bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanism of the Dual Action Self-Potentiating Antitubercular Drug Morphazinamide
Authors: Ostrer Lev , Crooks Taylor A. , Howe Michael D. , Vo Sang , Jia Ziyi , Hegde Pooja , Schacht Nathan , Aldrich Courtney C. , Baughn Anthony D. 
Published: October 2024

AbstractPyrazinamide (PZA) is a cornerstone of first-line antitubercular drug therapy and is unique in its ability to kill nongrowing populations ofMycobacterium tuberculosisthrough disruption of coenzyme A synthesis. Unlike other drugs, PZA action is conditional and requires potentiation by host-relevant environmental stressors, such as low pH and nutrient limitation. Despite its pivotal role in tuberculosis therapy, the durability of this crucial drug is challenged by the emergent spread of drug-resistance. To advance drug discovery efforts, we characterized the activity of a more potent PZA analog, morphazinamide (MZA). Here, we demonstrate that like PZA, MZA acts in part through impairment of coenzyme A synthesis. Unexpectedly, we find that, in contrast to PZA, MZA does not require potentiation and maintains bactericidal activity against PZA-resistant strains due to an additional mechanism involving aldehyde release. Further, we find that the principal mechanism for resistance to the aldehyde component is through promoter mutations that increase expression of the mycothiol oxidoreductase MscR. Our findings reveal a dual action synergistic mechanism of MZA that results in a faster kill rate and a higher barrier to resistance. These observations provide new insights for discovery of improved therapeutic approaches for addressing the growing problem of drug-resistant tuberculosis.Significance StatementPyrazinamide is the only antitubercular drug of its kind, capable of targeting persistentMycobacterium tuberculosisthrough disruption of the coenzyme A biosynthetic pathway. With the emergent spread of drug-resistant tuberculosis, it is imperative to identify more effective next-generation drugs. In this study, we characterized the mechanism of action of a more potent analog of pyrazinamide, morphazinamide. We demonstrate that like pyrazinamide, morphazinamide impairs coenzyme A metabolism. In contrast to pyrazinamide, we find that morphazinamide has an additional aldehyde-dependent mechanism that mediates potent bactericidal activity against both pyrazinamide-susceptible and pyrazinamide-resistant strains ofM. tuberculosis. These findings open up new opportunities for the development of next-generation antitubercular drugs to tackle the increasing challenge of drug-resistant tuberculosis.
Polarized exocytosis and anionic phospholipid species implicated in the initiation of clathrin-mediated endocytosis
Authors: Marchando Paul , Hu Gean , Sun Yidi , Drubin David G. 
Published: October 2024

AbstractUnderstanding of the mechanisms that initiate clathrin-mediated endocytosis (CME) is incomplete. Recent studies in budding yeast identified the endocytic adaptor protein Yap1801/Yap1802 (budding yeast AP180) as a key CME factor that promotes CME initiation in daughter cells during polarized growth, but how Yap1801/2 is recruited preferentially to the plasma membrane of daughter cells is not clear. The only known cargos for Yap1801/2 in yeast are the synaptobrevins Snc1 and Snc2, which act as v-SNARES for exocytic vesicles arriving at the plasma membrane and are essential for polarized cell growth. In this study, we analyze the spatiotemporal dynamics of functional, fluorescently-tagged Snc1/2 expressed from their endogenous loci and provide evidence that, in concert with anionic phospholipids, Snc1/2 recruit Yap1801/2 preferentially to growing daughter cells. These findings suggest that the coincidence of anionic phospholipids and Snc1/2 facilitates CME initiation in growing daughter cells and directly links polarized CME to polarized secretion.
A highly adaptable protocol for mapping spatial features of cellular aggregates in tissues
Authors: Sawyer Andrew , Weingaertner Nick , Patrick Ellis , Feng Carl G 
Published: October 2024

AbstractMultiplex imaging technologies have developed rapidly over the past decades. The advancement of multiplex imaging has been driven in part by the recognition the spatial organisation of cells can represent important prognostic biomarkers and that simply studying the composition of cells in diseased tissue is often insufficient. There remains a lack of tools that can perform spatial analysis at the level of cellular aggregates (a common histopathological presentation) such as tumors and granulomas, with most analysis packages focussing on smaller regions of interest and potentially missing patterns in the overall lesion structure and cellular distribution. Here we present a protocol to quantify the cellular structure of entire tissue lesions built around two novel metrics. The Total Cell Preference Index reports whether a lesion tends to change in density in its central vs peripheral areas and can indicate the extent of necrosis across the entire lesion. The Immune Cell Preference Index then reports whether each immune cell-type is located more centrally or peripherally across the entire lesion. The output of both indexes is a single number readout for simple interpretation and visualization, and they can be applied to lesions of any size or shape. Additionally, this protocol can be applied to any slide-scanning multiplexed imaging system, either based on protein and nucleic acid staining. Finally, the protocol uses the open-source software QuPath and can be utilized by researchers with a basic understanding of QuPath with the full protocol able to be applied on pre-generated images within one hour.
Traumatic brain injury (TBI) and mortality in older adults with and without pre-injury dementia
Authors: Lai Helen , Soreq Eyal , Bourke Niall J , Baker Claire , Zimmerman Karl A , Parkinson Megan E , Daniels Sarah JC , Gregg Edward W , Sharp David J , Li Lucia M 
Published: October 2024

AbstractImportanceIncidence of traumatic brain injury (TBI) is rising in older adults. Dementia is a common comorbidity amongst older adults and may worsen post-TBI outcomes, but this has not been systematically studied.ObjectiveTo compare all-cause mortality following TBI or non-TBI trauma (NTT), and quantify the impacts of age, deprivation, and pre-injury dementia.DesignPopulation-based retrospective cohort studySettingElectronic health records (EHRs) from primary and secondary careParticipantsAdult residents in Wales aged 18-100 with TBI or NTT from January 2000 to December 2022ExposuresTraumatic (intracranial) brain injury (TBI) or non-TBI trauma (NTT) recorded in secondary care. Pre-injury diagnosis of dementia within primary or secondary care.Main Outcomes and MeasuresAll-cause mortality within 1, 6, and 12 months of hospitalised TBI/NTT in those with and without pre-injury dementia. Cox proportional hazard models were used to estimate survival probability across groups. Groups were propensity-matched by age, sex, and health conditions. Models were stratified by sex, age, and deprivation.Results23,428 TBIs (n=18,940) and 589,169 NTTs (n=421,259) were identified. TBIs were associated with higher mortality than NTT at all timepoints and age bands. Older age was associated with high mortality after TBI, with 16.9% of patients aged 65-79 (Hazard Ratio (HR)=4.52, 95% CI=[4.05,5.05], p<0.0001, relative to patients aged 18-39) and 31% of patients aged 80-100 dead within one month (9.08 [8.17,10.1], p<0.0001).The impact of pre-injury dementia on post-TBI mortality was specifically during the chronic phase, 6 and 12 months after injury. Using NTT without dementia as a comparator, 12-month mortality was significantly higher in TBI patients with pre-injury dementia (2.15 [2.03,2.28], p<0.0001) than those without (1.52 [1.44,1.60], p<0.0001). Conversely, 30-day mortality was significant after TBI irrespective of dementia: TBI with (2.67 [2.42, 2.95], p<0.0001) or without pre-injury dementia (2.87 [2.65, 3.12], p<0.0001) had more than twice the mortality risk relative to NTT without dementia.Conclusions and relevanceTBI is associated with higher all-cause mortality than NTT, particularly in older age. Pre-injury dementia was associated with particularly high mortality at 6 and 12 months. There is an urgent need to understand the reasons for poor outcomes in older adult TBI populations, especially those with pre-injury dementia.
Rapid and modular workflows for same-day sequencing-based detection of bloodstream infections and antimicrobial resistance determinants
Authors: Sajib Mohammad Saiful Islam , Oravcova Katarina , Brunker Kirstyn , Everest Paul , Fuentes Manuel , Wilson Catherine , Murphy Michael E. , Forde Taya 
Published: October 2024

AbstractBackgroundBloodstream infections (BSI) are a major global health concern, and existing diagnostic methods are too slow to guide targeted antibiotic therapy for critically ill patients, risking poor clinical outcomes. Rapid metagenomic-sequencing (mNGS) can facilitate swift pathogen and antimicrobial resistance (AMR) detection, but identification is challenged by significant host versus bacterial DNA in blood. To accelerate microbiological diagnosis, we developed M-15, a rapid and modular mNGS-based host DNA depletion workflow, validated with suspected BSI blood-culture samples and rapid culture-enriched spiked blood.MethodsTo assess chemical host DNA depletion (CHDD) efficiency, M-15 was benchmarked with five commercial/published protocols. Later, M-15 was combined with rapid mNGS with/without adaptive sampling (AS) and tested on clinical blood-culture samples (n=33) from suspected BSI cases identified on BACT/ALERT VIRTUO (30 flagged positive, three remained negative). To determine whether it is possible to utilise M-15 mNGS prior to blood-culture flagging positive, a rapid enrichment method was tested starting with 1-10 colony forming units of the top 15 bacterial species causing BSI spiked into BACTEC medium enriched with 10 mL sheep blood.ResultsAll six chemical depletion protocols reduced host DNA by 2.5×100to 4.1×106-fold, with the in-house M-15 protocol performing best, while adaptive sampling depleted host >5-fold. With BACT/ALERT specimens, M-15 mNGS accurately identified 3/3 negative, 28/28 mono-bacterial, and 2/4 multi-bacterial species. With rapid culture-enrichment and M-15 mNGS, <18% DNA was classified as host and all bacterial species tested (n=10) were correctly identified. M-15 mNGS accurately predicted phenotypic AMR/susceptibility for 90.3% (232/257) of drug/bacteria combinations from BACT/ALERT positive samples.ConclusionsThis study demonstrates that M-15 mNGS can facilitate species and AMR gene detection within 5-7 hours of BACT/ALERT positivity. Including 8-hour culture enrichment, microbiological and AMR confirmation is possible within 13-15 hours of sample collection. Thus, the M-15 mNGS workflow has the potential to improve patient outcomes in BSI.
Short-term frailty index fluctuations in older adults: Noise or signal?
Authors: Stolz Erwin , Schultz Anna , Hoogendijk Emiel O. , Theou Olga , Rockwood Kenneth 
Published: October 2024

AbstractBackgroundReversible short-term fluctuations in the frailty index (FI) are often thought of as representing only noise or error. Here, we assess (1) size and source of short-term FI fluctuations, (2) variation across socio-demographics, (3) association with chronic diseases, (4) correlation with age, frailty level, frailty change, and mortality, and (5) whether fluctuations reflect discrete health transitions.MethodsNationwide, biweekly longitudinal data from 426 community-dwelling older adults (70+) were collected in the FRequent health Assessment In Later life (FRAIL70+) study using a measurement burst design (5,122 repeated observations, median of 13 repeated observations per person). We calculated the intraindividual standard deviation (iSD) of the FI and used location-scale mixed regression models.ResultsMean iSD was 0.04 (SD=0.03). Fluctuations were driven foremost by cognitive problems, somatic symptoms, and limitations in instrumental and mobility-related activities of daily living. Short-term fluctuations correlated with higher FI levels (r=0.62), one-year FI change (r=0.26), and older age (+3% per year). Older adults who took to bed due to a health problem (+50%), those who had an overnight hospital stay (+50%), and those who died during follow-up (+44%) exhibited more FI fluctuations.ConclusionsShort-term FI fluctuations were neither small nor random. Instead, as older adults become frailer, their measured health also becomes more unstable; hence short-term fluctuations in overall health status can be seen as a concomitant phenomenon of the aging process. Researchers and clinicians should be aware of existence of reversible fluctuations in the FI over weeks and months and its consequences for frailty monitoring.
Diabetes and all-cause mortality among middle-aged and older adults in China, England, Mexico, rural South Africa, and the United States: A population-based study of longitudinal aging cohorts
Authors: Green Hunter , Zhang Yuan S. , Li Chihua , Zaninotto Paola , Langa Kenneth M. , Lee Jinkook , Manne-Goehler Jennifer , Flood David 
Published: October 2024

ABSTRACTObjectiveThere is a need for comparable worldwide data on the impact of diabetes on mortality. This study assessed diabetes and all-cause mortality among middle-aged and older adults in five countries.Research Design and MethodsWe analyzed adults aged 51 years or older followed between 2010 and 2020 from population-based cohorts in China, England, Mexico, rural South Africa, and the United States. Diabetes was defined by self-report or an elevated diabetes blood-based biomarker meeting the clinical criteria for diabetes. All-cause mortality was assessed through linkages or informant interviews. We used Poisson regression models to estimate mortality rate ratios and mortality rate differences, comparing people with diabetes to those without diabetes. Models were adjusted for age, gender, education, smoking status, body mass index, and economic status.ResultsWe included 29,397 individuals, of whom 4,916 (16.7%) died during the study period. The median follow-up time ranged from 4.6 years in South Africa to 8.3 years in China. The adjusted all-cause mortality rate ratios for people with diabetes versus those without diabetes ranged from 1.53 (95% CI: 1.39-1.68) in the United States to 2.02 (95% CI: 1.34-3.06) in Mexico. The adjusted mortality rate differences (per 1,000 person-years) for people with diabetes versus those without diabetes ranged from 11.9 (95% CI: 4.8-18.9) in England to 24.6 (95% CI: 12.2-37.0) in South Africa.ConclusionsDiabetes was associated with increased all-cause mortality in population-based cohorts across five diverse countries. There is an urgent need to implement clinical and public health interventions to improve diabetes outcomes globally.ARTICLE HIGHLIGHTSWhy did we undertake this study?We aimed to address the need for comparable estimates of all-cause mortality among people with diabetes in diverse global settings.What is the specific question(s) we wanted to answer?How does diabetes impact all-cause mortality among middle-aged and older adults (aged 51 years or greater) in China, England, Mexico, rural South Africa, and the United States?What did we find?Middle-aged and older adults with diabetes had higher all-cause mortality than people without diabetes in all countries. Relative mortality differences ranged from mortality rate ratios of 1.53 in the United States to 2.02 in Mexico. Absolute mortality differences ranged from mortality rate differences (per 1,000 person-years) of 11.9 in England to 24.6 in South Africa.What are the implications of our findings?There is an urgent need to implement clinical and public health interventions to improve diabetes outcomes globally.
LeDNA: a cut-and-build toolkit to democratize education on CRISPR gene editing technology
Authors: Kundlatsch Guilherme E. , Rodrigues Alina S. L. , Zocca Vitória F. B. , Amorim Laura A. S. , de Paiva Gabriela B. , Neto Almiro P. S. , Campos Juliana A. D. B. , Pedrolli Danielle B. 
Published: October 2024

AbstractWe introduce LeDNA, a versatile educational toolkit designed for teaching fundamental genetics and CRISPR-Cas gene editing principles in diverse settings, regardless of existing infrastructure. Fabricated using laser-cutting techniques, LeDNA is an open-source resource suitable for students across educational levels, from high school to graduate studies. Given the transformative potential of CRISPR technology in various fields, including medicine and agriculture, a widespread understanding of its principles is essential for informed public discourse and acceptance. By providing a readily accessible and affordable tool, LeDNA aims to democratize genetics and CRISPR education globally, fostering a more informed and engaged community.
Economic value added and working capital efficiency linkages: an Indian context
Authors: Bhatia Prince , Kumar Rahul , Chattopadhyay Subir , Dubey Ritesh Kumar 
Published: October 2024

Purpose
This paper aims to explore the relationship between the economic value added (EVA) and the working capital efficiency (WCE) of the listed firms in India.

Design/methodology/approach
This paper uses annual data of 401 listed companies for the period 2012–2019. Furthermore, the dynamic panel data regression model was used to investigate the relationship between the variables of interest.

Findings
The results reveal that the net trade cycle (NTC) is significantly and negatively associated with listed firms’ economic value in India, indicating that a shorter NTC generates higher EVA for Indian firms. The authors further explore the association between individual components of the NTC with EVA. The authors also found that an inverse, and significant relationship exists between EVA and the individual components of the NTC. The findings also reported a meaningful relationship between EVA and control variables except for leverage and age. For listed firms, the results suggest that sales growth and firm size are crucial factors driving firms’ EVA.

Practical implications
Higher WCE enhances shareholder value creation, forming positive stakeholders’ expectations toward the company.

Originality/value
Over the years, many studies have been conducted to determine the relationship between WCE and traditional measures of firms’ profitability. However, hardly any study finds out the impact of WCE on the value-based measures of firms’ performance. This study fills the gap in the existing literature by analyzing the impact of WCE on firms’ EVA.
Traveling with family! A mediated-moderation model on the intention to use accommodation sharing
Authors: Parvez M. Omar , Eluwole Kayode Kolawole , Aureliano-Silva Leonardo , Cobanoglu Cihan 
Published: October 2024

Purpose
This study aims to examine the direct impact of perceived service quality (PSQ) on satisfaction and the intention to use accommodation sharing (IAS). Additionally, it investigates the mediating role of satisfaction between PSQ and IAS. To extend the findings, the study also analyzes the moderating roles of behavioral change and family status in the relationship between satisfaction and IAS within a collective group.

Design/methodology/approach
This study includes 413 accommodation sharing (AS) users in the USA using data collected through MTurk. The authors analyzed the data using the ordinary least squared regressions path analytical framework and bootstrapping methods in PROCESS Macro to estimate the hypothesized mediated moderation models.

Findings
The findings underscore the significant impact of PSQ on satisfaction and IAS. Moreover, they reveal the crucial role of satisfaction as a mediator in this relationship and the moderating influence of family status and behavior change on the observed indirect relationship. These insights are invaluable for understanding and navigating the dynamics of the accommodation-sharing industry.

Originality/value
This paper is a pioneering work that sheds new light on the roles of change in behavior and family status in the context of AS. It makes significant contributions to the sharing economy and offers valuable managerial insights for companies operating in this market. The study s originality lies in its explanation of the mediator role of satisfaction in the sharing economy and the moderator mechanism of change in behavior and family status on IAS.
The impact of corporate social advocacy on employee trust and distrust: an empirical study of #StopAsianHate
Authors: Park Keonyoung , Asthana Shivangi , Nie Songli 
Published: October 2024

PurposeThis study examines the relationship between corporate social advocacy (CSA) and employee trust and distrust, focusing on perceived employer support for the #StopAsianHate movement. We aim to explore how perceived CSA relates to employee perceptions and engagement in the workplace, answering for the following research questions: How do employees perceive their companies’ engagement in CSA, specifically the #StopAsianHate movement? To what extent do these perceptions influence trust and distrust toward their employers? How do trust and distrust, in turn, affect employees’ workplace engagement?Design/methodology/approachThe study conducted an online survey of 798 full-time employees across various industries in the USA in March 2022. To ensure a diverse and representative sample, the survey targeted demographic representation based on the latest US census data.FindingsCSA initiatives were found to be positively related to both trust and distrust by employees. Trust was significantly positively connected to employee engagement cognitively, emotionally and physically in the workplace, mediating the relationship between CSA and employee engagement.Originality/valueThis study adds to the empirical CSA research on employee–employer relations by incorporating a real-world context of the #StopAsianHate movement and illustrating the complexity of ambivalent CSA perceptions – both trust and distrust. It highlights the importance of understanding these dynamics within corporate advocacy efforts, offering an overview of CSA’s role in shaping workplace relations.
The role of snapchat in shaping workplace behavior and productivity
Authors: Bilderback Stephanie , Luck Patrick , Blackwell Isabella L. , Lobdell Michael D. 
Published: October 2024

PurposeThis paper explores the influence of Snapchat on workplace behavior, focusing on employee productivity, mental health and organizational policies. It examines how Millennials and Generation Z use Snapchat professionally, with implications for management strategies and workplace culture.Design/methodology/approachThe paper provides a conceptual analysis grounded in existing literature and theoretical frameworks, including uses and gratifications theory, social comparison theory and attention economy theory. The analysis covers the psychological effects of social media validation, social comparisons and the impact of Snapchat on attention and task management. Management strategies such as policy development and employee training are also examined.FindingsSnapchat positively impacts communication and team bonding but presents challenges to productivity, mental well-being and data security. The platform’s design encourages both community building and distractions. Organizations can mitigate these issues through effective policies, training and mental health support.Originality/valueThis paper offers a unique contribution by focusing specifically on Snapchat and its workplace impact. It addresses the balance between the benefits of social media and its drawbacks, presenting practical strategies for organizations to manage Snapchat usage effectively while maintaining productivity and supporting employee well-being.