bluuebunny/crossref_metadata_2025_split huggingface dataset:
Polycomb-mediated Genome Architecture Enables Long-range Spreading of H3K27 methylation
Authors: Kraft Katerina , Yost Kathryn E. , Murphy Sedona , Magg Andreas , Long Yicheng , Corces M.Ryan , Granja Jeffrey M. , Mundlos Stefan , Cech Thomas R. , Boettiger Alistair , Chang Howard Y. 
Published: July 2020

SUMMARYPolycomb-group proteins play critical roles in gene silencing through the deposition of histone H3 lysine 27 trimethylation (H3K27me3) and chromatin compaction1-5. This process is essential for embryonic stem cell (ESCs) pluripotency, differentiation, and development. Polycomb repressive complex 2 (PRC2) can both read and write H3K27me3, enabling progressive spread of H3K27me3 on the linear genome6. Long-range Polycomb-associated DNA contacts have also been described, but their regulation and role in gene silencing remains unclear7-10. Here, we apply H3K27me3 HiChIP11-13, a protein-directed chromosome conformation method, and optical reconstruction of chromatin architecture14to profile long-range Polycomb-associated DNA loops that span tens to hundreds of megabases across multiple topological associated domains in mouse ESCs and human induced pluripotent stem cells7-10. We find that H3K27me3 loop anchors are enriched for Polycomb nucleation points and coincide with key developmental genes, such asHmx1, Wnt6andHoxa. Genetic deletion of H3K27me3 loop anchors revealed a coupling of Polycomb-associated genome architecture and H3K27me3 deposition evidenced by disruption of spatial contact between distant loci and altered H3K27me3in cis, both locally and megabases away on the same chromosome. Further, we find that global alterations in PRC2 occupancy resulting from an EZH2 mutant15selectively deficient in RNA binding is accompanied by loss of Polycomb-associated DNA looping. Together, these results suggest PRC2 acts as a “genomic wormhole”, using RNA binding to enhance long range chromosome folding and H3K27me3 spreading. Additionally, developmental gene loci have novel roles in Polycomb spreading, emerging as important architectural elements of the epigenome.
Oligonucleotide capture sequencing of the SARS-CoV-2 genome and subgenomic fragments from COVID-19 individuals
Authors: Doddapaneni Harsha , Cregeen Sara Javornik , Sucgang Richard , Meng Qingchang , Qin Xiang , Avadhanula Vasanthi , Chao Hsu , Menon Vipin , Nicholson Erin , Henke David , Piedra Felipe-Andres , Rajan Anubama , Momin Zeineen , Kottapalli Kavya , Hoffman Kristi L. , Sedlazeck Fritz J. , Metcalf Ginger , Piedra Pedro A. , Muzny Donna M. , Petrosino Joseph F. , Gibbs Richard A. 
Published: July 2020

AbstractThe newly emerged and rapidly spreading SARS-CoV-2 causes coronavirus disease 2019 (COVID-19). To facilitate a deeper understanding of the viral biology we developed a capture sequencing methodology to generate SARS-CoV-2 genomic and transcriptome sequences from infected patients. We utilized an oligonucleotide probe-set representing the full-length genome to obtain both genomic and transcriptome (subgenomic open reading frames [ORFs]) sequences from 45 SARS-CoV-2 clinical samples with varying viral titers. For samples with higher viral loads (cycle threshold value under 33, based on the CDC qPCR assay) complete genomes were generated. Analysis of junction reads revealed regions of differential transcriptional activity and provided evidence of expression of ORF10. Heterogeneous allelic frequencies along the 20kb ORF1ab gene suggested the presence of a defective interfering viral RNA species subpopulation in one sample. The associated workflow is straightforward, and hybridization-based capture offers an effective and scalable approach for sequencing SARS-CoV-2 from patient samples.
Massive-scale biological activity-based modeling identifies novel antiviral leads against SARS-CoV-2
Authors: Huang Ruili , Xu Miao , Zhu Hu , Chen Catherine Z. , Lee Emily M. , He Shihua , Shamim Khalida , Bougie Danielle , Huang Wenwei , Hall Mathew D. , Lo Donald , Simeonov Anton , Austin Christopher P. , Qiu Xiangguo , Tang Hengli , Zheng Wei 
Published: July 2020

AbstractThe recent global pandemic caused by the new coronavirus SARS-CoV-2 presents an urgent need for new therapeutic candidates. While the importance of traditionalin silicoapproaches such as QSAR in such efforts in unquestionable, these models fundamentally rely on structural similarity to infer biological activity and are thus prone to becoming trapped in the very nearby chemical spaces of already known ligands. For novel and unprecedented threats such as COVID-19 much faster and efficient paradigms must be devised to accelerate the identification of new chemical classes for rapid drug development. Here we report the development of a new biological activity-based modeling (BABM) approach that builds on the hypothesis that compounds with similar activity patterns tend to share similar targets or mechanisms of action. In BABM, compound activity profiles established on massive scale across multiple assays are used as signatures to predict compound activity in a new assay or against a new target. We first trained and validated this approach by identifying new antiviral lead candidates for Zika and Ebola based on data from ~0.5 million compounds screened against ~2,000 assays. BABM models were then applied to predict ~300 compounds not previously reported to have activity for SARS-CoV-2, which were then tested in a live virus assay with high (>30%) hit rates. The most potent compounds showed antiviral activities in the nanomolar range. These potent confirmed compounds have the potential to be further developed in novel chemical space into new anti-SARS-CoV-2 therapies. These results demonstrate unprecedented ability using BABM to predict novel structures as chemical leads significantly beyond traditional methods, and its application in rapid drug discovery response in a global public health crisis.
Structure and inhibition of the SARS-CoV-2 main protease reveals strategy for developing dual inhibitors against Mproand cathepsin L
Authors: Sacco Michael Dominic , Ma Chunlong , Lagarias Panagiotis , Gao Ang , Townsend Julia Alma , Meng Xiangzhi , Dube Peter , Zhang Xiujun , Hu Yanmei , Kitamura Naoya , Hurst Brett , Tarbet Bart , Marty Michael Thomas , Kolocouris Antonios , Xiang Yan , Chen Yu , Wang Jun 
Published: July 2020

AbstractThe main protease (Mpro) of SARS-CoV-2, the pathogen responsible for the COVID-19 pandemic, is a key antiviral drug target. While most SARS-CoV-2 Mproinhibitors have a γ-lactam glutamine surrogate at the P1 position, we recently discovered several Mproinhibitors have hydrophobic moieties at the P1 site, including calpain inhibitors II/XII, which are also active against human cathepsin L, a host-protease that is important for viral entry. To determine the binding mode of these calpain inhibitors and establish a structure-activity relationship, we solved X-ray crystal structures of Mproin complex with calpain inhibitors II and XII, and three analogues ofGC-376, one of the most potent Mproinhibitorsin vitro. The structure of Mprowith calpain inhibitor II confirmed the S1 pocket of Mprocan accommodate a hydrophobic methionine side chain, challenging the idea that a hydrophilic residue is necessary at this position. Interestingly, the structure of calpain inhibitor XII revealed an unexpected, inverted binding pose where the P1’ pyridine inserts in the S1 pocket and the P1 norvaline is positioned in the S1’ pocket. The overall conformation is semi-helical, wrapping around the catalytic core, in contrast to the extended conformation of other peptidomimetic inhibitors. Additionally, the structures of threeGC-376analoguesUAWJ246,UAWJ247, andUAWJ248provide insight to the sidechain preference of the S1’, S2, S3 and S4 pockets, and the superior cell-based activity of the aldehyde warhead compared with the α-ketoamide. Taken together, the biochemical, computational, structural, and cellular data presented herein provide new directions for the development of Mproinhibitors as SARS-CoV-2 antivirals.
Transitions in symbiosis: evidence for environmental acquisition & social transmission within a clade of heritable symbionts
Authors: Drew Georgia C , Budge Giles E , Frost Crystal L , Neumann Peter , Siozios Stefanos , Yañez Orlando , Hurst Gregory DD 
Published: July 2020

AbstractA dynamic continuum exists from free-living environmental microbes to strict host associated symbionts that are vertically inherited. However, knowledge of the forces that drive transitions in the modes by which symbioses form is lacking.Arsenophonusis a diverse clade of bacterial symbionts, comprising reproductive parasites to coevolving obligate mutualists, in which the predominant mode of transmission is vertical. We describe a symbiosis between a member of the genusArsenophonusand the Western honey bee. We then present multiple lines of evidence that this symbiont deviates from a heritable model of transmission. Field sampling uncovered marked spatial and seasonal dynamics in symbiont prevalence, and rapid infection loss events were observed in field colonies and individuals in the laboratory. Fluorescent in-situ hybridization showedArsenophonuslocalised in the gut, and detection of the bacterium was rare in screens of early honey bee life stages. We directly show horizontal transmission ofArsenophonusbetween bees under varying social conditions. We conclude that honey bees acquireArsenophonusthrough a combination of environmental exposure and social contacts. Together these findings uncover a key link in theArsenophonusclades trajectory from free-living ancestral life to obligate mutualism, and provide a foundation for studying transitions in symbiotic lifestyle.
Oncogenic Gene Fusions in Non-Neoplastic Precursors as Evidence that Bacterial Infection Initiates Prostate Cancer
Authors: Shrestha Eva , Coulter Jonathan B. , Guzman William , Ozbek Busra , Mummert Luke , Ernst Sarah E. , Maynard Janielle P. , Meeker Alan K. , Heaphy Christopher M. , Haffner Michael C. , De Marzo Angelo M. , Sfanos Karen S. 
Published: July 2020

AbstractProstate adenocarcinoma is the second most commonly diagnosed cancer in men worldwide and the initiating factors are unknown. Oncogenic TMPRSS2:ERG (ERG+) gene fusions are facilitated by DNA breaks and occur in up to 50% of prostate cancers1,2. Infection-driven inflammation is implicated in the formation of ERG+ fusions3, and we hypothesized that these fusions initiate in early inflammation-associated prostate cancer precursor lesions, such as proliferative inflammatory atrophy (PIA), prior to cancer development. We investigated whether bacterial prostatitis is associated with ERG+ precancerous lesions in unique cases with active bacterial infections at time of radical prostatectomy. We identified a high frequency of ERG+ non-neoplastic-appearing glands in these cases, including ERG+ PIA transitioning to early invasive cancer. We verified TMPRSS2:ERG genomic rearrangements in precursor lesions using tri-color fluorescencein situhybridization. Identification of rearrangement patterns combined with whole prostate mapping in 3 dimensions confirmed multiple (up to 8) distinct ERG+ precancerous lesions in infected cases. Finally, we identified the pathogen-derived genotoxin colibactin as a potential source of DNA breaks in clinical cases as well as cultured prostate cells. Overall, we provide evidence that bacterial infections initiate driver gene alterations in prostate cancer. Furthermore, infection-induced ERG+ fusions are an early alteration in the carcinogenic process and PIA may serve as a direct precursor to prostate cancer.
Panoramic Insights into the Microevolution and Macroevolution ofPrevotella copri-containing Lineage in Primate Guts
Authors: Li Hao , Meier-Kolthoff Jan P. , Hu Can-Xin , Wang Zhong-Jie , Zhu Jun , Zheng Wei , Tian Yun , Guo Feng 
Published: July 2020

AbstractPrevotella copriand related taxa are widely detected in mammalian gut microbiomes and have been linked with one human enterotype. However, their microevolution and macroevolution among hosts are poorly characterized. In this study, extensively collected marker genes and genomes were analyzed to trace their evolutionary history, host specificity, and biogeographic distribution. Investigations based on 16S rRNA gene,gyrB, and genomes suggested that a multi-specificP. copri-containing lineage (PCL) harbors diverse species in higher primates. Firstly,P. copriis the dominant species of PCL in the human gut and consists of multiple groups exhibiting high genomic divergence and conspicuous but non-strict biogeographic pattern. Most African strains with high genomic divergence from other strains were phylogenetically placed near the species root, indicating the co-evolutionary history ofP. copriandHomo sapiens. Secondly, although long-term co-evolution between PCL and higher primates was revealed, sporadic signals of co-speciation and extensive host jumping of PCL members were observed among higher primates. Metagenomic and phylogenetic analyses indicated thatP. copriand other PCL species found in captive mammals have been recently transmitted from humans. Thirdly, strong evidence was found on the extensively horizontal transfer of genes (e.g., carbohydrate-active enzyme encoding genes) among sympatricP. coprigroups and PCL species in the same primate host. Our study provides panoramic insights into the complex effects of vertical and horizontal transmission, and potential niche adaption on speciation, host, and biogeographical distribution spanning microevolutionary and macroevolutionary history for a certain gut bacterial lineage.ImportancePrevotella copriand its related taxa, which we designated asPrevotella copri-containing lineage (PCL) in the present study, are widely detected in guts of human, non-human primates and many captive mammals, showing positive or negative correlation to some human diseases. However, a comprehensive understanding on its microevolutionary (withinP. copri) and macroevolutionary (among PCL members) history across host species and host biogeography is still lacking. According to our analysis based on 16S rRNA gene,gyrBand genomes, we provided the panoramic insights into the putative effects of vertical transfer, horizontal transmission and potential niche selection on host and biogeographical distribution of this gut bacterial lineage andP. copri. To our knowledge, it is the first time that a gut bacterial lineage was studied at both micro- and macroevolutionary levels, which can aid our systematic understanding on the host-microbe co-evolutionary interactions.
Combinatorial CRISPR screening reveals functional buffering in autophagy
Authors: Diehl Valentina , Wegner Martin , Grumati Paolo , Husnjak Koraljka , Schaubeck Simone , Gubas Andrea , Shah Varun Jayeshkumar , Langschied Felix , Kalousi Alkmini , Ebersberger Ingo , Dikic Ivan , Kaulich Manuel 
Published: July 2020

ABSTRACTFunctional genomics studies in model organisms and human cell lines provided important insights into gene functions and their context-dependent role in genetic circuits. However, our functional understanding of many of these genes and how they combinatorically regulate key biological processes, remains limited. To enable the SpCas9-dependent mapping of gene-gene interactions in human cells, we established 3Cs multiplexing for the generation of combinatorial gRNA libraries in a distribution-unbiased manner and demonstrate its robust performance. The optimal number for combinatorial hit calling was 16 gRNA pairs and the skew of a library’s distribution was identified as a critical parameter dictating experimental scale and data quality. Our approach enabled us to investigate 247,032 gRNA-pairs targeting 12,736 gene-interactions in human autophagy. We identified novel genes essential for autophagy and provide experimental evidence that gene-associated categories of phenotypic strengths exist in autophagy. Furthermore, circuits of autophagy gene interactions reveal redundant nodes driven by paralog genes. Our combinatorial 3Cs approach is broadly suitable to investigate unexpected gene-interaction phenotypes in unperturbed and diseased cell contexts.
Accounting for work conditions from modern slavery to decent work
Authors: Christ Katherine Leanne , Burritt Roger Leonard , Schaltegger Stefan 
Published: July 2020

PurposeWith the initial focus on the extreme end of the work conditions continuum where, in the last decade, legislation has been introduced to combat illegal and illegitimate practices, this issue's lead paper provides an overview on key topics of extreme work conditions of modern slavery and accounting. The paper introduces the Special Issue on “Accounting for modern slavery, employees and work conditions in business” and its selected papers.Design/methodology/approachThe method adopted is a wide-ranging literature review exploring the continuum of work conditions and their relationship to accounting, especially extreme exploitation of workers through modern slavery.FindingsEmployment and workplace conditions and practices in business can be viewed as a continuum ranging from the illegal and illegitimate practices of modern slavery, through unethical and often illegal practices such as wages theft, to decent work. Given this continuum, in this Special Issue avenues are identified for accounting research to provide an account of the effectiveness of actions taken to eliminate modern slavery and overcome grey areas of work conditions.Practical implicationsThe paper helps to create an improved understanding of different types of exploitation in work conditions in different industries and the role accounting might play in research and practice.Social implicationsSlavery did not end with abolition in the 19th century. Instead, it changed its forms and continues to harm people in every country in the world especially in certain industries, of which several are discussed and accounting advice proffered. Likewise, as reflected in Special Issue papers, the role of accounting in reducing less extreme forms of poor work conditions is also considered.Originality/valueThe paper provides an overview of different forms and degrees of exploitation in work conditions and identifies the need for and areas of accounting research in this emerging area.
Tradition, innovation and relationships: emergent profiles from agro-food Italian industry
Authors: Cosentino Antonietta , Paoloni Paola , Iannone Barbara , Temperini Valerio 
Published: July 2020

PurposeThe purpose of this study is to analyze the link between innovation technology (IT), relationships which affect the relational capital (RC), and intangible value for the environment, focusing on small and medium enterprises (SMEs) of agro-food sector (AFS) in which these topics are prominent.Design/methodology/approachThis paper adopts a qualitative research methodology, based on a multiple case study. The empirical data were obtained from interviews designed to reveal the determinants of the Paoloni's CAOS model (characteristics, ambience, organization, start-up) useful to analyze the relational capital from the firm's perspective. The content analysis shows the most important factors influence the relationships of the companies analyzed.FindingsThe empirical analysis highlights the strong link between tradition and innovation in the AFS and its positive effects on corporate sustainability and company relationships as well as in enhancing knowledge. The introduction of ITs and the positive effects it produces in terms of efficiency, product quality, environmental sustainability and new communication channels is an important factor that influences business's relationships.Originality/valueThis paper contributes to the RC literature by stressing how ITs improve not only the executive process and performance of SMEs, but also the intangible resources of the territory. Accordingly, it provides both triggers for future research in the AFS, as well as suggestions to SMEs decision-makers to enhance their competitiveness. Furthermore, the paper offers insights to push policy makers in adopting policies that favor ITs investments in the AFS.
An examination of associations between business process management capabilities and the benefits of digitalization: all capabilities are not equal
Authors: Antonucci Yvonne Lederer , Fortune Annetta , Kirchmer Mathias 
Published: July 2020

PurposeWhile organizations have learned to understand the importance of developing business process management (BPM) capabilities, digitalization now transforms business processes, and introduces new challenges. Extending prior research examining the value of BPM capabilities in organizations, this study examines the associations of BPM capabilities across direct and indirect digitalization benefits.Design/methodology/approachDrawing from the capabilities perspective of strategic management, the dynamic versus ordinary classification was used to classify eight BPM capabilities. An empirical investigation of associations between the eight BPM capabilities and 20 digitalization benefits is presented based on data collected from 165 BPM professionals across four continents. Factor analyses were performed to verify the framework measures for BPM capabilities and digitalization benefits. The Kendall's tau-b (τb) correlation coefficient was used to measure the strength and direction of associations.FindingsOverall results confirm positive associations between BPM capabilities and digitalization benefits, but the relationship was less dominant for ordinary BPM capabilities and indirect benefits. Furthermore, relationships between individual BPM capabilities and specific digitalization benefits vary both across and within the categories.Practical implicationsThese findings support the moderate capability-based view that puts ordinary and dynamic capabilities on equal footing in dynamic environments, while also providing insight for managers focused on specific outcomes with digitalization efforts.Originality/valueThis study reveals that the strength of associations between BPM capabilities and digitalization benefits varies. This highlights the relevance of ordinary-dynamic and direct-indirect distinctions, and the value of a more fine-grained understanding to better inform practice.
South Korean humanistic leadership
Authors: Kim Hak Yoon , Park Joon Hyung , Kim Hyun Jeong 
Published: July 2020

PurposeThe purpose of this study is to identify and explore what leadership characteristics constitute humanistic leadership in the South Korean context. Moreover, this study examines how these leadership characteristics are connected to Korean culture.Design/methodology/approachBased on the information gathered from semi-structured interviews and other sources, including books, case study articles and news articles, this study captures a more comprehensive perspective of Mr. Kook-Hyun Moon, the former CEO of Yuhan–Kimberly.FindingsThe key characteristics of Mr. Moon's humanistic leadership that are identified in this study are: respect for all mankind, benevolence (seeking the greater good), sincerity (building trusting relationships with stakeholders) and continuous learning and innovation (developing self and others). These key characteristics set Mr. Moon apart from other leaders and are connected to the fundamental values and philosophies of Korean culture.Originality/valueThis study contributes to the current leadership literature by identifying and exploring Mr. Moon's humanistic leadership characteristics that enable him to gain respect and contribute to communities and society in the South Korean context. This study also finds that the humanistic leadership characteristics of Mr. Moon reflect three major attributes of Korean culture: the ideology of the Dangun mythology, the principle of Neo-Confucianism in Korea and jeong – an indigenous cultural concept in Korea (these attributes will be discussed in detail in the South Korean values and philosophies section). Such reflection suggests that investigating how humanistic leadership characteristics are connected to local cultural roots is important to enhance the understanding of humanistic leadership.