bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tyrosine kinase inhibitors induce mitochondrial dysfunction during cardiomyocyte differentiation through alteration of GATA4-mediated networks
Authors: Liu Qing , Wu Haodi , Luo Qing-Jun , Jiang Chao , Duren Zhana , Van Bortle Kevin , Zhao Ming-tao , Zhao Bingqing , Liu Jun , Marciano David P , Lee-McMullen Brittany , Zhu Chenchen , Narasimha Anil M , Gruber Joshua J , Lipchik Andrew M , Guo Hongchao , Watson Nathaniel K , Tsai Ming-Shian , Furihata Takaaki , Tian Lei , Wei Eric , Li Yingxin , Steinmetz Lars M , Wong Wing Hung , Kay Mark A. , Wu Joseph C , Snyder Michael P 
Published: May 2020

SUMMARYMaternal drug exposure during pregnancy increases the risks of developmental cardiotoxicity, leading to congenital heart defects (CHDs). In this study, we used human stem cells as anin-vitrosystem to interrogate the mechanisms underlying drug-induced toxicity during cardiomyocyte differentiation, including anticancer tyrosine kinase inhibitor (TKI) drugs (imatinib, sunitinib, and vandetanib). H1-ESCs were treated with these drugs at sublethal levels during cardiomyocyte differentiation. We found that early exposure to TKIs during differentiation induced obvious toxic effects in differentiated cardiomyocytes, including disarranged sarcomere structure, interrupted Ca2+-handling, and impaired mitochondrial function. As sunitinib exposure showed the most significant developmental cardiotoxicity of all TKIs, we further examine its effect with in-vivo experiments. Maternal sunitinib exposure caused fetal death, bioaccumulation, and histopathologic changes in the neonatal mice. Integrative analysis of both transcriptomic and chromatin accessibility landscapes revealed that TKI-exposure altered GATA4-mediated regulatory network, which included key mitochondrial genes. Overexpression of GATA4 with CRISPR-activation restored morphologies, contraction, and mitochondria function in cardiomyocytes upon TKI exposure early during differentiation. Altogether, our study identified a novel crosstalk mechanism between GATA4 activity and mitochondrial function during cardiomyocyte differentiation, and revealed potential therapeutic approaches for reducing TKI-induced developmental cardiotoxicity for human health.HighlightsEarly-stage exposure to TKIs induced cardiotoxicity and mitochondrial dysfunctionGATA4 transcriptional activity is inhibited by TKIsNetwork analysis reveals interactions between GATA4 and mitochondrial genesGATA4-overexpression rescues cardiomyocytes and mitochondria from TKI exposure
Allele-specific alternative splicing in human tissues
Authors: Amoah Kofi , Hsiao Yun-Hua Esther , Bahn Jae Hoon , Sun Yiwei , Burghard Christina , Tan Boon Xin , Yang Ei-Wen , Xiao Xinshu 
Published: May 2020

AbstractAlternative splicing is an RNA processing mechanism that affects most genes in human, contributing to disease mechanisms and phenotypic diversity. The regulation of splicing involves an intricate network of cis-regulatory elements and trans-acting factors. Due to their high sequence specificity, cis-regulation of splicing can be altered by genetic variants, significantly affecting splicing outcomes. Recently, multiple methods have been applied to understanding the regulatory effects of genetic variants on splicing. However, it is still challenging to go beyond apparent association to pinpoint functional variants. To fill in this gap, we utilized large-scale datasets of the Genotype-Tissue Expression (GTEx) project to study genetically-modulated alternative splicing (GMAS) via identification of allele-specific splicing events. We demonstrate that GMAS events are shared across tissues and individuals more often than expected by chance, consistent with their genetically driven nature. Moreover, although the allelic bias of GMAS exons varies across samples, the degree of variation is similar across tissues vs. individuals. Thus, genetic background drives the GMAS pattern to a similar degree as tissue-specific splicing mechanisms. Leveraging the genetically driven nature of GMAS, we developed a new method to predict functional splicing-altering variants, built upon a genotype-phenotype concordance model across samples. Complemented by experimental validations, this method predicted >1000 functional variants, many of which may alter RNA-protein interactions. Lastly, 72% of GMAS-associated SNPs were in linkage disequilibrium with GWAS-reported SNPs, and such association was enriched in tissues of relevance for specific traits/diseases. Our study enables a comprehensive view of genetically driven splicing variations in human tissues.
Single Cell RNA Profiling Reveals Adipocyte to Macrophage Signaling Sufficient to Enhance Thermogenesis
Authors: Henriques Felipe , Bedard Alexander H. , Guilherme Adilson , Kelly Mark , Chi Jingyi , Zhang Peng , Lifshitz Lawrence M. , Bellvé Karl , Rowland Leslie , Yenilmez Batuhan , Kumar Shreya , Wang Yetao , Luban Jeremy , Weinstein Lee S. , Lin Jiandie D. , Cohen Paul , Czech Michael P. 
Published: May 2020

ABSTRACTThe “browning” of inguinal white adipose tissue (iWAT) through increased abundance of thermogenic beige/brite adipocytes is induced by cold exposure and many other perturbations in association with beneficial systemic metabolic effects. Adipose browning is reported to require activation of sympathetic nerve fibers (SNF), aided by alternately activated macrophages within iWAT. Here we demonstrate the first example of a non-cell autonomous pathway for iWAT browning that is fully independent of SNF activity. Thus, the strong induction of thermogenic adipocytes prompted by deletion of adipocyte fatty acid synthase (iAdFASNKO mice) was unaffected by denervation or the deletion of SNF modulator Neuregulin-4. However, browning of iWAT in iAdFASNKO mice does require adipocyte cAMP/protein kinase A signaling, as it was blocked in adipocyte- selective Fasn/Gsα double KO mice. Single-cell transcriptomic analysis of iAdFASNKO mouse adipose stromal cells revealed increased macrophages displaying gene expression signatures of the alternately activated type. Mechanistically, depletion of such phagocytic immune cells in iAdFASNKO mice fully abrogated appearance of thermogenic adipocytes in iWAT. Altogether, these findings reveal an unexpected pathway of cAMP/PKA-dependent iWAT browning that is initiated by adipocyte signals and caused by macrophage-like cells independent of sympathetic neuron involvement.
Heritable functional architecture in human visual cortex
Authors: Alvarez Ivan , Finlayson Nonie J. , Ei Shwe , de Haas Benjamin , Greenwood John A. , Schwarzkopf D. Samuel 
Published: May 2020

AbstractHow much of the functional organization of our visual system is inherited? Here we tested the heritability of retinotopic maps in human visual cortex using functional magnetic resonance imaging. We demonstrate that retinotopic organization shows a closer correspondence in monozygotic (MZ) compared to dizygotic (DZ) twin pairs, suggesting a partial genetic determination. Using population receptive field (pRF) analysis to examine the preferred spatial location and selectivity of these neuronal populations, we estimate a heritability around 30% for polar angle preferences and spatial selectivity, as quantified by pRF size, in extrastriate areas V2 and V3. Our findings are consistent with heritability in both the macroscopic arrangement of visual regions and stimulus tuning properties of visual cortex. This could constitute a neural substrate for variations in a range of perceptual effects, which themselves have been found to be at least partially genetically determined. These findings also add convergent evidence for the hypothesis that functional map topology is linked with cortical morphology.HighlightsWe analyzed retinotopic maps from monozygotic and dizygotic twin pairsVisual field maps in V1-V3 are more similar in monozygotic twinsHeritability is greater in V1 and V3 for polar angle and population receptive field sizesEccentricity maps show lesser degree of heritabilityFurther evidence for link between cortical morphology and topology of retinotopic mapsGraphical Abstract
Epigenetic modulation reveals differentiation state specificity of oncogene addiction
Authors: Khaliq Mehwish , Manikkam Mohan , Martinez Elisabeth D. , Fallahi-Sichani Mohammad 
Published: May 2020

AbstractHyperactivation of the MAPK signaling pathway motivates the clinical use of MAPK inhibitors for BRAF-mutant melanomas. Heterogeneity in differentiation state due to epigenetic plasticity, however, results in cell-to-cell variability in the state of MAPK dependency, diminishing the efficacy of MAPK inhibitors. To identify key regulators of such variability, we screened 276 epigenetic-modifying compounds, individually or combined with MAPK inhibitors, across genetically diverse and isogenic populations of melanoma cells. Following single-cell analysis and multivariate modeling, we identified three classes of epigenetic inhibitors that target distinct epigenetic states associated with either one of the lysine-specific histone demethylases KDM1A or KDM4B, or BET bromodomain proteins. While melanocytes remained insensitive, the anti-tumor efficacy of each inhibitor was predicted based on melanoma cells’ differentiation state and MAPK activity. Our systems pharmacology approach highlights a path toward identifying actionable epigenetic factors that extend the BRAF oncogene addiction paradigm on the basis of tumor cell differentiation state.
Change in terrestrial human footprint drives continued loss of intact ecosystems
Authors: Williams Brooke A. , Venter Oscar , Allan James R. , Atkinson Scott C. , Rehbein Jose A. , Ward Michelle S. , Marco Moreno Di , Grantham Hedley S. , Ervin Jamison , Goetz Scott , Hansen Andrew J. , Jantz Patrick , Pillay Rajeev , Rodríguez-Buriticá Susana , Supples Christina , Virnig Anne L. S. , Watson James E.M. 
Published: May 2020

SummaryOur ability to map humanity’s influence across Earth has evolved, thanks to powerful computing, a network of earth observing satellites, and new bottom-up census and crowd-sourced data. Here, we provide the latest temporally inter-comparable maps of the terrestrial Human Footprint, and assessment of change in human pressure at global, biome, and ecoregional scales. In 2013, 42% of terrestrial Earth could be considered relatively free of anthropogenic disturbance, and 25% could be classed as ‘wilderness’ (the least degraded end of the human footprint spectrum). Between 2000 and 2013, 1.9 million km2- an area the size of Mexico - of land relatively free of human disturbance became highly modified. The majority of this occurred within tropical and subtropical grasslands, savannah, and shrubland ecosystems, but the rainforests of Southeast Asia also underwent rapid modification. Our results show that humanity’s footprint is eroding Earth’s last intact ecosystems, and greater efforts are urgently needed to retain them.
Metagenomic alterations in gut microbiota precede and predict onset of colitis in the IL10 gene-deficient murine model
Authors: Miyoshi Jun , Lee Sonny T. M. , Kennedy Megan , Puertolas Mora , Frith Mary , Koval Jason C. , Miyoshi Sawako , Antonopoulos Dionysios A. , Leone Vanessa , Chang Eugene B. 
Published: May 2020

AbstractBackground & AimsInflammatory bowel diseases (IBD) are chronic inflammatory disorders where predictive biomarkers for the disease development and clinical course are sorely needed for development of prevention and early intervention strategies that can be implemented to improve clinical outcomes. Since gut microbiome alterations can reflect and/or contribute to impending host health changes, we examined whether gut microbiota metagenomic profiles would provide more robust measures for predicting disease outcomes in colitis-prone hosts.MethodsUsing the IL-10 gene-deficient (IL-10 KO) murine model where early life dysbiosis from antibiotic (cefoperozone, CPZ) treated dams vertically-transferred to pups increases risk for colitis later in life, we investigated temporal metagenomic profiles in the gut microbiota of post-weaning offspring and determined their relationship to eventual clinical outcomes.ResultsCompared to controls, offspring acquiring maternal CPZ-induced dysbiosis exhibited a restructuring of intestinal microbial membership both in bacteriome and mycobiome that were associated with alterations in specific functional subsystems. Furthermore, among IL-10 KO offspring from CPZ-treated dams, several functional subsystems, particularly nitrogen metabolism, diverged between mice that developed spontaneous colitis (CPZ-colitis) versus those that did not (CPZ-no-colitis) at a time point prior to eventual clinical outcome.ConclusionsOur findings provide support that functional metagenomic profiling of gut microbes has potential and promise meriting further study for development of tools to assess risk and manage human IBD.SynopsisCurrently, predictive markers for the development and course of inflammatory bowel diseases (IBD) are not available. This study supports the notion that gut microbiome metagenomic profiles could be developed into a useful tool to assess risk and manage human IBD.
High resolution imaging of nascent mitochondrial protein synthesis in cultured human cells
Authors: Zorkau Matthew , Albus Christin A , Berlinguer-Palmini Rolando , Chrzanowska-Lightowlers Zofia MA , Lightowlers Robert N. 
Published: May 2020

AbstractHuman mitochondria contain their own genome, mtDNA, that is expressed in the mitochondrial matrix. This genome encodes thirteen vital polypeptides that are components of the multi-subunit complexes that couple oxidative phosphorylation (OXPHOS). The inner mitochondrial membrane that houses these complexes comprises the inner boundary membrane that runs parallel to the outer membrane, infoldings that form the cristae membranes, and the cristae junctions that separate the two. It is in these cristae membranes that the OXPHOS complexes have been shown to reside in various species. The majority of the OXPHOS subunits are nuclear-encoded and must therefore be imported from the cytosol through the outer membrane at contact sites with the inner boundary membrane. As the mitochondrially-encoded components are also integral members of these complexes, where does nascent protein synthesis occur? Transcription, mRNA processing, maturation and at least part of the mitoribosome assembly process occur at the nucleoid and the spatially juxtaposed mitochondrial RNA granules, is protein synthesis also performed at the RNA granules close to these entities, or does it occur distal to these sites ? We have adapted a click chemistry based method, coupled with STED nanoscopy to address these questions. We report that in human cells in culture, within the limits of our methodology, the majority of mitochondrial protein synthesis occurs at the cristae membranes and is spatially separated from the sites of RNA processing and maturation.
On the functional annotation of open-channel structures in the glycine receptor
Authors: Cerdan Adrien Henri , Cecchini Marco 
Published: May 2020

AbstractThe glycine receptor (GlyR) is by far the best-characterized pentameric ligand-gated ion channel with several high-resolution structures from X-ray crystallography, cryo-EM and modeling. Nonetheless, the significance of the currently available open-pore conformations is debated due to their diversity in the pore geometry. Here, we discuss the physiological significance of existing models of the GlyR active state based on conductance and selectivity measurements by computational electrophysiology. The results support the conclusion that the original cryo-EM reconstruction of the active state obtained in detergents as well as its subsequent refinement by Molecular Dynamics simulations are likely to be non-physiological as they feature artificially dilated ion pores. In addition, the calculations indicate that a physiologically relevant open pore configuration should be constricted within a radius of 2.5 and 2.8Å, which is consistent with previous modeling, electrophysiology measurements, and the most recent cryo-EM structures obtained in a native lipid-membrane environment.
Structures of microRNA-precursor apical junctions and loops reveal non-canonical base pairs important for processing
Authors: Shoffner Grant M. , Peng Zhixiang , Guo Feng 
Published: May 2020

AbstractMetazoan pri-miRNAs and pre-miRNAs fold into characteristic hairpins that are recognized by the processing machinery. Essential to the recognition of these miR-precursors are their apical junctions where double-stranded stems meet single-stranded hairpin loops. Little is known about how apical junctions and loops fold in three-dimensional space. Here we developed a scaffold-directed crystallography method and determined the structures of eight human miR-precursor apical junctions and loops. Six structures contain non-canonical base pairs stacking on top of the hairpin stem. U-U pair contributes to thermodynamic stability in solution and is highly enriched at human miR-precursor apical junctions. Our systematic mutagenesis shows that U-U is among the most efficiently processed variants. The RNA-binding heme domain of pri-miRNA-processing protein DGCR8 binds longer loops more tightly and non-canonical pairs at the junction appear to modulate loop length. Our study provides structural and biochemical bases for understanding miR-precursors and molecular mechanisms of microRNA maturation.
Extrapolating acute bee sensitivity to insecticides using a phylogenetically informed interspecies scaling framework
Authors: Pamminger Tobias 
Published: May 2020

AbstractPlant protection products, including insecticides, are important for global food production. Historically, research of the adverse effects of insecticides on bees has focused on the honeybee (Apis mellifera), while non-Apisbee species remained understudied. Consequently, sensitivity assessment of insecticides for the majority of bees is lacking, which in turn hinders accurate risk characterization and consequently bee protection. Interspecies sensitivity extrapolation based on body weight offers a potential solution to this problem, but in the past such approaches have often ignored the phylogenetic background and consequently non independence of species used in such models. Using published data on the sensitivity of different bee species to commonly used insecticides, their body weight and phylogenetic background I build interspecies scaling models (ISMs) applying a phylogenetically informed framework. In addition, I compared, the relative sensitivity of the standard test speciesApis melliferato other bee species to evaluate their protectiveness when used as standards screening bee species in the risk assessment process. I found that overall 1) body weight is a predictor of bee sensitivity to insecticides for a range of insecticide classes and 2)A.melliferais the most sensitive standard test species currently available and consequently a suitable surrogate species for ecotoxicological risk assessment.
Targeted bisulfite sequencing: A novel tool for the assessment of DNA methylation with high sensitivity and increased coverage
Authors: Moser D.A. , Müller S. , Hummel E.M. , Limberg A.S. , Dieckmann L. , Frach L. , Pakusch J. , Flasbeck V , Brüne M. , Beygo J. , Klein-Hitpass L. , Kumsta R. 
Published: May 2020

AbstractDNA methylation analysis is increasingly used in stress research. Available methods are expensive, laborious and often limited by either the analysis of short CpG stretches or low assay sensitivity. Here, we present a cost-efficient next generation sequencing-based strategy for the simultaneous investigation of multiple candidate genes in large cohorts. To illustrate the method, we present analysis of four candidate genes commonly assessed in psychoneuroendocrine research:Glucocorticoid receptor(NR3C1), Serotonin transporter (SLC6A4), FKBP Prolyl isomerase 5 (FKBP5), and theOxytocin receptor(OXTR).DNA methylation standards and DNA of a female and male donor were bisulfite treated in three independent trials and were used to generate sequencing libraries for 42 CpGs from theNR3C1 1Fpromoter region, 83 CpGs of theSLC6A45’ regulatory region, 5 CpGs located inFKBP5intron 7, and additional 12 CpGs located in a potential enhancer element in intron 3 of theOXTR. In addition, DNA of 45 patients with borderline personality disorder (BPD) and 45 healthy controls was assayed. Multiplex libraries of all samples were sequenced on a MiSeq system and analyzed for mean methylation values of all CpG sites using amplikyzer2 software.Results indicated excellent accuracy of the assays when investigating replicates generated from the same bisulfite converted DNA, and very high linearity (R2> 0.9) of the assays shown by the analysis of differentially methylated DNA standards. Comparing DNA methylation between BPD and healthy controls revealed no biologically relevant differences.The technical approach as described here facilitates targeted DNA methylation analysis and represents a highly sensitive, cost-efficient and high throughput tool to close the gap between coverage and precision in epigenetic research of stress-associated phenotypes.
Proteomic Investigation of the Signal Transduction Pathways Controlling Colistin Resistance inKlebsiella pneumoniae
Authors: Cheung Ching Hei Phoebe , Dulyayangkul Punyawee , Heesom Kate J. , Avison Matthew B. 
Published: May 2020

AbstractColistin resistance inKlebsiella pneumoniaeis predominantly caused by mutations that increase expression of thearn(also known aspbgorpmrF) operon. Expression is activated by the PhoPQ and PmrAB two-component systems. Constitutive PhoPQ activation occurs directly by mutation or following loss of MgrB. PhoPQ may also cross-activate PmrAB via the linker protein PmrD. Using proteomics, we show that MgrB loss causes a wider proteomic effect than direct PhoPQ activation, suggesting additional targets for MgrB. DifferentmgrBmutations cause different amounts of Arn protein production, which correlated with colistin MIC. Disruption ofphoPin anmgrBmutant had a reciprocal effect to direct activation of PhoQ in a wild-type background, but the regulated proteins showed almost total overlap. Disruption ofpmrDorpmrAslightly reduced Arn protein production in anmgrBmutant, but production was still high enough to confer colistin resistance; disruption ofphoPconferred wild-type Arn production and colistin MIC. Activation of PhoPQ directly, or throughmgrBmutation did not significantly activate PmrAB or PmrC production but direct activation of PmrAB by mutation did, and also activated Arn production and conferred colistin resistance. There was little overlap between the PmrAB and PhoPQ regulons. We conclude that under the conditions used for colistin susceptibility testing, PhoPQ-PmrD-PmrAB cross-regulation is not significant and that independent activation of PhoPQ or PmrAB is the main reason that Arn protein production increases above the threshold required for colistin resistance.