Biology subjects

Shi, M.

Publications and source records attributed to Shi, M..

At least 109 records · Page 6Linked to original sources

bioRxiv2023

Characterizing the quality metric in genotype imputation

Large-scale imputation reference panels are now available and have contributed to efficient genome-wide association studies through genotype imputation. However, it is still under debate whether large-size multi-ancestry or small-size population-specific reference panels are the optimal choices for under-represented populations. We imputed genotypes of East Asian (EAS; 180k Japanese) subjects using the Trans-Omics for Precision Medicine (TOPMed) reference panel and found that the standard imputation quality metric (Rsq) substantially overestimated the dosage r2 (squared correlation between imputed dosage and true genotype). Variance component analysis of Rsq revealed that the increased imputed-genotype certainty (dosages closer to 0, 1, or 2) caused upward bias, indicating some systemic bias in the imputation. Through systematic simulations using different template switching rates ({theta} value) in the hidden Markov model, we uncovered that the lower {theta} value increased the imputed-genotype certainty and Rsq; however, dosage r2 was insensitive to the {theta} value, thereby causing a deviation. In simulated reference panels with different sizes and ancestral diversities, the {theta} value estimates from Minimac decreased with the size of a single ancestry and increased with the ancestral diversity. Thus, Rsq could overestimate or underestimate dosage r2 for a subpopulation in the multi-ancestry panel and the deviation represents different imputed-dosage distributions. Finally, despite the impact of {theta} value, distant ancestries in the reference panel contributed only a few additional variants passing a predefined Rsq threshold. We conclude that the {theta} value has a substantial impact on the imputed dosage and the imputation quality metric value.

bioinformatics↗

bioRxiv2023

Population genomics reveals extensive inbreeding and purging of mutational load in wild Amur tigers

The inbreeding is a big threat for the persistence of genetic diversity in small and isolated populations of endangered species. The homozygous genome could exacerbate inbreeding depression by introducing homozygous deleterious alleles in the population. However, purging of inbreeding loads as they become homozygotes in small populations could alleviate the depression. The Amur tiger (Panthera tigris altaica) is typically exists in small population living in forests in Northeast Asia and is among the most endangered animals on the planet with great symbolic significance of conservation. By comparing with captive individuals, we revealed substantially higher and more extensive inbreeding in the wild Amur tiger population (FROH=0.51) than in captive Amur tigers (FROH=0.26). We further found much less mutational loads in wild populations when compared with captive Amur tigers. However, the frequency of loss of function and deleterious nonsynonymous mutations inside ROH regions are much lower than that in non-ROH regions in both wild and captive Amur tigers, indicating the purging may had occurred in both populations but much effective in the wild population. In addition, we found the average frequency of deleterious alleles was much lower than that of neutral alleles in the wild population, indicating that the purifying selection contributed to the purging of mutational loads in the wild Amur tigers. These findings provide valuable genome-wide evidence to support the making of future conservation plans of wild Amur tigers.

genomics↗

bioRxiv2023

Novel discovery of a lymphatic bridge connecting Schlemm's canal to limbal and conjunctival lymphatic pathway

PurposeSchlemms canal (SC) is a critical structure regulating aqueous humor (AH) drainage and intraocular pressure (IOP). It is known that in the conventional outflow pathway, AH flows from SC to episcleral veins. We recently reported a high-resolution three-dimensional (3D) imaging technology for intact eyeballs, SC and ocular surface. Using this advanced technology, we herein report the discovery of a new structure, termed lymphatic bridge, that directly connects SC to the limbal and conjunctival lymphatic pathway. Further investigation on this novel outflow pathway may provide new mechanisms and therapeutic approaches for glaucoma. MethodsAs reported previously, intact eyeballs were harvested from Prox-1-GFP (green fluorescent protein) mice and processed by a tissue clearing technique with CLARITY. Samples were immunolabeled with specific antibodies for CD31 (pan-endothelial marker) and LYVE-1 (lymphatic vessel endothelial hyaluronan receptor-1) and imaged by light-sheet fluorescent microscopy. The limbal areas were examined to locate connecting channels between SC and limbal and conjunctival lymphatic vessels. Moreover, in vivo anterior chamber dye injection was performed with Texas Red dextran for functional analysis on AH outflow. ResultsA novel lymphatic bridge structure that expressed both Prox-1 and LYVE-1 was discovered between the SC and limbal lymphatic vessels connected with conjunctival lymphatic pathway. Results from the anterior chamber dye injection showed AH drainage into the conjunctival lymphatic outflow pathway. ConclusionsThis study provides the first evidence on the direct connection between SC and limbal and conjunctival lymphatic pathway. This new pathway is distinctive from the conventional episcleral vein pathway and merits further investigation.

physiology↗

bioRxiv2023

Artificial intelligence redefines RNA virus discovery

Current metagenomic tools can fail to identify highly divergent RNA viruses. We developed a deep learning algorithm, termed LucaProt, to discover highly divergent RNA-dependent RNA polymerase (RdRP) sequences in 10,487 metatranscriptomes generated from diverse global ecosystems. LucaProt integrates both sequence and predicted structural information, enabling the accurate detection of RdRP sequences. Using this approach we identified 161,979 potential RNA virus species and 180 RNA virus supergroups, including many previously poorly studied groups, as well as RNA virus genomes of exceptional length (up to 47,250 nucleotides) and genomic complexity. A subset of these novel RNA viruses were confirmed by RT-PCR and RNA/DNA sequencing. Newly discovered RNA viruses were present in diverse environments, including air, hot springs and hydrothermal vents, and both virus diversity and abundance varied substantially among ecosystems. This study advances virus discovery, highlights the scale of the virosphere, and provides computational tools to better document the global RNA virome. In briefA deep learning algorithm (LucaProt) that integrates both sequence and predicted structural information was employed to identify highly divergent RNA viral "dark matter" in 10,487 metatranscriptomes from diverse global ecosystems. A total of 161,979 potential RNA virus species and 180 RNA virus supergroups was unveiled using this AI approach, including many understudied groups.

microbiology↗

bioRxiv2023

Histone demethylase KDM5 regulates cardiomyocyte maturation by promoting fatty acid oxidation, oxidative phosphorylation, and myofibrillar organization

RationaleHuman pluripotent stem cell-derived CMs (iPSC-CMs) are a valuable tool for disease modeling, cell therapy and to reconstruct the CM maturation process and identify, characterize factors that regulate maturation. The transition from immature fetal to adult CM entails coordinated regulation of the mature gene programming, which is characterized by the induction of myofilament and OXPHOS gene expression among others. Recent studies in Drosophila, C. elegans, and C2C12 myoblast cell lines have implicated the histone H3K4me3 demethylase KDM5 and its homologs, as a potential regulator of developmental gene program and mitochondrial function. We speculated that KDM5 may potentiate the maturation of iPSC-CMs by targeting a conserved epigenetic program that encompass mitochondrial OXPHOS and other CM specific maturation genes. ObjectivesThe purpose of this study is to determine the role of KDM5 in iPSC-CM maturation. Methods and ResultsImmunoblot analysis revealed that KDM5A, B, and C expression was progressively downregulated in postnatal cardiomyocytes and absent in adult hearts and CMs. Additionally, KDM5 proteins were found to be persistently expressed in iPSC-CMs up to 60 days after the onset of myogenic differentiation, consistent with the immaturity of these cells. Inhibition of KDM5 by KDM5-C70 -a pan-KDM5 inhibitor-resulted in differential regulation of 2,372 genes including upregulation of Fatty acid oxidation (FAO), OXPHOS, and myogenic gene programs in iPSC-CMs. Likewise, genome-wide profiling of H3K4me3 binding sites by the CUT&RUN assay revealed enriched H3K4me3 peaks at the promoter regions of FAO, OXPHOS, and sarcomere genes. Consistent with the chromatin and gene expression data, KDM5 inhibition led to increased expression of multiple sarcomere proteins, enhanced myofibrillar organization and improved calcium handling. Furthermore, inhibition of KDM5 increased H3K4me3 deposits at the promoter region of the ESRRA gene, which is known to regulate OXPHOS and cardiomyocyte maturation, and resulted in its increased RNA and protein levels. Finally, KDM5 inhibition increased baseline, peak, and spare oxygen consumption rates in iPSC-CMs. ConclusionsKDM5 regulates the maturation of iPSC-CMs by epigenetically regulating the expression of ESRRA, OXPHOS, FAO, and sarcomere genes and enhancing myofibril organization and mitochondrial function.

genomics↗

bioRxiv2023

Whose energy cost would birds like to save? a revisit of the migratory formation flight

Line formation of migrating birds is well-accepted to be caused by birds exploiting wake benefits to save energy expenditure. A flying bird generates wingtip trailing vortices that stir the surrounding air upward and downward, and the following bird can get a free supportive lift when positioned at the upward airflow region. However, little to no attention has been paid to clarifying birds interests in energy saving, namely, do birds intend to reduce their individual energy consumption or the total energy of the flock? Here, by explicitly considering birds interests, we employ a modified fixed-wing wake model that includes the wake dissipation to numerically reexamine the energy saving mechanism in line formation. Surprisingly, our computations show that line formation cannot be explained simply by energy optimization. This remains true whether birds are selfish or cooperative. However, line formations may be explained by strategies optimizing energy cost and either avoiding collision or maintaining vision comfort. We also find that the total wake benefit of the formation attained by selfish birds does not differ much from that got by cooperative birds, the maximum that birds can attain. This implies that selfish birds are still able to fly in formation with very high efficiency of energy saving. In addition, we explore the hypothesis that birds are empathetic and would like to optimize their own energy cost and the neighbors. Our analysis shows that if birds are more empathetic, the resulting line formation shape deviates more from a straight line, and the flock enjoys higher total wake benefit. Author summaryMigratory birds can achieve remarkable performance and efficiency in energy exploitation during annual round-trip migration flight. Theoretical and experimental results have shown that this might be achieved because birds fly together in formation with specific shapes, e.g. the noticeable V formation, to utilize the aerodynamic benefits generated by their flock mates. However, it is still unclear whether energy-guided behavior indeed can lead to these formations. We show that the special formation adopted by migratory birds cannot be explained purely by the energy exploitation mechanism, and that birds vision performance and collision avoidance very likely also play important roles in the formation emergence. Our results imply that birds fly together in formation because of energy saving, but the specific shape of the formation depends on non-aerodynamic reasons. The research provides further understandings of the emergence of migratory formation and the energy saving mechanism of animal groups. It may also indicate that wing flapping, currently not considered, has an important effect on the way birds exploit aerodynamic benefits from others during the formation flight.

animal behavior and cognition↗

bioRxiv2023

scDecouple: Decoupling cellular response and infection bias in scCRISPR-seq

MotivationscCRISPR-seq is an emerging high-throughput CRISPR screening technology that combines CRISPR screening with single-cell sequencing technologies. It provides rich information on the mechanism of gene regulation. However, when scCRISPR-seq is applied in a population of heterogeneous cells, the true cellular response to perturbation is coupled with infected proportion bias of guide RNAs (gRNAs) across different cell clusters. The mixing of these effects introduces noise into scCRISPR-seq data analysis and thus obstacles to relevant studies. ResultsWe developed scDecouple to decouple true cellular response of perturbation from the influence of infected proportion bias. scDecouple first models the distribution of gene expression profiles in perturbed cells and then iteratively finds the maximum likelihood of cell cluster proportions as well as the cellular response for each gRNA. We demonstrated its performance in a series of simulation experiments. By applying scDecouple to real scCRISPR-seq data, we found that scDecouple enhances the identification of biologically perturbation-related genes. scDecouple can benefit scCRISPR-seq data analysis, especially in the case of heterogeneous samples or complex gRNA libraries. AvailabilityscDecouple is freely available at https://github.com/MengQiuchen/scDecouple. Contactweilei92@tsinghua.edu.cn, yinqingl@tsinghua.edu.cn

bioinformatics↗

bioRxiv2023

EMBER multi-dimensional spectral microscopy enables quantitative determination of disease- and cell-specific amyloid strains

In neurodegenerative diseases proteins fold into amyloid structures with distinct conformations (strains) that are characteristic of different diseases. However, there is a need to rapidly identify amyloid conformations in situ. Here we use machine learning on the full information available in fluorescent excitation/emission spectra of amyloid binding dyes to identify six distinct different conformational strains in vitro, as well as A{beta} deposits in different transgenic mouse models. Our EMBER (excitation multiplexed bright emission recording) imaging method rapidly identifies conformational differences in A{beta} and tau deposits from Down syndrome, sporadic and familial Alzheimers disease human brain slices. EMBER has in situ identified distinct conformational strains of tau inclusions in astrocytes, oligodendrocytes, and neurons from Picks disease. In future studies, EMBER should enable high-throughput measurements of the fidelity of strain transmission in cellular and animal neurodegenerative diseases models, time course of amyloid strain propagation, and identification of pathogenic versus benign strains. SignificanceIn neurodegenerative diseases proteins fold into amyloid structures with distinct conformations (strains) that are characteristic of different diseases. There is a need to rapidly identify these amyloid conformations in situ. Here we use machine learning on the full information available in fluorescent excitation/emission spectra of amyloid binding dyes to identify six distinct different conformational strains in vitro, as well as A{beta} deposits in different transgenic mouse models. Our imaging method rapidly identifies conformational differences in A{beta} and tau deposits from Down syndrome, sporadic and familial Alzheimers disease human brain slices. We also identified distinct conformational strains of tau inclusions in astrocytes, oligodendrocytes, and neurons from Picks disease. These findings will facilitate the identification of pathogenic protein aggregates to guide research and treatment of protein misfolding diseases.

neuroscience↗

bioRxiv2023

Spike substitution T813S increases Sarbecovirus fusogenicity by enhancing the usage of TMPRSS2.

SARS-CoV Spike (S) protein shares considerable homology with SARS-CoV-2 S, especially in the conserved S2 subunit (S2). S protein mediates coronavirus receptor binding and membrane fusion, and the latter activity can greatly influence coronavirus infection. We observed that SARS-CoV S is less effective in inducing membrane fusion compared with SARS-CoV-2 S. We identify that S813T mutation is sufficient in S2 interfering with the cleavage of SARS-CoV-2 S by TMPRSS2, reducing spike fusogenicity and pseudoparticle entry. Conversely, the mutation of T813S in SARS-CoV S increased fusion ability and viral replication. Our data suggested that residue 813 in the S was critical for the proteolytic activation, and the change from threonine to Serine at 813 position might be an evolutionary feature adopted by SARS-2-related viruses. This finding deepened the understanding of Spike fusogenicity and could provide a new perspective for exploring Sarbecovirus evolution. Author SummaryThe Spike strain of SARS-CoV-2 has accumulated many mutations during its time in circulation, most of which have occurred in the S1 region, and more specifically in the RBD, in an effort to either improve the viruss affinity for the receptor ACE2 or to enhance its ability to evade the immune system. Mutations in the Spike S2 region have more far-reaching effects than those in the S1 region because it is more conserved across sarbecoviruses. By comparing SARS and SARS2, we found that an important substitution at amino acid position 813 in the S2 region (T813S) disrupts the utilization of TMPRSS2 and can significantly influence viral entry into cells. This discovery deepens our knowledge of S proteins and provides new prospects for tracing the evolution of Sarbecoviruses.

microbiology↗

bioRxiv2022

Alteration of pro-carcinogenic gut microbiota is associated with clear cell renal cell carcinoma tumorigenesis

Increasing evidence suggests that gut microbiota is involved in the occurrence and progression of urinary system diseases such as clear cell renal cell carcinoma (ccRCC). However, the mechanism of how alteration of gut metagenome promotes ccRCC remains unclear. Here we aim to elucidate the association of specific gut bacteria and their metabolites with ccRCC. In a pilot case-control study among 30 ccRCC patients and 30 healthy controls, 16S ribosomal RNA (rRNA) gene sequencing were analyzed from fecal samples collected prior to surgery or hospitalization. Alpha diversity and beta diversity analysis of the gut microbiota were performed, and differential taxa were identified by multivariate statistics. Meanwhile, serum metabolism was measured by UHPLC-MS, and differential genes were identified based on the TCGA database. Random Forests revealed the relative abundances of 20 species differed significantly between the RCC group and the Control group, among which 9 species, such as Desulfovibrionaceae, were enriched in the RCC group, and 11 species, such as four kinds of Lactobacillus, were less abundant. Concomitantly, serum level of taurine, which was considered to be consumed by Desulfovibrionaceae and released by Lactobacillus, has decreased in the RCC group. In addition, macrophage-related genes such as Gabbr1 was upregulated in ccRCC patients from our results. IMPORTANCETo our knowledge, few studies investigate the correlation of gut microbiota and ccRCC tumorigenesis. Overall, our sequencing data suggest that changes in the composition of specific gut microbiota, especially Lactobacillus and Desulfovibrionaceae, may be involved in ccRCC. Numerous serum metabolites, for example, taurine, which were modified in concert with dysregulation of gut microbiota, were associated with metabolic status during ccRCC development. Furthermore, through comparative analysis of clinical indicators, we found that gut dysbiosis could potentially reshape systemic inflammation, which participated in ccRCC tumorigenesis and we performed bioinformatics analysis to draw this conclusion. In Summary, it could be concluded from our study that the reduction of protective bacteria Lactobacillus, proliferation of sulfide-degrading bacteria Desulfovibrionaceae, reduction of taurine, and enrichment of macrophage related genes might be the risk predictors of ccRCC.

microbiology↗

bioRxiv2022

Individual bat viromes reveal the co-infection, spillover and emergence risk of potential zoonotic viruses

Bats are reservoir hosts for many zoonotic viruses. Despite this, relatively little is known about the diversity and abundance of viruses within bats at the level of individual animals, and hence the frequency of virus co-infection and inter-species transmission. Using an unbiased meta-transcriptomics approach we characterised the mammalian associated viruses present in 149 individual bats sampled from Yunnan province, China. This revealed a high frequency of virus co-infection and species spillover among the animals studied, with 12 viruses shared among different bat species, which in turn facilitates virus recombination and reassortment. Of note, we identified five viral species that are likely to be pathogenic to humans or livestock, including a novel recombinant SARS-like coronavirus that is closely related to both SARS-CoV-2 and SARS-CoV, with only five amino acid differences between its receptor-binding domain sequence and that of the earliest sequences of SARS-CoV-2. Functional analysis predicts that this recombinant coronavirus can utilize the human ACE2 receptor such that it is likely to be of high zoonotic risk. Our study highlights the common occurrence of inter-species transmission and co-infection of bat viruses, as well as their implications for virus emergence.

microbiology↗

bioRxiv2022

Structural basis for the Rad6 activation by the Bre1 N-terminal domain

The mono-ubiquitination of the histone protein H2B (H2Bub1) is a highly conserved histone post-translational modification that plays critical roles in many fundamental processes. In yeast, this modification is catalyzed by the conserved Bre1-Rad6 complex. Bre1 contains a unique N-terminal Rad6 binding domain (RBD), how it interacts with Rad6 and contributes to the H2Bub1 catalysis is unclear. Here, we present crystal structure of the Bre1 RBD-Rad6 complex and structure-guided functional studies. Our structure provides a detailed picture of the interaction between the dimeric Bre1 RBD and a single Rad6 molecule. We further found that the interaction stimulates Rad6s enzymatic activity by allosterically increasing its active site accessibility and likely contribute to the H2Bub1 catalysis through additional mechanisms. In line with these important functions, we found that the interaction is crucial for multiple H2Bub1-regulated processes. Our study provides molecular insights into the H2Bub1 catalysis.

biochemistry↗

bioRxiv2022

FishSCT: a zebrafish-centric database for exploration and visualization of fish single-cell transcriptome

With the advancement of single-cell sequencing technology in recent years, an increasing number of researchers have turned their attention to the study of cell heterogeneity. In this study, we created a fish single-cell transcriptome database centered on zebrafish (Danio rerio). FishSCT currently contains single-cell transcriptomic data on zebrafish and 8 other fish species. We used a unified pipeline to analyze 129 datasets from 44 projects from SRA and GEO, resulting in 964/26,965 marker/potential marker information for 245 cell types, as well as expression profiles at single-cell resolution. There are 117 zebrafish datasets in total, covering 25 different types of tissues/organs at 36 different time points during the growth and development stages. This is currently the largest and most comprehensive online resource for zebrafish single-cell transcriptome data, as well as the only database dedicated to the collection of marker gene information of specific cell type and expression profiles at single-cell resolution for a variety of fish. A user-friendly web interface for information browsing, cell type identification, and expression profile visualization has been developed to meet the basic demand in related studies on fish transcriptome at the single-cell resolution.

bioinformatics↗

bioRxiv2022

Genome-wide single cell annotation of the human protein-coding genes

An important quest for the life science community is to deliver a complete annotation of the human building-blocks of life, the genes and the proteins. Here, we report on a genome-wide effort to annotate all protein-coding genes based on single cell transcriptomics data representing all major tissues and organs in the human body, integrated with data from bulk transcriptomics and antibody-based tissue profiling. Altogether, 25 tissues have been analyzed with single cell transcriptomics resulting in genome-wide expression in 444 single cell types using a strategy involving pooling data from individual cells to obtain genome-wide expression profiles of individual cell type. We introduce a new genome-wide classification tool based on clustering of similar expression profiles across single cell types, which can be visualized using dimensional reduction maps (UMAP). The clustering classification is integrated with a new "tau" score classification for all protein-coding genes, resulting in a measure of single cell specificity across all cell types for all individual genes. The analysis has allowed us to annotate all human protein-coding genes with regards to function and spatial distribution across individual cell types across all major tissues and organs in the human body. A new version of the open access Human Protein Atlas (www.proteinatlas.org) has been launched to enable researchers to explore the new genome-wide annotation on an individual gene level.

systems biology↗

bioRxiv2022

The ENCODE Imputation Challenge: A critical assessment of methods for cross-cell type imputation of epigenomic profiles

Functional genomics experiments are invaluable for understanding mechanisms of gene regulation. However, comprehensively performing all such experiments, even across a fixed set of sample and assay types, is often infeasible in practice. A promising alternative to performing experiments exhaustively is to, instead, perform a core set of experiments and subsequently use machine learning methods to impute the remaining experiments. However, questions remain as to the quality of the imputations, the best approaches for performing imputations, and even what performance measures meaningfully evaluate performance of such models. In this work, we address these questions by comprehensively analyzing imputations from 23 imputation models submitted to the ENCODE Imputation Challenge. We find that measuring the quality of imputations is significantly more challenging than reported in the literature, and is confounded by three factors: major distributional shifts that arise because of differences in data collection and processing over time, the amount of available data per cell type, and redundancy among performance measures. Our systematic analyses suggest several steps that are necessary, but also simple, for fairly evaluating the performance of such models, as well as promising directions for more robust research in this area.

bioinformatics↗

bioRxiv2022

α1 adrenergic receptor - PKC - Pyk2 - Src signaling boosts L-type Ca2+ channel Cav1.2 activity and long-term potentiation in rodents

The cellular mechanisms mediating norepinephrine functions in brain to result in behaviors are unknown. We identified the L-type Ca2+ channel (LTCC) CaV1.2 as a principal target for Gq- coupled 1-adrenergic receptors (ARs). 1AR signaling increased LTCC activity in hippocampal neurons. This regulation required PKC-mediated activation of the tyrosine kinases Pyk2 and, downstream, Src. Pyk2 and Src were associated with CaV1.2. In model neuroendocrine PC12 cells, stimulation of PKC induced tyrosine phosphorylation of CaV1.2, a modification abrogated by inhibition of Pyk2 and Src. Upregulation of LTCC activity by 1AR and formation of a signaling complex with PKC, Pyk2, and Src suggests that CaV1.2 is a central conduit for signaling by norepinephrine. Indeed, a form of hippocampal LTP in young mice requires both the LTCC and 1AR stimulation. Inhibition of Pyk2 and Src blocked this LTP, indicating that enhancement of CaV1.2 activity via 1AR - Pyk2 - Src signaling regulates synaptic strength.

neuroscience↗

bioRxiv2022

CREWdb: Optimizing Chromatin Readers, Erasers, and Writers Database using Machine Learning-Based Approach

Aberration in heterochromatin and euchromatin states contributes to various disease phenotypes. The transcriptional regulation between these two states is significantly governed by post-translational modifications made by three functional types of chromatin regulators: readers, writers, and erasers. Writers introduce a chemical modification to DNA and histone tails, readers bind the modification to histone tails using specialized domains, and erasers remove the modification introduced by writers. Altered regulation of these chromatin regulators results in complex diseases such as cancer, neurodevelopmental diseases, myocardial diseases, kidney diseases, and embryonic development. Due to the reversible nature of chromatin modifications, we can develop therapeutic approaches targeting these chromatin regulators. However, a limited number of chromatin regulators have been identified thus far, and a subset of them are ambiguously classified as multiple chromatin regulator functional types. Thus, we have developed machine learning-based approaches to predict and classify the functional roles of chromatin regulator proteins, thereby optimizing the accuracy of the first comprehensive database of chromatin regulators known as CREWdb. GitHub URLCREWdb source code is available at https://github.com/smollahlab/CREWdb Database URLCREWdb webtool is available at http://mollahlab.wustl.edu/crewdb

bioinformatics↗

bioRxiv2022

Niclosamide targets macrophages to rescue the disrupted peritoneal homeostasis in endometriosis

Due to the vital roles of macrophages in the pathogenesis of endometriosis, targeting macrophages could be a new therapeutic direction. Here, we investigated the efficacy of niclosamide for the resolution of perturbed microenvironment caused by dysregulated macrophages in a mouse model of endometriosis. Single-cell transcriptomic analysis revealed the heterogeneity of macrophage subpopulations including three newly identified intermediate subtypes with sharing characteristics of traditional "small" or "large" peritoneal macrophages (SPMs and LPMs) in the peritoneal cavity. Endometriosis-like lesions (ELL) enhanced the differentiation of recruited macrophages, promoted the replenishment of resident LPMs, and increased ablation of embryo-derived LPMs, which were stepwise suppressed by niclosamide. In addition, niclosamide reversed intercellular communications between macrophages and B cells which were disrupted by ELL. Therefore, niclosamide rescued the perturbed microenvironment in endometriosis through its fine regulations on the dynamic progression of macrophages and could be a new promising therapy for endometriosis. SummaryNiclosamide tunes the dynamic progression of peritoneal macrophages and their intercellular communications with B cells to rescue the disrupted microenvironment in the peritoneal cavity in a mouse model of endometriosis. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=155 SRC="FIGDIR/small/487220v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@e6700eorg.highwire.dtl.DTLVardef@c6c557org.highwire.dtl.DTLVardef@1c60b92org.highwire.dtl.DTLVardef@121bce6_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphic AbstractC_FLOATNO C_FIG

molecular biology↗