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Mashup Score: 0Sex-specific single cell-level transcriptomic signatures of Rett syndrome disease progression - 6 hour(s) ago
Dominant X-linked diseases are uncommon due to female X chromosome inactivation (XCI). While random XCI usually protects females against X-linked mutations, Rett syndrome (RTT) is a female neurodevelopmental disorder caused by heterozygous MECP2 mutation. After 6-18 months of typical neurodevelopment, RTT girls undergo poorly understood regression. We performed longitudinal snRNA-seq on cerebral cortex in a construct-relevant Mecp2e1 mutant mouse model of RTT, revealing transcriptional effects of cell type, mosaicism, and sex on progressive disease phenotypes. Across cell types, we observed sex differences in the number of differentially expressed genes (DEGs) with 6x more DEGs in mutant females than males. Unlike males, female DEGs emerged prior to symptoms, were enriched for homeostatic gene pathways in distinct cell types over time, and correlated with disease phenotypes and human RTT cortical cell transcriptomes. Non-cell-autonomous effects were dynamic across disease progression o
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Mashup Score: 0Evaluation of enzyme activity predictions for variants of unknown significance in Arylsulfatase A - 6 hour(s) ago
Continued advances in variant effect prediction are necessary to demonstrate the ability of machine learning methods to accurately determine the clinical impact of variants of unknown significance (VUS). Towards this goal, the ARSA Critical Assessment of Genome Interpretation (CAGI) challenge was designed to characterize progress by utilizing 219 experimentally assayed missense VUS in the Arylsulfatase A (ARSA) gene to assess the performance of community-submitted predictions of variant functional effects. The challenge involved 15 teams, and evaluated additional predictions from established and recently released models. Notably, a model developed by participants of a genetics and coding bootcamp, trained with standard machine-learning tools in Python, demonstrated superior performance among submissions. Furthermore, the study observed that state-of-the-art deep learning methods provided small but statistically significant improvement in predictive performance compared to less elaborat
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Mashup Score: 1fmo-4 promotes longevity and stress resistance via ER to mitochondria calcium regulation in C. elegans - 6 hour(s) ago
Flavin-containing monooxygenases (FMOs) are a conserved family of xenobiotic enzymes upregulated in multiple longevity interventions, including nematode and mouse models. Previous work supports that C. elegans fmo-2 promotes longevity, stress resistance, and healthspan by rewiring endogenous metabolism. However, there are five C. elegans FMOs and five mammalian FMOs, and it is not known whether promoting longevity and health benefits is a conserved role of this gene family. Here, we report that expression of C. elegans fmo-4 promotes lifespan extension and paraquat stress resistance downstream of both dietary restriction and inhibition of mTOR. We find that overexpression of fmo-4 in just the hypodermis is sufficient for these benefits, and that this expression significantly modifies the transcriptome. By analyzing changes in gene expression, we find that genes related to calcium signaling are significantly altered downstream of fmo-4 expression. Highlighting the importance of calcium
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Mashup Score: 0The landscape of gene loss and missense variation across the mammalian tree informs on gene essentiality - 6 hour(s) ago
Background: The degree of gene and sequence preservation across species provides valuable insights into the relative necessity of genes from the perspective of natural selection. Here, we developed novel interspecies metrics across 462 mammalian species, GISMO (Gene identity score of mammalian orthologs) and GISMO-mis (GISMO-missense), to quantify gene loss traversing millions of years of evolution. GISMO is a measure of gene loss across mammals weighed by evolutionary distance relative to humans, whereas GISMO-mis quantifies the ratio of missense to synonymous variants across mammalian species for a given gene. Rationale: Despite large sample sizes, current human constraint metrics are still not well calibrated for short genes. Traversing over 100 million years of evolution across hundreds of mammals can identify the most essential genes and improve gene-disease association. Beyond human genetics, these metrics provide measures of gene constraint to further enable mammalian genetics r
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Mashup Score: 0Identification of distinct rodent-associated adenovirus lineages from a mixed-use landscape in the Western Ghats biodiversity hotspot - 6 hour(s) ago
Shifts in land-use patterns and increased human-livestock-wildlife interactions have generated numerous possibilities for pathogen spillover. This demands increased efforts of pathogen surveillance in wildlife, especially in changing landscapes with high biodiversity. We investigated adenovirus diversity in small mammals, an understudied host taxon, from a forest-plantation mosaic in the Western Ghats biodiversity hotspot. Using PCR-based screening followed by Sanger sequencing and phylogenetic analyses, we attempted to detect and characterize adenovirus diversity in seven species of small mammals. We observed high prevalence (up to 38.8%) and identified five lineages of adenoviruses with unique mutations in the endemic and dominant small mammal species, Rattus satarae . These lineages significantly differed from other known Murine adenoviruses (p-distance > 25%), indicating the likelihood of novel adenovirus diversity in this endemic small mammal. Collectively, our results highlight t
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Mashup Score: 1Previously unmeasured genetic diversity explains part of Lewontin's paradox in a k-mer-based meta-analysis of 112 plant species - 6 hour(s) ago
At the molecular level, most evolution is expected to be neutral. A key prediction of this expectation is that the level of genetic diversity in a population should scale with population size. However, as was noted by Richard Lewontin in 1974 and reaffirmed by later studies, the relationship between population size and diversity in nature is much weaker than expected. We hypothesize that one contributor to this apparent paradox is that current methods relying on single nucleotide polymorphisms (SNPs) called from aligning short reads to a reference genome underestimate levels of genetic diversity in many species. To test this idea, we calculated nucleotide diversity (π) and k-mer-based metrics of genetic diversity across 112 plant species, amounting to over 205 terabases of DNA sequencing data from 27,488 individual plants. We then compared how these different metrics correlated with proxies of population size that account for both range size and population density variation across spec
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Mashup Score: 0Recruitment of CTCF to the SIRT1 promoter after Oxidative Stress mediates Cardioprotective Transcription - 6 hour(s) ago
Because most DNA-binding transcription factors (dbTFs), including the architectural regulator CTCF, bind RNA and exhibit di-/multimerization, a central conundrum is whether these distinct properties are regulated post-transcriptionally to modulate transcriptional programs. Here, investigating stress-dependent activation of SIRT1, encoding an evolutionarily-conserved protein deacetylase, we show that induced phosphorylation of CTCF acts as a rheostat to permit CTCF occupancy of low-affinity promoter DNA sites to precisely the levels necessary. This CTCF recruitment to the SIRT1 promoter is eliciting a cardioprotective cardiomyocyte transcriptional activation program and provides resilience against the stress of the beating heart in vivo. Mice harboring a mutation in the conserved low-affinity CTCF promoter binding site exhibit an altered, cardiomyocyte-specific transcriptional program and a systolic heart failure phenotype. This transcriptional role for CTCF reveals that a covalent dbTF
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Mashup Score: 0Harnessing homeostatically active RhoC at cell junctions preserves human endothelial barrier function during inflammation - 6 hour(s) ago
The GTPase RhoA plays a critical role in generating actomyosin-mediated contractile forces that cause endothelial hyperpermeability during systemic inflammatory diseases. RhoA is almost identical to RhoB and RhoC, all of which are molecular targets of specific bacterial toxins. Searching for new treatments to modulate Rho-dependent endothelial integrity, we demonstrate that the selective and simultaneous activation of these three Rho GTPases with a chimeric recombinant toxin does not induce cell contraction but enhances microvascular endothelial barrier function in response to pathological inflammatory challenges in vitro and in vivo. This pro-barrier effect is specifically mediated by RhoC, whose activity is increased by cell confluence. The uniqueness of RhoC relies on an arginine residue (R188) within its hypervariable region that determines its junctional localization, high homeostatic activity, and barrier-protective function, in contrast to the permeability-inducing, low homeosta
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Mashup Score: 0Circadian Coupling Orchestrates Cell Growth - 6 hour(s) ago
Single-cell circadian oscillators exchange extracellular information to sustain coherent circadian rhythms at the tissue level. Within cells, the circadian clock and the cell cycle couple, yet the mechanisms governing this interplay remain poorly elucidated. Here, we study the role of extracellular circadian communication in the intracellular coordination between the circadian clock and the cell cycle. We demonstrate that the loss of extracellular circadian synchronization disrupts circadian and cell cycle coordination within individual cells, impeding collective tissue growth. Coherent circadian rhythms yield oscillatory growth patterns, unveiling a global timing regulator of tissue dynamics. Knocking down core circadian elements abolishes observed effects, highlighting the central role of circadian clock regulation. Our research underscores the significance of tissue-level circadian disruption in regulating proliferation, thereby linking disrupted circadian clocks with oncogenic proc
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Mashup Score: 0Morphological single-cell analysis of peripheral blood mononuclear cells from 390 healthy blood donors with Blood Cell Painting - 6 hour(s) ago
Recent molecular profiling and phenotyping methods combined with machine learning based analyses enable genotype-phenotype discovery at an unprecedented scale. The challenge now lies in unraveling the biological mechanisms underpinning these associations. High content imaging is a cost-effective approach for morphological and functional profiling of single cells that has provided insight into mechanisms of disease phenotypes, and consequences of genetic and drug perturbations. However, the morphological variability of healthy immune cells – instrumental to understanding disease-specific deviations from the healthy state – is still relatively uncharacterized. To elucidate this variability at scale, we generated high-resolution fluorescent confocal imaging data of peripheral blood mononuclear cell (PBMC) samples from 390 healthy blood donors with the Blood Cell Painting protocol. The protocol, developed here from the popular Cell Painting morphological profiling assay, optimizes for effi
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Sex-specific single cell-level transcriptomic signatures of Rett syndrome disease progression https://t.co/joMInrJIkZ #bioRxiv