bluuebunny/crossref_metadata_2025_split huggingface dataset:
A histone methylation-MAPK signaling axis drives durable epithelial-mesenchymal transition in hypoxic pancreas cancer
Authors: Brown Brooke A. , Myers Paul J. , Adair Sara J. , Pitarresi Jason R. , Sah-Teli Shiv K. , Campbell Logan A. , Hart William S. , Barbeau Michelle , Leong Kelsey , Seyler Nicholas , Kane William , Lee Kyoung Eun , Stelow Edward , Jones Marieke , Simon M. Celeste , Koivunen Peppi , Bauer Todd W. , Stanger Ben Z. , Lazzara Matthew J. 
Published: October 2022

ABSTRACTHere, we show that hypoxia drives especially long-lasting epithelial-mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma (PDAC) primarily through a positive-feedback histone methylation-MAPK signaling axis. We find that transformed cells preferentially undergo EMT in hypoxic tumor regions in multiple model systems and that hypoxia drives a cell-autonomous EMT in PDAC cells which, unlike EMT in response to growth factors, can last for weeks. We further demonstrate that hypoxia reduces histone demethylase KDM2A activity, suppresses PP2 family phosphatase expression, and activates MAPKs to post-translationally stabilize histone methyltransferase NSD2, leading to an H3K36me2-dependent EMT in which hypoxia-inducible factors play only a supporting role. This mechanism can be antagonizedin vivoby combinations of MAPK inhibitors that may be effective in multi-drug therapies designed to target EMT.
Mapping genetic variants for nonsense-mediated mRNA decay regulation across human tissues
Authors: Sun Bo , Chen Liang 
Published: October 2022

AbstractBackgroundNonsense-mediated mRNA decay (NMD) was originally conceived as an mRNA surveillance mechanism to prevent the production of potentially deleterious truncated proteins. Recent research shows NMD is an important post-transcriptional gene regulation mechanism selectively targeting many non-aberrant mRNAs. However, how natural genetic variants affect NMD and modulate gene expressions remains elusive.ResultsHere we elucidate NMD regulation of individual genes across human tissues through genetical genomics. Genetic variants corresponding to NMD regulation are identified based on the GTEx data through unique and robust transcript expression modelling. We identify genetic variants that influence the percentage of NMD-targeted transcripts (pNMD-QTLs), as well as genetic variants regulating the decay efficiency of NMD-targeted transcripts (dNMD-QTLs). Many such variants are missed in traditional expression quantitative trait locus (eQTL) mapping. NMD-QTLs show strong tissue specificity especially in the brain. They are more likely to colocalize with disease single-nucleotide polymorphisms (SNPs). Compared to eQTLs, NMD-QTLs are more likely to be located within gene bodies and exons, especially the penultimate exons from the 3’ end. Furthermore, NMD-QTLs are more likely to be found in the binding sites of miRNAs and RNA binding proteins (RBPs).ConclusionsWe reveal the genome-wide landscape of genetic variants associated with NMD regulation across human tissues. Our analysis results indicate important roles of NMD in the brain. The preferential genomic positions of NMD-QTLs suggest key attributes for NMD regulation. Furthermore, the colocalization with disease-associated SNPs and post-transcriptional regulatory elements implicate regulatory roles of NMD-QTLs in disease manifestation and their interactions with other post-transcriptional regulators.
Distinct Neutralizing Antibody Escape of SARS-CoV-2 Omicron Subvariants BQ.1, BQ.1.1, BA.4.6, BF.7 and BA.2.75.2
Authors: Qu Panke , Evans John P. , Faraone Julia , Zheng Yi-Min , Carlin Claire , Anghelina Mirela , Stevens Patrick , Fernandez Soledad , Jones Daniel , Lozanski Gerard , Panchal Ashish , Saif Linda J. , Oltz Eugene M. , Xu Kai , Gumina Richard J. , Liu Shan-Lu 
Published: October 2022

AbstractContinued evolution of SARS-CoV-2 has led to the emergence of several new Omicron subvariants, including BQ.1, BQ. 1.1, BA.4.6, BF.7 and BA.2.75.2. Here we examine the neutralization resistance of these subvariants, as well as their ancestral BA.4/5, BA.2.75 and D614G variants, against sera from 3-dose vaccinated health care workers, hospitalized BA.1-wave patients, and BA.5-wave patients. We found enhanced neutralization resistance in all new subvariants, especially the BQ.1 and BQ.1.1 subvariants driven by a key N460K mutation, and to a lesser extent, R346T and K444T mutations, as well as the BA.2.75.2 subvariant driven largely by its F486S mutation. The BQ.1 and BQ.1.1 subvariants also exhibited enhanced fusogenicity and S processing dictated by the N460K mutation. Interestingly, the BA.2.75.2 subvariant saw an enhancement by the F486S mutation and a reduction by the D1199N mutation to its fusogenicity and S processing, resulting in minimal overall change. Molecular modelling revealed the mechanisms of receptor-binding and non-receptor binding monoclonal antibody-mediated immune evasion by R346T, K444T, F486S and D1199N mutations. Altogether, these findings shed light on the concerning evolution of newly emerging SARS-CoV-2 Omicron subvariants.
SARS-CoV-2 infected cells sprout actin-rich filopodia that facilitate viral invasion
Authors: Zhang Yue , Zhang Xiaowei , Li Zhongyi , Zhao Weisong , Yang Hui , Tang Daijiao , Zhao Shuangshuang , Zhang Qian , Liu Huisheng , Li Haoyu , Li Bo , Lappalainen Pekka , Cui Zongqiang , Jiu Yaming 
Published: October 2022

AbstractEmerging COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a great threat to human health and economics. Although SARS-CoV-2 entry mechanism has been explored, little is known about how SARS-CoV-2 regulates the host cell remodeling to facilitate virus invasion process. Here we unveil that SARS-CoV-2 boosts and repurposes filopodia for entry to the target cells. Using SARS-CoV-2 virus-like particle (VLP), real-time live-cell imaging and simulation of active gel model, we reveal that VLP-induced Cdc42 activation leads to the formation of filopodia, which reinforce the viral entry to host cells. By single-particle tracking and sparse deconvolution algorithm, we uncover that VLP particles utilize filopodia to reach the entry site in two patterns, ‘surfing’ and ‘grabbing’, which are more efficient and faster than entry via flat plasma membrane regions. Furthermore, the entry process via filopodia is dependent on the actin cytoskeleton and actin-associated proteins fascin, formin, and Arp2/3. Importantly, either inhibition the actin cross-linking protein fascin or the active level of Cdc42 could significantly hinders both the VLP and the authentic SARS-CoV-2 entry. Together, our results highlight that the spatial-temporal regulation of the actin cytoskeleton by SARS-CoV-2 infection makes filopodia as a ‘highway’ for virus entry, which emerges as an antiviral target.Significance StatementRevealing the mechanism of SARS-CoV-2 invasion is of great significance to explain its high pathogenic and rapid transmission in the world. We discovered a previously unknown route of SARS-CoV-2 entry. SARS-CoV-2 virus-like particles boost cellular filopodia formation by activating Cdc42. Using state-of-art-technology, we spatial-temporally described how virus utilize filopodia to enter the target cell in two modes: ‘surfing’ and ‘grabbing’. Filopodia can directly transport the virus to endocytic hot spots to avoid the virus from disorderly searching on the plasma membrane. Our study complements current knowledge of SARS-CoV-2 that filopodia and its components not only play an important role in virus release and cell-cell transmission, but also in the entry process, and provides several potential therapeutic targets for SARS-CoV-2.HighlightsSARS-CoV-2 VLP infection promotes filopodia formation by activating Cdc42SARS-CoV-2 VLP utilizes filopodia to enter target cell via two modes, ‘surfing’ and ‘grabbing’Filopodia disruption compromises the invasion of both VLP and authentic SARS-CoV-2
Language-Informed Basecalling Architecture for Nanopore Direct RNA Sequencing
Authors: Sneddon Alexandra , Shirokikh Nikolay , Eyras Eduardo 
Published: October 2022

AbstractAlgorithms developed for basecalling Nanopore signals have primarily focused on DNA to date and utilise the raw signal as the only input. However, it is known that messenger RNA (mRNA), which dominates Nanopore direct RNA (dRNA) sequencing libraries, contains specific nucleotide patterns that are implicitly encoded in the Nanopore signals since RNA is always sequenced from the 3’ to 5’ direction. In this study we present an approach to exploit the sequence biases in mRNA as an additional input to dRNA basecalling. We developed a probabilistic model of mRNA language and propose a modified CTC beam search decoding algorithm to conditionally incorporate the language model during basecalling. Our findings demonstrate that inclusion of mRNA language is able to guide CTC beam search decoding towards the more probable nucleotide sequence. We also propose a time efficient approach to decoding variable length nanopore signals. This work provides the first demonstration of the potential for biological language to inform Nanopore basecalling. Code is available at:https://github.com/comprna/radian.
Immunity induced by vaccination with recombinant influenza B virus neuraminidase protein breaks viral transmission chains in guinea pigs in an exposure intensity-dependent manner
Authors: McMahon Meagan , Tan Jessica , O’Dell George , Roubidoux Ericka Kirkpatrick , Strohmeier Shirin , Krammer Florian 
Published: October 2022

AbstractMucosal vaccines and vaccines that block pathogen transmission are under-appreciated in vaccine development. However, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has shown that blocking viral transmission is an important attribute of efficient vaccines. Here, we investigated if recombinant influenza virus neuraminidase (NA) vaccines delivered at a mucosal site could protect from onward transmission of influenza B viruses in the guinea pig model. We tested four different scenarios in which sequential transmission was investigated in chains of four guinea pigs. The variables tested included a low and a high viral inoculum (104vs 105plaque forming units) in the initial donor guinea pig and variation of exposure/cohousing time (1 day vs 6 days). In three out of four scenarios – low inoculum-long exposure, low inoculum-short exposure and high inoculum-short exposure – transmission chains were efficiently blocked. Based on this data we believe an intranasal recombinant NA vaccine could be used to efficiently curtail influenza virus spread in the human population during influenza epidemics.ImportanceVaccines that can slow respiratory virus transmission in the population are urgently needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza virus. Here we describe how a recombinant neuraminidase-based influenza virus vaccines reduces transmission in vaccinated guinea pigs in an exposure-intensity based manner.
Altered infective competence of the human gut microbiome in COVID-19
Authors: de Nies Laura , Galata Valentina , Martin-Gallausiaux Camille , Despotovic Milena , Busi Susheel Bhanu , Snoeck Chantal J. , Delacour Lea , Budagavi Deepthi Poornima , Laczny Cédric Christian , Habier Janine , Lupu Paula-Cristina , Halder Rashi , Fritz Joëlle V. , Marques Taina , Sandt Estelle , O’Sullivan Marc Paul , Ghosh Soumyabrata , Satagopam Venkata ,   CON-VINCE Consortium, Krüger Rejko , Fagherazzi Guy , Ollert Markus , Hefeng Feng Q. , May Patrick , Wilmes Paul 
Published: October 2022

AbstractObjectives:Infections with SARS-CoV-2 have a pronounced impact on the gastrointestinal tract and its resident microbiome. Clear differences between severe cases of infection and healthy individuals have been reported, including the loss of commensal taxa. We aimed to understand if microbiome alterations including functional shifts are unique to severe cases or a common effect of COVID-19.Design:We used high-resolution systematic multi-omic analyses to profile the gut microbiome in asymptomatic-to-moderate COVID-19 individuals compared to a control group.Results:We found a striking increase in the overall abundance and expression of both virulence factors and antimicrobial resistance genes in COVID-19. Importantly, these genes are encoded and expressed by commensal taxa from families such as Acidaminococcaceae and Erysipelatoclostridiaceae, which we found to be enriched in COVID-19 positive individuals. We also found an enrichment in the expression of a betaherpesvirus and rotavirus C genes in COVID-19 positive individuals compared to healthy controls.Conclusion:Our analyses identified an altered and increased infective competence of the gut microbiome in COVID-19 patients.
ImprovedKCNQ2gene missense variant interpretation with artificial intelligence
Authors: Saez-Matia Alba , Muguruza-Montero Arantza , M-Alicante Sara , Núñez Eider , Ramis Rafael , Ballesteros Óscar R. , Ibarluzea Markel G , Fons Carmen , Leonardo Aritz , Bergara Aitor , Villarroel Alvaro 
Published: October 2022

ABSTRACTAdvances in DNA sequencing technologies have revolutionized rare disease diagnosis, resulting in an increasing volume of available genomic data. Despite this wealth of information and improved procedures to combine data from various sources, identifying the pathogenic causal variants and distinguishing between severe and benign variants remains a key challenge. Mutations in the Kv7.2 voltage-gated potassium channel gene (KCNQ2) have been linked to different subtypes of epilepsies, such as benign familial neonatal epilepsy (BFNE) and epileptic encephalopathy (EE). To date, there is a wide variety of genome-wide computational tools aiming at predicting the pathogenicity of variants. However, previous reports suggest that these genome-wide tools have limited applicability to theKCNQ2gene related diseases due to overestimation of deleterious mutations and failure to correctly identify benign variants, being, therefore, of limited use in clinical practice. In this work, we found that combining readily available features, such as AlphaFold structural information, Missense Tolerance Ratio (MTR) and other commonly used protein descriptors, provides foundations to build reliable gene-specific machine learning ensemble models. Here, we present a transferable methodology able to accurately predict the pathogenicity ofKCNQ2missense variants with unprecedented sensitivity and specificity scores above 90%.
aRgus: multilevel visualization of non-synonymous single nucleotide variants & advanced pathogenicity score modeling for genetic vulnerability assessment
Authors: Schröter Julian , Dattner Tal , Hüllein Jennifer , Jayme Alejandra , Heuveline Vincent , Hoffmann Georg F. , Kölker Stefan , Lenz Dominic , Opladen Thomas , Popp Bernt , Schaaf Christian P. , Staufner Christian , Syrbe Steffen , Uhrig Sebastian , Hübschmann Daniel , Brennenstuhl Heiko 
Published: October 2022

AbstractThe widespread use of high-throughput sequencing techniques is leading to a rapidly increasing number of disease-associated variants of unknown significance and candidate genes. Integration of knowledge concerning their genetic, protein as well as functional and conservational aspects is necessary for an exhaustive assessment of their relevance and for prioritization of further clinical and functional studies investigating their role in human disease. In order to collect the necessary information, a multitude of different databases has to be accessed and data extraction from the original sources commonly is not user-friendly and requires advanced bioinformatics skills. This leads to a decreased data accessibility for a relevant number of potential users such as clinicians, geneticist, and clinical researchers. Here, we present aRgus (https://argus.urz.uni-heidelberg.de/), a standalone webtool for simple extraction and intuitive visualization of multi-layered gene, protein, variant, and variant effect prediction data. aRgus provides interactive exploitation of these data within seconds for any known gene of the human genome. In contrast to existing online platforms for compilation of variant data, aRgus complements visualization of chromosomal exon-intron structure and protein domain annotation with ClinVar and gnomAD variant distributions as well as position-specific variant effect prediction score modeling. aRgus thereby enables timely assessment of protein regions vulnerable to variation with single amino acid resolution and provides numerous applications in variant and protein domain interpretation as well as in the design ofin vitroexperiments.
Auditor industry expertise and external audit prices: empirical evidence from Amman Stock Exchange-listed companies
Authors: Alharasis Esraa Esam , Alidarous Manal , Jamaani Fouad 
Published: October 2022

PurposeThis study aims to examine the relationship between auditor industry specialization (IS) and audit fees.Design/methodology/approachThe authors utilize 2,100 firm-year data of Jordanian companies from 2005 to 2018. Two conflicting theoretical approaches of IS were employed: the product differentiation approach, as assessed by market share (MS); and the shared efficiency approach, as evaluated by portfolio share (PS).FindingsResults of the ordinary least squares (OLS) regression support product differentiation (shared efficiency) and show that employing experts' auditors exerts a very substantial and favorable direct impact on audit fees (negative).Originality/valueThis research contributes new empirical data to the auditing literature by examining if IS does influence Jordanian businesses' audit fees. The findings offer useful data for Jordanian officials to examine the auditing industry's difficulties while refining regulations and revising auditor pricing. Additionally, the results offer advice to Jordan's regulatory bodies who oversee the auditing industry. Arguably, results from Jordan may be extrapolated to other Middle Eastern nations.
The purposeful use of Kolb’s learning styles in online learning design
Authors: Cohen Jay Andrew 
Published: October 2022

Purpose
The intent of this paper is in readdressing Kolb’s work on learning styles and its relevance to the learning design process in online learning.

Design/methodology/approach
Not a research paper – viewpoint. No research has been conducted as such.

Findings
This paper introduces a number of learning design interventions aligned to Kolb’s learning styles inventory (LSI).

Practical implications
This paper is designed to assist practitioners (Learning Designers) design learning environments in consideration of Kolb’s LSI.

Originality/value
This is a viewpoint paper that revisits Kolb’s LSI.
Incarceration, menstruation and COVID-19: a viewpoint of the exacerbated inequalities and health disparities in South African correctional facilities
Authors: Moodley Janice Kathleen , Parry Bianca Rochelle , Van Hout Marie Claire 
Published: October 2022

Purpose
The menstrual health and menstrual hygiene management (MHM) of incarcerated women remains relatively low on the agenda of public health interventions globally, widening the inequitable access of incarcerated women to safe and readily available menstrual health products (MHP). The COVID-19 pandemic has adversely impacted on the MHM gains made in various development sectors in the global North and South, through its amplification of vulnerability for already at-risk populations. This is especially significant to developing countries such as South Africa where the incarcerated female population are an often-forgotten minority.

Design/methodology/approach
This viewpoint highlights the ignominious silence of research and policy attention within the South African carceral context in addressing MHM. The ethical and political implications of such silences are unpacked by reviewing international and local literature that confront issues of inequality and equitable access to MHP and MHM resources within incarcerated contexts.

Findings
Structural inequalities in various contexts around the world have exacerbated COVID-19 and MHM. Within the prison context in South Africa, women face multiple layers of discrimination and punishment that draw attention to the historical discourses of correctional facilities as a site of surveillance and discipline.

Research limitations/implications
This study acknowledges that while this viewpoint is essential in rising awareness about gaps in literature, it is not empirical in nature.

Practical implications
The authors believe that this viewpoint is essential in raising critical awareness on MHM in carceral facilities in South Africa. The authors hope to use this publication as the theoretical argument to pursue empirical research on MHM within carceral facilities in South Africa. The authors hope that this publication would provide the context for international and local funders, to assist in the empirical research, which aims to roll out sustainable MHP to incarcerated women in South Africa.

Social implications
The authors believe that this viewpoint is the starting point in accelerating the roll out of sustainable MHP to incarcerated females in South Africa. These are females who are on the periphery of society that are in need of practical interventions. Publishing this viewpoint would provide the team with the credibility to apply for international and national funding to roll out sustainable solutions.

Originality/value
It is hoped that the gaps in literature and nodes for social and human rights activism highlighted within this viewpoint establish the need for further participatory research, human rights advocacy and informed civic engagement to ensure the voices of these women and their basic human rights are upheld.
Coming out ahead while losing a partner: the Thoroughbred industry stays on course
Authors: Fudge Kamal Darcy , Nistor Cristina , Sinha Charu 
Published: October 2022

Purpose
In many industries, firms collaborate as business partners, which helps them achieve superior outcomes and ensure survival in a crisis. Business relationships help companies access limited resources, share information and build trust within the community. This paper aims to highlight the strategies that firms can use to adapt to the loss of a business partner.

Design/methodology/approach
This study considers qualitative examples from what happens when a business partner disappears in the Thoroughbred horse industry. The authors draw attention to several types of partner loss due to firm bankruptcy, owner death and strategic restructuring.

Findings
This paper proposes a framework of strategies for surviving the loss of business partners. Specifically, surviving partners may respond by strategic distancing, relationship self-repair or reconfiguration through asset purchases or mimicry by minimizing exit risks.

Practical implications
The proposed framework can be used by strategists and managers to determine a course of action when faced with the loss of a business partner. Managers can quickly respond to a partner’s exit with the appropriate action to distance their business or stabilize alternate relationships.

Originality/value
The novel framework, informed by examples from the Thoroughbred horse industry, conceptualizes an important theoretical and practical problem. This paper proposes strategies for how businesses react and adapt to survive after losing a business partner.