bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anin vivodrug repurposing screen and transcriptional analyses reveals the serotonin pathway and GSK3 as major therapeutic targets for NGLY1 deficiency
Authors: Hope Kevin A. , Berman Alexys R. , Peterson Randall T. , Chow Clement Y. 
Published: November 2021

AbstractNGLY1 deficiency, a rare disease with no effective treatment, is caused by autosomal recessive, loss-of-function mutations in theN-glycanase 1 (NGLY1)gene and is characterized by global developmental delay, hypotonia, alacrima, and seizures. We used an adultDrosophilamodel of NGLY1 deficiency to conduct anin vivo,unbiased, small molecule, repurposing screen of FDA-approved drugs to identify therapeutic compounds. Seventeen molecules rescued lethality in a patient-specific NGLY1 deficiency model, including multiple serotonin and dopamine modulators. ExclusivedNGLY1expression in serotonin and dopamine neurons, in an otherwisedNGLY1-null fly, was sufficient to rescue lethality. Further, genetic modifier and transcriptomic data supports the importance of serotonin signaling in NGLY1 deficiency. Connectivity Map analysis identified glycogen synthase kinase 3 (GSK3) inhibition as a potential therapeutic mechanism for NGLY1 deficiency, which we experimentally validated with TWS119 and lithium. Strikingly, GSK3 inhibitors and a serotonin modulator rescued size defects indNGLY1deficient larvae upon proteasome inhibition, suggesting that these compounds act through NRF1, a transcription factor that regulates proteasome expression. This study reveals the importance of the serotonin pathway in NGLY1 deficiency, and serotonin modulators or GSK3 inhibitors may be effective therapeutics for this rare disease.
An individualized causal framework for learning intercellular communication networks that define microenvironments of individual tumors
Authors: Chen Xueer , Chen Lujia , Kürten Cornelius H.L. , Jabbari Fattaneh , Vujanovic Lazar , Ding Ying , Lu Binfeng , Lu Kevin , Kulkarni Aditi , Tabib Tracy , Lafyatis Robert , Cooper Gregory , Ferris Robert , Lu Xinghua 
Published: November 2021

AbstractCells within a tumor microenvironment (TME) dynamically communicate and influence each other’s cellular states through an intercellular communication network (ICN). In cancers, intercellular communications underlie immune evasion mechanisms of individual tumors. We developed an individualized causal analysis framework for discovering tumor-specific ICNs. Using head and neck squamous cell carcinoma (HNSCC) tumors as a testbed, we first mined single-cell RNA-sequencing data to discover gene expression modules (GEMs) that reflect the states of transcriptomic processes within tumor and stromal single cells. By deconvoluting bulk transcriptomes of HNSCC tumors profiled by The Cancer Genome Atlas (TCGA), we estimated the activation states of these transcriptomic processes in individual tumors. Finally, we applied individualized causal network learning to discover an ICN within each tumor. Our results show that cellular states of cells in TMEs are coordinated through ICNs that enable multi-way communications among epithelial, fibroblast, endothelial, and immune cells. Further analyses of individual ICNs revealed structural patterns that were shared across subsets of tumors, leading to the discovery of 4 different subtypes of networks that underlie disparate TMEs of HNSCC. Patients with distinct TMEs exhibited significantly different clinical outcomes. Our results show that the capability of estimating individual ICNs reveals heterogeneity of ICNs and sheds light on the importance of intercellular communication in impacting disease development and progression.
Glypican-1 drives unconventional secretion of Fibroblast Growth Factor 2
Authors: Sparn Carola , Dimou Eleni , Meyer Annalena , Saleppico Roberto , Wegehingel Sabine , Gerstner Matthias , Klaus Severina , Ewers Helge , Nickel Walter 
Published: November 2021

AbstractFibroblast Growth Factor 2 (FGF2) is a tumor cell survival factor that is transported into the extracellular space by an unconventional secretory mechanism. Cell surface heparan sulfate proteoglycans are known to play an essential role in this process. Unexpectedly, we found that among the diverse sub-classes consisting of syndecans, perlecans, glypicans and others, Glypican-1 (GPC1) is both the principle and rate-limiting factor that drives unconventional secretion of FGF2. By contrast, we demonstrate GPC1 to be dispensable for FGF2 signaling into cells. We provide first insights into the structural basis for GPC1-dependent FGF2 secretion, identifying disaccharides with N-linked sulfate groups to be enriched in the heparan sulfate chains of GPC1 to which FGF2 binds with high affinity. Our findings have broad implications for the role of GPC1 as a key molecule in tumor progression.
Spontaneous DNA synapsis by forming noncanonical intermolecular structures
Authors: Severov V.V. , Tsvetkov V.B. , Barinov N.A. , Babenko V.V. , Klinov D.V. , Pozmogova G.E. 
Published: November 2021

ABSTRACTWe report the spontaneous formation of DNA–DNA junctions in solution in the absence of proteins visualised using atomic force microscopy. The synapsis position fits with potential G-quadruplex (G4) sites. In contrast to the Holliday structure, these conjugates have affinity for G4 antibodies. Molecular modelling was used to elucidate the possible G4/IM-synaptic complex structures. Our results indicate a new role of the intermolecular noncanonical structures in chromatin architecture and genomic rearrangement.
G6b-B regulates an essential step in megakaryocyte maturation
Authors: Becker Isabelle C. , Nagy Zoltan , Manukjan Georgi , Haffner-Luntzer Melanie , Englert Maximilian , Heib Tobias , Vögtle Timo , Gross Carina , Bharti Richa , Dietrich Sascha , Mott Kristina , Heck Johannes , Jeschke Anke , Schinke Thorsten , Schlegel Nicolas , Heckel Tobias , Stegner David , Pleines Irina , Ignatius Anita , Schulze Harald , Nieswandt Bernhard 
Published: November 2021

AbstractG6b-B is a megakaryocyte lineage-specific immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptor, essential for platelet homeostasis. Mice with a genomic deletion of the entireMpig6blocus develop severe macrothrombocytopenia and myelofibrosis, which is reflected in humans with null-mutations inMPIG6B. The current model proposes that megakaryocytes lacking G6b-B develop normally, while proplatelet release is hampered, but the underlying molecular mechanism remains unclear. Here, we report on a spontaneous recessive single nucleotide mutation in C57BL/6 mice, localized within the intronic region of theMpig6blocus that abolishes G6b-B expression and reproduces macrothrombocytopenia, myelofibrosis and osteosclerosis. As the mutation is based on a single nucleotide exchange,Mpig6bmutmice represent an ideal model to study the role of G6b-B. Megakaryocytes from these mice were smaller in size, displayed a less developed demarcation membrane system and reduced expression of receptors. RNA sequencing revealed a striking global reduction in the level of megakaryocyte-specific transcripts, in conjunction with decreased protein levels of the transcription factor GATA-1, and impaired thrombopoietin signaling. The reduced number of mature MKs in the bone marrow was corroborated on a newly developedMpig6bnull mouse strain. Our findings highlight an unexpected essential role of G6b-B in the early differentiation within the megakaryocytic lineage.
Disruption of Mitochondrial Quality Control Genes Promotes Caspase-Resistant Cell Survival Following Apoptotic Stimuli
Authors: Kushnareva Yulia , Moraes Vivian , Suess Julian , Peters Bjoern , Newmeyer Donald D. , Kuwana Tomomi 
Published: November 2021

ABSTRACTIn cells undergoing cell-intrinsic apoptosis, mitochondrial outer membrane permeabilization (MOMP) typically marks an irreversible step in the cell death process. However, in some cases a subpopulation of the treated cells can exhibit a sublethal response, termed “minority MOMP”. In this phenomenon, the affected cells survive, despite a low level of caspase activation and a subsequent limited activation of the endonuclease CAD (DFFB). Consequently, these cells can experience DNA damage, increasing the probability of oncogenesis. To discover genes affecting MOMP response in individual cells, we conducted an imaging-based phenotypic siRNA screen. We identified multiple candidate genes whose downregulation increased the heterogeneity of MOMP within single cells. Among these were genes related to mitochondrial dynamics and mitophagy, which participate in the mitochondrial quality control (MQC) system. To test the hypothesis that functional MQC is important for reducing the frequency of minority MOMP, we developed an assay to measure the clonogenic survival of caspase-engaged cells. We found that cells deficient in various MQC genes were indeed prone to aberrant post-MOMP survival. Our data highlight the important role of proteins involved in mitochondrial dynamics and mitophagy in preventing apoptotic dysregulation and oncogenesis.
Merlin Tumor Suppressor Function is Regulated by PIP2-Mediated Dimerization
Authors: Hennigan Robert F. , Thomson Craig S. , Stachowski Kye , Nassar Nicolas , Ratner Nancy 
Published: November 2021

AbstractNeurofibromatosis Type 2 is an inherited disease characterized by Schwann cell tumors of cranial and peripheral nerves. TheNF2gene encodes Merlin, a member of the ERM family consisting of an N-terminal FERM domain, a central α-helical region and a C-terminal domain that binds to the FERM domain. Changes in the intermolecular FERM-CTD interaction allow Merlin to transition between an open, FERM accessible conformation and a closed, FERM-inaccessible conformation, modulating Merlin activity. These conformational transitions are regulated by both phosphorylation and phosphoinositide binding. Merlin has been shown to dimerize, but the regulation and function Merlin dimerization is not clear. We used a nanobody based binding assay and found that Merlin dimerizes via a FERM-FERM interaction, orientated with each C-terminus in close proximity. Dimerization. Patient derived and structural mutants show that dimerization controls interactions with specific binding partners, including HIPPO pathway components, and correlates with tumor suppressor activity. We demonstrate that dimerization occurs after a PIP2 mediated transition from a closed to open conformation monomers that are then able dimerize. This process requires the first 18 amino acids of the FERM domain and is inhibited by phosphorylation at serine 518. The discovery that active, open conformation Merlin is a dimer represents a new paradigm for Merlin function with implications for the development of therapies designed to compensate for Merlin loss.
Leukocyte proliferation mediates disease pathogenesis in theNdufs4(KO) mouse model of Leigh syndrome
Authors: Stokes Julia C , Bornstein Rebecca L , James Katerina , Park Kyung Yeon , Spencer Kira , Vo Katie , Snell John C , Johnson Brittany M , Morgan Philip G , Sedensky Margaret M , Baertsch Nathan , Johnson Simon C 
Published: November 2021

AbstractSymmetric, progressive, necrotizing lesions in the brainstem are a defining feature of Leigh syndrome (LS). A mechanistic understanding of the pathogenesis of these lesions has been elusive. Here, we report that leukocyte proliferation is causally involved in the pathogenesis of Leigh syndrome. Directly depleting leukocytes with a colony-stimulating factor 1 receptor (CSF1R) inhibitor dramatically attenuates disease, including complete prevention of CNS lesion formation and substantial extension of survival. Leukocyte depletion rescues a range of symptoms including hyperlactemia, seizures, respiratory function, and neurologic symptoms. These data provide a mechanistic explanation for the beneficial effects of mTOR inhibition. More importantly, these findings dramatically alter our understanding of the pathogenesis of LS, demonstrating that immune involvement directly drives disease. These findings have significant implication for the mechanisms of disease resulting from mitochondrial dysfunction, and may lead to novel therapeutic strategies.One-Sentence SummaryPharmacologic targeting of leukocytes prevents CNS lesions, neurological disease, and metabolic dysfunction in theNdufs4(KO) mouse model of Leigh syndrome.
Integration of the Salmonella Typhimurium methylome and transcriptome reveals DNA methylation and transcriptional regulation are largely decoupled under virulence-related conditions
Authors: Bourgeois Jeffrey S. , Anderson Caroline E. , Wang Liuyang , Modliszewski Jennifer L. , Chen Wei , Schott Benjamin H. , Devos Nicolas , Ko Dennis C. 
Published: November 2021

AbstractDespite being in a golden age of bacterial epigenomics, little work has systematically examined the plasticity and functional impacts of the bacterial DNA methylome. Here, we leveraged SMRT sequencing to examine the m6A DNA methylome of two Salmonella enterica ser. Typhimurium strains: 14028s and a ΔmetJ mutant with derepressed methionine metabolism, grown in Luria Broth or a media that simulates the intracellular environment. We find that the methylome is remarkably static—over 95% of adenosine bases retain their methylation status across conditions. Integration of methylation with transcriptomic data revealed limited correlation between changes in methylation and gene expression. Further, examining the transcriptome in ΔyhdJ bacteria, lacking the m6A methylase with the most dynamic methylation pattern in our dataset, revealed little evidence of YhdJ-mediated gene regulation. Curiously, despite G(m6A)TC motifs being particularly resistant to change across conditions, incorporating dam mutants into our analyses revealed two examples where changes in methylation and transcription may be linked across conditions. This includes the novel finding that the ΔmetJ motility defect may be partially driven by hypermethylation of the chemotaxis gene tsr. Together, these data redefine the S. Typhimurium epigenome as a highly stable system that has rare, but important, roles in transcriptional regulation. Incorporating these lessons into future studies will be critical as we progress through the epigenomic era.ImportanceWhile recent breakthroughs have enabled intense study of bacterial DNA modifications, limitations in current work have potentiated a surprisingly untested narrative that DNA methylation is a common mechanism of the bacterial response to environmental conditions. Essentially, whether epigenetic regulation of bacterial transcription is a common, generalizable phenomenon is a critical unanswered question that we address here. We find that most DNA methylation is static in Salmonella enterica serovar Typhimurium, even when the bacteria are grown under dramatically different conditions that cause broad changes in the transcriptome. Further, even when the methylation of individual bases change, these changes generally do not correlate with changes in gene expression. Finally, we demonstrate methods by which data can be stratified in order to identify coupled changes in methylation and gene expression.
Work stress related cardiovascular diseases among construction professionals
Authors: Kamardeen Imriyas 
Published: November 2021

PurposeCardiovascular diseases (CVDs) are responsible for one-third of global deaths. Work stress is a major risk factor for CVDs in the workforce. Construction professionals endure excessive work stress, yet their vulnerability to CVDs remains underexplored. The study investigated the prevalence of CVDs among construction professionals and its relationships to job stressors, stress coping methods and socio-demographics.Design/methodology/approachAn online survey was conducted among construction professionals in Australia wherein data related to job stressor experiences, stress management methods adopted, and incidents of CVDs were collected. Structural path analysis was conducted to discover associations.FindingsJunior level professionals reported higher incidents of angina and heart muscle weakening than others. Statistically significant positive associations were discovered between the reported CVDs, and job stressors such as excessive workload, unpredictable work hours, lack of support, discrimination and work–life conflict and negative stress coping methods such as consuming alcohol and/or drugs, emotional eating and aggression. However, no evidence was found to support the claim that demographic factors such as age and gender were also risk factors for CVDs.Originality/valueThe workers' compensation system provides financial protection to injured employees. It extends similar protection for work-related illnesses; however, it is more difficult to prove work-related causes for illnesses. The study provides scientific evidence to support the recognition of CVDs among construction professionals as work-related diseases, mediated by work stress.
Electronic service quality (e-SQ) measurement: a cross-functional review
Authors: Nandankar Sunil , Sachan Amit , Mukherjee Arindam , Adhikari Arnab 
Published: November 2021

PurposeAlthough comprehensive work has been conducted in several scholarly journals in electronic service quality (e-SQ) measurement, there has been no cross-functional review of these studies. The majority of the review studies focus on e-SQ assessment in the field of electronic retail. This paper explores and synthesizes e-SQ evaluation work across the various functional domains in the last two decades and maps critical methodological challenges. It further classifies the dimensions used by researchers in six broad categories for better comprehension.Design/methodology/approachTo analyze and appreciate past e-SQ measurement research, a content assessment of the 50 most relevant research papers from various functional domains drawn from prestigious repositories was undertaken.FindingsThe results indicate shortcomings noticed in methodological issues in the e-SQ measurement research like research approaches, data analysis procedures, sampling methods, generation and purification of items, validity and reliability assessment, and dimensionality analysis. It further reveals that though e-SQ is multi-dimensional and context-specific, dimensions like content/information quality, website design, ease of use/usability, efficiency, security/and privacy, responsiveness, reliability, customer service, trust and fulfillment have been consistently cited in the reviewed studies across the various functional domains.Originality/valueAn assessment of 50 publications over the past 2 decades identifies key areas of concern in the existing research on e-SQ measurement in various functional domains for scholars and professionals. This study also provides a unique categorization of e-SQ dimensions used in various functional domains and has the potential to guide future research.
The impact of task description linguistic style on task performance: a text mining of crowdsourcing contests
Authors: Yang Keng , Qi Hanying , Huang Qian 
Published: November 2021

PurposeExisting studies on the relationship between task description and task performance are insufficient, with many studies considering description length rather than content to measure quality or only evaluating a single aspect of task performance. To address this gap, this study analyzes the linguistic styles of task descriptions from 2,545 tasks on the Taskcn.com crowdsourcing platform.Design/methodology/approachAn empirical analysis was completed for task description language styles and task performance. The paper used text mining tool Simplified Chinese Linguistic Inquiry and Word Count to extract eight linguistic styles, namely readability, self-distancing, cognitive complexity, causality, tentative language, humanizing personal details, normative information and language intensity. And it tests the relationship between the eight language styles and task performance.FindingsThe study found that more cognitive complexity markers, tentative language, humanized details and normative information increase the quantity of submissions for a task. In addition, more humanized details and normative information in a task description improves the quality of task. Conversely, the inclusion of more causal relationships in a task description reduces the quantity of submissions. Poorer readability of the task description, less self-estrangement and higher language intensity reduces the quality of the task.Originality/valueThis study first reveals the importance of the linguistic styles used in task descriptions and provides a reference for how to attract more task solvers and achieve higher quality task performance by improving task descriptions. The research also enriches existing knowledge on the impact of linguistic styles and the applications of text mining.
Are school leaders culturally intelligent? Validation of the cultural intelligence (CQ) scale in the UAE
Authors: Al Dhaheri Ali 
Published: November 2021

Purpose
The purpose of this paper is to report results of testing and validation of the cultural intelligence (CQ) Scale in a new location, the culturally diverse United Arab Emirates (UAE) and in a new sector: public and private school leaders.

Design/methodology/approach
This study surveys 167 school leaders from public and private schools in the UAE using the 20-item version of the CQ Scale, which uses a seven-point Likert response scale of strongly agree to strongly disagree. An examination of the dimensionality of the 20 items was conducted using both principal components analysis and confirmatory factor analysis. Demographics were also gathered.

Findings
Results from testing and validation of the scale indicated a high level of CQ among school leaders in the Emirate of Abu Dhabi. An examination of the dimensionality of the 20 items showed them to fall into the same structure of four sub-components as conceptually conceived: knowledge, strategy, motivation and behaviour. The mean scores for the four components of CQ in this study indicate high CQ amongst Abu Dhabi school leaders, although the knowledge dimension measured slightly lower. The results confirm previous research that found CQ to be higher in culturally diverse settings, which, according to socio-demographic details gathered in the study applies to the UAE.

Originality/value
This is the first known study to test the Cultural Intelligence Scale in UAE schools. It answers the call from the CQ Scale developers to validate the scale in diverse contexts.