negwer, M.
AU  - Biray-Avci, C.*
AU  - Guler, A.T.*
AU  - Ertürk, A.
AU  - Yildirim, E.*
AU  - Yesil-Celiktas, O.*
C1  - 72672
C2  - 56705
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - ICU patient-on-a-chip emulating orchestration of mast cells and cerebral organoids in neuroinflammation.
JO  - Comm. Biol.
VL  - 7
IS  - 1
PB  - Nature Portfolio
PY  - 2024
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - Overweight and obesity are associated with altered stress reactivity and increased inflammation. However, it is not known whether stress-induced changes in brain function scale with BMI and if such associations are driven by peripheral cytokines. Here, we investigate multimodal stress responses in a large transdiagnostic sample using predictive modeling based on spatio-temporal profiles of stress-induced changes in activation and functional connectivity. BMI is associated with increased brain responses as well as greater negative affect after stress and individual response profiles are associated with BMI in females (pperm < 0.001), but not males. Although stress-induced changes reflecting BMI are associated with baseline cortisol, there is no robust association with peripheral cytokines. To conclude, alterations in body weight and energy metabolism might scale acute brain responses to stress more strongly in females compared to males, echoing observational studies. Our findings highlight sex-dependent associations of stress with differences in endocrine markers, largely independent of peripheral inflammation.
AU  - Kühnel, A.*
AU  - Hagenberg, J.
AU  - Knauer-Arloth, J.
AU  - Ködel, M.*
AU  - Czisch, M.*
AU  - Sämann, P.G.*
AU  - Binder, E.B.*
AU  - Kroemer, N.B.*
C1  - 68666
C2  - 54871
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Stress-induced brain responses are associated with BMI in women.
JO  - Comm. Biol.
VL  - 6
IS  - 1
PB  - Nature Portfolio
PY  - 2023
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - Aberrant DNA methylation accompanies genetic alterations during oncogenesis and tumour homeostasis and contributes to the transcriptional deregulation of key signalling pathways in cancer. Despite increasing efforts in DNA methylation profiling of cancer patients, there is still a lack of epigenetic biomarkers to predict treatment efficacy. To address this, we analyse 721 cancer cell lines across 22 cancer types treated with 453 anti-cancer compounds. We systematically detect the predictive component of DNA methylation in the context of transcriptional and mutational patterns, i.e., in total 19 DNA methylation biomarkers across 17 drugs and five cancer types. DNA methylation constitutes drug sensitivity biomarkers by mediating the expression of proximal genes, thereby enhancing biological signals across multi-omics data modalities. Our method reproduces anticipated associations, and in addition, we find that the NEK9 promoter hypermethylation may confer sensitivity to the NEDD8-activating enzyme (NAE) inhibitor pevonedistat in melanoma through downregulation of NEK9. In summary, we envision that epigenomics will refine existing patient stratification, thus empowering the next generation of precision oncology.
AU  - Ohnmacht, A.
AU  - Rajamani, A.*
AU  - Avar, G.
AU  - Kutkaite, G.
AU  - Gonçalves, E.*
AU  - Saur, D.*
AU  - Menden, M.P.
C1  - 68013
C2  - 54491
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - The pharmacoepigenomic landscape of cancer cell lines reveals the epigenetic component of drug sensitivity.
JO  - Comm. Biol.
VL  - 6
IS  - 1
PB  - Nature Portfolio
PY  - 2023
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - Several drug screening campaigns identified Calpeptin as a drug candidate against SARS-CoV-2. Initially reported to target the viral main protease (Mpro), its moderate activity in Mpro inhibition assays hints at a second target. Indeed, we show that Calpeptin is an extremely potent cysteine cathepsin inhibitor, a finding additionally supported by X-ray crystallography. Cell infection assays proved Calpeptin's efficacy against SARS-CoV-2. Treatment of SARS-CoV-2-infected Golden Syrian hamsters with sulfonated Calpeptin at a dose of 1 mg/kg body weight reduces the viral load in the trachea. Despite a higher risk of side effects, an intrinsic advantage in targeting host proteins is their mutational stability in contrast to highly mutable viral targets. Here we show that the inhibition of cathepsins, a protein family of the host organism, by calpeptin is a promising approach for the treatment of SARS-CoV-2 and potentially other viral infections.
AU  - Reinke, P.Y.A.*
AU  - de Souza, E.E.*
AU  - Gunther, S.*
AU  - Falke, S.*
AU  - Lieske, J.*
AU  - Ewert, W.*
AU  - Loboda, J.*
AU  - Herrmann, A.
AU  - Rahmani Mashhour, A.*
AU  - Karničar, K.*
AU  - Usenik, A.*
AU  - Lindič, N.*
AU  - Sekirnik, A.*
AU  - Botosso, V.F.*
AU  - Santelli, G.M.M.*
AU  - Kapronezai, J.*
AU  - de Araújo, M.V.*
AU  - Silva-Pereira, T.T.*
AU  - Filho, A.F.S.*
AU  - Tavares, M.S.*
AU  - Flórez-Álvarez, L.*
AU  - de Oliveira, D.B.L.*
AU  - Durigon, E.L.*
AU  - Giaretta, P.R.*
AU  - Heinemann, M.B.*
AU  - Hauser, M.*
AU  - Seychell, B.*
AU  - Böhler, H.*
AU  - Rut, W.*
AU  - Drag, M.*
AU  - Beck, T.*
AU  - Cox, R.*
AU  - Chapman, H.N.*
AU  - Betzel, C.*
AU  - Brehm, W.*
AU  - Hinrichs, W.*
AU  - Ebert, G.
AU  - Latham, S.L.*
AU  - Guimarães, A.M.S.*
AU  - Turk, D.*
AU  - Wrenger, C.*
AU  - Meents, A.*
C1  - 68642
C2  - 54845
TI  - Calpeptin is a potent cathepsin inhibitor and drug candidate for SARS-CoV-2 infections.
JO  - Comm. Biol.
VL  - 6
IS  - 1
PY  - 2023
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - The angiotensin-converting enzyme 2 (ACE2) is a viral receptor used by sarbecoviruses to infect cells. Fusion proteins comprising extracellular ACE2 domains and the Fc part of immunoglobulins exhibit high virus neutralization efficiency, but the structure and stability of these molecules are poorly understood. We show that although the hinge between the ACE2 and the IgG4-Fc is highly flexible, the conformational dynamics of the two ACE2 domains is restricted by their association. Interestingly, the conformational stability of the ACE2 moiety is much lower than that of the Fc part. We found that chemical compounds binding to ACE2, such as DX600 and MLN4760, can be used to strongly increase the thermal stability of the ACE2 by different mechanisms. Together, our findings reveal a general concept for stabilizing the labile receptor segments of therapeutic antiviral fusion proteins by chemical compounds.
AU  - Svilenov, H.L.*
AU  - Delhommel, F.
AU  - Siebenmorgen, T.
AU  - Rührnößl, F.*
AU  - Popowicz, G.M.
AU  - Reiter, A.*
AU  - Sattler, M.
AU  - Brockmeyer, C.*
AU  - Buchner, J.*
C1  - 67620
C2  - 53927
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Extrinsic stabilization of antiviral ACE2-Fc fusion proteins targeting SARS-CoV-2.
JO  - Comm. Biol.
VL  - 6
IS  - 1
PB  - Nature Portfolio
PY  - 2023
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - Dysregulation of sphingomyelin and ceramide metabolism have been implicated in Alzheimer's disease. Genome-wide and transcriptome-wide association studies have identified various genes and genetic variants in lipid metabolism that are associated with Alzheimer's disease. However, the molecular mechanisms of sphingomyelin and ceramide disruption remain to be determined. We focus on the sphingolipid pathway and carry out multi-omics analyses to identify central and peripheral metabolic changes in Alzheimer's patients, correlating them to imaging features. Our multi-omics approach is based on (a) 2114 human post-mortem brain transcriptomics to identify differentially expressed genes; (b) in silico metabolic flux analysis on context-specific metabolic networks identified differential reaction fluxes; (c) multimodal neuroimaging analysis on 1576 participants to associate genetic variants in sphingomyelin pathway with Alzheimer's disease pathogenesis; (d) plasma metabolomic and lipidomic analysis to identify associations of lipid species with dysregulation in Alzheimer's; and (e) metabolite genome-wide association studies to define receptors within the pathway as a potential drug target. We validate our hypothesis in amyloidogenic APP/PS1 mice and show prolonged exposure to fingolimod alleviated synaptic plasticity and cognitive impairment in mice. Our integrative multi-omics approach identifies potential targets in the sphingomyelin pathway and suggests modulators of S1P metabolism as possible candidates for Alzheimer's disease treatment.
AU  - Baloni, P.*
AU  - Arnold, M.
AU  - Buitrago, L.E.*
AU  - Nho, K.*
AU  - Moreno, H.D.*
AU  - Huynh, K.*
AU  - Brauner, B.
AU  - Louie, G.*
AU  - Kueider-Paisley, A.*
AU  - Suhre, K.*
AU  - Saykin, A.J.*
AU  - Ekroos, K.*
AU  - Meikle, P.J.*
AU  - Hood, L.*
AU  - Price, N.D.*
AU  - Doraiswamy, P.M.*
AU  - Funk, C.C.*
AU  - Hernández, A.I.*
AU  - Kastenmüller, G.
AU  - Baillie, R.*
AU  - Han, X.*
AU  - Kaddurah-Daouk, R.*
C1  - 66337
C2  - 53140
TI  - Multi-Omic analyses characterize the ceramide/sphingomyelin pathway as a therapeutic target in Alzheimer's disease.
JO  - Comm. Biol.
VL  - 5
IS  - 1
PY  - 2022
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - Dimensionality reduction approaches are commonly used for the deconvolution of high-dimensional metabolomics datasets into underlying core metabolic processes. However, current state-of-the-art methods are widely incapable of detecting nonlinearities in metabolomics data. Variational Autoencoders (VAEs) are a deep learning method designed to learn nonlinear latent representations which generalize to unseen data. Here, we trained a VAE on a large-scale metabolomics population cohort of human blood samples consisting of over 4500 individuals. We analyzed the pathway composition of the latent space using a global feature importance score, which demonstrated that latent dimensions represent distinct cellular processes. To demonstrate model generalizability, we generated latent representations of unseen metabolomics datasets on type 2 diabetes, acute myeloid leukemia, and schizophrenia and found significant correlations with clinical patient groups. Notably, the VAE representations showed stronger effects than latent dimensions derived by linear and non-linear principal component analysis. Taken together, we demonstrate that the VAE is a powerful method that learns biologically meaningful, nonlinear, and transferrable latent representations of metabolomics data.
AU  - Gomari, D.P.
AU  - Schweickart, A.*
AU  - Cerchietti, L.*
AU  - Paietta, E.*
AU  - Fernandez, H.H.*
AU  - Al-Amin, H.*
AU  - Suhre, K.*
AU  - Krumsiek, J.*
C1  - 65586
C2  - 52388
TI  - Variational autoencoders learn transferrable representations of metabolomics data.
JO  - Comm. Biol.
VL  - 5
IS  - 1
PY  - 2022
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - South Asians are at high risk of developing type 2 diabetes (T2D). We carried out a genome-wide association meta-analysis with South Asian T2D cases (n = 16,677) and controls (n = 33,856), followed by combined analyses with Europeans (neff = 231,420). We identify 21 novel genetic loci for significant association with T2D (P = 4.7 × 10-8 to 5.2 × 10-12), to the best of our knowledge at the point of analysis. The loci are enriched for regulatory features, including DNA methylation and gene expression in relevant tissues, and highlight CHMP4B, PDHB, LRIG1 and other genes linked to adiposity and glucose metabolism. A polygenic risk score based on South Asian-derived summary statistics shows ~4-fold higher risk for T2D between the top and bottom quartile. Our results provide further insights into the genetic mechanisms underlying T2D, and highlight the opportunities for discovery from joint analysis of data from across ancestral populations.
AU  - Loh, M.*
AU  - Zhang, W.*
AU  - Ng, H.K.*
AU  - Schmid, K.
AU  - Lamri, A.*
AU  - Tong, L.*
AU  - Ahmad, M.*
AU  - Lee, J.J.*
AU  - Ng, M.C.Y.*
AU  - Petty, L.E.*
AU  - Spracklen, C.N.*
AU  - Takeuchi, F.*
AU  - Islam, M.T.*
AU  - Jasmine, F.*
AU  - Kasturiratne, A.*
AU  - Kibriya, M.G.*
AU  - Mohlke, K.L.*
AU  - Paré, G.*
AU  - Prasad, G.*
AU  - Shahriar, M.*
AU  - Chee, M.L.*
AU  - de Silva, H.J.*
AU  - Engert, J.C.*
AU  - Gerstein, H.C.*
AU  - Mani, K.R.*
AU  - Sabanayagam, C.*
AU  - Vujkovic, M.R.*
AU  - Wickremasinghe, A.R.*
AU  - Wong, T.Y.*
AU  - Yajnik, C.S.*
AU  - Yusuf, S.*
AU  - Ahsan, H.*
AU  - Bharadwaj, D.*
AU  - Anand, S.S.*
AU  - Below, J.E.*
AU  - Boehnke, M.*
AU  - Bowden, D.W.*
AU  - Chandak, G.R.*
AU  - Cheng, C.Y.*
AU  - Kato, N.*
AU  - Mahajan, A.*
AU  - Sim, X.*
AU  - McCarthy, M.I.*
AU  - Morris, A.P.*
AU  - Kooner, J.S.*
AU  - Saleheen, D.*
C1  - 64803
C2  - 52015
TI  - Identification of genetic effects underlying type 2 diabetes in South Asian and European populations.
JO  - Comm. Biol.
VL  - 5
IS  - 1
PY  - 2022
SN  - 2399-3642
ER  - 

TY  - JOUR
AU  - Loh, M.*
AU  - Zhang, W.*
AU  - Ng, H.K.*
AU  - Schmid, K.
AU  - Lamri, A.*
AU  - Tong, L.*
AU  - Ahmad, M.*
AU  - Lee, J.J.*
AU  - Ng, M.C.Y.*
AU  - Petty, L.E.*
AU  - Spracklen, C.N.*
AU  - Takeuchi, F.*
AU  - Islam, M.T.*
AU  - Jasmine, F.*
AU  - Kasturiratne, A.*
AU  - Kibriya, M.G.*
AU  - Mohlke, K.L.*
AU  - Paré, G.*
AU  - Prasad, G.*
AU  - Shahriar, M.*
AU  - Chee, M.L.*
AU  - de Silva, H.J.*
AU  - Engert, J.C.*
AU  - Gerstein, H.C.*
AU  - Mani, K.R.*
AU  - Sabanayagam, C.*
AU  - Vujkovic, M.R.*
AU  - Wickremasinghe, A.R.*
AU  - Wong, T.Y.*
AU  - Yajnik, C.S.*
AU  - Yusuf, S.*
AU  - Ahsan, H.*
AU  - Bharadwaj, D.*
AU  - Anand, S.S.*
AU  - Below, J.E.*
AU  - Boehnke, M.*
AU  - Bowden, D.W.*
AU  - Chandak, G.R.*
AU  - Cheng, C.Y.*
AU  - Kato, N.*
AU  - Mahajan, A.*
AU  - Sim, X.*
AU  - McCarthy, M.I.*
AU  - Morris, A.P.*
AU  - Kooner, J.S.*
AU  - Saleheen, D.*
C1  - 64967
C2  - 52016
TI  - Erratum: Author Correction: Identification of genetic effects underlying type 2 diabetes in South Asian and European populations (Communications biology (2022) 5 1 (329)).
JO  - Comm. Biol.
VL  - 5
IS  - 1
PY  - 2022
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - Suitable animal models are essential for translational research, especially in the case of complex, multifactorial conditions, such as obesity. The non-inbred mouse (Mus musculus) line Titan, also known as DU6, is one of the world’s longest selection experiments for high body mass and was previously described as a model for metabolic healthy (benign) obesity. The present study further characterizes the geno- and phenotypes of this non-inbred mouse line and tests its suitability as an interventional obesity model. In contrast to previous findings, our data suggest that Titan mice are metabolically unhealthy obese and short-lived. Line-specific patterns of genetic invariability are in accordance with observed phenotypic traits. Titan mice also show modifications in the liver transcriptome, proteome, and epigenome linked to metabolic (dys)regulations. Importantly, dietary intervention partially reversed the metabolic phenotype in Titan mice and significantly extended their life expectancy. Therefore, the Titan mouse line is a valuable resource for translational and interventional obesity research.
AU  - Müller-Eigner, A.*
AU  - Sanz-Moreno, A.
AU  - de-Diego, I.*
AU  - Venkatasubramani, A.V.*
AU  - Langhammer, M.*
AU  - Gerlini, R.
AU  - Rathkolb, B.
AU  - Aguilar-Pimentel, J.A.
AU  - Klein-Rodewald, T.
AU  - Calzada-Wack, J.
AU  - Becker, L.
AU  - Palma-Vera, S.*
AU  - Gille, B.*
AU  - Forne, I.*
AU  - Imhof, A.*
AU  - Meng, C.*
AU  - Ludwig, C.*
AU  - Koch, F.*
AU  - Heiker, J.T.
AU  - Kuhla, A.*
AU  - Caton, V.*
AU  - Brenmoehl, J.*
AU  - Reyer, H.*
AU  - Schoen, J.*
AU  - Fuchs, H.
AU  - Gailus-Durner, V.
AU  - Hoeflich, A.*
AU  - Hrabě de Angelis, M.
AU  - Peleg, S.*
C1  - 64953
C2  - 52031
TI  - Dietary intervention improves health metrics and life expectancy of the genetically obese Titan mouse.
JO  - Comm. Biol.
VL  - 5
IS  - 1
PY  - 2022
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - Coronavirus infections are a world-wide threat to human health. A promising strategy to develop a broadly active antiviral is the use of fusion proteins consisting of an antibody IgG Fc region and a human ACE2 domain to which the viral spike proteins bind. Here we create antiviral fusion proteins based on IgM scaffolds. The hexameric ACE2-IgM-Fc fusions can be efficiently produced in mammalian cells and they neutralize the infectious virus with picomolar affinity thus surpassing monomeric ACE2-IgM-Fc by up to 96-fold in potency. In addition, the ACE2-IgM fusion shows increased neutralization efficiency for the highly infectious SARS-CoV-2 omicron variant in comparison to prototypic SARS-CoV-2. Taken together, these multimeric IgM fusions proteins are a powerful weapon to fight coronavirus infections.
AU  - Svilenov, H.L.*
AU  - Bester, R.
AU  - Sacherl, J.
AU  - Absmeier, R.*
AU  - Peters, C.*
AU  - Protzer, U.
AU  - Brockmeyer, C.*
AU  - Buchner, J.*
C1  - 66675
C2  - 53264
TI  - Multimeric ACE2-IgM fusions as broadly active antivirals that potently neutralize SARS-CoV-2 variants.
JO  - Comm. Biol.
VL  - 5
IS  - 1
PY  - 2022
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - Oat (Avena sativa L.) is an important and nutritious cereal crop, and there is a growing need to identify genes that contribute to improved oat varieties. Here we utilize a newly sequenced and annotated oat reference genome to locate and characterize quantitative trait loci (QTLs) affecting agronomic and grain-quality traits in five oat populations. We find strong and significant associations between the positions of candidate genes and QTL that affect heading date, as well as those that influence the concentrations of oil and β-glucan in the grain. We examine genome-wide recombination profiles to confirm the presence of a large, unbalanced translocation from chromosome 1 C to 1 A, and a possible inversion on chromosome 7D. Such chromosome rearrangements appear to be common in oat, where they cause pseudo-linkage and recombination suppression, affecting the segregation, localization, and deployment of QTLs in breeding programs.
AU  - Tinker, N.A.*
AU  - Wight, C.P.*
AU  - Bekele, W.A.*
AU  - Yan, W.*
AU  - Jellen, E.N.*
AU  - Renhuldt, N.T.*
AU  - Sirijovski, N.*
AU  - Lux, T.
AU  - Spannagl, M.
AU  - Mascher, M.*
C1  - 65085
C2  - 52663
TI  - Genome analysis in Avena sativa reveals hidden breeding barriers and opportunities for oat improvement.
JO  - Comm. Biol.
VL  - 5
IS  - 1
PY  - 2022
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (nDM = 178,691, nnoDM = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.
AU  - Winkler, T.W.*
AU  - Rasheed, H.*
AU  - Teumer, A.*
AU  - Gorski, M.*
AU  - Rowan, B.X.*
AU  - Stanzick, K.J.*
AU  - Thomas, L.F.*
AU  - Tin, A.*
AU  - Hoppmann, A.*
AU  - Chu, A.Y.*
AU  - Tayo, B.O.*
AU  - Thio, C.H.L.*
AU  - Cusi, D.*
AU  - Chai, J.F.*
AU  - Sieber, K.B.*
AU  - Horn, K.*
AU  - Li, M.*
AU  - Scholz, M.*
AU  - Cocca, M.*
AU  - Wuttke, M.*
AU  - van der Most, P.J.*
AU  - Yang, Q.*
AU  - Ghasemi, S.*
AU  - Nutile, T.*
AU  - Li, Y.*
AU  - Pontali, G.*
AU  - Günther, F.*
AU  - Dehghan, A.*
AU  - Correa, A.*
AU  - Parsa, A.*
AU  - Feresin, A.*
AU  - de Vries, A.P.J.*
AU  - Zonderman, A.B.*
AU  - Smith, A.V.*
AU  - Oldehinkel, A.J.*
AU  - de Grandi, A.*
AU  - Rosenkranz, A.R.*
AU  - Franke, A.*
AU  - Teren, A.*
AU  - Metspalu, A.*
AU  - Hicks, A.A.*
AU  - Morris, A.P.*
AU  - Tönjes, A.*
AU  - Morgan, A.*
AU  - Podgornaia, A.I.*
AU  - Peters, A.
AU  - Körner, A.*
AU  - Mahajan, A.*
AU  - Campbell, A.*
AU  - Freedman, B.I.*
AU  - Spedicati, B.*
AU  - Ponte, B.*
AU  - Schöttker, B.*
AU  - Brumpton, B.M.*
AU  - Banas, B.*
AU  - Krämer, B.K.*
AU  - Jung, B.*
AU  - Asvold, B.O.*
AU  - Smith, B.H.*
AU  - Ning, B.*
AU  - Penninx, B.W.J.H.*
AU  - Vanderwerff, B.R.*
AU  - Psaty, B.M.*
AU  - Kammerer, C.M.*
AU  - Langefeld, C.D.*
AU  - Hayward, C.*
AU  - Spracklen, C.N.*
AU  - Robinson-Cohen, C.*
AU  - Hartman, C.A.*
AU  - Lindgren, C.M.*
AU  - Wang, C.*
AU  - Sabanayagam, C.*
AU  - Heng, C.K.*
AU  - Lanzani, C.*
AU  - Khor, C.C.*
AU  - Cheng, C.Y.*
AU  - Fuchsberger, C.*
AU  - Gieger, C.
AU  - Shaffer, C.M.*
AU  - Schulz, C.A.*
AU  - Willer, C.J.*
AU  - Chasman, D.I.*
AU  - Gudbjartsson, D.F.*
AU  - Ruggiero, D.*
AU  - Toniolo, D.*
AU  - Czamara, D.*
AU  - Porteous, D.J.*
AU  - Waterworth, D.M.*
AU  - Mascalzoni, D.*
AU  - Mook-Kanamori, D.O.*
AU  - Reilly, D.F.*
AU  - Daw, E.W.*
AU  - Hofer, E.*
AU  - Boerwinkle, E.*
AU  - Salvi, E.*
AU  - Bottinger, E.P.*
AU  - Tai, E.S.*
AU  - Catamo, E.*
AU  - Rizzi, F.*
AU  - Guo, F.*
AU  - Rivadeneira, F.*
AU  - Guilianini, F.*
AU  - Sveinbjornsson, G.*
AU  - Ehret, G.*
AU  - Waeber, G.*
AU  - Biino, G.*
AU  - Girotto, G.*
AU  - Pistis, G.*
AU  - Nadkarni, G.N.*
AU  - Delgado, G.E.*
AU  - Montgomery, G.W.*
AU  - Snieder, H.*
AU  - Campbell, H.*
AU  - White, H.D.*
AU  - Gao, H.*
AU  - Stringham, H.M.*
AU  - Schmidt, H.*
AU  - Li, H.*
AU  - Brenner, H.*
AU  - Holm, H.*
AU  - Kirsten, H.*
AU  - Kramer, H.*
AU  - Rudan, I.*
AU  - Nolte, I.M.*
AU  - Tzoulaki, I.*
AU  - Olafsson, I.*
AU  - Martins, J.*
AU  - Cook, J.P.*
AU  - Wilson, J.F.*
AU  - Halbritter, J.*
AU  - Felix, J.F.*
AU  - Divers, J.*
AU  - Kooner, J.S.*
AU  - Lee, J.J.*
AU  - O'Connell, J.*
AU  - Rotter, J.I.*
AU  - Liu, J.*
AU  - Xu, J.*
AU  - Thiery, J.*
AU  - Ärnlöv, J.*
AU  - Kuusisto, J.*
AU  - Jakobsdottir, J.*
AU  - Tremblay, J.*
AU  - Whitfield, J.B.*
AU  - Gaziano, J.M.*
AU  - Marten, J.*
AU  - Coresh, J.*
AU  - Jonas, J.B.*
AU  - Mychaleckyj, J.C.*
AU  - Christensen, K.*
AU  - Eckardt, K.U.*
AU  - Mohlke, K.L.*
AU  - Endlich, K.*
AU  - Dittrich, K.*
AU  - Ryan, K.A.*
AU  - Rice, K.M.*
AU  - Taylor, K.D.*
AU  - Ho, K.*
AU  - Nikus, K.*
AU  - Matsuda, K.*
AU  - Strauch, K.
AU  - Miliku, K.*
AU  - Hveem, K.*
AU  - Lind, L.*
AU  - Wallentin, L.*
AU  - Yerges-Armstrong, L.M.*
AU  - Raffield, L.M.*
AU  - Phillips, L.S.*
AU  - Launer, L.J.*
AU  - Lyytikäinen, L.P.*
AU  - Lange, L.A.*
AU  - Citterio, L.*
AU  - Klaric, L.*
AU  - Ikram, M.A.*
AU  - Ising, M.*
AU  - Kleber, M.E.*
AU  - Francescatto, M.*
AU  - Concas, M.P.*
AU  - Ciullo, M.*
AU  - Piratsu, M.*
AU  - Orho-Melander, M.*
AU  - Laakso, M.*
AU  - Loeffler, M.*
AU  - Perola, M.*
AU  - de Borst, M.H.*
AU  - Gögele, M.*
AU  - Bianca, M.R.*
AU  - Lukas, M.A.*
AU  - Feitosa, M.F.*
AU  - Biggs, M.L.*
AU  - Wojczynski, M.K.*
AU  - Kavousi, M.*
AU  - Kanai, M.*
AU  - Akiyama, M.*
AU  - Yasuda, M.*
AU  - Nauck, M.*
AU  - Waldenberger, M.
AU  - Chee, M.L.*
AU  - Boehnke, M.*
AU  - Preuss, M.H.*
AU  - Stumvoll, M.*
AU  - Province, M.A.*
AU  - Evans, M.K.*
AU  - O'Donoghue, M.L.*
AU  - Kubo, M.*
AU  - Kähönen, M.*
AU  - Kastarinen, M.*
AU  - Nalls, M.A.*
AU  - Kuokkanen, M.*
AU  - Ghanbari, M.*
AU  - Bochud, M.*
AU  - Josyula, N.S.*
AU  - Martin, N.G.*
AU  - Tan, N.Y.Q.*
AU  - Palmer, N.D.*
AU  - Pirastu, N.*
AU  - Schupf, N.*
AU  - Verweij, N.*
AU  - Hutri-Kähönen, N.*
AU  - Mononen, N.*
AU  - Bansal, N.*
AU  - Devuyst, O.*
AU  - Melander, O.*
AU  - Raitakari, O.T.*
AU  - Polasek, O.*
AU  - Manunta, P.*
AU  - Gasparini, P.*
AU  - Mishra, P.P.*
AU  - Sulem, P.*
AU  - Magnusson, P.K.E.*
AU  - Elliott, P.*
AU  - Ridker, P.M.*
AU  - Hamet, P.*
AU  - Svensson, P.O.*
AU  - Joshi, P.K.*
AU  - Kovacs, P.*
AU  - Pramstaller, P.P.*
AU  - Rossing, P.*
AU  - Vollenweider, P.*
AU  - van der Harst, P.*
AU  - Dorajoo, R.*
AU  - Sim, R.Z.H.*
AU  - Burkhardt, R.*
AU  - Tao, R.*
AU  - Noordam, R.*
AU  - Mägi, R.*
AU  - Schmidt, R.*
AU  - de Mutsert, R.*
AU  - Rueedi, R.*
AU  - van Dam, R.M.*
AU  - Carroll, R.J.*
AU  - Gansevoort, R.T.*
AU  - Loos, R.J.F.*
AU  - Felicita, S.C.*
AU  - Sedaghat, S.*
AU  - Padmanabhan, S.*
AU  - Freitag-Wolf, S.*
AU  - Pendergrass, S.A.*
AU  - Graham, S.E.*
AU  - Gordon, S.D.*
AU  - Hwang, S.J.*
AU  - Kerr, S.M.*
AU  - Vaccargiu, S.*
AU  - Patil, S.B.*
AU  - Hallan, S.*
AU  - Bakker, S.J.L.*
AU  - Lim, S.C.*
AU  - Lucae, S.*
AU  - Vogelezang, S.*
AU  - Bergmann, S.*
AU  - Corre, T.*
AU  - Ahluwalia, T.S.*
AU  - Lehtimäki, T.*
AU  - Boutin, T.S.*
AU  - Meitinger, T.
AU  - Wong, T.Y.*
AU  - Bergler, T.*
AU  - Rabelink, T.J.*
AU  - Esko, T.*
AU  - Haller, T.*
AU  - Thorsteinsdottir, U.*
AU  - Völker, U.*
AU  - Foo, V.H.X.*
AU  - Salomaa, V.*
AU  - Vitart, V.*
AU  - Giedraitis, V.*
AU  - Gudnason, V.*
AU  - Jaddoe, V.W.V.*
AU  - Huang, W.*
AU  - Zhang, W.*
AU  - Wei, W.B.*
AU  - Kiess, W.*
AU  - Marz, W.*
AU  - Koenig, W.*
AU  - Lieb, W.*
AU  - Gao, X.*
AU  - Sim, X.*
AU  - Wang, Y.X.*
AU  - Friedlander, Y.*
AU  - Tham, Y.C.*
AU  - Kamatani, Y.*
AU  - Okada, Y.*
AU  - Milaneschi, Y.*
AU  - Yu, Z.*
AU  - Stark, K.J.*
AU  - Stefansson, K.*
AU  - Böger, C.A.*
AU  - Hung, A.M.*
AU  - Kronenberg, F.*
AU  - Köttgen, A.*
AU  - Pattaro, C.*
AU  - Heid, I.M.*
C1  - 65433
C2  - 52238
TI  - Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals.
JO  - Comm. Biol.
VL  - 5
IS  - 1
PY  - 2022
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - Central to the diversity of wheat products was the origin of hexaploid bread wheat, which added the D-genome of Aegilops tauschii to tetraploid wheat giving rise to superior dough properties in leavened breads. The polyploidization, however, imposed a genetic bottleneck, with only limited diversity introduced in the wheat D-subgenome. To understand genetic variants for quality, we sequenced 273 accessions spanning the known diversity of Ae. tauschii. We discovered 45 haplotypes in Glu-D1, a major determinant of quality, relative to the two predominant haplotypes in wheat. The wheat allele 2 + 12 was found in Ae. tauschii Lineage 2, the donor of the wheat D-subgenome. Conversely, the superior quality wheat allele 5 + 10 allele originated in Lineage 3, a recently characterized lineage of Ae. tauschii, showing a unique origin of this important allele. These two wheat alleles were also quite similar relative to the total observed molecular diversity in Ae. tauschii at Glu-D1. Ae. tauschii is thus a reservoir for unique Glu-D1 alleles and provides the genomic resource to begin utilizing new alleles for end-use quality improvement in wheat breeding programs.
AU  - Delorean, E.*
AU  - Gao, L.*
AU  - Lopez, J.F.C.*
AU  - Open Wild Wheat Consortium (Mayer, K.F.X.)
AU  - Wulff, B.B.H.*
AU  - Ibba, M.I.*
AU  - Poland, J.*
C1  - 64147
C2  - 51675
TI  - High molecular weight glutenin gene diversity in Aegilops tauschii demonstrates unique origin of superior wheat quality.
JO  - Comm. Biol.
VL  - 4
IS  - 1
PY  - 2021
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - Fungi produce a wide variety of volatile organic compounds (VOCs), which play central roles in the initiation and regulation of fungal interactions. Here we introduce a global overview of fungal VOC patterns and chemical diversity across phylogenetic clades and trophic modes. The analysis is based on measurements of comprehensive VOC profiles of forty-three fungal species. Our data show that the VOC patterns can describe the phyla and the trophic mode of fungi. We show different levels of phenotypic integration (PI) for different chemical classes of VOCs within distinct functional guilds. Further computational analyses reveal that distinct VOC patterns can predict trophic modes, (non)symbiotic lifestyle, substrate-use and host-type of fungi. Thus, depending on trophic mode, either individual VOCs or more complex VOC patterns (i.e., chemical communication displays) may be ecologically important. Present results stress the ecological importance of VOCs and serve as prerequisite for more comprehensive VOCs-involving ecological studies.
AU  - Guo, Y.
AU  - Jud, W.
AU  - Weikl, F.
AU  - Ghirardo, A.
AU  - Junker, R.R.*
AU  - Polle, A.*
AU  - Benz, J.P.*
AU  - Pritsch, K.
AU  - Schnitzler, J.-P.
AU  - Rosenkranz, M.
C1  - 62197
C2  - 50727
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Volatile organic compound patterns predict fungal trophic mode and lifestyle.
JO  - Comm. Biol.
VL  - 4
IS  - 1
PB  - Nature Research
PY  - 2021
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - Central nervous system (CNS) involvement remains a challenge in the diagnosis and treatment of acute lymphoblastic leukemia (ALL). In this study, we identify CD79a (also known as Igα), a signaling component of the preB cell receptor (preBCR), to be associated with CNS-infiltration and -relapse in B-cell precursor (BCP)-ALL patients. Furthermore, we show that downregulation of CD79a hampers the engraftment of leukemia cells in different murine xenograft models, particularly in the CNS.
AU  - Lenk, L.*
AU  - Carlet, M.
AU  - Vogiatzi, F.*
AU  - Spory, L.*
AU  - Winterberg, D.*
AU  - Cousins, A.*
AU  - Vossen-Gajcy, M.*
AU  - Ibruli, O.*
AU  - Vokuhl, C.*
AU  - Cario, G.*
AU  - El Ayoubi, O.*
AU  - Krämer, L.*
AU  - Ritgen, M.*
AU  - Brüggemann, M.*
AU  - Häsler, R.*
AU  - Schrappe, M.*
AU  - Fuhrmann, S.*
AU  - Halsey, C.*
AU  - Jeremias, I.
AU  - Hobeika, E.*
AU  - Jumaa, H.*
AU  - Alsadeq, A.*
AU  - Schewe, D.M.*
C1  - 61100
C2  - 50045
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - CD79a promotes CNS-infiltration and leukemia engraftment in pediatric B-cell precursor acute lymphoblastic leukemia.
JO  - Comm. Biol.
VL  - 4
IS  - 1
PB  - Nature Research
PY  - 2021
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - During the cancerous transformation of normal hepatocytes into hepatocellular carcinoma (HCC), the enzyme catalyzing the first rate-limiting step of glycolysis, namely the glucokinase (GCK), is replaced by the higher affinity isoenzyme, hexokinase 2 (HK2). Here, we show that in HCC tumors the highest expression level of HK2 is inversely correlated to GCK expression, and is associated to poor prognosis for patient survival. To further explore functional consequences of the GCK-to-HK2 isoenzyme switch occurring during carcinogenesis, HK2 was knocked-out in the HCC cell line Huh7 and replaced by GCK, to generate the Huh7-GCK+/HK2− cell line. HK2 knockdown and GCK expression rewired central carbon metabolism, stimulated mitochondrial respiration and restored essential metabolic functions of normal hepatocytes such as lipogenesis, VLDL secretion, glycogen storage. It also reactivated innate immune responses and sensitivity to natural killer cells, showing that consequences of the HK switch extend beyond metabolic reprogramming.
AU  - Perrin-Cocon, L.*
AU  - Vidalain, P.O.*
AU  - Jacquemin, C.*
AU  - Aublin-Gex, A.*
AU  - Olmstead, K.
AU  - Panthu, B.*
AU  - Rautureau, G.J.P.*
AU  - André, P.*
AU  - Nyczka, P.*
AU  - Hütt, M.T.*
AU  - Amoedo, N.*
AU  - Rossignol, R.*
AU  - Filipp, F.V.
AU  - Lotteau, V.*
AU  - Diaz, O.*
C1  - 61398
C2  - 50209
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - A hexokinase isoenzyme switch in human liver cancer cells promotes lipogenesis and enhances innate immunity.
JO  - Comm. Biol.
VL  - 4
IS  - 1
PB  - Nature Research
PY  - 2021
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - Malate dehydrogenases (MDHs) sustain tumor growth and carbon metabolism by pathogens including Plasmodium falciparum. However, clinical success of MDH inhibitors is absent, as current small molecule approaches targeting the active site are unselective. The presence of an allosteric binding site at oligomeric interface allows the development of more specific inhibitors. To this end we performed a differential NMR-based screening of 1500 fragments to identify fragments that bind at the oligomeric interface. Subsequent biophysical and biochemical experiments of an identified fragment indicate an allosteric mechanism of 4-(3,4-difluorophenyl) thiazol-2-amine (4DT) inhibition by impacting the formation of the active site loop, located >30 Å from the 4DT binding site. Further characterization of the more tractable homolog 4-phenylthiazol-2-amine (4PA) and 16 other derivatives are also reported. These data pave the way for downstream development of more selective molecules by utilizing the oligomeric interfaces showing higher species sequence divergence than the MDH active site.
AU  - Reyes Romero, A.*
AU  - Lunev, S.*
AU  - Popowicz, G.M.
AU  - Calderone, V.*
AU  - Gentili, M.*
AU  - Sattler, M.
AU  - Plewka, J.*
AU  - Taube, M.*
AU  - Kozak, M.*
AU  - Holak, T.A.*
AU  - Dömling, A.S.S.*
AU  - Groves, M.R.*
C1  - 62796
C2  - 51067
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - A fragment-based approach identifies an allosteric pocket that impacts malate dehydrogenase activity.
JO  - Comm. Biol.
VL  - 4
IS  - 1
PB  - Nature Portfolio
PY  - 2021
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - Genome-wide association studies have identified SLC16A13 as a novel susceptibility gene for type 2 diabetes. The SLC16A13 gene encodes SLC16A13/MCT13, a member of the solute carrier 16 family of monocarboxylate transporters. Despite its potential importance to diabetes development, the physiological function of SLC16A13 is unknown. Here, we validate Slc16a13 as a lactate transporter expressed at the plasma membrane and report on the effect of Slc16a13 deletion in a mouse model. We show that Slc16a13 increases mitochondrial respiration in the liver, leading to reduced hepatic lipid accumulation and increased hepatic insulin sensitivity in high-fat diet fed Slc16a13 knockout mice. We propose a mechanism for improved hepatic insulin sensitivity in the context of Slc16a13 deficiency in which reduced intrahepatocellular lactate availability drives increased AMPK activation and increased mitochondrial respiration, while reducing hepatic lipid content. Slc16a13 deficiency thereby attenuates hepatic diacylglycerol-PKCε mediated insulin resistance in obese mice. Together, these data suggest that SLC16A13 is a potential target for the treatment of type 2 diabetes and non-alcoholic fatty liver disease.
AU  - Schumann, T.
AU  - König, J.*
AU  - von Loeffelholz, C.*
AU  - Vatner, D.F.*
AU  - Zhang, D.*
AU  - Perry, R.J.*
AU  - Bernier, M.*
AU  - Chami, J.*
AU  - Henke, C.
AU  - Kurzbach, A.
AU  - El-Agroudy, N.N.
AU  - Willmes, D.M.
AU  - Pesta, D.*
AU  - de Cabo, R.*
AU  - O Sullivan, J.F.*
AU  - Simon, E.*
AU  - Shulman, G.I.*
AU  - Hamilton, B.S.*
AU  - Birkenfeld, A.L.
C1  - 62431
C2  - 50826
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Deletion of the diabetes candidate gene Slc16a13 in mice attenuates diet-induced ectopic lipid accumulation and insulin resistance.
JO  - Comm. Biol.
VL  - 4
IS  - 1
PB  - Nature Research
PY  - 2021
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - The original published version of the Article contained an error in the abstract whereby the words “loss of” were inadvertently omitted from the following sentence: “We show that loss of Slc16a13 increases mitochondrial respiration in the liver, leading to reduced hepatic lipid accumulation and increased hepatic insulin sensitivity in high-fat diet fed Slc16a13 knockout mice.” The error has been corrected in the HTML and PDF versions of the Article.
AU  - Schumann, T.
AU  - König, J.*
AU  - von Loeffelholz, C.*
AU  - Vatner, D.F.*
AU  - Zhang, D.*
AU  - Perry, R.J.*
AU  - Bernier, M.*
AU  - Chami, J.*
AU  - Henke, C.
AU  - Kurzbach, A.
AU  - El-Agroudy, N.N.
AU  - Willmes, D.M.
AU  - Pesta, D.*
AU  - de Cabo, R.*
AU  - O Sullivan, J.F.*
AU  - Simon, E.*
AU  - Shulman, G.I.*
AU  - Hamilton, B.S.*
AU  - Birkenfeld, A.L.
C1  - 62573
C2  - 50825
TI  - Publisher Correction: Deletion of the diabetes candidate gene Slc16a13 in mice attenuates diet-induced ectopic lipid accumulation and insulin resistance.
JO  - Comm. Biol.
VL  - 4
IS  - 1
PY  - 2021
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - The non-invasive investigation of multiple biological processes remains a methodological challenge as it requires capturing different contrast mechanisms, usually not available with any single modality. Intravital microscopy has played a key role in dynamically studying biological morphology and function, but it is generally limited to resolving a small number of contrasts, typically generated by the use of transgenic labels, disturbing the biological system. We introduce concurrent 5-modal microscopy (Co5M), illustrating a new concept for label-free in vivo observations by simultaneously capturing optoacoustic, two-photon excitation fluorescence, second and third harmonic generation, and brightfield contrast. We apply Co5M to non-invasively visualize multiple wound healing biomarkers and quantitatively monitor a number of processes and features, including longitudinal changes in wound shape, microvascular and collagen density, vessel size and fractality, and the plasticity of sebaceous glands. Analysis of these parameters offers unique insights into the interplay of wound closure, vasodilation, angiogenesis, skin contracture, and epithelial reformation in space and time, inaccessible by other methods. Co5M challenges the conventional concept of biological observation by yielding multiple simultaneous parameters of pathophysiological processes in a label-free mode.
AU  - Seeger, M.
AU  - Dehner, C.
AU  - Jüstel, D.
AU  - Ntziachristos, V.
C1  - 62953
C2  - 51202
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Label-free concurrent 5-modal microscopy (Co5M) resolves unknown spatio-temporal processes in wound healing.
JO  - Comm. Biol.
VL  - 4
IS  - 1
PB  - Nature Portfolio
PY  - 2021
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - Calcium dynamics control synaptic transmission. Calcium triggers synaptic vesicle fusion, determines release probability, modulates vesicle recycling, participates in long-term plasticity and regulates cellular metabolism. Mitochondria, the main source of cellular energy, serve as calcium signaling hubs. Mitochondrial calcium transients are primarily determined by the balance between calcium influx, mediated by the mitochondrial calcium uniporter (MCU), and calcium efflux through the sodium/lithium/calcium exchanger (NCLX). We identified a human recessive missense SLC8B1 variant that impairs NCLX activity and is associated with severe mental retardation. On this basis, we examined the effect of deleting NCLX in mice on mitochondrial and synaptic calcium homeostasis, synaptic activity, and plasticity. Neuronal mitochondria exhibited basal calcium overload, membrane depolarization, and a reduction in the amplitude and rate of calcium influx and efflux. We observed smaller cytoplasmic calcium transients in the presynaptic terminals of NCLX-KO neurons, leading to a lower probability of release and weaker transmission. In agreement, synaptic facilitation in NCLX-KO hippocampal slices was enhanced. Importantly, deletion of NCLX abolished long term potentiation of Schaffer collateral synapses. Our results show that NCLX controls presynaptic calcium transients that are crucial for defining synaptic strength as well as short- and long-term plasticity, key elements of learning and memory processes.
AU  - Stavsky, A.*
AU  - Stoler, O.*
AU  - Kostic, M.*
AU  - Katoshevsky, T.*
AU  - Assali, E.A.*
AU  - Savic, I.*
AU  - Amitai, Y.*
AU  - Prokisch, H.
AU  - Leiz, S.*
AU  - Daumer-Haas, C.*
AU  - Fleidervish, I.A.*
AU  - Perocchi, F.
AU  - Gitler, D.*
AU  - Sekler, I.*
C1  - 62206
C2  - 50599
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Aberrant activity of mitochondrial NCLX is linked to impaired synaptic transmission and is associated with mental retardation.
JO  - Comm. Biol.
VL  - 4
IS  - 1
PB  - Nature Research
PY  - 2021
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - The original version of this Article contained an error in the spelling of the author Fabiana Perocchi, which was incorrectly given as Fabiana Perrochi. This has now been corrected in both the PDF and HTML versions of the Article.
AU  - Stavsky, A.*
AU  - Stoler, O.*
AU  - Kostic, M.*
AU  - Katoshevsky, T.*
AU  - Assali, E.A.*
AU  - Savic, I.*
AU  - Amitai, Y.*
AU  - Prokisch, H.
AU  - Leiz, S.*
AU  - Daumer-Haas, C.*
AU  - Fleidervish, I.A.*
AU  - Perocchi, F.
AU  - Gitler, D.*
AU  - Sekler, I.*
C1  - 62303
C2  - 50600
TI  - Author Correction: Aberrant activity of mitochondrial NCLX is linked to impaired synaptic transmission and is associated with mental retardation (Communications Biology, (2021), 4, 1, (666), 10.1038/s42003-021-02114-0).
JO  - Comm. Biol.
VL  - 4
IS  - 1
PY  - 2021
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - Crop productivity must increase at unprecedented rates to meet the needs of the growing worldwide population. Exploiting natural variation for the genetic improvement of crops plays a central role in increasing productivity. Although current genomic technologies can be used for high-throughput identification of genetic variation, methods for efficiently exploiting this genetic potential in a targeted, systematic manner are lacking. Here, we developed a haplotype-based approach to identify genetic diversity for crop improvement using genome assemblies from 15 bread wheat (Triticum aestivum) cultivars. We used stringent criteria to identify identical-by-state haplotypes and distinguish these from near-identical sequences (~99.95% identity). We showed that each cultivar shares ~59 % of its genome with other sequenced cultivars and we detected the presence of extended haplotype blocks containing hundreds to thousands of genes across all wheat chromosomes. We found that genic sequence alone was insufficient to fully differentiate between haplotypes, as were commonly used array-based genotyping chips due to their gene centric design. We successfully used this approach for focused discovery of novel haplotypes from a landrace collection and documented their potential for trait improvement in modern bread wheat. This study provides a framework for defining and exploiting haplotypes to increase the efficiency and precision of wheat breeding towards optimising the agronomic performance of this crucial crop.
AU  - Brinton, J.*
AU  - Ramirez-Gonzalez, R.H.*
AU  - Simmonds, J.*
AU  - Wingen, L.*
AU  - Orford, S.*
AU  - Griffiths, S.*
AU  - Haberer, G.
AU  - Spannagl, M.
AU  - Walkowiak, S.*
AU  - Pozniak, C.*
AU  - Uauy, C.*
C1  - 60617
C2  - 49425
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - A haplotype-led approach to increase the precision of wheat breeding.
JO  - Comm. Biol.
VL  - 3
IS  - 1
PB  - Nature Research
PY  - 2020
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - The transcription factor PAX6 is involved in the development of the eye and pancreatic islets, besides being associated with sleep-wake cycles. Here, we investigated a point mutation in the RED subdomain of PAX6, previously described in a human patient, to present a comprehensive study of a homozygous Pax6 mutation in the context of adult mammalian metabolism and circadian rhythm. Pax6(Leca2) mice lack appropriate retinal structures for light perception and do not display normal daily rhythmic changes in energy metabolism. Despite beta cell dysfunction and decreased insulin secretion, mutant mice have normal glucose tolerance. This is associated with reduced hepatic glucose production possibly due to altered circadian variation in expression of clock and metabolic genes, thereby evading hyperglycemia. Hence, our findings show that while the RED subdomain is important for beta cell functional maturity, the Leca2 mutation impacts peripheral metabolism via loss of circadian rhythm, thus revealing pleiotropic effects of PAX6. Nirav Chhabra et al. characterize adult mice carrying a homozygous mutation in Pax6 that was identified in a patient with foveal hypoplasia. They find that the Pax6 point mutation has pleiotropic effects, including defects in the mouse retinal structures, loss of the optic nerve, changes in energy metabolism and circadian rhythms, and dysregulation of genes expressed in the pancreas.
AU  - Chhabra, N.F.
AU  - Amarie, O.V.
AU  - Wu, M.
AU  - Amend, A.-L.
AU  - Rubey, M.
AU  - Gradinger, D.
AU  - Irmler, M.
AU  - Beckers, J.
AU  - Rathkolb, B.
AU  - Wolf, E.*
AU  - Feuchtinger, A.
AU  - Huypens, P.
AU  - Teperino, R.
AU  - Rozman, J.
AU  - Przemeck, G.K.H.
AU  - Hrabě de Angelis, M.
C1  - 60419
C2  - 49220
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - PAX6 mutation alters circadian rhythm and beta cell function in mice without affecting glucose tolerance.
JO  - Comm. Biol.
VL  - 3
IS  - 1
PB  - Nature Research
PY  - 2020
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11/FBLN2 rs2630445, RBP3 rs11204213); others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia.
AU  - Fan, Q.*
AU  - Pozarickij, A.*
AU  - Tan, N.Y.Q.*
AU  - Guo, X.*
AU  - Verhoeven, V.J.M.*
AU  - Vitart, V.*
AU  - Guggenheim, J.A.*
AU  - Miyake, M.*
AU  - Tideman, J.W.L.*
AU  - Khawaja, A.P.*
AU  - Zhang, L.*
AU  - MacGregor, S.*
AU  - Höhn, R.*
AU  - Chen, P.*
AU  - Biino, G.*
AU  - Wedenoja, J.*
AU  - Saffari, S.E.*
AU  - Tedja, M.S.*
AU  - Xie, J.*
AU  - Lanca, C.*
AU  - Wang, Y.X.*
AU  - Sahebjada, S.*
AU  - Mazur, J.*
AU  - Mirshahi, A.*
AU  - Martin, N.G.*
AU  - Yazar, S.*
AU  - Pennell, C.E.*
AU  - Yap, M.*
AU  - Haarman, A.E.G.*
AU  - Enthoven, C.A.*
AU  - Polling, J.R.*
AU  - Hewitt, A.W.*
AU  - Jaddoe, V.W.V.*
AU  - van Duijn, C.M.*
AU  - Hayward, C.*
AU  - Polasek, O.*
AU  - Tai, E.-S.*
AU  - Yoshikatsu, H.*
AU  - Hysi, P.G.*
AU  - Young, T.L.*
AU  - Tsujikawa, A.*
AU  - Wang, J.J.*
AU  - Mitchell, P.*
AU  - Pfeiffer, N.*
AU  - Pärssinen, O.*
AU  - Foster, P.J.*
AU  - Fossarello, M.*
AU  - Yip, S.P.*
AU  - Williams, C.*
AU  - Hammond, C.J.*
AU  - Jonas, J.B.*
AU  - He, M.*
AU  - Mackey, D.A.*
AU  - Wong, T.-Y.*
AU  - Klaver, C.C.W.*
AU  - Saw, S.-M.*
AU  - Baird, P.N.*
AU  - Cheng, C.-Y.*
AU  - Consortium for Refractive Error and Myopia (CREAM) (Oexle, K.)
C1  - 59514
C2  - 48896
TI  - Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error.
JO  - Comm. Biol.
VL  - 3
IS  - 1
PY  - 2020
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - The nucleoside analogue nelarabine, the prodrug of arabinosylguanine (AraG), is effective against T-cell acute lymphoblastic leukaemia (T-ALL) but not against B-cell ALL (B-ALL). The underlying mechanisms have remained elusive. Here, data from pharmacogenomics studies and a panel of ALL cell lines reveal an inverse correlation between nelarabine sensitivity and the expression of SAMHD1, which can hydrolyse and inactivate triphosphorylated nucleoside analogues. Lower SAMHD1 abundance is detected in T-ALL than in B-ALL in cell lines and patient-derived leukaemic blasts. Mechanistically, T-ALL cells display increased SAMHD1 promoter methylation without increased global DNA methylation. SAMHD1 depletion sensitises B-ALL cells to AraG, while ectopic SAMHD1 expression in SAMHD1-null T-ALL cells induces AraG resistance. SAMHD1 has a larger impact on nelarabine/AraG than on cytarabine in ALL cells. Opposite effects are observed in acute myeloid leukaemia cells, indicating entity-specific differences. In conclusion, SAMHD1 promoter methylation and, in turn, SAMHD1 expression levels determine ALL cell response to nelarabine. Rothenburger et al. combine the analysis of data from large pharmacogenomics screens with cell line experiments to elucidate mechanisms behind nelarabine resistance in acute lymphoblastic leukaemia (ALL). They identify low expression of the dNTP hydrolase SAMHD1 as a determinant of nelarabine sensitivity, suggesting the enzyme as a biomarker.
AU  - Rothenburger, T.*
AU  - McLaughlin, K.M.*
AU  - Herold, T.
AU  - Schneider, C.*
AU  - Oellerich, T.*
AU  - Rothweiler, F.*
AU  - Feber, A.*
AU  - Fenton, T.R.*
AU  - Wass, M.N.*
AU  - Keppler, O.T.*
AU  - Michaelis, M.*
AU  - Cinatl, J.*
C1  - 59497
C2  - 48882
CY  - 75 Varick St, 9th Flr, New York, Ny 10013-1917 Usa
TI  - SAMHD1 is a key regulator of the lineage-specific response of acute lymphoblastic leukaemias to nelarabine.
JO  - Comm. Biol.
VL  - 3
IS  - 1
PB  - Nature Publishing Group
PY  - 2020
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - Protecting the nervous system from chronic effects of physical and chemical stress is a pressing clinical challenge. The obligate pro-degenerative protein Sarm1 is essential for Wallerian axon degeneration. Thus, blocking Sarm1 function is emerging as a promising neuroprotective strategy with therapeutic relevance. Yet, the conditions that will most benefit from inhibiting Sarm1 remain undefined. Here we combine genome engineering, pharmacology and high-resolution intravital videmicroscopy in zebrafish to show that genetic elimination of Sarm1 increases Schwann-cell resistance to toxicity by diverse chemotherapeutic agents after axonal injury. Synthetic degradation of Sarm1-deficient axons reversed this effect, suggesting that glioprotection is a non-autonomous effect of delayed axon degeneration. Moreover, loss of Sarm1 does not affect macrophage recruitment to nerve-wound microenvironment, injury resolution, or neural-circuit repair. These findings anticipate that interventions aimed at inhibiting Sarm1 can counter heightened glial vulnerability to chemical stressors and may be an effective strategy to reduce chronic consequences of neurotrauma.Tian et al. showed that systemic elimination of Sarm1 in zebrafish increases Schwann-cell resistance to chemotherapeutics and protects axons from Wallerian degeneration. They use genetics, pharmacology, and high resolution intravital videomicroscopy to study Sarm1 in vivo.
AU  - Tian, W.
AU  - Czopka, T.*
AU  - López-Schier, H.
C1  - 58102
C2  - 48026
CY  - 75 Varick St, 9th Flr, New York, Ny 10013-1917 Usa
TI  - Systemic loss of Sarm1 protects Schwann cells from chemotoxicity by delaying axon degeneration.
JO  - Comm. Biol.
VL  - 3
IS  - 1
PB  - Nature Publishing Group
PY  - 2020
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply. In the original published version of the article, Valerie Vancollie was mistakenly omitted from the list of members of the International Mouse Phenotyping Consortium. In addition, recognition of funding from Wellcome Trust grant WT098051 was mistakenly omitted from the Acknowledgements.The errors have been corrected in both the PDF and HTML versions of the paper.
AU  - Moore, B.A.*
AU  - Leonard, B.C.*
AU  - Sebbag, L.*
AU  - Edwards, S.G.*
AU  - Cooper, A.*
AU  - Imai, D.M.*
AU  - Straiton, E.*
AU  - Santos, L.*
AU  - Reilly, C.*
AU  - Griffey, S.M.*
AU  - Bower, L.*
AU  - Clary, D.*
AU  - Mason, J.*
AU  - Roux, M.J.*
AU  - Meziane, H.*
AU  - Herault, Y.*
AU  - McKerlie, C.*
AU  - Flenniken, A.M.*
AU  - Nutter, L.M.J.*
AU  - Berberovic, Z.*
AU  - Owen, C.*
AU  - Newbigging, S.*
AU  - Adissu, H.*
AU  - Eskandarian, M.*
AU  - Hsu, C.W.*
AU  - Kalaga, S.*
AU  - Udensi, U.*
AU  - Asomugha, C.*
AU  - Bohat, R.*
AU  - Gallegos, J.J.*
AU  - Seavitt, J.R.*
AU  - Heaney, J.D.*
AU  - Beaudet, A.L.*
AU  - Dickinson, M.E.*
AU  - Justice, M.J.*
AU  - Philip, V.*
AU  - Kumar, V.*
AU  - Svenson, K.L.*
AU  - Braun, R.E.*
AU  - Wells, S.*
AU  - Cater, H.*
AU  - Stewart, M.*
AU  - Clementson-Mobbs, S.*
AU  - Joynson, R.*
AU  - Gao, X.*
AU  - Suzuki, T.*
AU  - Wakana, S.*
AU  - Smedley, D.*
AU  - Seong, J.K.*
AU  - Tocchini-Valentini, G.*
AU  - Moore, M.*
AU  - Fletcher, C.*
AU  - Karp, N.*
AU  - Ramirez-Solis, R.*
AU  - White, J.K.*
AU  - Hrabě de Angelis, M.
AU  - Wurst, W.
AU  - Thomasy, S.M.*
AU  - Flicek, P.*
AU  - Parkinson, H.*
AU  - Brown, S.D.M.*
AU  - Meehan, T.F.*
AU  - Nishina, P.M.*
AU  - Murray, S.A.*
AU  - Krebs, M.P.*
AU  - Mallon, A.M.*
AU  - Kent Lloyd, K.C.*
AU  - Murphy, C.J.*
AU  - Moshiri, A.*
C1  - 55652
C2  - 46508
TI  - Author Correction: Identification of genes required for eye development by high-throughput screening of mouse knockouts (Communications Biology, (2018), 1, 1, (236), 10.1038/s42003-018-0226-0).
JO  - Comm. Biol.
VL  - 2
IS  - 1
PY  - 2019
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - The internal organs embedded in the cavities are lined by an epithelial monolayer termed the mesothelium. The mesothelium is increasingly implicated in driving various internal organ pathologies, as many of the normal embryonic developmental pathways acting in mesothelial cells, such as those regulating epithelial-to-mesenchymal transition, also drive disease progression in adult life. Here, we summarize observations from different animal models and organ systems that collectively point toward a central role of epithelial-to-mesenchymal transition in driving tissue fibrosis, acute scarring, and cancer metastasis. Thus, drugs targeting pathways of mesothelium's transition may have broad therapeutic benefits in patients suffering from these diseases.
AU  - Koopmans, T.
AU  - Rinkevich, Y.
C1  - 54578
C2  - 45676
TI  - Mesothelial to mesenchyme transition as a major developmental and pathological player in trunk organs and their cavities.
JO  - Comm. Biol.
VL  - 1
PY  - 2018
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - Despite advances in next generation sequencing technologies, determining the genetic basis of ocular disease remains a major challenge due to the limited access and prohibitive cost of human forward genetics. Thus, less than 4,000 genes currently have available phenotype information for any organ system. Here we report the ophthalmic findings from the International Mouse Phenotyping Consortium, a large-scale functional genetic screen with the goal of generating and phenotyping a null mutant for every mouse gene. Of 4364 genes evaluated, 347 were identified to influence ocular phenotypes, 75% of which are entirely novel in ocular pathology. This discovery greatly increases the current number of genes known to contribute to ophthalmic disease, and it is likely that many of the genes will subsequently prove to be important in human ocular development and disease.
AU  - Moore, B.A.*
AU  - Leonard, B.C.*
AU  - Sebbag, L.*
AU  - Edwards, S.G.*
AU  - Cooper, A.*
AU  - Imai, D.M.*
AU  - Straiton, E.*
AU  - Santos, L.*
AU  - Reilly, C.*
AU  - Griffey, S.M.*
AU  - Bower, L.*
AU  - Clary, D.*
AU  - Mason, J.*
AU  - Roux, M.J.*
AU  - Meziane, H.*
AU  - Herault, Y.*
AU  - McKerlie, C.*
AU  - Flenniken, A.M.*
AU  - Nutter, L.M.J.*
AU  - Berberovic, Z.*
AU  - Owen, C.*
AU  - Newbigging, S.*
AU  - Adissu, H.*
AU  - Eskandarian, M.*
AU  - Hsu, C.W.*
AU  - Kalaga, S.*
AU  - Udensi, U.*
AU  - Asomugha, C.*
AU  - Bohat, R.*
AU  - Gallegos, J.J.*
AU  - Seavitt, J.R.*
AU  - Heaney, J.D.*
AU  - Beaudet, A.L.*
AU  - Dickinson, M.E.*
AU  - Justice, M.J.*
AU  - Philip, V.*
AU  - Kumar, V.*
AU  - Svenson, K.L.*
AU  - Braun, R.E.*
AU  - Wells, S.*
AU  - Cater, H.*
AU  - Stewart, M.*
AU  - Clementson-Mobbs, S.*
AU  - Joynson, R.*
AU  - Gao, X.*
AU  - Suzuki, T.*
AU  - Wakana, S.*
AU  - Smedley, D.*
AU  - Seong, J.K.*
AU  - Tocchini-Valentini, G.*
AU  - Moore, M.*
AU  - Fletcher, C.*
AU  - Karp, N.*
AU  - Ramirez-Solis, R.*
AU  - White, J.K.*
AU  - Hrabě de Angelis, M.
AU  - Wurst, W.
AU  - Thomasy, S.M.*
AU  - Flicek, P.*
AU  - Parkinson, H.*
AU  - Brown, S.D.M.*
AU  - Meehan, T.F.*
AU  - Nishina, P.M.*
AU  - Murray, S.A.*
AU  - Krebs, M.P.*
AU  - Mallon, A.M.*
AU  - Lloyd, K.C.K.*
AU  - Murphy, C.J.*
AU  - Moshiri, A.*
C1  - 55064
C2  - 46020
TI  - Identification of genes required for eye development by high-throughput screening of mouse knockouts.
JO  - Comm. Biol.
VL  - 1
PY  - 2018
SN  - 2399-3642
ER  - 

TY  - JOUR
AB  - Corals are threatened worldwide due to prevalence of disease and bleaching. Recent studies suggest the ability of corals to resist disease is dependent on maintaining healthy microbiomes that span coral tissues and surfaces, the holobiont. Although our understanding of the role endosymbiotic microbes play in coral health has advanced, the role surface-associated microbes and their chemical signatures play in coral health is limited. Using minimally invasive water sampling, we show that the corals and harbor unique bacteria and metabolites at their surface, distinctly different from surrounding seawater. The surface metabolites released by the holobiont create concentration gradients at 0-5 cm away from the coral surface. These molecules are identified as chemo-attractants, antibacterials, and infochemicals, suggesting they may structure coral surface-associated microbes. Further, we detect surface-associated metabolites characteristic of healthy or white syndrome disease infected corals, a finding which may aid in describing effects of diseases.
AU  - Ochsenkühn, M.A.*
AU  - Schmitt-Kopplin, P.
AU  - Harir, M.
AU  - Amin, S.A.*
C1  - 54716
C2  - 45807
TI  - Coral metabolite gradients affect microbial community structures and act as a disease cue.
JO  - Comm. Biol.
VL  - 1
PY  - 2018
SN  - 2399-3642
ER  -