bluuebunny/crossref_metadata_2025_split huggingface dataset:
CNVpytor: a tool for CNV/CNA detection and analysis from read depth and allele imbalance in whole genome sequencing
Authors: Suvakov Milovan , Panda Arijit , Diesh Colin , Holmes Ian , Abyzov Alexej 
Published: January 2021

AbstractDetecting copy number variations (CNVs) and copy number alterations (CNAs) based on whole genome sequencing data is important for personalized genomics and treatment. CNVnator is one of the most popular tools for CNV/CNA discovery and analysis based on read depth (RD). Herein, we present an extension of CNVnator developed in Python -- CNVpytor. CNVpytor inherits the reimplemented core engine of its predecessor and extends visualization, modularization, performance, and functionality. Additionally, CNVpytor uses B-allele frequency (BAF) likelihood information from single nucleotide polymorphism and small indels data as additional evidence for CNVs/CNAs and as primary information for copy number neutral losses of heterozygosity. CNVpytor is significantly faster than CNVnator—particularly for parsing alignment files (2 to 20 times faster)—and has (20-50 times) smaller intermediate files. CNV calls can be filtered using several criteria and annotated. Modular architecture allows it to be used in shared and cloud environments such as Google Colab and Jupyter notebook. Data can be exported into JBrowse, while a lightweight plugin version of CNVpytor for JBrowse enables nearly instant and GUI-assisted analysis of CNVs by any user. CNVpytor release and the source code are available on GitHub at https://github.com/abyzovlab/CNVpytor under the MIT license.
Genomic signatures of recent convergent transitions to social life in spiders
Authors: Tong Chao , Avilés Leticia , Rayor Linda S. , Mikheyev Alexander S. , Linksvayer Timothy A. 
Published: January 2021

AbstractThe transition from solitary to social life is a major phenotypic innovation, but its genetic underpinnings are largely unknown. To identify genomic changes associated with this transition, we compare the genomes of 22 spider species representing eight recent and independent origins of sociality. Hundreds of genes tend to experience shifts in selection during the repeated transition to social life. These genes are associated with several key functions, such as neurogenesis, behavior, and metabolism, and include genes that previously have been implicated in animal social behavior and human behavioral disorders. In addition, social species have elevated genome-wide rates of molecular evolution associated with relaxed selection caused by reduced effective population size. Altogether, our study provides unprecedented insights into the genomic signatures of social evolution and the specific genetic changes that repeatedly underpin the evolution of sociality. Our study also highlights the heretofore unappreciated potential of transcriptomics using ethanol-preserved specimens for comparative genomics and phylotranscriptomics.
Obligate movements of an active site-linked surface domain control RNA polymerase elongation and pausing via a Phe-pocket anchor
Authors: Bao Yu , Landick Robert 
Published: January 2021

ABSTRACTThe catalytic trigger loop (TL) in RNA polymerase (RNAP) alternates between unstructured and helical hairpin conformations to admit and then contact the NTP substrate during transcription. In many bacterial lineages, the TL is interrupted by insertions of 2–5 surface-exposed, sandwich-barrel hybrid motifs (SBHMs) of poorly understood function. The 188-aa, 2-SBHME. coliinsertion, called SI3, occupies different locations in halted, NTP-bound, and paused transcription complexes, but its dynamics during active transcription and pausing are undefined. Here we report design, optimization, and use of a Cys-triplet reporter to measure the positional bias of SI3 in different transcription complexes and to determine the effect of restricting SI3 movement on nucleotide addition and pausing. We describe use of H2O2as a superior oxidant for RNAP disulfide reporters. NTP binding biases SI3 toward the closed conformation whereas transcriptional pausing biases SI3 toward a swiveled position that inhibits TL folding. We find that SI3 must change location in every round of nucleotide addition and that restricting its movements inhibits both transcript elongation and pausing. These dynamics are modulated by a crucial Phe pocket formed by the junction of the two SBHM domains. This SI3 Phe pocket captures a Phe residue in the RNAP jaw when the TL unfolds, explaining the similar phenotypes of alterations in the jaw and SI3. Our findings establish that SI3 functions by modulating the TL folding to aid transcriptional regulation and to reset secondary channel trafficking in every round of nucleotide addition.SIGNIFICANCERNA synthesis by cellular RNA polymerases depends on an active-site component called the trigger loop that oscillates between an unstructured loop that admits NTP substrates and a helical hairpin that positions the NTP in every round of nucleotide addition. In most bacteria, the trigger loop contains a large, surface-exposed insertion module that occupies different positions in halted transcription complexes but whose function during active transcription is unknown. By developing and using a novel disulfide reporter system, we find the insertion module also must alternate between in and out positions for every nucleotide addition, must swivel to a paused position to support regulation, and, in enterobacteria, evolved a “Phe pocket” that captures a key phenylalanine in the out and swivel positions.
DECODE: ADeep-learning Framework forCondensing Enhancers and Refining Boundaries with Large-scale Functional Assays
Authors: Chen Zhanlin , Zhang Jing , Liu Jason , Dai Yi , Lee Donghoon , Min Martin Renqiang , Xu Min , Gerstein Mark 
Published: January 2021

AbstractSummaryMapping distal regulatory elements, such as enhancers, is the cornerstone for investigating genome evolution, understanding critical biological functions, and ultimately elucidating how genetic variations may influence diseases. Previous enhancer prediction methods have used either unsupervised approaches or supervised methods with limited training data. Moreover, past approaches have operationalized enhancer discovery as a binary classification problem without accurate enhancer boundary detection, producing low-resolution annotations with redundant regions and reducing the statistical power for downstream analyses (e.g., causal variant mapping and functional validations). Here, we addressed these challenges via a two-step model called DECODE. First, we employed direct enhancer activity readouts from novel functional characterization assays, such as STARR-seq, to train a deep neural network classifier for accurate cell-type-specific enhancer prediction. Second, to improve the annotation resolution (∼500 bp), we implemented a weakly-supervised object detection framework for enhancer localization with precise boundary detection (at 10 bp resolution) using gradient-weighted class activation mapping.ResultsOur DECODE binary classifier outperformed thestate-of-the-artenhancer prediction methods by 24% in transgenic mouse validation. Further, DECODE object detection can condense enhancer annotations to only 12.6% of the original size, while still reporting higher conservation scores and genome-wide association study variant enrichments. Overall, DECODE improves the efficiency of regulatory element mapping with graphic processing units for deep-learning applications and is a powerful tool for enhancer prediction and boundary localization.AvailabilityDEOCDE is available atdecode.gersteinlab.orgContactpi@gersteinlab.org
Prevention and therapy of SARS-CoV-2 and the B.1.351 variant in mice
Authors: Martinez David R. , Schaefer Alexandra , Leist Sarah R. , Li Dapeng , Gully Kendra , Yount Boyd , Feng Joy Y. , Bunyan Elaine , Porter Danielle P. , Cihlar Tomas , Montgomery Stephanie A. , Haynes Barton F. , Baric Ralph S. , Nussenzweig Michel C. , Sheahan Timothy P. 
Published: January 2021

SUMMARYImproving the standard of clinical care for individuals infected with SARS-CoV-2 variants is a global health priority. Small molecule antivirals like remdesivir (RDV) and biologics such as human monoclonal antibodies (mAb) have demonstrated therapeutic efficacy against SARS-CoV-2, the causative agent of COVID-19. However, it is not known if combination RDV/mAb will improve outcomes over single agent therapies or whether antibody therapies will remain efficacious against variants. In kinetic studies in a mouse-adapted model of ancestral SARS-CoV-2 pathogenesis, we show that a combination of two mAbs in clinical trials, C144 and C135, have potent antiviral effects against even when initiated 48 hours after infection. The same antibody combination was also effective in prevention and therapy against the B.1.351 variant of concern (VOC). Combining RDV and antibodies provided a modest improvement in outcomes compared to single agents. These data support the continued use of RDV to treat SARS-CoV-2 infections and support the continued clinical development of the C144 and C135 antibody combination to treat patients infected with SARS-CoV-2 variants.
Games of risk and reward in carnivore communities
Authors: Ruprecht Joel , Eriksson Charlotte E. , Forrester Tavis D. , Spitz Derek B. , Clark Darren A. , Wisdom Michael J. , Bianco Marcus , Rowland Mary M. , Smith Joshua B. , Johnson Bruce K. , Levi Taal 
Published: January 2021

AbstractMesopredator release theory suggests that dominant predators suppress subordinate carnivores and ultimately shape community dynamics, but the assumption that subordinate species are only negatively affected ignores the possibility of facilitation through scavenging. We examined the interplay within a carnivore community consisting of cougars, coyotes, black bears, and bobcats using contemporaneous Global Positioning System telemetry data from 51 individuals, diet analysis from 972 DNA-metabarcoded scats, and data from 128 physical investigations of cougar kill sites, 28 of which were monitored with remote cameras. Resource provisioning from competitively-dominant cougars to coyotes through scavenging was so prolific as to be an overwhelming determinant of coyote behavior, space use, and resource acquisition. This was evident via strong attraction of coyotes to cougar kill sites, frequent scavenging of cougar-killed prey, and coyote diets that nearly matched cougars in the magnitude of ungulate consumption. Yet coyotes were often killed by cougars and used space to minimize encounters, complicating the fitness benefits gained from scavenging. We estimated that 23% (95% CI: 8–55%) of the coyote population in our study area was killed by cougars annually suggesting that coyote interactions with cougars are a complex behavioral game of risk and reward. In contrast, we found no indication that bobcat space use or diet was influenced by cougars. Black bears avoided cougars, but there was no evidence of attraction to cougar kill sites, and much lower levels of ungulate consumption and carcass visitation than for coyotes. Interspecific interactions among carnivores are multifaceted encompassing both suppression and facilitation.Significance StatementAn incomplete understanding of the total influence competitively-dominant predators exert on subordinate species hinders our ability to anticipate the effects that changing carnivore populations will have in ecological communities. Here we show that cougars are the architects of a complex behavioral game of risk and reward, as subordinate or co-occurring carnivores are both provisioned and preyed on by the dominant predators. Each co-occurring carnivore species considered here employed a different strategy to approach the risk-reward tradeoff suggesting there are multiple viable solutions to the game. By not considering the multitude of effects dominant predators have on other carnivores, we are missing important linkages in terrestrial food webs.
Ultraviolet light-induced collagen degradation inhibits melanoma invasion
Authors: Budden Timothy , Gaudy Caroline , Porter Andrew , Kay Emily , Gurung Shilpa , Earnshaw Charles , Roeck Katharina , Craig Sarah , Traves Víctor , Krutmann Jean , Muller Patricia , Motta Luisa , Zanivan Sara , Malliri Angeliki , Furney Simon J , Nagore Eduardo , Virós Amaya 
Published: January 2021

AbstractUltraviolet radiation (UVR) increases the incidence of cutaneous melanoma1–4. The ageing, sun-exposed dermis accumulates UVR damage5, and older patients develop more melanomas at UVR-exposed sites4,6,7. As fibroblasts are functionally heterogeneous and play key roles in the stromal contribution to cancer8,9, we asked whether UVR modifies dermal fibroblast function. Here we confirmed the expression of collagen-cleaving matrix metalloprotein-1 (MMP1) by UVR-damaged fibroblasts was persistently upregulated to reduce local levels of collagen 1 (COL1A1), and found dermal COL1A1 degradation by MMP1 decreased melanoma invasion. Conversely, we show inhibiting extracellular matrix degradation and MMP1 expression restored melanoma invasion to UVR damaged dermis. We confirmedin vitrofindings in a cohort of primary cutaneous melanomas of aged humans, showing more cancer cells invade as single cells at the invasive front of melanomas expressing and depositing more collagen. We found collagen and single melanoma cell invasion are robust predictors of poor melanoma-specific survival. These data indicate melanomas arising over UVR-damaged, collagen-poor skin of the elderly are less invasive, and this reduced invasion improves survival. Consequently, although UVR increases tumour incidence, it delays primary melanoma invasion by degrading collagen. However, we show melanoma-associated fibroblasts can restore invasion in low-collagen primary tumours by increasing collagen synthesis. Finally, we demonstrate highCOL1A1gene expression is a biomarker of poor outcome across a broad range of primary cancers.
Seroprevalence ofToxoplasma gondiiamong sylvatic rodents in Poland
Authors: Grzybek Maciej , Antolová Daniela , Tołkacz Katarzyna , Alsarraf Mohammed , Behnke-Borowczyk Jolanta , Nowicka Joanna , Paleolog Jerzy , Biernat Beata , Behnke Jerzy M. , Bajer Anna 
Published: January 2021

ABSTRACTToxoplasma gondiiis a significant pathogen affecting humans and animals. We conducted seromonitoring forT. gondiiin four sylvatic rodent species in Poland. We report an overall seroprevalence of 5.5% (3.6% forMyodes glareolusand 20% for other vole species). Seroprevalence in bank voles varied significantly between host age and sex.
Loss of Foxc1 and Foxc2 function in chondroprogenitor cells disrupts endochondral ossification
Authors: Almubarak Asra , Lavy Rotem , Srnic Nikola , Hu Yawen , Maripuri Devi P. , Kume Tsutomo , Berry Fred B 
Published: January 2021

AbstractEndochondral ossification forms and grows the majority of the mammalian skeleton and is tightly controlled through gene regulatory networks. The forkhead box transcription factorsFoxc1andFoxc2have been demonstrated to regulate aspects of osteoblast function in the formation of the skeleton but their roles in chondrocytes to control endochondral ossification are less clear. We demonstrate that Foxc1 expression is directly regulated by SOX9 activity, one of the earliest transcription factors to specify the chondrocyte lineages. Moreover we demonstrate that elevelated expression of Foxc1 promotes chondrocyte differentiation in mouse embryonic stem cells and loss of Foxc1 function inhibits chondrogenesis in vitro. Using chondrocyte-targeted deletion of Foxc1 and Foxc2 in mice, we reveal a role for these factors in chondrocyte differentiation in vivo. Loss of both Foxc1 and Foxc2 caused a general skeletal dysplasia predominantly affecting the vertebral column. The long bones of the limb were smaller and mineralization was reduced and organization of the growth plate was disrupted. In particular, the stacked columnar organization of the proliferative chondrocyte layer was reduced in size and cell proliferation in growth plate chondrocytes was reduced. Differential gene expression analysis indicated disrupted expression patterns in chondrogenesis and ossification genes throughout the entire process of endochondral ossification inCol2-cre;Foxc1Δ/Δ;Foxc2Δ/Δembryos. Our results suggest thatFoxc1andFoxc2are required for correct chondrocyte differentiation and function. Loss of both genes results in disorganization of the growth plate, reduced chondrocyte proliferation and delays in chondrocyte hypertrophy that prevents correct ossification of the endochondral skeleton.
Pore structure controls stability and molecular flux in engineered protein cages
Authors: Adamson Lachlan S. R. , Tasneem Nuren , Andreas Michael P. , Close William , Jenner Eric N. , Szyszka Taylor N. , Young Reginald , Cheah Li Chen , Norman Alexander , MacDermott-Opeskin Hugo I. , O’Mara Megan L. , Sainsbury Frank , Giessen Tobias W. , Lau Yu Heng 
Published: January 2021

AbstractProtein cages are a common architectural motif used by living organisms to compartmentalize and control biochemical reactions. While engineered protein cages have recently been featured in the construction of nanoreactors and synthetic organelles, relatively little is known about the underlying molecular parameters that govern cage stability and molecular flux through their pores. In this work, we systematically designed a 24-member library of protein cage variants based on the T. maritima encapsulin, each featuring pores of different size and charge. Twelve encapsulin pore variants were successfully assembled and purified, including eight designs with exceptional and prolonged thermal stability. While pores lined with negatively charged residues resulted in more robust assemblies than their corresponding positively charged variants, we were able to form stable assemblies covering a full range of pore sizes and charges, as observed in seven new cryo-EM structures of pore variants elucidated at resolutions between 2.5-3.6 Å. Alongside these structures, molecular dynamics simulations and stopped flow kinetics experiments reveal the importance of considering both pore size and surface charge, together with flexibility and rate determining steps, when designing protein cages for controlling molecular flux.Abstract Figure
Golden hamster piRNAs are necessary for early embryonic development and establishment of spermatogonia
Authors: Loubalova Zuzana , Fulka Helena , Horvat Filip , Pasulka Josef , Malik Radek , Hirose Michiko , Ogura Atsuo , Svoboda Petr 
Published: January 2021

ABSTRACTPIWI-associated RNAs (piRNAs) support the germline by suppressing retrotransposons and genes. In mice, piRNAs are essential for spermatogenesis but not oogenesis. To test how this applies to other mammals, we deletedMov10l1helicase in golden hamster, whose piRNA pathway is configured more similarly to that of other mammals.Mov10l1−/−male hamsters showed impaired establishment of spermatogonia accompanied by transcriptome dysregulation and a surge in MYSERV retrotransposon expression. The rare viable spermatogenic cells showed a meiotic failure phenotype likeMov10l1−/−mice. FemaleMov10l1−/−hamsters were sterile due to post-meiotic loss of developmental competence in zygotes. Unique phenotypes ofMov10l1−/−hamsters demonstrate the adaptive nature of piRNA-mediated control of genes and retrotransposons in order to confront emerging genomic threats or acquire new physiological roles.
Epigenetic state determines inflammatory sensing in neuroblastoma
Authors: Wolpaw Adam J. , Grossmann Liron D. , Dong May M. , Dessau Jessica L. , Brafford Patricia A. , Volgina Darya , Rodriguez-Garcia Alba , Uzun Yasin , Powell Daniel J. , Tan Kai , Hogarty Michael D. , Maris John M. , Dang Chi V. 
Published: January 2021

AbstractImmunotherapy has revolutionized cancer treatment, but many cancers are not impacted by currently available immunotherapeutic strategies. Here, we investigated inflammatory signaling pathways in neuroblastoma, a classically “cold” pediatric cancer. By testing the functional response of a panel of 20 diverse neuroblastoma cell lines to three different inflammatory stimuli, we found that all cell lines have intact interferon signaling and all but one lack functional cGAS-STING signaling. However, toll-like receptor (TLR) signaling, particularly through TLR3, was heterogeneous. Six cell lines showed robust response, five of which are in the mesenchymal epigenetic state, while all 14 unresponsive cell lines are in the adrenergic state. Genetically switching the adrenergic BE2(c) cell line towards the mesenchymal state fully restored TLR responsiveness. In responsive cells, TLR3 activation results in the secretion of pro-inflammatory cytokines, enrichment of inflammatory transcriptomic signatures, and increased tumor killing by T-cellsin vitro. Using single cell RNA sequencing data, we show that human neuroblastoma cells with stronger mesenchymal signatures have a higher basal inflammatory state, demonstrating intra-tumoral heterogeneity in inflammatory signaling that has significant implications for immunotherapeutic strategies in this aggressive childhood cancer.
The environment topography alters the transition from single-cell populations to multicellular structures inMyxococcus xanthus
Authors: Hernández Ramos Karla C. , Rodríguez-Sánchez Edna , Arias del Angel Juan Antonio , Arzola Alejandro V. , Benítez Mariana , Escalante Ana E. , Franci Alessio , Volpe Giovanni , Rivera-Yoshida Natsuko 
Published: January 2021

ABSTRACTThe social soil-dwelling bacteria Myxococcus xanthus can form multicellular structures, known as fruiting bodies. Experiments in homogeneous environments have shown that this process is affected by the physico-chemical properties of the substrate, but they have largely neglected the role of complex topographies. We experimentally demonstrate that the topography alters single-cell motility and multicellular organization in M. xanthus. In topographies realized by randomly placing silica particles over agar plates, we observe that the cells’ interaction with particles drastically modifies the dynamics of cellular aggregation, leading to changes in the number, size and shape of the fruiting bodies, and even to arresting their formation in certain conditions. We further explore this type of cell-particle interaction in a minimal computational model. These results provide fundamental insights into how the environment topography influences the emergence of complex multicellular structures from single cells, which is a fundamental problem of biological, ecological and medical relevance.