bluuebunny/crossref_metadata_2025_split huggingface dataset:
Small Molecule Modulators of β-arrestins
Authors: Kahsai Alem W. , Pakharukova Natalia , Kwon Henry Y. , Shah Kunal S. , Liang-Lin Jason G. , del Real Caroline T. , Shim Paul J. , Lee Mason A. , Ngo Van A. , Shreiber Bowie N. , Liu Samuel , Schwalb Allison M. , Espinoza Emmanuel F. , Thomas Brittany N. , Kunzle Cal A. , Smith Jeffrey S. , Wang Jialu , Kim Jihee , Zhang Xingdong , Rockman Howard A. , Thomsen Alex R. B. , Rein Lindsay A.M. , Shi Lei , Ahn Seungkirl , Masoudi Ali , Lefkowitz Robert J. 
Published: December 2024

Summaryβ-arrestins (βarrs) are key regulators of G protein-coupled receptors (GPCRs), essential for modulating signaling pathways and physiological processes. While current pharmacological strategies target GPCR orthosteric and allosteric sites, as well as G protein transducers, comparable tools for studying βarrs are lacking. Here, we present the discovery and characterization of novel small-molecule allosteric inhibitors of βarrs through comprehensive biophysical, biochemical, pharmacological, and structural analyses. These inhibitors disrupt βarr interactions with agonist-activated GPCRs, impairing receptor internalization, desensitization, and βarr-mediated physiological functions. A cryo-EM structure of βarr1 in complex with the allosteric inhibitor Cmpd-5, complemented by molecular dynamics simulations and mutagenesis studies, reveals that Cmpd-5 binds within a cryptic cleft formed by the middle, C-, and lariat loops–a critical site for βarr activation and recruitment to GPCRs. Thus, Cmpd-5 acts as a molecular lock, hindering βarr1 activation via an allosteric mechanism. These findings introduce novel strategies and tools for probing βarr functions.HighlightsSmall molecule strategies for modulating βarr functions in both GPCR-dependent and independent contexts.Modulators disrupt βarr interaction with GPCRs, impairing their critical functions.Cryo-EM structures reveal the allosteric inhibitor Cmpd-5 binding to a cryptic pocket between the N and C domains in the central crest of βarr1, inhibiting its activation.Structural analyses, including cryo-EM, MD simulations, and mutagenesis, reveal a unique βarr1 conformation induced by Cmpd-5, shedding light on its mechanism of allosteric inhibition.
Combinations of genomic alterations and immune microenvironmental features associate with patient survival in multiple cancer types
Authors: Bayati Masroor , Klein Zoe P. , Bahcheli Alexander T. , Slobodyanyuk Mykhaylo , To Jeffrey , Cheng Kevin C. L. , Mishra Jigyansa , Pellegrina Diogo , Guevara-Hoyer Kissy , McIntosh Chris , Bhat Mamatha , Reimand Jüri 
Published: December 2024

AbstractOncogenesis and tumor progression are shaped by somatic alterations in the cancer genome and features of the tumor immune microenvironment (TME). How interactions of these two systems influence tumor development and clinical outcomes remains incompletely understood. To address this challenge, we developed the multi-omics analysis framework PACIFIC to systematically integrate genetic cancer drivers and infiltration profiles of immune cells with clinical information. In an analysis of 8500 cancer samples, we report 34 immunogenomic interactions (IGXs) in 13 cancer types in which context-specific combinations of genomic alterations and immune cell activities associate with disease outcomes. Risk associations of IGXs are potentially explained by tumor-intrinsic and microenvironmental metrics of immunogenicity and differential expression of therapeutic targets. In luminal-A breast cancer,MEN1deletion combined with reduced neutrophils is associated with poor prognosis and deregulation of immune signalling pathways. These findings help elucidate how cancer drivers interact with TME to contribute to tumorigenesis.
Glycerol-3-phosphate activates ChREBP, FGF21 transcription and lipogenesis in Citrin Deficiency
Authors: Tiwari Vinod , Jin Byungchang , Sun Olivia , Lopez Gonzalez Edwin D.J. , Chen Min-Hsuan , Wu Xiwei , Shah Hardik , Zhang Andrew , Herman Mark A. , Spracklen Cassandra N. , Goodman Russell P. , Brenner Charles 
Published: December 2024

AbstractCitrin Deficiency (CD) is caused by inactivation of SLC25A13, a mitochondrial membrane protein required to move electrons from cytosolic NADH to the mitochondrial matrix in hepatocytes. People with CD do not like sweets. We discovered that SLC25A13 loss causes accumulation of glycerol-3-phosphate (G3P), which activates carbohydrate response element binding protein (ChREBP) to transcribe FGF21, which acts in the brain to restrain intake of sweets and alcohol, and to transcribe key genes ofde novolipogenesis. Mouse and human data establish G3P-ChREBP as a new mechanistic component of the Randle Cycle that contributes to metabolic dysfunction-associated steatotic liver disease (MASLD) and forms part of a system that communicates metabolic states from liver to brain in a manner that alters food and alcohol choices. The data provide a framework for understanding FGF21 induction in varied conditions, suggest ways to develop FGF21-inducing drugs, and drug candidates for both lean MASLD and support of urea cycle function in CD.
Effects of meglumine antimoniate and allopurinol treatment on the fecal microbiome profile in dogs with leishmaniosis
Authors: Martí-Carreras Joan , Carrasco Marina , Noguera-Julian Marc , Francino Olga , Oliveira Leal Rodolfo , Ferrer Lluís , Oliva Gaetano , Molina Jenifer , Roura Xavier 
Published: December 2024

AbstractThe combination of meglumine antimoniate and allopurinol is considered one of the most effective treatments for canine leishmaniosis caused byLeishmania infantum. This study investigated the effects of this treatment on the gut microbiome of 10 dogs from Spain, Portugal, and Italy via fecal shotgun metagenomic sequencing over six months. Dogs were sampled at baseline (BL) and at one (M1) and six (M6) months post-treatment. The gut microbiome ofLeishmania-infected dogs (BL) is dominated byPrevotella,Collinsella,Bacteroides, andBlautia, with individual variability being the primary determinant of microbiome composition. No significant changes in alpha diversity (Shannon index, gene number) or beta diversity (Bray-Curtis dissimilarity, UniFrac distance) were detected between pre- and post-treatment time points, suggesting that treatment with meglumine antimoniate and allopurinol does not disrupt the gut microbiota. Minor trends in taxonomic shifts were noted, with slight increases inBifidobacterium pseudocantenulatum,Collinsella tanakaei, andSlackia piriformisafter treatment, but these changes were not statistically significant after correction for multiple testing. Linear discriminant analysis and multivariable modeling confirmed that the microbial community structure was resilient to treatment effects. Individual-specific microbiome differences in diversity accounted for 52% of the observed variability, underscoring the personalized nature of the gut microbiota in dogs. Importantly, no adverse microbiome disruptions were detected, even with prolonged allopurinol use. This study highlights the robustness of the canine gut microbiome during antileishmanial therapy and highlights the use of meglumine antimoniate and allopurinol without compromising gut microbial diversity or health. Further studies with larger cohorts are recommended to confirm these findings and explore the functional roles of the gut microbiota in modulating immune responses inLeishmania-infected dogs.
Huntingtin interactome reveals huntingtin role in regulation of double strand break DNA damage response (DSB/DDR), chromatin remodeling and RNA processing pathways
Authors: Ratovitski Tamara , Holland Chloe D. , O’Meally Robert N. , Shevelkin Alexey V. , Shi Tianze , Cole Robert N. , Jiang Mali , Ross Christopher A. 
Published: December 2024

AbstractHuntington’s Disease (HD), a progressive neurodegenerative disorder with no disease-modifying therapies, is caused by a CAG repeat expansion in the HD gene encoding polyglutamine-expanded huntingtin (HTT) protein. Mechanisms of HD cellular pathogenesis and cellular functions of the normal and mutant HTT proteins are still not completely understood. HTT protein has numerous interaction partners, and it likely provides a scaffold for assembly of multiprotein complexes many of which may be altered in HD. Previous studies have implicated DNA damage response in HD pathogenesis. Gene transcription and RNA processing has also emerged as molecular mechanisms associated with HD. Here we used multiple approaches to identify HTT interactors in the context of DNA damage stress. Our results indicate that HTT interacts with many proteins involved in the regulation of interconnected DNA repair/remodeling and RNA processing pathways. We present evidence for a role for HTT in double strand break repair mechanism. We demonstrate HTT functional interaction with a major DNA damage response kinase DNA-PKcs and association of both proteins with nuclear speckles. We show that S1181 phosphorylation of HTT is regulated by DSB, and can be carried out (at leastin vitro) by DNA-PK. Furthermore, we show HTT interactions with RNA binding proteins associated with nuclear speckles, including two proteins encoded by genes at HD modifier loci, TCERG1 and MED15, and with chromatin remodeling complex BAF. These interactions of HTT may position it as an important scaffolding intermediary providing integrated regulation of gene expression and RNA processing in the context of DNA repair mechanisms.
Cell Morphology accurately predicts the nuclear shape of adherent cells
Authors: Lawton Sebastian , Danzman Rosaline A. , Spagnuolo Renzo , Stephan Skylar , Graul Sydney , Wiggan O’Neil , Ghosh Soham , Prasad Ashok 
Published: December 2024

SummaryCells are internally tensed, or prestressed, largely by actomyosin contractility. We hypothesized that nuclear shape is quantitatively predictable from cell shape since prestress couples them both. We trained machine learning models on a publicly available image database of the WTC-11 cell line and predicted shape modes of the nucleus with high accuracy. We develop a U-Net architecture-based model, Cell2Nuc, that predicted nuclear voxels from the cell membrane with accuracies between 74%-87%. To investigate prestress, we cultured and imaged HeLa cells after inhibiting actomyosin contractility. The Cell2Nuc model retrained on the HeLa cells predicted nuclear voxels with slightly lower accuracy. Statistical analysis revealed changes in nuclear size and chromatin organization upon prestress inhibition. Similar trends were seen in images taken from NIH3T3 cells. Thus, cell shape encodes features of nuclear shape, their coupling is partly due to actomyosin contractility, whose abrogation leads to changes in chromatin organization of mechanosensitive origin.
The spiraling effect of incivility enacted through information and communication technology (ICT) in the workplace
Authors: Zivnuska Suzanne , Harris Ken , Valle Matthew , Harris Ranida , Carlson John , Carlson Dawn S. 
Published: December 2024

PurposeThis research provides an empirical test of Andersson and Pearson’s (1999) theoretical incivility spiral. Rather than investigate the incidence of incivility perpetration following incivility victimization in face-to-face interactions, this study tests for evidence of an incivility spiral due to communications enacted through information and communication technology (ICT) based on affective events theory (AET) (Weiss and Cropanzano, 1996). Further, the moderating impacts of both gender and incivility climate on this relationship are considered.Design/methodology/approachThe sample for this Time 1–Time 2 survey-based research was comprised of 354 full-time working adults from a wide range of organizations. We employed hierarchical moderated regression analyses as our primary data analytic technique.FindingsResults demonstrate that victims of ICT incivility at Time 1 are likely to be perpetrators of ICT incivility at Time 2. Furthermore, this relationship is stronger for men than it is for women and is exacerbated in cultures that have a low tolerance for ICT incivility.Originality/valueThis is the first known test of the incidence of an incivility spiral due to communications enacted through ICT. There is special cause for concern given the often-impersonal nature of ICT use (and abuse) in organizations. Individuals may feel emboldened by the distance and perceived safety ICT mediation affords and may be less likely to moderate their online interactions with colleagues. Absent the physical intimacy and non-verbal signals that face-to-face interactions provide, individuals may be more likely to perpetuate incivility in ICT interactions even if there is no implicit intent to harm others.
Analyzing the influence of coopetition on resilience in the open innovation network from the perspective of knowledge diffusion
Authors: Lv Jiaxin , Zou Xingqi , Yang Qing , Zhang Ke 
Published: December 2024

PurposeIn the realm of open innovation (OI) networks, coopetition—where competition and cooperation coexist—plays a pivotal role in shaping the dynamics between diverse projects. This dual relationship is crucial for the propagation of knowledge and the bolstering of the network's overall resilience. While competition drives the quality of products and services, thereby reinforcing network resilience, cooperation facilitates knowledge diffusion, which is essential for the network's robustness.Design/methodology/approachWe delve into the interplay between coopetition intensity and network resilience through the lens of knowledge diffusion. Our methodology begins with a sensitivity analysis to gauge the direct effects of coopetition on resilience. This is followed by a principal component analysis to identify the key determinants of coopetition intensity among projects. Finally, we utilize linear regression and moderation analysis to explore the mediating role of knowledge diffusion in the resilience of OI networks.FindingsOur work is grounded in network theory, which provides a robust theoretical framework for understanding project coopetition and knowledge diffusion within the OI paradigm. This research not only offers a nuanced understanding of coopetition's impact on OI network resilience but also highlights the significance of knowledge diffusion as a critical mediating variable.Originality/value1) Identifies the significant influences in project coopetition (competition and cooperation). (2) Puts the conceptual framework and calculation method of the open innovation network resilience based on the project coopetition and knowledge diffusion. (3) Explores the moderating role of knowledge diffusion in project coopetition influencing open innovation networks resilience. (4) Measures the influence of project coopetition relationship on open innovation network resilience from the perspective of knowledge diffusion. (5) Encourages project management to consider the portfolios of coopetition.
Guidelines to enhance stakeholder management in higher education institutions
Authors: Anholon Rosley , Rampasso Izabela Simon , Ávila Lucas Veiga , Sigahi Tiago F.A.C. , Moraes Gustavo Hermínio Salati Marcondes de , Pavan Serafim Milena , Leal Filho Walter 
Published: December 2024

Purpose
The relationship with internal and external actors on the part of higher education institutions (HEIs) is a fundamental factor for them to fully exercise their role in sustainable development and the evolution of individuals, organizations and society as a whole. In this sense, this study aims to analyze the literature about stakeholder management in HEIs and to provide guidelines to support managers of HEIs to enhance stakeholder management practices.

Design/methodology/approach
This research was conducted through a bibliometric analysis followed by a content analysis to propose the guidelines to support HEIs’ managers in improving stakeholder management practices.

Findings
The guidelines were proposed for each of the following seven areas: engagement and governance; innovation and knowledge management; education for sustainable development; responsible research, innovation and collaborative partnerships; organisational change management; social responsibility; and performance management and sustainability report.

Originality/value
Although the topic addressed has gained traction in the academic community, the literature fails to provide guidelines to support managers of HEIs enhance stakeholder management practices. From a theoretical standpoint, the increasing recognition of the importance of stakeholder engagement reflects a paradigm shift in understanding sustainability and social responsibility in HEIs. On a practical level, managers can use the guidelines to promote effective dialogue, increase stakeholder engagement and collaborative partnerships.
SDG4 academic research productivity in the EU27: economic factors and COVID-19 impacts
Authors: Alfirević Nikša , Malešević Perović Lena , Mihaljević Kosor Maja 
Published: December 2024

Purpose
This paper aims to examine the factors influencing 2018–2022 research productivity related to Sustainable Development Goal 4 (SDG4) in the EU-27 considering the COVID-19 epidemic.

Design/methodology/approach
This paper applies the two-panel estimators to bibliometric data from Scopus and relevant indicators, focusing on the previously achieved scientific productivity levels, national GDP, government education expenditures and the COVID-19 contingency variables. This study addresses the information gap regarding pertinent elements influencing SDG4 research productivity.

Findings
Research productivity in SDG4 is negatively impacted by government spending on education and the SDG4 goal score and positively impacted by the lagged number of prior SDG4 publications and GDP per capita.

Research limitations/implications
The robustness of the results across several panel estimators, the necessity of evaluating interactions with other SDGs and the possibly restricted generalizability of the findings outside the EU-27 sample are limitations acknowledged in this work.

Originality/value
Nations with high levels of SDG4 implementation are becoming less interested in conducting related studies or hinting at a possible systemic mismatch between research and policy at the EU level. The COVID-19 epidemic has had a positive effect on SDG4 research output, indicating that external obstacles to the research process should be contextualized by examining a range of contingency elements in addition to being perceived as general obstacles.
Effect of global oil shocks on the sectoral returns
Authors: Jarral Raazia , Rehman Mobeen Ur 
Published: December 2024

PurposeThis study examines the effects of global oil shocks on sectoral returns during the Pakistani market’s bearish, normal and bullish behavior by controlling VIX and SP500.Design/methodology/approachWe analyze daily sectoral return data from the Pakistan Stock Exchange, covering the period from January 2, 2012, to February 17, 2022. Oil shocks are classified into demand, risk and supply shocks using Ready (2018) methodology, distinguishing their unique characteristics and importance. We utilize quantile regression to evaluate how these oil shocks affect sectoral returns, considering market dynamics. Additionally, we employ the Granger causality test to validate our findings.FindingsThe quantile regression results indicate that the effects of oil shocks on each sector are heterogeneous and significant during both bullish and bearish market phases. Specifically, supply shocks demonstrate a more substantial influence than other shocks, consistent with Kilian’s (2009) findings. Furthermore, the Granger causality test outcomes, conducted after removing control variables, reinforce our findings.Practical implicationsThis study offers evidence that aids investors in understanding how shocks affect sectoral returns. Additionally, it provides insights for policymakers to develop policies that respond effectively to market fluctuations caused by these shocks.Originality/valueThis study holds value for researchers investigating the causes of shocks and their implications for the stock market. Moreover, the insights from this study, focusing on the Pakistani market, could provide a fundamental reference for other oil-dependent nations aiming to mitigate the impacts of global oil price volatility.
The impact of social support on individual health knowledge creation in online patient communities: the mediating role of attitude
Authors: Zhao Haibao 
Published: December 2024

Purpose
This study aims to explore the impact mechanism of social support on individual health knowledge creation among users in online patient communities, guide and promote the creation of health knowledge and provide insights into managing online patient communities.

Design/methodology/approach
A theoretical model was constructed by integrating social impact and social support theories. Data were collected through questionnaires, and 750 valid responses were analysed using a structural equation model.

Findings
This study found the following. (1) Social support influences individual health knowledge creation through the mediating effects of creative self-efficacy and positive emotions. (2) The general rule of the strength of the influencing factors on individual health knowledge creation is that creative self-efficacy > positive emotions. (3) The general pattern of the mediating effect of attitude factors between social support and health knowledge creation is that creative self-efficacy > positive emotions. (4) The key path for social support to influence individual health knowledge creation is “social support → creative self-efficacy → health knowledge creation”. (5) The dimensions of social support in online patient communities can be divided into information, emotional, respect and network support. Individual health knowledge creation can be divided into health knowledge externalisation, combination, socialisation and internalisation.

Originality/value
This study expands the application scope of social influence theory and opens up the “black box” of the impact of social support on individual health knowledge creation behaviour. Simultaneously, the dimensions of social support, individual health knowledge creation and the mediating role between social support and health knowledge creation are discussed.