bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic and compound screens uncover factors modulating cancer cell response to indisulam
Authors: Pogacar Ziva , Groot Kelvin , Jochems Fleur , Dos Santos Dias Matheus , Morris Ben , Roosen Mieke , Wardak Leyma , De Conti Giulia , Velds Arno , Lieftink Cor , Beijersbergen Roderick L. , Bernards René , de Oliveira Rodrigo Leite 
Published: December 2021

ABSTRACTDiscovering biomarkers of drug response and finding powerful drug combinations can support the reuse of previously abandoned cancer drugs in the clinic. Indisulam is an abandoned drug that acts as a molecular glue, inducing degradation of splicing factor RBM39 through interaction with CRL4DCAF15. Here, we performed genetic and compound screens to uncover factors mediating indisulam sensitivity and resistance. First, a dropout CRISPR screen identified SRPK1 loss as a synthetic lethal interaction with indisulam that can be exploited therapeutically by the SRPK1 inhibitor SPHINX31. Moreover, a CRISPR resistance screen identified components of the degradation complex that mediate resistance to indisulam: DCAF15, DDA1, and CAND1. Lastly, we show that cancer cells readily acquire spontaneous resistance to indisulam. Upon acquiring indisulam resistance, pancreatic cancer (Panc10.05) cells still degrade RBM39 and are vulnerable to BCL-xL inhibition. The better understanding of the factors that influence the response to indisulam can assist rational reuse of this drug in the clinic.
Single cell RNA sequencing and lineage tracing confirm mesenchyme to epithelial transformation (MET) contributes to repair of the endometrium at menstruation
Authors: Kirkwood Phoebe M , Gibson Douglas A , Shaw Isaac , Dobie Ross , Kelepouri Olympia , Henderson Neil C , Saunders Philippa TK 
Published: December 2021

ABSTRACTThe human endometrium experiences repetitive cycles of tissue wounding characterised by piecemeal shedding of the surface epithelium and rapid restoration of tissue homeostasis. In this study we used a mouse model of endometrial repair and three transgenic lines of mice to investigate whether epithelial cells that become incorporated into the newly formed luminal epithelium have their origins in one or more of the mesenchymal cell types present in the stromal compartment of the endometrium. Using scRNAseq we identified a novel population of PDGFRb+ mesenchymal stromal cells that developed a unique transcriptomic signature in response to endometrial breakdown/repair. These cells expressed genes usually considered specific to epithelial cells and in silico trajectory analysis suggested they were stromal fibroblasts in transition to becoming epithelial cells. To confirm our hypothesis we used a lineage tracing strategy to compare the fate of stromal fibroblasts (PDGFRa+) and stromal perivascular cells (NG2/CSPG4+). We demonstrated that stromal fibroblasts can undergo a mesenchyme to epithelial transformation and become incorporated into the re-epithelialised luminal surface of the repaired tissue. This study is the first to discover a novel population of wound-responsive, plastic endometrial stromal fibroblasts that contribute to the rapid restoration of an intact luminal epithelium during endometrial repair. These findings form a platform for comparisons both to endometrial pathologies which involve a fibrotic response (Ashermans syndrome, endometriosis) as well as other mucosal tissues which have a variable response to wounding.HighlightsSingle cell RNA sequencing identified a population of PDGFRβ+ mesenchymal cells with a unique transcriptomic signature that arises in response to induction of a menses-like woundThe repair-specific mesenchymal cells express genes considered specific to both mesenchymal and epithelial lineages indicative of an intermediate phenotype and a mesenchymal to epithelial transition (MET)in silicotrajectory analysis revealed that repair-specific cells originate from the fibroblast cell clusters, were distinct from perivascular cells, and had a predicted trans-differentiation trajectory towards definitive epithelial cellsin vivolineage tracing in adult mice provides definitive evidence that PDGFRα+ endometrial fibroblasts, and not NG2+ perivascular cells, undergo MET and can become incorporated into the luminal epithelium of the post repair tissue
The adolescent pattern of sleep spindle development revealed by HD-EEG polysomnography
Authors: Bocskai Gábor , Pótári Adrián , Gombos Ferenc , Kovács Ilona 
Published: December 2021

AbstractSleep spindles are developmentally relevant cortical oscillatory patterns; however, they have mostly been studied by considering the entire spindle frequency range (11 to 15 Hz) without a distinction between the functionally and topographically different slow and fast spindles, using relatively few electrodes and analysing wide age-ranges. Here, we employ HD-EEG polysomnography in three age-groups between 12 to 20 years of age, with an equal distribution between the two genders, and analyse the adolescent developmental pattern of the four major parameters of slow and fast sleep spindles. Most of our findings corroborate those very few previous studies that also make a distinction between slow and fast spindles in their developmental analysis. We find spindle frequency increasing with age, although spindle density change is not obvious in our study. We confirm the declining tendencies for amplitude and duration, although within narrower, more specific age-windows than previously. Spindle frequency seems to be higher in females in the oldest age-group. Based on the pattern of our findings, we suggest that HD-EEG, specifically targeting slow and fast spindle ranges and relatively narrow age-ranges would advance the understanding of both adolescent development and the functional relevance of sleep spindles in general.
Informeasure: an R/Bioconductor package to quantify nonlinear dependence between variables in biological networks from an information theory perspective
Authors: Pan Chu , Jing Limei , Luo Jiawei , Zeng Xiangxiang 
Published: December 2021

AbstractUsing information measures to infer biological regulatory networks can observe nonlinear relationship between variables, but it is computationally challenging and there is currently no convenient tool available. We here describe an information theory R package named Informeasure that devotes to quantifying nonlinear dependence between variables in biological regulatory networks from an information theory perspective. This package compiles most of the information measures currently available: mutual information, conditional mutual information, interaction information, partial information decomposition and part mutual information. The first estimator is used to infer bivariate networks while the last four estimators are dedicated to analysis of trivariate networks. The base installation of this turn-key package allows users to approach these information measures out of the box. Informeasure is implemented in R program and is available as an R/Bioconductor package at https://bioconductor.org/packages/Informeasure.
Structural and biophysical characterization of HNF-1A as a tool to study MODY3 diabetes variants
Authors: Kind Laura , Raasakka Arne , Molnes Janne , Aukrust Ingvild , Bjørkhaug Lise , Njølstad Pål Rasmus , Kursula Petri , Arnesen Thomas 
Published: December 2021

AbstractHepatocyte nuclear factor 1A (HNF-1A) is a transcription factor expressed in several embryonic and adult tissues, modulating expression of numerous target genes. Pathogenic variants in theHNF1Agene cause maturity-onset diabetes of the young 3 (MODY3 orHNF1AMODY), characterized by dominant inheritance, age of onset before 25-35 years of age, and pancreatic β-cell dysfunction. A precise diagnosis alters management as insulin can be exchanged with sulfonylurea tablets and genetic counselling differs from polygenic forms of diabetes. More knowledge on mechanisms of HNF-1A function and the level of pathogenicity of the numerousHNF1Avariants identified by exome sequencing is required for precise diagnostics. Here, we have structurally and biophysically characterized an HNF-1A protein containing both the DNA binding domain and the dimerization domain. We also present a novel approach to characterize HNF-1A variants. The folding and DNA binding capacity of two established MODY3 HNF-1A variant proteins (P112L, R263C) and one variant of unknown significance (N266S) were determined. All three variants showed reduced functionality compared to the wild-type protein. While the R263C and N266S variants displayed reduced binding to an HNF-1A target promoter, the P112L variant was unstablein vitroand in cells. Our results support and mechanistically explain disease causality for all investigated variants and allow for the dissection of structurally unstable and DNA binding defective variants. This points towards structural and biochemical investigation of HNF-1A being a valuable aid in reliable variant classification needed for precision diagnostics and management.
BISoN: A Bayesian Framework for Inference of Social Networks
Authors: Hart Jordan D. A. , Weiss Michael N. , Franks Daniel W. , Brent Lauren J. N. 
Published: December 2021

AbstractSocial networks are often constructed from point estimates of edge weights. In many contexts, edge weights are inferred from observational data, and the uncertainty around estimates can be affected by various factors. Though this has been acknowledged in previous work, methods that explicitly quantify uncertainty in edge weights have not yet been widely adopted, and remain undeveloped for many common types of data. Furthermore, existing methods are unable to cope with some of the complexities often found in observational data, and do not propagate uncertainty in edge weights to subsequent statistical analyses.We introduce a unified Bayesian framework for modelling social networks based on observational data. This framework, which we call BISoN, can accommodate many common types of observational social data, can capture confounds and model effects at the level of observations, and is fully compatible with popular methods used in social network analysis.We show how the framework can be applied to common types of data and how various types of downstream statistical analyses can be performed, including non-random association tests and regressions on network properties.Our framework opens up the opportunity to test new types of hypotheses, make full use of observational datasets, and increase the reliability of scientific inferences. We have made example R scripts available to enable adoption of the framework.
Profiles and Dynamics of the Transcriptome of Microglial Cells Reveal their Inflammatory Status
Authors: Zohar Keren , Lezmi Elyad , Reichert Fanny , Eliyahu Tsiona , Rotshenker Shlomo , Weinstock Marta , Linial Michal 
Published: December 2021

AbstractThe primary role of microglia in the maintenance of brain homeostasis is to respond to disturbances in the microenvironment. In this study, we cultured murine neonatal microglia and activated them with lipopolysaccharide (LPS) and benzoyl ATP (bzATP) to characterize changes in the transcriptome in response to variousin vivostimuli caused by pathogens, injury, or toxins. Activation by bzATP, an agonist of purinergic receptors, induces a transient wave of transcriptional changes. However, a long-lasting transcriptional profile affecting thousands of genes occurs only following a combination of bzATP and LPS. This profile is dominated by a coordinated induction of cytokines (e.g., IL1-α and IL1-β), chemokines, and their direct regulators. Many of these inflammatory-related genes are up-regulated by several orders of magnitude. We identified the TNF-α and NF-κB pathways as the principal hubs for signaling of interleukin and chemokine induction in this cell system. We propose that primary microglia under controlled activation paradigms can be used for testing reagents that could attenuate their activated state. Such a microglial system could serve as a model for changes occurring in the aging brain and neurodegenerative diseases.Highlight points*Primary murine microglia cultures release cytokines following activation with bzATP and LPS*The wave of changes in gene expression by bzATP is transient.*bzATP+LPS causes a transcription program dominated by the induction of interleukins and chemokines.
Background selection under evolving recombination rates
Authors: Booker Tom R. , Payseur Bret A. , Tigano Anna 
Published: December 2021

AbstractBackground selection (BGS), the effect that purifying selection exerts on sites linked to deleterious alleles, is expected to be ubiquitous across eukaryotic genomes. The effects of BGS reflect the interplay of the rates and fitness effects of deleterious mutations with recombination. A fundamental assumption of BGS models is that recombination rates are invariant over time. However, in some lineages recombination rates evolve rapidly, violating this central assumption. Here, we investigate how recombination rate evolution affects genetic variation under BGS. We show that recombination rate evolution modifies the effects of BGS in a manner similar to a localised change in the effective population size, potentially leading to an underestimation of the genome-wide effects of selection. Furthermore, we find evidence that recombination rate evolution in the ancestors of modern house mice may have impacted inferences of the genome-wide effects of selection in that species.
Insight into the mechanism of H+-coupled nucleobase transport
Authors: Weng Jun , Zhou Xiaoming , Wiriyasermkul Pattama , Ren Zhenning , Yan Xiuwen , Chen Kehan , Iturbe Eva Gil , Zhou Ming , Quick Matthias 
Published: December 2021

AbstractMembers of the nucleobase/ascorbic acid transporter (NAT) gene family are found in all kingdoms of life. In mammals, the concentrative uptake of ascorbic acid (vitamin C) by members of the NAT family is driven by the Na+ gradient, while the uptake of nucleobases in bacteria is powered by the H+ gradient. Here we report the structure and function PurTCp, a NAT family member from Colwellia psychrerythraea. The structure of PurTCp was determined to 2.80 Å resolution by X-ray crystallography. PurTCp forms a homodimer and each protomer has 14 transmembrane segments folded into a substrate-binding domain (core domain) and an interface domain (gate domain) A purine base is present in the structure and defines the location of the substrate binding site. Functional studies reveal that PurTCp transports purines but not pyrimidines, and that purine binding and transport is dependent on the pH. Mutation of a conserved aspartate residue close to the substrate binding site reveals the critical role of this residue in H+-dependent transport of purines. Comparison of the PurTCp structure with transporters of the same structural fold suggests that rigid-body motions of the substrate-binding domain are central for substrate translocation across the membrane.
Interpersonal brain synchronization during face-to-face economic exchange between acquainted dyads
Authors: Kikuchi Yuto , Tanioka Kensuke , Hiroyasu Tomoyuki , Hiwa Satoru 
Published: December 2021

AbstractInterpersonal brain synchronization (IBS) has been observed during social interactions and involves various factors, such as familiarity with the partner and type of social activity. A previous study has shown that face-to-face interactions in pairs of strangers increase IBS. However, it is unclear whether this can be observed when the nature of the interacting partners is different. Herein, we aimed to extend these findings to pairs of acquaintances. Neural activity in the frontal and temporal regions was recorded using functional near-infrared spectroscopy hyperscanning. Participants played an ultimatum game that required virtual economic exchange in two experimental settings: the face-to-face and face-blocked conditions. Random pair analysis confirmed whether IBS was induced by social interaction. Contrary to the aforementioned study, our results did not show any cooperative behavior or task-induced IBS increase. Conversely, the random pair analysis results revealed that the pair-specific IBS was significant only in the task condition at the left and right superior frontal, middle frontal, orbital superior frontal, right superior temporal, precentral, and postcentral gyri. Our results revealed that face-to-face interaction in acquainted pairs did not increase IBS and supported the idea that IBS is affected by “with whom we interact and how.”
Fine mapping of goat polledness variant in six Chinese native breeds
Authors: Li Yong , Chen Tao , Yang Man-Man , Han Hu , jiang Dan , Wei Qiang , Zhang Xing-Ju , Ao Yan , Zhang Qingfeng , Miao Ze-Pu , Wang Ran , Li Yuan-Lun , Chao Sheng-Yu , Li Lin , Zhang Ting-Ting , Fang Ming 
Published: December 2021

AbstractBackgroundThe genetic mechanism of goat polledness has been studied for decades, but identifying causative variants and functional genes remains challenging.ResultsUsing a genome-wide association study (GWAS), we identified a significant striking locus for polledness in two different goat breeds. To reduce the linkage disequilibrium among variants for localizing causative variants in the finer region, we sequenced 79 goats from six Chinese native breeds (Jining Gray, Matou, Guizhou black, Yunnan black bone, Chaidamu, and Ujumqin) and identified 483.5 kb CNV (150,334,567-150,818,099) translocated into the previously identified 11.7 kb polled intersex syndrome region, which was consistent with previous research using intersex goat populations. Within the 483.5 kb CNV, a ~322 bp horn-specific element, similar to the superfamily of tRNA-derived families of SINEs, located at the first intron of theERGgene was identified. The results of the GO enrichment analysis showed that the Horn-SINE element-associated genes were involved in both nervous system and head development. Finally, we used RNA sequencing to investigate gene expression profiles in the horn bud and skin tissues of horned and polled goats. We identified 1077 and 1222 differentially expressed genes between the horn bud and skin tissue in polled and horned goats, respectively. We also identified 367 differentially expressed genes in horn buds between polled and horned animals, and found that the two CNV-related genes,ERGandFOXL2, were upregulated in the horn bud of polled goats. Gene functional enrichment analysis demonstrated that the downregulated genes in the horn bud of polled goats were enriched in skeletal system development, whereas the upregulated genes were significantly overexpressed in muscle tissue development.ConclusionsBroadly, this study describes a novel structural variant responsible for polledness/intersex traits and contributes to the discovery of molecular mechanisms underlying the development and regulation of the polledness trait.
Overactive STAT3 drives accumulation of disease-associated CD21lowB cells
Authors: Masle-Farquhar Etienne , Peters Timothy , Jackson Katherine JL , Singh Mandeep , Ma Cindy S , Suan Daniel , Uzel Gulbu , Chua Ignatius , Leiding Jennifer W , Heiskanen Kaarina , Preece Kahn , Kainulainen Leena , O’Sullivan Michael , Cooper Megan A , Seppänen Mikko RJ , Mustjoki Satu , Brothers Shannon , Vogel Tiphanie P , Brink Robert , Tangye Stuart G , Reed Joanne H , Goodnow Christopher C 
Published: December 2021

SUMMARYDysregulated STAT3 signalling is correlated with antibody-mediated autoimmunity and B- cell neoplasia, but its effect on B cells is underexplored. Here we address this in children with STAT3 gain-of-function (GOF) syndrome and in mice with STAT3T716M, the most common STAT3 GOF syndrome human mutation, or STAT3K658N, a dimerization interface mutation responsible for STAT3 GOF syndrome in two children. The main B cell consequence of overactive STAT3 was accumulation of CD19highCD21lowatypical memory B cells in humans and of CD21lowCD23lowB cells in mice resembling age-associated B cells expressing T-bet, CD11c and plasma cell differentiation genes. Overactive STAT3 within B cells increased expression of many genes in the B cell receptor and T cell help pathways, increased the tolerogenic receptor CD22, but opposed B cell tolerance checkpoints and increased formation of T-bet+ B cells upon BCR and CD40 stimulation. These results reveal overactive STAT3 as a central driver of a key class of disease- associated B-lymphocytes in humans and mice.
High-Resolution Structure of the Nuclease Domain of the Human Parvovirus B19 Main Replication Protein NS1
Authors: Sanchez Jonathan L. , Ghadirian Niloofar , Horton Nancy C. 
Published: December 2021

ABSTRACTTwo new structures of the N-terminal domain of the main replication protein, NS1, of Human Parvovirus B19 (B19V) are presented. This domain (NS1-nuc) plays an important role in the “rolling hairpin” replication of the single-stranded B19V DNA genome, recognizing origin of replication sequences in double-stranded DNA, and cleaving (i.e. nicking) single-stranded DNA at a nearby site known as the trs. One structure of NS1-nuc is solved to 2.4 Å and shows the positions of two bound phosphate ions. A second structure shows the position of a single divalent cation in the DNA nicking active site. The threedimensional structure of NS1-nuc is well conserved between the two forms, as well as with a previously solved structure of a sequence variant of the same domain, however shown here at significantly higher resolution. Using structures of NS1-nuc homologues bound to single- and double-stranded DNA, models for DNA recognition and nicking by B19V NS1-nuc are presented which predict residues important for DNA cleavage and for sequence specific recognition at the viral origin of replication.