bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of multi-condition single-cell data with latent embedding multivariate regression
Authors: Ahlmann-Eltze Constantin , Huber Wolfgang 
Published: March 2023

AbstractIdentifying gene expression differences in heterogeneous tissues across experimental or observational conditions is a fundamental biological task, enabled by single-cell assays such as multi-condition sc-RNA-seq. Current data analysis approaches divide the constituent cells into clusters meant to represent cell types, and identify differentially expressed genes for each cluster. However, such discrete categorization tends to be an unsatisfactory model of the underlying biology. Use of more gradual representations of cell type or cell state promises higher statistical power, better usability and better interpretability. Here, we introduce Latent Embedding Multivariate Regression (LEMUR), a generative model that enables differential expression analysis using a continuous low-dimensional latent space parameterization of cell type and state diversity. It operates without, or before, commitment to discrete categorization. LEMUR (1) integrates data from the different conditions, (2) predicts how each cell’s gene expression would change as a function of the conditions and its position in latent space, and (3) for each gene, identifies compact neighborhoods of cells with consistent differential expression. Unlike statically defined clusters, these neighborhoods adapt to the underlying gene expression changes. We assess LEMUR’s performance on a compendium of single-cell datasets and show applications to the identification of tumor subpopulations with distinct drug responses, the interplay between cell state and developmental time in zebrafish embryos, and the discovery of cell state×environment interactions in a spatial single-cell study of plaques in Alzheimer’s disease. LEMUR is broadly applicable as a first-line analysis approach to multi-condition sc-RNA-seq data.Software availabilityhttps://bioconductor.org/packages/lemurContactconstantin.ahlmann@embl.de
Morphine Re-arranges Chromatin Spatial Architecture of Primate Cortical Neurons
Authors: Wang Liang , Wang Xiaojie , Liu Chunqi , Xu Wei , Kuang Weihong , Bu Qian , Li Hongchun , Zhao Ying , Jiang Linhong , Chen Yaxing , Qin Feng , Li Shu , Wei Qinfan , Liu Xiaocong , Liu Bin , Chen Yuanyuan , Dai Yanping , Wang Hongbo , Tian Jingwei , Cao Gang , Zhao Yinglan , Cen Xiaobo 
Published: March 2023

AbstractThe expression of linear DNA sequences is precisely regulated by the three–dimensional (3D) architecture of chromatin. Morphine-induced aberrant gene networks of neurons have been extensively investigated; however, how morphine impacts the 3D genomic architecture of neuorns is still unknown. Here, we applied digestion-ligation-only high-throughput chromosome conformation capture (DLO Hi-C) technology to investigate the affection of morphine on 3D chromatin architecture of primate cortical neurons. After receiving continuous morphine administration for 90 days on rhesus monkeys, we discovered that morphine re-arranged chromosome territories, with a total of 391 segmented compartments being switched. Morphine altered over half of the detected topologically associated domains (TADs), most of which exhibited a variety of shifts, followed by separating and fusing types. Analysis of the looping events at kilobase-scale resolution revealed that morphine increased not only the number but also the length of differential loops. Moreover, all identified differentially expressed genes (DEGs) from the RNA sequencing (RNA-seq) were mapped to the specific TAD boundaries or differential loops, and were further validated to be significantly changed. Collectively, an altered 3D genomic architecture of cortical neurons may regulate the gene networks associated-morphine effects. Our finding provides critical hubs connecting chromosome spatial organization and gene networks associated with the morphine effects in humans.
BMP signaling to pharyngeal muscle in theC. elegansresponse to a bacterial pathogen regulates anti-microbial peptide expression and pharyngeal pumping
Authors: Ciccarelli Emma Jo , Bendelstein Moshe , Yamamoto Katerina K. , Reich Hannah , Savage-Dunn Cathy 
Published: March 2023

AbstractHost response to pathogens recruits multiple tissues in part through conserved cell signaling pathways. InC. elegans, the bone morphogenetic protein (BMP) like DBL-1 signaling pathway has a role in the response to infection in addition to other roles in development and post-developmental functions. In the regulation of body size, the DBL-1 pathway acts through cell autonomous signal activation in the epidermis (hypodermis). We have now elucidated the tissues that respond to DBL-1 signaling upon exposure to two bacterial pathogens. The receptors and Smad signal transducers for DBL-1 are expressed in pharyngeal muscle, intestine, and epidermis. We demonstrate that expression of receptor-regulated Smad (R-Smad) genesma-3in the pharynx is sufficient to improve the impaired survival phenotype ofsma-3mutants and that expression ofsma-3in the intestine has no effect when exposing worms to bacterial infection of the intestine. We also show that two antimicrobial peptide genes –abf-2andcnc-2– are regulated by DBL-1 signaling through R-Smad SMA-3 activity in the pharynx. Finally, we show that pharyngeal pumping activity is reduced insma-3mutants and that other pharynx-defective mutants also have reduced survival on a bacterial pathogen. Our results identify the pharynx as a tissue that responds to BMP signaling to coordinate a systemic response to bacterial pathogens.Significance StatementInnate immunity is the first line of defense against pathogens. Conserved cell signaling pathways are known to be involved in host-pathogen response, but how they coordinate a systemic response is less well understood.In the nematodeC. elegans,bone morphogenetic protein (BMP) signaling is required for survival on pathogenic bacteria. Using transgenic strains, the authors identify a major role for a specific organ, the pharynx, in BMP-dependent survival.These findings demonstrate that an organ can serve as a pathogen sensor to trigger multiple modes of response to bacterial pathogens, include a barrier response and regulation of anti-microbial peptide expression.
Modelling capture efficiency of single cell RNA-sequencing data improves inference of transcriptome-wide burst kinetics
Authors: Tang Wenhao , Jørgensen Andreas Christ Sølvsten , Marguerat Samuel , Thomas Philipp , Shahrezaei Vahid 
Published: March 2023

AbstractGene expression is characterised by stochastic bursts of transcription that occur at brief and random periods of promoter activity. The kinetics of gene expression burstiness differs across the genome and is dependent on the promoter sequence, among other factors. Single-cell RNA sequencing (scRNA-seq) has made it possible to quantify the cell-to-cell variability in transcription at a global genome-wide level. However, scRNA-seq data is prone to technical variability, including low and variable capture efficiency of transcripts from individual cells. Here, we propose a novel mathematical theory for the observed variability in scRNA-seq data. Our method captures burst kinetics and variability in both cell size and capture efficiency, which allows us to propose several likelihood-based and simulation-based methods for the inference of burst kinetics from scRNA-seq data. Using both synthetic and real data, we show that the simulation-based methods provide an accurate, robust and flexible tool for inferring burst kinetics from scRNA-seq data. In particular, in supervised manner, a simulation-based inference method based on neural networks proves to be accurate and useful in application to both allele and non-allele specific scRNA-seq data.
Atherosclerosis is a smooth muscle cell-driven tumor-like disease
Authors: Pan Huize , Ho Sebastian E. , Xue Chenyi , Cui Jian , Ross Leila S. , Li Fang , Solomon Robert A. , Connolly E. Sander , Reilly Muredach P. 
Published: March 2023

AbstractAtherosclerosis, the leading cause of cardiovascular disease, is a chronic inflammatory disease involving pathological activation of multiple cell types, such as immunocytes (e.g., macrophage, T cells), smooth muscle cells (SMCs), and endothelial cells. Multiple lines of evidence have suggested that SMC “phenotypic switching” plays a central role in atherosclerosis development and complications. Yet, SMC roles and mechanisms underlying the disease pathogenesis are poorly understood. Here, employing SMC lineage tracing mice, comprehensive molecular, cellular, histological, and computational profiling, coupled to genetic and pharmacological studies, we reveal that atherosclerosis, in terms of SMC behaviors, share extensive commonalities with tumors. SMC-derived cells in the disease show multiple characteristics of tumor cell biology, including genomic instability, replicative immortality, malignant proliferation, resistance to cell death, invasiveness, and activation of comprehensive cancer-associated gene regulatory networks. SMC-specific expression of oncogenicKrasG12Daccelerates SMC phenotypic switching and exacerbates atherosclerosis. Moreover, we present a proof of concept showing that niraparib, an anti-cancer drug targeting DNA damage repair, attenuates atherosclerosis progression and induces regression of lesions in advanced disease in mouse models. Our work provides systematic evidence that atherosclerosis is a tumor-like disease, deepening the understanding of its pathogenesis and opening prospects for novel precision molecular strategies to prevent and treat atherosclerotic cardiovascular disease.
Peroxisomal compartmentalization of amino acid biosynthesis reactions imposes an upper limit on compartment size
Authors: Gu Ying , Alam Sara , Oliferenko Snezhana 
Published: March 2023

SummaryCellular metabolism relies on just a few redox cofactors. Selective compartmentalization may prevent competition between metabolic reactions requiring the same cofactor. Is such compartmentalization necessary for optimal cell function? Is there an optimal compartment size? Here we probe these fundamental questions using peroxisomal compartmentalization of the last steps of lysine and histidine biosynthesis in the fission yeastSchizosaccharomyces japonicus. We show that compartmentalization of these NAD+dependent reactions together with a dedicated NADH/NAD+recycling enzyme supports optimal growth when an increased demand for anabolic reactions taxes cellular redox balance. In turn, compartmentalization constrains the size of individual organelles, with larger peroxisomes accumulating all the required enzymes but unable to support both biosynthetic reactions at the same time. We propose that compartmentalized biosynthetic reactions are sensitive to the size of the compartment, likely due to scaling-dependent changes within the system, such as enzyme packing density.
MK2 deficiency decreases mortality during the inflammatory phase after myocardial infarction in mice
Authors: Trépanier Joëlle , Nawaito Sherin A. , Sahadevan Pramod , Sahmi Fatiha , Duquette Natacha , Gélinas Danielle , Gillis Marc-Antoine , Shi Yanfen , Torok Cynthia , Clavet-Lanthier Marie-Élaine , Matthias Gaestel , Sirois Martin G. , Tardif Jean-Claude , Allen Bruce G. 
Published: March 2023

AbstractBackground:Altering the onset, intensity, or duration of inflammation can impact the recovering heart’s structure and function following myocardial infarction (MI). Substrates of MAP kinase-activated protein kinase 2 (MK2) include proteins that regulate the stability of AU-rich transcripts, including those of several pro-inflammatory cytokines. This study was to determine if MK2-deficiency impaired the inflammatory phase of post-MI wound repair.Methods and Results:Myocardial infarctions were induced by permanent ligation of the left anterior descending coronary artery in 12-week-old male MK2+/+and MK2-/-littermate mice. Five days post-MI, survival was 100% in MI-MK2-/-(n = 20) and 79% in MI-MK2+/+mice (n = 29; Mandel-Cox test:P< 0.05). Area at risk and infarct size were similar. Echocardiographic imaging revealed that both systolic and diastolic LV diameters were greater in MI-MK2+/+than MI-MK2-/-mice. MK2-deficiency did not affect the increase in wall motion score index. Infiltration of neutrophils or monocytes did not differ significantly. Cytokine and chemokine transcripts were quantified in infarcted and non-infarcted LV tissue using qPCR arrays (QIAGEN). Three days post-MI,Ifna2was increased andIl16was decreased in infarcted tissue from MK2-/-hearts, compared with infarcted MK2+/+tissue, whereas in the non-infarcted MK2-/-myocardiumIl27increased andTnfsf11,Ccl3, andIl1rnwere decreased. Five days post-MI,Ctf16andIl10increased in infarcted MK2-/-tissue whereas in the non-infarcted MK2-/-myocardiumCcl9, Nodal, and Xcl2increased andIl15decreased.Conclusions:The findings of this study suggest MK2-deficiency is an advantage during the inflammatory phase of cardiac wound repair post-MI.Clinical PerspectiveWhat is new?-The effects of MAP kinase-activated protein kinase 2 (MK2) deficiency on survival, cardiac structure and function, and the inflammatory phase of wound healing following myocardial infarction were assessed using a constitutive, pan MK2-null mouse model.-MK2-deficiency reduced mortality but did not alter area at risk or infarct size post-myocardial infarction. Inflammatory cell infiltration was also unaffected.-MK2-deficiency altered the abundance of several cytokines (increased, decreased) in infarcted and non-infarcted myocardium post-MI.What are the clinical implications?-The initial phase of wound repair post-MI involves inflammation.-The risk of damage to the myocardium and mortality may be reduced by inhibition of MK2 activity during the inflammatory phase of wound healing post-MI.
Single-Cell Map of Dynamic Multicellular Ecosystem of Radiation-Induced Intestinal Injury
Authors: Lu Hao , Yan Hua , Xing Yuan , Ye Yumeng , Jiang Siao , Ma Luyu , Zuo Hongyan , Hao Yanhui , Yu Chao , Li Yang , Lu Yiming , Zhou Gangqiao 
Published: March 2023

AbstractIntestine is a highly radiation-sensitive organ that could be injured during the radiotherapy for abdominal or pelvic cavity tumors. However, the dynamic change of the intestinal microenvironment related to radiation-induced intestine injury (RIII) is still unclear. Using single-cell RNA sequencing, we pictured a dynamic landscape of the intestinal microenvironment during RIII and regeneration. We showed that the multicellular ecosystem of intestine exhibited heterogeneous radiosensitivities. We revealed the distinct dynamic patterns of three subtypes of intestinal stem cells (ISCs), and the cellular trajectory analysis suggested a complex interconversion pattern among them. For the immune cells, we found thatLy6c+monocytes can give rise to both pro-inflammatory macrophages and resident macrophages after RIII. Besides, through cellular communication analysis, we identified a positive feedback loop between the macrophages and endothelial cells, which could amplify the inflammatory response induced by radiation. Overall, our study provides a valuable single-cell map of the dynamic multicellular ecosystem during RIII and regeneration, which may facilitate the understanding of the mechanism of RIII.
Lethal giant larvae gene family (Llgl1andLlgl2) functions as a tumor suppressor in mouse skin epidermis
Authors: Bii Victor M. , Rudoy Dmytro , Klezovitch Olga , Vasioukhin Valeri 
Published: March 2023

ABSTRACTLoss of cell polarity and tissue disorganization occurs in majority of epithelial cancers. Studies in simple model organisms identified molecular mechanisms responsible for the establishment and maintenance of cellular polarity, which play a pivotal role in establishing proper tissue architecture. The exact role of these cell polarity pathways in mammalian cancer is not completely understood. Here we analyzed the mammalian orthologs of drosophila apical-basal polarity gene lethal giant larvae (lgl), which regulates asymmetric stem cell division and functions as a tumor suppressor in flies. There are two mammalian orthologs oflgl(Llgl1andLlgl2). To determine the role of the entire lgl signaling pathway in mammals we generated mice with ablation of bothLlgl1andLlgl2in skin epidermis using K14-Cre (Llgl1/2-/-cKO mice). Surprisingly, we found that ablation ofLlgl1/2genes does not impact epidermal polarity in adult mice. However, oldLlgl1/2cKO mice present with focal skin lesions which are missing epidermal layer and ripe with inflammation. To determine the role of lgl signaling pathway in cancer we generatedTrp53-/-/Llgl1/2-/-cKO andTrp53-/+/Llgl1/2-/-cKO mice. Loss ofLlgl1/2promoted squamous cell carcinoma (SCC) development inTrp53-/-cKO and caused SCC inTrp53-/+cKO mice, while no cancer was observed inTrp53-/+cKO controls. Mechanistically, we show that ablation ofLlgl1/2causes activation of aPKC and upregulation of NF-kB signaling pathway, which may be necessary for SCC inTrp53-/+/Llgl1/2-/-cKO mice. We conclude that Lgl signaling pathway functions as a tumor suppressor in mammalian skin epidermis.
adequaSSE: Model Adequacy Testing for Trait-Dependent Diversification Models
Authors: Schwery Orlando , Freyman Will , Goldberg Emma E. 
Published: March 2023

AbstractThe presence of large variation in speciation and extinctin rates across the tree of life has long been hypothesized to be driven by the evolution of traits that affect diversification. To test such hypotheses, phylogenetic biologists have developed a wide class of state-dependent birth-death processes that jointly model trait evolution and the diversification process. However, it has since been shown that these models are sensitive to falsely linking traits to diversification. Here we present a Bayesian approach to test the adequacy of statedependent birth-death models by statistically checking whether they describe the variation observed in the data. Our method generates posterior predictive distributions for a suite of informative test statistics, providing a general framework for testing diversification processes and models of trait evolution. We simulate data sets under different violations of model assumptions and find that our approach successfully detects the inadequacy of the model for them. We further show that the manner in which a model fails to fit the data can reveal insights into the processes of trait evolution and diversification.
Potentially causal associations between placental DNA methylation and schizophrenia and other neuropsychiatric disorders
Authors: Cilleros-Portet Ariadna , Lesseur Corina , Marí Sergi , Cosin-Tomas Marta , Lozano Manuel , Irizar Amaia , Burt Amber , García-Santisteban Iraia , Martín Diego Garrido , Escaramís Geòrgia , Hernangomez-Laderas Alba , Soler-Blasco Raquel , Breeze Charles E. , Gonzalez-Garcia Bárbara P. , Santa-Marina Loreto , Chen Jia , Llop Sabrina , Fernández Mariana F. , Vrijhed Martine , Ibarluzea Jesús , Guxens Mònica , Marsit Carmen , Bustamante Mariona , Bilbao Jose Ramon , Fernandez-Jimenez Nora 
Published: March 2023

AbstractIncreasing evidence supports the role of placenta in neurodevelopment and potentially, in the later onset of neuropsychiatric disorders. Recently, methylation quantitative trait loci (mQTL) and interaction QTL (iQTL) maps have proven useful to understand SNP-genome wide association study (GWAS) relationships, otherwise missed by conventional expression QTLs. In this context, we propose that part of the genetic predisposition to complex neuropsychiatric disorders acts through placental DNA methylation (DNAm). We constructed the first public placentalcis-mQTL database including nearly eight million mQTLs calculated in 368 fetal placenta DNA samples from the INMA project, ran cell type- and gestational age-imQTL models and combined those data with the summary statistics of the largest GWAS on 10 neuropsychiatric disorders using Summary-based Mendelian Randomization (SMR) and colocalization. Finally, we evaluated the influence of the DNAm sites identified on placental gene expression in the RICHS cohort. We found that placentalcis-mQTLs are highly enriched in placenta-specific active chromatin regions, and useful to map the etiology of neuropsychiatric disorders at prenatal stages. Specifically, part of the genetic burden for schizophrenia, bipolar disorder and major depressive disorder confers risk through placental DNAm. The potential causality of several of the observed associations is reinforced by secondary association signals identified in conditional analyses, regional pleiotropic methylation signals associated to the same disorder, and cell type- imQTLs, additionally associated to the expression levels of relevant immune genes in placenta. In conclusion, the genetic risk of several neuropsychiatric disorders could operate, at least in part, through DNAm and associated gene expression in placenta.
Uracil Repair - A Source of DNA Glycosylase Dependent Genome Instability
Authors: Krawczyk Claudia , Bentele Marc , Latypov Vitaly , Woolcock Katrina , Noreen Faiza , Fritsch Olivier , Schär Primo 
Published: March 2023

ABSTRACTUracil DNA glycosylases (UDGs) excise uracil from DNA arising from dUMP misincorporation during replication or from cytosine deamination. Besides functioning in canonical uracil repair, UDGs cooperate with DNA base modifying enzymes to effect mutagenesis or DNA demethylation. Mammalian cells express four UDGs, the functional dissection of which represents a challenge. Here, we usedSchizosaccharomyces pombewith only two UDGs, Ung1 and Thp1, as a simpler model to study functional interactions in uracil repair. We show that despite a predominance of Ung1 activity in cell extracts, both UDGs act redundantly against genomic uracil accumulation and mutations from cytosine deamination in cells. Notably, Thp1 but not Ung1-dependent repair is cytotoxic under genomic uracil stress induced by 5-fluorouracil exposure or AID expression. Also, Thp1-but not Ung1-mediated base excision is recombinogenic, accounting for more than 60% of spontaneous mitotic recombination events in a recombination assay. Hence, the qualitative outcome of uracil repair depends on the initiating UDG; while Ung1 shows expected features of a bona-fide DNA repair enzyme, Thp1-initiated repair appears slow and rather non-productive, suggesting a function beyond canonical DNA repair. Given the epigenetic role of TDGs, the mammalian orthologs of Thp1, we performed transcriptome analyses and identified a possible function of Thp1 in stabilizing gene expression.