bluuebunny/crossref_metadata_2025_split huggingface dataset:
Shotgun Transcriptome and Isothermal Profiling of SARS-CoV-2 Infection Reveals Unique Host Responses, Viral Diversification, and Drug Interactions
Authors: Butler Daniel J. , Mozsary Christopher , Meydan Cem , Danko David , Foox Jonathan , Rosiene Joel , Shaiber Alon , Afshinnekoo Ebrahim , MacKay Matthew , Sedlazeck Fritz J. , Ivanov Nikolay A. , Sierra Maria , Pohle Diana , Zietz Michael , Gisladottir Undina , Ramlall Vijendra , Westover Craig D. , Ryon Krista , Young Benjamin , Bhattacharya Chandrima , Ruggiero Phyllis , Langhorst Bradley W. , Tanner Nathan , Gawrys Justyna , Meleshko Dmitry , Xu Dong , Steel Peter A. D. , Shemesh Amos J. , Xiang Jenny , Thierry-Mieg Jean , Thierry-Mieg Danielle , Schwartz Robert E. , Iftner Angelika , Bezdan Daniela , Sipley John , Cong Lin , Craney Arryn , Velu Priya , Melnick Ari M. , Hajirasouliha Iman , Horner Stacy M. , Iftner Thomas , Salvatore Mirella , Loda Massimo , Westblade Lars F. , Cushing Melissa , Levy Shawn , Wu Shixiu , Tatonetti Nicholas , Imielinski Marcin , Rennert Hanna , Mason Christopher E. 
Published: April 2020

AbstractThe Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused thousands of deaths worldwide, including >18,000 in New York City (NYC) alone. The sudden emergence of this pandemic has highlighted a pressing clinical need for rapid, scalable diagnostics that can detect infection, interrogate strain evolution, and identify novel patient biomarkers. To address these challenges, we designed a fast (30-minute) colorimetric test (LAMP) for SARS-CoV-2 infection from naso/oropharyngeal swabs, plus a large-scale shotgun metatranscriptomics platform (total-RNA-seq) for host, bacterial, and viral profiling. We applied both technologies across 857 SARS-CoV-2 clinical specimens and 86 NYC subway samples, providing a broad molecular portrait of the COVID-19 NYC outbreak. Our results define new features of SARS-CoV-2 evolution, nominate a novel, NYC-enriched viral subclade, reveal specific host responses in interferon, ACE, hematological, and olfaction pathways, and examine risks associated with use of ACE inhibitors and angiotensin receptor blockers. Together, these findings have immediate applications to SARS-CoV-2 diagnostics, public health, and new therapeutic targets.
Anthrax Toxin Translocation Complex Reveals insight into the Lethal Factor Unfolding and Refolding Mechanism
Authors: Machen Alexandra J , Fisher Mark T , Freudenthal Bret D 
Published: April 2020

AbstractTranslocation is essential to the anthrax toxin mechanism. Protective antigen (PA), the translocon component of this AB toxin, forms an oligomeric pore with three key clamp sites that aid in the efficient entry of lethal factor (LF) or edema factor (EF), the enzymatic components of the toxin, into the cell. LF and EF translocate through the PA pore (PApore) with the pH gradient between the endosome and the cytosol facilitating rapid translocationin vivo. Structural details of the translocation process have remained elusive despite their biological importance. To overcome the technical challenges of studying translocation intermediates, we developed a novel method to immobilize, transition, and stabilize anthrax toxin to mimic important physiological steps in the intoxication process. Here, we report a cryoEM snapshot of PAporetranslocating the N-terminal domain of LF (LFN). The resulting 3.3 Å structure of the complex shows density of partially unfolded LFNnear the canonical PAporebinding site as well as in the α clamp, the Φ clamp, and the charge clamp. We also observe density consistent with an α helix emerging from the 100 Å β barrel channel suggesting LF secondary structural elements begin to refold in the pore channel. We conclude the anthrax toxin β barrel aids in efficient folding of its enzymatic payload prior to channel exit. Our hypothesized refolding mechanism has broader implications for pore length of other protein translocating toxins.Significance StatementToxins like the anthrax toxin aid bacteria in establishing an infection, evading the immune system, and proliferating inside a host. The anthrax toxin, a proteinaceous AB toxin secreted byBacillus anthracis, consists of lethal factor and protective antigen. In this work, we explore the molecular details of lethal factor translocation through protective antigen pore necessary for cellular entry. Our cryo electron microscopy results provide evidence of lethal factor secondary structure refolding prior to protective antigen pore exit. Similar to the ribosome exit tunnel, the toxin pore channel likely contributes to native folding of lethal factor. We predict other AB toxins with extended pores also initiate substrate refolding inside the translocon for effective intoxication during bacterial infection, evasion, and proliferation.
Cells recognize osmotic stress through liquid-liquid phase separation lubricated with poly(ADP-ribose)
Authors: Watanabe Kengo , Morishita Kazuhiro , Zhou Xiangyu , Shiizaki Shigeru , Uchiyama Yasuo , Koike Masato , Naguro Isao , Ichijo Hidenori 
Published: April 2020

AbstractCells are under threat of osmotic perturbation; and cell volume maintenance is critical in cerebral edema, inflammation and aging, in which prominent changes in intracellular or extracellular osmolality emerge. After osmotic stress-enforced cell swelling or shrinkage, the cells regulate intracellular osmolality to recover their volume. However, the mechanisms recognizing osmotic stress remain obscured. We previously clarified that apoptosis signal-regulating kinase 3 (ASK3) bidirectionally responds to osmotic stress and regulates cell volume recovery. Here, we report that macromolecular crowding induces liquid-demixing condensates of ASK3 under hyperosmotic stress, which transduce osmosensing signal into ASK3 inactivation. A genome-wide small interfering RNA (siRNA) screen identified an ASK3 inactivation regulator, nicotinamide phosphoribosyltransferase (NAMPT), related to poly(ADP-ribose) signaling. Furthermore, we clarify that poly(ADP-ribose) keeps ASK3 condensates in the liquid phase and enables ASK3 to become inactivated under hyperosmotic stress. Our findings demonstrate that cells rationally incorporate physicochemical phase separation into their osmosensing systems.
Identifying genomic markers associated with female re-mating rate inDrosophila pseudoobscuraby replicated bulk segregant analysis
Authors: Wiberg R Axel W , Price Tom A R , Wedell Nina , Ritchie Michael G 
Published: April 2020

ABSTRACTIdentifying loci associated with a phenotype is a critical step in many evolutionary studies. Most methods require large sample sizes or breeding designs that can be prohibitively difficult. Here we apply a rarely used approach to identify SNP loci associated with a complex phenotype. We mate siblings from isofemale lines isolate genotypes from three wild populations. After phenotyping we perform whole genome sequencing of isofemale lines from the extremes of the phenotypic distribution of each population and identify SNPs that are consistently fixed for alternative alleles across line pairs. The focal phenotype is female remating rate in the flyDrosophila pseudoobscura,defined as the willingness of a female to mate with a second male after her first mating. This is an integral part of mating system evolution, sexual selection and sexual conflict, and is a quantitative polygenic trait.About 200 SNPs are consistently fixed for alternate alleles in the three pairs of isofemale lines. We use different simulation approaches to explore how many SNPs would be expected to be fixed. We find the surprising result that we uncoverfewerobserved fixed SNPs than are expected by either simulation approach. We also complete functional analyses of these SNPs. Many lie near genes or regulatory regions known to be involved inDrosophilacourtship and mating behaviours, and some have previously been associated with re-mating rates in Genome-Wide Association Studies. Given the small sample size, these results should be treated with caution. Nevertheless, this study suggests that even from a relatively small number of isofemale lines established from wild populations, it is possible to identify candidate loci potentially associated with a complex quantitative trait. However, further work is required to understand modelling the expected distribution of differences.
“Identification and enrichment of SECReTEcis-acting RNA elements in theCoronaviridaeand other (+) single-strand RNA viruses”
Authors: Haimovich Gal , Olender Tsviya , Baez Camila , Gerst Jeffrey E. 
Published: April 2020

Abstractcis-acting RNA motifs play a major role in regulating many aspects of RNA biology including posttranscriptional processing, nuclear export, RNA localization, translation and degradation. Here we analyzed the genomes of SARS-CoV-2 and other single-strand RNA (ssRNA) viruses for the presence of a uniquecisRNA element called SECReTE. This motif consists of 10 or more consecutive triplet nucleotide repeats where a pyrimidine nucleotide (C or U) in present every third base, and which we identified in mRNAs encoding secreted proteins in bacteria, yeast, and humans. This motif facilitates mRNA localization to the endoplasmic reticulum (ER), along with the enhanced translation and secretion of translated protein. We now examined for SECReTE presence in Group IV and V RNA viruses, the former including theCoronaviridae, like SARS-CoV-2 and other positive (+)ssRNA viruses, and the latter consisting of negative (-) ssRNA viruses. Interestingly, the SARS-CoV-2 genome contains 40 SECReTE motifs at an abundance of ~1.3 SECReTEs/kilobase (kb). Moreover, all ssRNA viruses we examined contain multiple copies of this motif and appears in (+)ssRNA viruses as non-random in occurrence and independent of genome length. Importantly, (+)ssRNA viruses (e.g.Coronaviruses and Hepaciviruses), which utilize ER membranes to create double membrane vesicles to serve as viral replication centers (VRCs), contain more SECReTE motifs per kb as compared to (−)ssRNA viruses (e.g. Rabies, Mumps, and Influenza), that replicate in the nucleus or the cytoplasm, or other (+)ssRNA viruses (e.g. Enteroviruses and Flaviviruses) which employ different organellar membranes. As predicted by our earlier work, SECReTE sequences are mostly found in membranal or ER-associated/secreted proteins. Thus, we propose that SECReTE motifs could be important for the efficient translation and secretion of secreted viral proteins, as well as for VRC formation. Future studies of SECReTE function and identification of SECReTE-binding proteins could provide new drug targets to treat COVID-19 and other (+)ssRNA related diseases.
Multiple particle tracking detects changes in brain extracellular matrix structure and predicts neurodevelopmental age
Authors: McKenna Michael , Shackelford David , Pontes Hugo Ferreira , Ball Brendan , Gao Tora , Nance Elizabeth 
Published: April 2020

Abstract SummaryBrain extracellular matrix (ECM) structure mediates many aspects of neuronal function. Probing changes in ECM structure could provide insights into aging and neurological disease. Herein, we demonstrate the ability to characterize changes in brain ECM structure using multiple particle tracking (MPT). MPT was carried out in organotypic rat brain slices to detect induced and naturally occurring changes in ECM structure. Induced degradation of neural ECM led to a significant increase in nanoparticle diffusive ability in the brain extracellular space. For structural changes that occur naturally during development, an inverse relationship existed between age and nanoparticle diffusion. Using the age-dependent dataset, we applied extreme gradient boosting (XGBoost) to generate models capable of classifying nanoparticle trajectories. Collectively, this work demonstrates the utility of MPT combined with machine learning for measuring changes in brain ECM structure and predicting associated complex features such as developmental age.
Dysregulated gene expression throughTP53promoter swapping in osteosarcoma
Authors: Saba Karim H. , Difilippo Valeria , Kovac Michal , Cornmark Louise , Magnusson Linda , Nilsson Jenny , van den Bos Hilda , Spierings Diana C. J. , Bidgoli Mahtab , Jonson Tord , Sumathi Vaiyapuri P. , Brosjö Otte , Staaf Johan , Foijer Floris , Styring Emelie , Nathrath Michaela , Baumhoer Daniel , Nord Karolin H. 
Published: April 2020

AbstractHow massive genome rearrangements confer a competitive advantage to a cancer cell has remained an enigma. The malignant bone tumour osteosarcoma harbours an extreme number of structural variations and thereby holds the key to understand complex cancer genomes. Genome integrity in osteosarcoma is generally lost together with disruption of normalTP53gene function, the latter commonly through either missense mutations or structural alterations that separate the promoter region from the coding parts of the gene. To unravel the consequences of aTP53promoter relocated in this manner, we performed in-depth genetic analyses of osteosarcoma biopsies (n=148) and cell models. We show thatTP53structural variations are early events that not only facilitate further chromosomal alterations, but also allow theTP53promoter to upregulate genes erroneously placed under its control. Paradoxically, many of the induced genes are part of theTP53-associated transcriptome, suggesting a need to counterbalance loss ofTP53function through ‘separation-of-function’ mutations via promoter swapping. Our findings demonstrate how massive genome errors can functionally turn the promoter region of a tumour suppressor gene into a constitutively active oncogenic driver.
G9a methyltransferase governs cell identity in the lung and is required for KRAS G12D tumor development and propagation
Authors: Pribluda Ariel , Daemen Anneleen , Lima Anthony , Wang Xi , Hafner Marc , Poon Chungkee , Modrusan Zora , Katakam Anand Kumar , Foreman Oded , Eastham Jeffrey , Hung Jefferey , Haley Benjamin , Garcia Julia T , Jackson Erica L. , Junttila Melissa R. 
Published: April 2020

AbstractLung development, integrity and repair rely on precise Wnt signaling, which is corrupted in diverse diseases, including cancer. Here, we discover that G9a methyltransferase regulates Wnt signaling in the lung by controlling the transcriptional activity of chromatin-bound β-catenin, through a non-histone substrate. Inhibition of G9a induces transcriptional, morphologic, and molecular changes consistent with alveolar type 2 (AT2) lineage commitment. Mechanistically, G9a activity functions to support regenerative properties of KrasG12D tumors and normal AT2 cells – the predominant cell of origin of this cancer. Consequently, G9a inhibition preventsKrasG12Dlung adenocarcinoma tumor formation and propagation,and disrupts normal AT2 cell trans-differentiation. Consistent with these findings, low G9a expression in human lung adenocarcinoma correlates with enhanced AT2 gene expression and improved prognosis. These data reveal G9a as a critical regulator of Wnt signaling, implicating G9a as a potential target in lung cancer and other AT2-mediated lung pathologies.
Multiple plasmid origin-of-transfer substrates enable the spread of natural antimicrobial resistance to human pathogens
Authors: Zrimec Jan 
Published: April 2020

AbstractAntimicrobial resistance poses a great danger to humanity, in part due to the widespread horizontal transfer of plasmids via conjugation. Modeling of plasmid transfer is essential to uncovering the fundamentals of resistance transfer and for development of predictive measures to limit the spread of resistance. However, a major limitation in the current understanding of plasmids is the inadequate characterization of the DNA transfer mechanisms, which conceals the actual potential for plasmid transfer in nature. Here, we consider that the plasmid-borne origin-of-transfer substrates encode specific DNA structural properties that can facilitate finding these regions in large datasets, and develop a DNA structure-based alignment procedure for typing the transfer substrates that outperforms mere sequence-based approaches. We identify thousands of yet undiscovered DNA transfer substrates, showing that actual plasmid mobility can in fact be 2-fold higher and span almost 2-fold more host species than is currently known. Over half of all mobile plasmids contain the means to transfer between different mobility groups, which links previously confined host ranges across ecological habitats into a robust plasmid transfer network. We show that this network in fact serves to transfer antimicrobial resistance from the environmental genetic reservoirs to human pathogens, which might be an important driver of the observed rapid resistance development in humans and thus an important point of focus for future prevention measures.
NMR backbone assignment and dynamics of Profilin from Heimdallarchaeota
Authors: Haq Syed Razaul , Survery Sabeen , Hurtig Fredrik , Lindås Ann-Christin , Chi Celestine N. 
Published: April 2020

AbstractThe origin of the eukaryotic cell is an unsettled scientific question. The Asgard superphylum has emerged as a compelling target for studying eukaryogenesis due to the previously unseen diversity of eukaryotic signature proteins. However, our knowledge about these proteins is still relegated to metagenomic data and very little is known about their structural properties. Additionally, it is still unclear if these proteins are functionally homologous to their eukaryotic counterparts. Here, we expressed, purified and structurally characterized profilin from Heimdallarchaeota in the Asgard superphylum. The structural analysis shows that while this profilin possess similar secondary structural elements as eukaryotic profilin, it contains additional secondary structural elements that could be critical for its function and an indication of divergent evolution.
An angle-changeable tracked robot with human-robot interaction in unstructured environments
Authors: Zong Chengguo , Ji Zhijian , Yu Junzhi , Yu Haisheng 
Published: April 2020

Purpose
The purpose of this paper is to study the adaptability of the tracked robot in complex working environment. It proposes an angle-changeable tracked robot with human–robot interaction in unstructured environment. The study aims to present the mechanical structure and human–robot interaction control system of the tracked robot and analyze the static stability of the robot working in three terrains, i.e. rugged terrain, sloped terrain and stairs.

Design/methodology/approach
The paper presents the mechanical structure and human–robot interaction control system of the tracked robot. To prevent the detachment of the tracks during obstacle navigation, a new type of passively adaptive device based on the relationship between the track’s variable angle and the forces is presented. Then three types of rough terrain are chosen to analyze the static stability of the tracked robot, i.e. rugged terrain, sloped terrain and stairs.

Findings
This paper provides the design method of the tracked robot. Owing to its appropriate dimensions, good mass distribution and limited velocity, the tracked robot remains stable on the complex terrains. The experimental results verify the effectiveness of the design method.

Originality/value
The theoretical analysis of this paper provides basic reference for the structural design of tracked robots.
CEO career horizons and earnings quality in family firms
Authors: Che-Ahmad Ayoib B. , Olarinoye Abdulmalik Salau , Mohamad Yusof Nor Zalina 
Published: April 2020

PurposeThe present study examines the effect of the chief executive officer (CEO) career horizon (CH) problem on earnings quality (ERN) for selected family-controlled firms known to have a unique operational goal.Design/methodology/approachThe generalised method of moment linear regression model was used on a sample of family-controlled firms in Malaysia from 2005 to 2016.FindingsThe study found a negative relationship between CH and ERN, measured by earnings persistence and earnings predictability. However, in the earnings predictability model, the reverse was found to be the case after interacting CH with CEO family affiliation, CEO experience and CEO equity. However, the use of a reputable auditor could not mitigate the CH problem. Also, the study obtained a closely related result in the earnings persistence model. The result aligns with the socio-emotional wealth (SEW) theory, which states that the goals of family-controlled firms go beyond financial objectives to include other non-financial objectives, and hence, their commitment to perpetuating their dynasty encourages them to preserve the quality of their earnings.Originality/valueExisting studies on family firms and ERN have treated family firms as homogeneous entities by comparing family and non-family firms, using the underlying theoretical justification of the agency theory. However, this study departs from the agency theory, by considering those factors (i.e. the extent of CEO alignment with family owners and the choice of auditor), using the SEW theory, which establishes the differences among family firms. This work builds on that of Chen et al., (2018) and Ali and Zhang (2015), which suggested that corporate governance can mitigate the CH problem. Therefore, the strength of a CEO's attachment to the family firm (measured by CEO equity ownership and CEO affiliation to family members in family firms) and the choice of the auditor can explain the variation in the effect of the CH problem in family firms.
International ambidexterity in firms' innovation of multinational enterprises from emerging economies: an investigation of TMT attributes
Authors: Wu Hang , Chen Jin 
Published: April 2020

PurposeExtant research has integrated ambidexterity perspective into international business studies and calls for emerging market multinational enterprises (EM MNEs) to implement exploration and exploitation activities simultaneously in foreign markets. However, less attention has been paid to empirically test whether and how international ambidexterity can benefit the innovation performance of EM MNEs. Based on the data of international manufacturing firms in China, this paper explores the relationship between international ambidexterity and innovation performance and investigates four contingency factors of top management team (TMT): two external resource accumulation elements (i.e. TMT business ties and TMT political ties) and two internal resource integration elements (i.e. TMT contingency rewards and TMT social integration).Design/methodology/approachThe author conducts multiple hierarchical linear regression analysis to test the hypothesis by collecting survey data from 227 MNEs from several Economic Development Zones located in Zhejiang province in China.FindingsThe results show that international ambidexterity is positively related to innovation performance, and the international ambidexterity–innovation performance relationship is amplified when TMTs build strong ties with external business partners and political departments, when EM MNEs link top managers' income to team collective performance and create a highly social integrated TMT.Originality/valueThe results contributes to answer the question that how well EM MNEs will succeed and enrich the context specificity of international ambidexterity. The findings also help us better understand the inconsistent empirical findings in organizational ambidexterity by uncovering the contingency role of several TMT attributes.