bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome-Wide Mapping of Human DNA Replication by Optical Replication Mapping Supports a Stochastic Model of Eukaryotic Replication
Authors: Wang Weitao , Klein Kyle , Proesmans Karel , Yang Hongbo , Marchal Claire , Zhu Xiaopeng , Borrman Tyler , Hastie Alex , Weng Zhiping , Bechhoefer John , Chen Chun-Long , Gilbert David M. , Rhind Nicholas 
Published: August 2020

AbstractDNA replication is regulated by the location and timing of replication initiation. Therefore, much effort has been invested in identifying and analyzing the sites of human replication initiation. However, the heterogeneous nature of eukaryotic replication kinetics and the low efficiency of individual initiation site utilization in metazoans has made mapping the location and timing of replication initiation in human cells difficult. A potential solution to the problem of human replication mapping is single-molecule analysis. However, current approaches do not provide the throughput required for genome-wide experiments. To address this challenge, we have developed Optical Replication Mapping (ORM), a high-throughput single-molecule approach to map newly replicated DNA, and used it to map early initiation events in human cells. The single-molecule nature of our data, and a total of more than 2000-fold coverage of the human genome on 27 million fibers averaging ~300 kb in length, allow us to identify initiation sites and their firing probability with high confidence. In particular, for the first time, we are able to measure genome-wide the absolute efficiency of human replication initiation. We find that the distribution of human replication initiation is consistent with inefficient, stochastic initiation of heterogeneously distributed potential initiation complexes enriched in accessible chromatin. In particular, we find sites of human replication initiation are not confined to well-defined replication origins but are instead distributed across broad initiation zones consisting of many initiation sites. Furthermore, we find no correlation of initiation events between neighboring initiation zones. Although most early initiation events occur in early-replicating regions of the genome, a significant number occur in late-replicating regions. The fact that initiation sites in typically late-replicating regions have some probability of firing in early S phase suggests that the major difference between initiation events in early and late replicating regions is their intrinsic probability of firing, as opposed to a qualitative difference in their firing-time distributions. Moreover, modeling of replication kinetics demonstrates that measuring the efficiency of initiation-zone firing in early S phase suffices to predict the average firing time of such initiation zones throughout S phase, further suggesting that the differences between the firing times of early and late initiation zones are quantitative, rather than qualitative. These observations are consistent with stochastic models of initiation-timing regulation and suggest that stochastic regulation of replication kinetics is a fundamental feature of eukaryotic replication, conserved from yeast to humans.
A putative origin of insect chemosensory receptors in the last common eukaryotic ancestor
Authors: Benton Richard , Dessimoz Christophe , Moi David 
Published: August 2020

AbstractThe insect chemosensory repertoires of Gustatory Receptors (GRs) and Odorant Receptors (ORs) together represent one of the largest families of ligand-gated ion channels. Previous analyses have identified homologous “Gustatory Receptor-Like (GRL)” proteins across Animalia, but the evolutionary origin of this novel class of ion channels is unknown. We describe a survey of unicellular eukaryotic genomes for GRLs, identifying several candidates in fungi, protists and algae that contain many structural features characteristic of animal GRLs. The existence of these proteins in unicellular eukaryotes, together withab initioprotein structure predictions, supports homology between GRLs and a large family of uncharacterised plant proteins containing the DUF3537 domain. Together, this evidence suggests an origin of this protein family in the last common eukaryotic ancestor.
Identification and characterization of distinct murine brown adipocyte lineages
Authors: Karlina Ruth , Lutter Dominik , Miok Viktorian , Fischer David , Altun Irem , Schöttl Theresa , Schorpp Kenji , Israel Andreas , Cero Cheryl , Johnson James W. , Kapser-Fischer Ingrid , Böttcher Anika , Keipert Susanne , Feuchtinger Annette , Graf Elisabeth , Strom Tim , Walch Axel , Lickert Heiko , Walzthoeni Thomas , Heinig Matthias , Theis Fabian J. , García-Cáceres Cristina , Cypess Aaron M. , Ussar Siegfried 
Published: August 2020

AbstractBrown adipose tissue (BAT) plays an important role in the regulation of body weight and glucose homeostasis. While increasing evidence supports white adipose tissue heterogeneity, little is known about heterogeneity within murine BAT. Using single cell RNA sequencing of the stromal vascular fraction of murine BAT and analysis of 67 brown preadipocyte and adipocyte clones we unravel heterogeneity within brown preadipocytes. Statistical analysis of gene expression profiles from these clones identifies markers distinguishing brown adipocyte lineages. We confirm the presence of distinct brown adipocyte populationsin vivousing three identified markers; Eif5, Tcf25, and Bin1. Functionally, we demonstrate that loss of Bin1 enhances UCP1 expression and mitochondrial respiration, suggesting that Bin1 marks a dormant brown adipocyte type. The existence of multiple brown adipocyte lineages suggests distinct functional properties of BAT depending on its cellular composition, with potentially distinct function in thermogenesis and the regulation of whole body energy homeostasis.
St. Jude Cloud—a Pediatric Cancer Genomic Data Sharing Ecosystem
Authors: McLeod Clay , Gout Alexander M. , Zhou Xin , Rahbarinia Delaram , Thrasher Andrew , Newman Scott , Birch Kirby , Macias Michael , Finkelstein David , Sunny Jobin , Mudunuri Rahul , Orr Brent A. , Treadway Madison , Davidson Bob , Ard Tracy , Swistak Andrew , Wiggins Stephanie , Foy Scott , Brady Samuel W. , Wang Jian , Sioson Edgar , Wang Shuoguo , Michael J. Robert , Liu Yu , Ma Xiaotu , Patel Aman , Edmonson Michael N. , Wilkinson Mark R. , Frantz Andrew , Chang Ti-Cheng , Tian Liqing , Lei Shaohua , Meyer Christopher , Thangaraj Naina , Tater Pamella , Kandali Vijay , Ma Singer , Nguyen Tuan , Serang Omar , McGuire Irina , Robison Nedra , Gentry Darrell , Tang Xing , Palmer Lance , Wu Gang , Suh Ed , Tanner Leigh , McMurry James , Lear Matthew , Wang Zhaoming , Wilson Carmen , Cheng Yong , Weiss Mitch , Armstrong Gregory T. , Robison Leslie L. , Yasui Yutaka , Nichols Kim E. , Ellison David W. , Bangur Chitanya , Mullighan Charles G. , Baker Suzanne J. , Dyer Michael , Miller Geralyn , Rusch Michael , Daly Richard , Perry Keith , Downing James R. , Zhang Jinghui 
Published: August 2020

ABSTRACTEffective data sharing is key to accelerating research that will improve the precision of diagnoses, efficacy of treatments and long-term survival of pediatric cancer and other childhood catastrophic diseases. We present St. Jude Cloud (https://www.stjude.cloud), a cloud-based data sharing ecosystem developed via collaboration between St. Jude Children’s Research Hospital, DNAnexus, and Microsoft, for accessing, analyzing and visualizing genomic data from >10,000 pediatric cancer patients, long-term survivors of pediatric cancer and >800 pediatric sickle cell patients. Harmonized genomic data totaling 1.25 petabyes on St. Jude Cloud include 12,104 whole genomes, 7,697 whole exomes and 2,202 transcriptomes, which are freely available to researchers worldwide. The resource is expanding rapidly with regular data uploads from St. Jude’s prospective clinical genomics programs, providing public access as soon as possible rather than holding data back until publication. Three interconnected apps within the St. Jude Cloud ecosystem—Genomics Platform, Pediatric Cancer Knowledgebase (PeCan) and Visualization Community—provide a unique experience for simultaneously performing advanced data analysis in the cloud and enhancing the pediatric cancer knowledgebase. We demonstrate the value of the St. Jude Cloud ecosystem through use cases that classify 48 pediatric cancer subtypes by gene expression profiling and map mutational signatures across 35 subtypes of pediatric cancer.
Double-transmembrane domain of SNAREs decelerates the fusion by increasing the protein-lipid mismatch
Authors: Bu Bing , Tian Zhiqi , Li Dechang , Zhang Kai , Chen Wei , Ji Baohua , Diao Jiajie 
Published: August 2020

ABSTRACTSNARE is the essential mediator of membrane fusion that highly relies on the molecular structure of SNAREs. For instance, the protein syntaxin-1 involving in neuronal SNAREs, has a single transmembrane domain (sTMD) leading to fast fusion, while the syntaxin 17 has a V-shape double TMDs (dTMDs), taking part in the autophagosome maturation. However, it is not clear how the TMD structure influences the fusion process. Here, we demonstrate that the dTMDs significantly reduce fusion rate compared with the sTMD by using an in vitro reconstitution system. Through theoretical analysis, we reveal that the V-shape dTMDs can significantly increase protein-lipid mismatch, thereby raising the energy barrier of the fusion, and that increasing the number of SNAREs can reduce the energy barrier or protein-lipid mismatch. This study provides a physical-chemical mechanistic understanding of SNARE-regulated membrane fusion.
Factors influencing the accuracy and precision in dating single gene trees
Authors: Louvel Guillaume , Crollius Hugues Roest 
Published: August 2020

AbstractMolecular dating is the inference of divergence time from genetic sequences. Knowing the time of appearance of a taxon sets the evolutionary context by connecting it with past ecosystems and species. Knowing the divergence times of gene lineages would provide a context to understand adaptation at the genomic level. However, molecular clock inference faces uncertainty due to the variability of the rate of substitution between species, between genes and between sites within genes. When dating speciations, per-lineage rate variability can be informed by fossil calibrations, and gene-specific rates can be either averaged out or modeled by concatenating multiple genes. By contrast when dating gene-specific events, fossil calibrations only inform about speciation nodes and concatenation does not apply to divergences other than speciations.This study aims at benchmarking the accuracy of molecular dating applied to single gene trees, and identify how it is affected by gene tree characteristics. We analyze 5205 alignments of genes from 21 Primates in which no duplication or loss is observed. We also simulated alignments based on characteristics from Primates under a relaxed clock model, to analyze the dating accuracy. Divergence times were estimated with the bayesian program Beast2.From the empirical dataset, we find that the date estimates deviate more from the median age with shorter alignments, high rate heterogeneity between branches and low average rate, features that underlie the amount of dating information in alignments, hence statistical power. The smallest deviation is associated with core biological functions such as ATP binding, cellular organization and anatomical development, categories that are expected to be under strong negative selection.We then investigated the accuracy of dating with simulated alignments, by controlling the three above parameters separately. It confirmed the factors of precision, but also revealed biases when branch rates are highly heterogeneous. This suggests that in the case of the relaxed uncorrelated molecular clock, biases arise from the tree prior when calibrations are lacking and rate heterogeneity is high. Our study finally reports the scale of the gene tree features that influence the dating consistency with median ages, so that comparisons can be made with other genes and taxa. To tackle the molecular dating of events only observed in single gene trees, like deep coalescence, horizontal gene transfers and gene duplications, future models should overcome the lack of power due to limited information from single genes.
The influence of major S protein mutations of SARS-CoV-2 on the potential B cell epitopes
Authors: Yuan Xianlin , li liangping 
Published: August 2020

AbstractSARS-CoV-2 has rapidly transmitted worldwide and results in the COVID-19 pandemic. Spike glycoprotein on surface is a key factor of viral transmission, and has appeared a lot of variants due to gene mutations, which may influence the viral antigenicity and vaccine efficacy. Here, we used bioinformatic tools to analyze B-cell epitopes of prototype S protein and its 9 common variants. 12 potential linear and 53 discontinuous epitopes of B-cells were predicted from the S protein prototype. Importantly, by comparing the epitope alterations between prototype and variants, we demonstrate that B-cell epitopes and antigenicity of 9 variants appear significantly different alterations. The dominant D614G variant impacts the potential epitope least, only with moderately elevated antigenicity, while the epitopes and antigenicity of some mutants(V483A, V367F, etc.) with small incidence in the population change greatly. These results suggest that the currently developed vaccines should be valid for a majority of SARS-CoV-2 infectors. This study provides a scientific basis for large-scale application of SARS-CoV-2 vaccines and for taking precautions against the probable appearance of antigen escape induced by genetic variation after vaccination.Author SummaryThe global pandemic of SARS-CoV-2 has lasted for more than half a year and has not yet been contained. Until now there is no effective treatment for SARS-CoV-2 caused disease (COVID-19). Successful vaccine development seems to be the only hope. However, this novel coronavirus belongs to the RNA virus, there is a high mutation rate in the genome, and these mutations often locate on the Spike proteins of virus, the gripper of the virus entering the cells. Vaccination induce the generation of antibodies, which block Spike protein. However, the Spike protein variants may change the recognition and binding of antibodies and make the vaccine ineffective. In this study, we predict neutralizing antibody recognition sites (B cell epitopes) of the prototype S protein of SARS-COV2, along with several common variants using bioinformatics tools. We discovered the variability in antigenicity among the mutants, for instance, in the more widespread D614G variant the change of epitope was least affected, only with slight increase of antigenicity. However, the antigenic epitopes of some mutants change greatly. These results could be of potential importance for future vaccine design and application against SARS-CoV2 variants.
Molecular Characterization of Carbapenem-ResistantAcinetobacter baumanniiClinical Isolates from Egyptian Patients
Authors: Hassan Reem M , Salem Sherifa T , Mostafa Hassan Saly Ismail , Hegab Asmaa Sayed , Elkholy Yasmine S 
Published: August 2020

AbstractAcinetobacter baumannii(A. baumannii) represents a global threat owing to its ability to resist most of the currently available antimicrobial agents. Moreover, emergence of carbapenem resistantA. baumannii(CR-AB) isolates limits the available treatment options. Enzymatic degradation by variety of ß-lactamases, have been identified as the most common mechanism of carbapenem resistance inA. baumannii. The alarming increase in the prevalence of CR-AB necessitates continuous screening and molecular characterization to appreciate the problem. The present study was performed to assess the prevalence and characterize carbapenemases among 206 CR-AB isolated from various clinical specimens collected from different intensive care units at Kasr Al-Aini Hospital.All isolates were confirmed to beA. baumanniiby detection of the blaOXA-51-like gene. Molecular screening of 13 common Ambler class bla carbapenemases genes in addition to insertion sequence (IS-1)upstreamOXA-23 was performed by using four sets of multiplex PCR, followed by identification using gene sequencing technology. Among the investigated genes, the prevalence of blaOXA-23, and blaOXA-58 were 77.7%, and 1.9%, respectively. The ISAba1was detected in 10% of the blaOXA-23 positive isolates. The prevalence of metallo-β-lactamases (MBLs) studied; blaNDM-1, blaSPM, blaVIM, blaSIM-1 were 11.7%, 6.3%, 0.5%, and 0.5% respectively. One of class A; bla KPC was detected in 10.7% of the investigated isolates. blaOXA-24/40, blaIMP, blaGES, blaVEB and blaGIM were not detected in any of the studied isolates. Moreover, 18.4% of the isolates have shown to harbor two or more of the screened bla genes. We concluded that the most prevalent type of ß-lactamases genes among CR-AB isolates collected from Egyptian patients were blaOXA-23 followed by blaNDM-1 and blaKPC.Author summaryCarbapenem-resistantA. baumanniihas become a real global health threat. The aim of the present study was to characterize and to assess the prevalence of carbapenemases among 206 CR-AB clinical isolates from Egyptian patients. We concluded that the most prevalent type of ß-lactamases genes among CR-AB isolates collected from Egyptian patients were blaOXA-23 followed by blaNDM-1 and blaKPC. In this study, ISAba1was detected upstream 10% of blaOXA-23 positive isolates only which indicates that the spread of resistance amongAcinetobacterisolates could be either chromosomal or plamid-mediated.
Distinct Cellular Strategies Determine Sensitivity to Mild Drought of Arabidopsis Natural Accessions
Authors: Chen Ying , Dubois Marieke , Vermeersch Mattias , Inzé Dirk , Vanhaeren Hannes 
Published: August 2020

AbstractThe world-wide distribution ofArabidopsis thaliana(Arabidopsis) accessions imposes different types of evolutionary pressures, which contributes to various responses of these accessions to environmental stresses. Drought stress responses have been well studied, particularly in Columbia, a common Arabidopsis accession. However, the reactions to drought stress are complex and our understanding of which of these responses contribute to the plant’s tolerance to mild drought is very limited. Here, we studied the mechanisms by which natural accessions react to mild drought at a physiological and molecular level during early leaf development. We documented variations in mild drought tolerance among natural accessions and used transcriptome sequencing of a drought-sensitive accession, ICE163, and a drought-tolerant accession, Yeg-1, to get insights into the mechanisms underlying this tolerance. This revealed that ICE163 preferentially induces jasmonates and anthocyanin-related pathways, which are beneficial in biotic stress defense, while Yeg-1 has a more pronounced activation of abscisic acid signaling, the classical abiotic stress response. Related physiological traits, including content of proline, anthocyanins and ROS, stomatal closure and cellular leaf parameters, were investigated and linked to the transcriptional responses. We conclude that most of these processes constitute general drought response mechanisms that are regulated similarly in drought-tolerant and -sensitive accessions. However, the capacity to close stomata and maintain cell expansion under mild drought appeared to be major factors that contribute to a better leaf growth under mild drought.One-sentence summaryThis paper demonstrates that an efficient closure of stomata and maintenance of cell expansion during drought conditions are crucial to maximally preserve plant growth during water deficit.
Non-autonomous regulation of germline stem cell proliferation by somatic MPK-1/MAPK activity inC. elegans
Authors: Robinson-Thiewes Sarah , Dufour Benjamin , Martel Pier-Olivier , Lechasseur Xavier , Brou Amani Ange Danielle , Roy Vincent , Chen Yunqing , Kimble Judith , Narbonne Patrick 
Published: August 2020

AbstractExtracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) is a major positive regulator of cell proliferation that is often upregulated in cancer. Yet few studies have addressed ERK/MAPK regulation of proliferation within a complete organism. TheC. elegansERK/MAPK ortholog MPK-1 is best known for its control of somatic organogenesis and germline differentiation, but it also stimulates germline stem cell proliferation. Here we identify tissue-specific MPK-1 isoforms and characterize their distinct roles in germline function. The germline-specific MPK-1B isoform promotes germline differentiation, but has no apparent role in germline stem cell proliferation. By contrast, the soma-specific MPK-1A isoform promotes germline proliferation non-autonomously. Indeed, MPK-1A functions in the intestine or somatic gonad to promote germline proliferation, independently of its other known roles. We propose that a non-autonomous role of ERK/MAPK in stem cell proliferation may be conserved across species and other tissue types, with major clinical implications for cancer and other diseases.
Small RNA directs symbiosis, virulence, and natural products biosynthesis in entomopathogenic bacteria
Authors: Neubacher Nick , Tobias Nicholas J. , Huber Michaela , Cai Xiaofeng , Glatter Timo , Pidot Sacha J. , Stinear Timothy P. , Lütticke Anna Lena , Papenfort Kai , Bode Helge B. 
Published: August 2020

AbstractRapid modulation of gene expression is a key feature for the success of bacteria, particularly for those that rapidly have to adapt to different niches. The lifecycles ofPhotorhabdusandXenorhabdusinvolve a mutualistic association with nematodes as well as an entomopathogenic phase1,2, both of which rely on the production of numerous specialized metabolites (SMs)3,4. Several regulators have been previously implicated in the regulation of SM production in these genera3,4. However, the molecular underpinnings regulating SM production and the role of small regulatory RNAs (sRNAs) in this process are unknown. Here we describe the mechanism underlying RNA-mediated control of SM synthesis. We show that the Hfq-dependent sRNA, ArcZ, is an essential requirement for SM production. We discovered that ArcZ directly base-pairs with the mRNA encoding HexA, a key repressor of SM genes. We further demonstrate that the ArcZ regulon is not restricted to SM production, but rather modulates up to ~15% of the transcriptional output in bothPhotorhabdusandXenorhabdus. Together, our study shows that sRNAs are crucial for SM production in these species, reveals previously unknown targets for biosynthetic pathway manipulations, and offers a new tool for the (over)production, isolation and identification of unknown natural products.