bluuebunny/crossref_metadata_2025_split huggingface dataset:
Repeated fasting events sensitize enhancers, transcription factor activity and gene expression to support augmented ketogenesis
Authors: Korenfeld Noga , Charni-Natan Meital , Bruse Justine , Goldberg Dana , Marciano-Anaki Dorin , Rotaro Dan , Gorbonos Tali , Radushkevitz-Frishman Talia , Polizzi Arnaud , Nasereddin Abed , Bar-Shimon Meirav , Fougerat Anne , Guillou Hervé , Goldstein Ido 
Published: May 2024

AbstractMammals withstand frequent and prolonged fasting periods due to hepatic production of ketone bodies. Because the fasting response is transcriptionally-regulated, we asked whether enhancer dynamics impose a transcriptional program during recurrent fasting and whether this generates effects distinct from a single fasting bout. We found that mice undergoing alternate-day fasting (ADF) respond profoundly differently to a following fasting bout compared to mice first experiencing fasting. Hundreds of genes enabling ketogenesis are ‘sensitized’ (induced more strongly by fasting following ADF). Liver enhancers regulating these genes are also sensitized and harbor increased binding of PPARα, the main ketogenic transcription factor. ADF leads to augmented ketogenesis compared to a single fasting bout in wild-type, but not hepatocyte-specific PPARα-deficient mice. Thus, we found that past fasting events are ‘remembered’ in hepatocytes, sensitizing their enhancers to the next fasting bout and augment ketogenesis. Our findings shed light on transcriptional regulation mediating adaptation to repeated signals.
When does a parasite become a disease? eDNA unravels complex host-pathogen dynamics across environmental stress gradients in wild salmonid populations
Authors: Eloïse Duval , Simon Blanchet , Erwan Quéméré , Lisa Jacquin , Charlotte Veyssière , Géraldine Loot 
Published: May 2024

AbstractInfectious diseases stem from disrupted interactions among hosts, parasites, and the environment. Both abiotic and biotic factors can influence infection outcomes by shaping the abundance of a parasite’s infective stages, as well as the host’s ability to fight infection. However, disentangling these mechanisms within natural ecosystems remains challenging. Here, combining environmental DNA analysis and niche modeling at a regional scale, we uncovered the biotic and abiotic drivers of a lethal infectious disease of salmonid fish, triggered by the parasiteTetracapsuloides bryosalmonae.We found that the occurrence and abundance of the parasite in the water—i.e., the propagule pressure— were mainly correlated to the abundances of its two primary hosts, the bryozoanFredericella sultanaand the fishSalmo trutta, but poorly to local abiotic environmental stressors. In contrast, the occurrence and abundance of parasites within fish hosts—i.e., proxies for disease emergence—were closely linked to environmental stressors (water temperature, agricultural activities, dams), and to a lesser extent to parasite propagule pressure. These results suggest that pathogen distribution alone cannot predict the risk of disease in wildlife, and that local anthropogenic stressors may play a pivotal role in disease emergence among wild host populations, likely by compromising the hosts’ ability to fight the parasite. Our study sheds light on the intricate interplay between biotic and abiotic factors in shaping pathogen distribution and raises concerns about the effects of global change on disease emergence.
Purinergic Signaling Drives Multiple Aspects of Rotavirus Pathophysiology
Authors: Engevik Kristen A. , Scribano Francesca J. , Gebert J. Thomas , Hyser Joseph M. 
Published: May 2024

AbstractRotavirus causes life-threatening diarrhea in children, resulting in ∼200,000 deaths/year. The current treatment during infection is Oral Rehydration Solution which successfully replenishes fluids but does not alleviate diarrhea volume or severity. As a result, there is an urgent need to better understand rotavirus pathophysiology and develop more effective pediatric therapeutics. Rotavirus primarily infects the tips of small intestinal villi, yet has far-reaching effects on cell types distant from infected cells. We recently identified that rotavirus infected cells release the purinergic signaling molecule ADP, which activates P2Y1 receptors on nearby uninfected cellsin vitro. To elucidate the role of purinergic signaling via P2Y1 receptors during rotavirus infectionin vivo, we used the mouse-like rotavirus strain D6/2 which generates a severe infection in mice. C57BL/6J mouse pups were given an oral gavage of D6/2 rotavirus and assessed over the course of 5-7 days. Beginning at day 1 post infection, infected pups were treated daily by oral gavage with saline or 4 mg/kg MRS2500, a selective P2Y1 antagonist. Mice were monitored for diarrhea severity, diarrhea incidence, and viral shedding. Neonatal mice were euthanized at days 3 and 5 post-infection and small intestine was collected to observe infection. MRS2500 treatment decreased the severity, prevalence, and incidence of rotavirus diarrhea. Viral stool shedding, assessed by qPCR for rotavirus gene levels, revealed that MRS2500 treated pups had significantly lower viral shedding starting at day 4 post infection compared to saline treated pups, which suggests P2Y1 signaling may enhance rotavirus replication. Finally, we found that inhibition of P2Y1 with MRS2500 limited transmitted rotavirus diarrhea to uninfected pups within a litter. Together, these results suggest that P2Y1 signaling is involved in the pathogenesis of a homologous murine rotavirus strain, making P2Y1 receptors a promising anti-diarrheal, anti-viral therapeutic target to reduce rotavirus disease burden.
Compartmentalized CRISPR Reactions (CCR) for High-Throughput Screening of Guide RNA Potency and Specificity
Authors: Supakar Tinku , Herring-Nicholas Ashley , Josephs Eric A. 
Published: May 2024

ABSTRACTCRISPR ribonucleoproteins (RNPs) use a variable segment in their guide RNA (gRNA) called a spacer to determine the DNA sequence at which the effector protein will exhibit nuclease activity and generate target-specific genetic mutations. However, nuclease activity with different gRNAs can vary considerably, in a spacer sequence-dependent manner that can be difficult to predict. While computational tools are helpful in predicting a CRISPR effector’s activity and/or potential for off-target mutagenesis with different gRNAs, individual gRNAs must still be validated in vitro prior to their use. Here, we present compartmentalized CRISPR reactions (CCR) for screening large numbers of spacer/target/off-target combinations simultaneously in vitro for both CRISPR effector activity and specificity, by confining the complete CRISPR reaction of gRNA transcription, RNP formation, and CRISPR target cleavage within individual water-in-oil microemulsions. With CCR, large numbers of the candidate gRNAs (output by computational design tools) can be immediately validated in parallel, and we show that CCR can be used to screen hundreds of thousands of extended gRNA (x-gRNAs) variants that can completely block cleavage at off-target sequences while maintaining high levels of on-target activity. We expect CCR can help to streamline the gRNA generation and validation processes for applications in biological and biomedical research.
Structures of native SV2A reveal the binding mode for tetanus neurotoxin and anti-epileptic racetams
Authors: Schenck Stephan , Laeremans Toon , Steyaert Jan , Brunner Janine D. 
Published: May 2024

AbstractThe synaptic vesicle glycoprotein 2A (SV2A) is abona fidesynaptic vesicle (SV) constituent of controversial function with homology to the major facilitator superfamily (MFS) and essential in vertebrate neurotransmission. Despite its high medical relevance as the target of the anti-epileptic drug Levetiracetam (LEV) and as receptor for clostridial neurotoxins (CNTs), among them several botulinum neurotoxin (BoNT) serotypes and potentially tetanus neurotoxin (TeNT), we lack detailed insight about these molecular interactions. We purified native SV2A from brain and subjected it to a structural analysis to advance our understanding of drug-binding to this enigmatic protein and explore structurally uncharacterized toxin-SV2A interfaces. Our analysis uncovered that TeNT binds SV2 proteins strikingly different from BoNT/A and delivers visual evidence for the dual receptor hypothesis through structurally resolved, co-purified gangliosides in the complex. The structures provide compelling support for SV2A as the protein receptor for TeNT in central neurons, recapitulate the geometry of CNT binding to dipartite SV2-ganglioside receptors on neuronal surfaces in a membrane-like constellation and have implications for toxin-engineering through a previously unknown SV2A-toxin interface. Further, a LEV-bound structure of SV2A reveals the drug-interacting residues and delineates a putative substrate pocket in SV2A. Our work provides an explanation for the SV2-isoform-specificity of LEV and its derivatives and paves the way for improved design of anti-convulsant drugs in epilepsy treatment.
AR coactivators, CBP/p300, are critical mediators of DNA repair in prostate cancer
Authors: Sardar Sumaira , McNair Christopher M. , Ravindranath Lakshmi , Chand Saswati N. , Yuan Wei , Bogdan Denisa , Welti Jon , Sharp Adam , Ryan Natalie K. , Schiewer Matthew J. , DeArment Elise G. , Janas Thomas , Su Xiaofeng A. , Butler Lisa M. , de Bono Johann S. , Frese Kris , Brooks Nigel , Pegg Neil , Knudsen Karen E. , Shafi Ayesha A. 
Published: May 2024

AbstractCastration resistant prostate cancer (CRPC) remains an incurable disease stage with ineffective treatments options. Here, the androgen receptor (AR) coactivators CBP/p300, which are histone acetyltransferases, were identified as critical mediators of DNA damage repair (DDR) to potentially enhance therapeutic targeting of CRPC. Key findings demonstrate that CBP/p300 expression increases with disease progression and selects for poor prognosis in metastatic disease. CBP/p300 bromodomain inhibition enhances response to standard of care therapeutics. Functional studies, CBP/p300 cistrome mapping, and transcriptome in CRPC revealed that CBP/p300 regulates DDR. Further mechanistic investigation showed that CBP/p300 attenuation via therapeutic targeting and genomic knockdown decreases homologous recombination (HR) factorsin vitro,in vivo, and in human prostate cancer (PCa) tumorsex vivo. Similarly, CBP/p300 expression in human prostate tissue correlates with HR factors. Lastly, targeting CBP/p300 impacts HR-mediate repair and patient outcome. Collectively, these studies identify CBP/p300 as drivers of PCa tumorigenesis and lay the groundwork to optimize therapeutic strategies for advanced PCa via CBP/p300 inhibition, potentially in combination with AR-directed and DDR therapies.
A 3D whole-face movement analysis system to uncover underlying physiology in mice
Authors: Daruwalla Kyle , Martin Irene Nozal , Frankel Andrew , Naglič Diana , Ahmad Zainab , Hou Xun Helen 
Published: May 2024

AbstractSynchronous movements of the entire face, from chewing to grimacing, offer significant insights into internal physiological processes. Mice, with discernible facial responses and evolutionarily conserved mammalian facial movement control circuits, provide an ideal model to unravel the link between facial movement and internal physiological states in mammals. However, existing frameworks lack the spatial or temporal resolution to track motion of the entire mouse face, due to its small and conical form factor. We introduce Cheese3D, a computer vision system that first captures high-speed 3D motion of the entire mouse face (including ears, eyes, whisker pad, jaw, while covering both sides of the face) using a calibrated six-camera array. The interpretable framework extracts dynamics of anatomically-meaningful 3D facial features in absolute world units at sub-millimeter precision. The precise face-wide motion data generated by Cheese3D provides clear physiological insights, as shown by proof-of-principle experiments predicting time under anesthetic from subtle facial patterns, and inferring tooth and muscle anatomy from fast chewing motions. Cheese3D can serve as a discovery tool that renders facial movements highly interpretable as a read-out of otherwise hidden internal states.
Profiling genetically driven alternative splicing across the Indonesian Archipelago
Authors: Ibeh Neke , Kusuma Pradiptajati , Crenna Darusallam Chelzie , Malik Safarina , Sudoyo Herawati , McCarthy Davis J. , Romero Irene Gallego 
Published: May 2024

AbstractOne of the regulatory mechanisms influencing the functional capacity of genes is alternative splicing (AS). Previous studies exploring the splicing landscape of human tissues have shown that AS has contributed to human biology, especially in disease progression and the immune response. Nonetheless, this phenomenon remains poorly characterised across human populations, and it is unclear how genetic and environmental variation contribute to alternative splicing. Here, we examine a set of 115 Indonesian samples from three traditional island populations spanning the genetic ancestry cline that characterizes Island Southeast Asia. We conduct a global AS analysis between islands to ascertain the degree of functionally significant AS events and their consequences. Using a hierarchical event-based statistical model, we detected over 1,000 significant differential AS events across all comparisons. Additionally, we identify over 6,000 genetic variants associated with changes in splicing (splicing quantitative trait loci; sQTLs), some of which are driven by Papuan-like genetic ancestry, and only show partial overlap with other publicly available sQTL datasets derived from other populations. Computational predictions of RNA binding activity revealed that a fraction of these sQTLs directly modulate the binding propensity of proteins involved in the splicing regulation of immune genes. Overall, these results contribute towards elucidating the role of genetic variation in shaping gene regulation in one of the most diverse regions in the world.
Understanding the link between supervisor and co-worker support, job characteristics, work engagement and employee resilience: evidence from Uganda
Authors: Nabawanuka Hamidah , Ekmekcioglu Emre Burak 
Published: May 2024

PurposeThe purpose of this study is to investigate the relationship between support (i.e. supervisor support (SS) and co-worker support (CS)), job characteristics (job autonomy, job complexity and skill variety) and work engagement (WE). Furthermore, the study examined whether there is a mediating effect of employee resilience (ER) on the aforementioned variables.Design/methodology/approachData were collected from employees working in SMEs in Uganda. A sample of 324 responses was used for data analysis. Structural equation modelling and bootstrapping procedures were used to test the hypothesized relationships.FindingsThe study findings confirmed that SS, CS and job characteristics were positively related to WE. The study revealed that SS, job autonomy, job complexity and skill variety were found to foster WE through ER. Yet, CS was found not to have an indirect impact on WE through ER.Research limitations/implicationsBecause this study was conducted using a cross-sectional research methodology, it makes it hard to draw causal inferences.Originality/valueThis study’s findings contribute to the existing body of literature on WE and job characteristics and also adds to the growing body of research on ER.
Knowledge management drivers and its results: a quantitative study in a public higher education institution
Authors: Alves Juliano Nunes , Cogo Moisés Pivetta , Klein Leander Luiz , Pereira Breno Augusto Diniz 
Published: May 2024

PurposeThe purpose of this study was to evaluate the influence of knowledge management (KM) drivers on perceived KM results in a public higher education institution. A structured theoretical model based on leadership, people, processes, knowledge processes, technology, learning and KM results was developed and tested.Design/methodology/approachA survey was conducted with the employees of a public higher education institution where an administrative reform was initiated. A valid sample of 257 respondents was obtained. The data were obtained from the application of a structured questionnaire based on the KM drivers and their results. A five-point Likert-type scale was used to measure respondents' answers. The main data analysis technique was structural equation modeling.FindingsThe results indicate knowledge processes, leadership and people factors have a positive and significant impact on KM results. On the other hand, organizational processes, technology and learning factors were not significant. However, the service length of servants in the institution influences the perception of knowledge drivers.Practical implicationsPublic institutions should be attentive to people with more time of service because they may have difficulties with technological advances, reorganization of processes and adaptation to new ways of sharing knowledge.Originality/valueThis study advances on the analysis of KM results in the public sector and tests the moderation effect of time of service.
Knowledge sharing and NPD performance for UK cross – border M&A firms: the moderating role of behavior and outcome controls
Authors: Lee Hanna , Um Ki-Hyun 
Published: May 2024

Purpose
This paper aims to explore how the effect of knowledge sharing through mergers and acquisitions (M&As) on new product development (NPD) performance is contingent upon two different types of control mechanisms: behavior control and outcome control.

Design/methodology/approach
Leveraging the theory from transaction cost economics, this study provides answers regarding the roles of behavior and outcome controls. The hypotheses were tested empirically across a sample of 143 UK cross-border M&A firms.

Findings
The results provide the increasing call for an integrative perspective and theory in the M&A literature in that knowledge sharing through M&As is deemed decisive for NPD performance, and while both control mechanisms are effective, behavior control is more effective in enhancing NPD performance than outcome control.

Originality/value
The relevant M&A studies lack insights into the use of control mechanisms as a way to monitor the target firm’s behavior and performance and reduce the risk of its opportunistic behavior. Appreciating the need for M&A literature that elaborates control strategy and structure, this study incorporates behavior control and outcome control into M&A mechanisms.
Medical secretaries’ fears and opportunities in an increasingly digitalised workplace environment
Authors: Qvarfordt Maria , Lagrosen Stefan , Nilsson Lina 
Published: May 2024

PurposeThe purpose of this mixed-methods study was to explore how medical secretaries experience digital transformation in a Swedish healthcare organisation, with a focus on workplace climate and health.Design/methodology/approachData were collected using a sequential exploratory mixed-methods design based on grounded theory, with qualitative data collection (a Quality Café and individual interviews) followed by quantitative data collection (a questionnaire).FindingsFour categories with seven underlying factors were identified, emphasising the crucial need for effective organisation of digital transformation. This is vital due to the increased knowledge and skills in utilising technology. The evolving roles and responsibilities of medical secretaries in dynamic healthcare settings should be clearly defined and acknowledged, highlighting the importance of professionality. Ensuring proper training for medical secretaries and other occupations in emerging techniques is crucial, emphasising equal value and knowledge across each role. Associations were found between some factors and the health of medical secretaries.Research limitations/implicationsThis study adds to the knowledge on digital transformation in healthcare by examining an important occupation. Most data were collected online, which may be a limitation of this study.Practical implicationsSeveral aspects of the medical secretaries’ experiences were identified. Knowledge of these is valuable for healthcare managers to make digital transformation more effective while avoiding excessive strain on medical secretaries.Originality/valueMedical secretaries are expected to contribute to the digitalisation of healthcare. However, minimal research has been conducted on the role of medical secretaries in workplace digitalisation, focusing on workplace roles and its dynamics.
CIV-MIL integration in the transformation of the EU healthcare network: a dual-gain strategy
Authors: Frassini Jacopo 
Published: May 2024

PurposeThis article aims to address the need for a more structured partnership between civilian and military healthcare, particularly in the context of cross-border threats in the EU. While both systems are driven by the same goal of providing high-quality healthcare services and achieving optimal patient outcomes, they operate under different national approaches and resources.Design/methodology/approachTwo recent crises are presented as examples that highlight the necessity of cooperation between civilian and military medical systems. The Covid-19 Pandemic and the Ukrainian Conflict are described based on the experience gathered by the author as a member of the NATO Centre of Excellence for Military Medicine and form the base to shape a broader perspective on the future of civil-military interaction in healthcare at the European Union level.FindingsThe ability to deliver coordinated responses during crises depend on the level of interoperability, preparation and mutual understanding. To improve synergies, a structured partnership should be established, prioritizing common standards of care and shared best practices. Integrating military and civilian healthcare pathways can be especially beneficial in situations where patients are moved from the point of injury or sickness across different military and civilian structures to receive the most appropriate treatment and rehabilitation for their conditions.Originality/valueThe relationship between military and civilian healthcare systems is often discussed at multinational level, but a clear focus is lacking concerning their shared mission, distinct functions and potential for cross-border collaboration.