bluuebunny/crossref_metadata_2025_split huggingface dataset:
The fetal hydrops-associated single-residue mutation L322P abolishes mechanical but not chemical activation of the PIEZO1 ion channel
Authors: Jiang Jinghui , Guo Wei , Chen Xudong , Wang Yubo , Zhu Xiaohui , Yan Liying , Qiao Jie , Xiao Bailong 
Published: February 2025

AbstractThe mechanically activated PIEZO1 ion channel is genetically linked to numerous physiological and pathophysiological processes. For example, deletingPIEZO1in mice leads to defective lymphatic vessel development, while nonsense mutations in humans are associated with autosomal recessive generalized lymphatic dysplasia (GLD) and non-immune hydrops fetalis. However, it remains unclear whether PIEZO1-dependent biological processes are directly mediated by its intrinsic mechanosensitivity. Here we identified a human fetal hydrops-associated single-residue mutation, L322P (corresponding to L329P in mouse PIEZO1), which completely abolishes PIEZO1’s response to mechanical stimuli while maintaining normal plasma membrane expression and responsiveness to its chemical activators, Yoda1 and Jedi1. Remarkably, the mechanical response of the mutant can be restored by Yoda1. These findings demonstrate a direct link between the loss of PIEZO1’s mechanosensitivity and the pathophysiological phenotype of fetal hydrops, and raise the therapeutic potential of using PIEZO1 chemical activators to restore the mechanosensitivity of PIEZO1 missense mutants that are associated with genetic diseases such as GLD and hydrops fetalis.Significance StatementGenetic deletion studies have revealed the diverse cellular, physiological, and pathophysiological roles of the mechanically activated PIEZO1 ion channel. However, whether these functions are directly mediated by its mechanosensitivity has remained experimentally unaddressed. In this study, we identified a novel fetal hydrops-associated single-residue mutation, hPIEZO1-L322P, which specifically abolishes PIEZO1’s mechanical response while retaining its chemical activation. Remarkably, the mechanical response of the mutant can be fully restored by the PIEZO1 chemical activator Yoda1. These findings address the long-standing question of whether PIEZO1 relies on its mechanosensitivity to mediate in vivo functions, provide critical insights into the mechanosensing mechanism of PIEZO1, and highlight the therapeutic potential of using PIEZO1 chemical activators to rescue the loss of mechanosensitivity caused by missense mutations.
The development of a World Health Organization transdiagnostic chatbot intervention for distressed adolescents and young adults
Authors: Keyan Dharani , Hall Jennifer , Jordan Stewart , Watts Sarah , Au Teresa , Dawson Katie S. , Sway Rajiah Abu , Crawford Joy , Sorsdahl Katherine , Luitel Nagendra P , de Graaff Anne M. , Ghalayini Heba , Habashneh Rand , EL-Dardery Hafsa , Fanatseh Sarah , Malik Aiysha , Servili Chiara , Faroun Muhannad , Abualhaija Adnan , Aqel Ibrahim Said , Hamdani Syed Usman , Dardas Latefa , Akhtar Aemal , Bryant Richard A. , Carswell Kenneth 
Published: February 2025

AbstractBackgroundCommon mental disorders are prevalent in young people in low- and middle-income countries (LMICs). Digitally delivered interventions have the potential to overcome many structural and psychosocial barriers to mental health care. Chatbots have been proposed as one potentially acceptable and feasible method that may increase engagement. Yet, there is currently limited evidence for their efficacy in reducing psychological distress. This paper summarises the development of a World Health Organization digital psychological intervention for young people experiencing impairing psychological distress, developed in line with Human Centred Design (HCD) principles.ObjectiveThis study refined and adapted a chatbot intervention initially developed for adolescents aged 15-18 years that was completed in consultation with end-users in this age group (N =236), community members (N =73), and psychology intervention experts (N =9) across varied settings. The purpose was to create an adaptation fit for use by young adults aged 18-21 years experiencing psychological distress in Jordan.MethodsThe current study followed a limited user-centred design process involving focus groups and key informant interviews with stakeholders including young adults aged 18-21 years (N =33), community members (N= 13), and psychology intervention experts (N= 11). Iterative design development occurred throughout the cultural adaptation and refinement process.ResultsThere was a clear preference for a chatbot based intervention that included interactions with fictional characters with relatable problems. The chatbot content followed a transdiagnostic model that addressed common problems including low mood, stress and anger with reference to vocational, familial and interpersonal stressors that the target population commonly faced. It followed a non-AI decision tree format with multiple sessions and was designed to be adaptable for use in different countries with different populations and software systems. Prototype versions of the chatbot were well-received by adolescents (15– 18-year-old) and young adults (18–21-year-old).ConclusionsThis is the first report of the development of a chatbot intervention for adolescents and young adults in LMICs that was designed using a HCD framework. Systematic end-user engagement through all phases of the research aimed to make this intervention acceptable and useable for adolescents and young adults in a wide variety of settings. The chatbot is currently being tested in randomised controlled trials in Jordan and Lithuania.
An outpatient integrated management program reduced the need for hospitalizations of CKD patients: findings from the PIRP project
Authors: Santoro Antonio , Gibertoni Dino , Albertazzi Vittorio , Buscaroli Andrea , Cimino Simonetta , Donati Gabriele , Fiaccadori Enrico , Gregorini Mariacristina , La Manna Gaetano , Mambelli Emanuele , Rapanà Renato , Scarpioni Roberto , Storari Alda , Zucchelli Annalisa , Mandreoli Marcora 
Published: February 2025

ABSTRACTBackground and hypothesisIn patients with moderate or severe renal disease, hospitalization is often required because of poorly controlled co-morbidities. We aimed to provide evidence that an outpatient health program involving a close collaboration between nephrologists and General Practitioners can be successful in reducing hospitalizations in non-dialysis chronic kidney disease patients.MethodsObservational cohort study on 17,036 stage 1-5 chronic kidney disease patients enrolled in the Emilia-Romagna (Italy) PIRP project between 1st April 2004 and 31st December 2015, and their 70,560 hospitalizations registered in the four years preceding and following their enrolment in the project. Interrupted Time Series analysis was used to estimate hospitalizations’ trend summarized on 4-monthly basis.ResultsAmong patients who survived 4 years in non-dialysis chronic kidney disease condition, a 2.9% reduction in hospitalizations was observed in the four years following the enrolment in PIRP compared to the four years previously. The change in hospitalizations’ trend was estimated at −8.09 admission per 1,000 patients and 4-month period. This decrease was mainly accountable to hospitalizations whose main diagnoses at discharge were diseases of the circulatory system and the genitourinary system (−2.68 and −4.76 admissions per 1,000 patients respectively). Patients with heart failure and those with coronary artery disease displayed large reductions in hospitalization trend (−17.08 and −9.48 admissions per 1,000 patients respectively). A reduction of hospitalizations with similar magnitude was also observed for the advanced stages of CKD.ConclusionThe implementation of an integrated public health project that provides for the early management and continuity of care of CKD patients may be a way to reduce hospitalizations, particularly those related to cardiovascular and genitourinary diagnoses.Key learning pointsWhat was knownWith an integrated and structured program based on the collaboration between nephrologists and General Practitioners, it is possible to better control progression and comorbidity in CKD.This study addsBy continuously following CKD patients with a close collaboration between nephrologists and General Practitioners, hospitalizations can be reduced.Potential impactThe implementation of an integrated model of outpatient management of CKD patients like the PIRP might be beneficial also on hospitals’ organization and costs, and ultimately on patients’ quality of life.Graphical abstract
Fine-tuning Large Language Models in Behavioral Psychology for Scalable Physical Activity Coaching
Authors: Mantena Sriya , Johnson Anders , Oppezzo Marily , Schuetz Narayan , Tolas Alexander , Doijad Ritu , Mattson C. Mikael , Lawrie Allan , Ramirez-Posada Mariana , Linos Eleni , King Abby C. , Rodriguez Fatima , Kim Daniel Seung , Ashley Euan A. 
Published: February 2025

ABSTRACTPersonalized, smartphone-based coaching improves physical activity but relies on static, human-crafted messages. We introduce My Heart Counts (MHC)-Coach, a large language model fine-tuned on the Transtheoretical Model of Change. MHC-Coach generates messages tailored to an individual’s psychology (their “stage of change”), providing personalized support to foster long-term physical activity behavior change. To evaluate MHC-Coach’s efficacy, 632 participants compared human-expert and MHC-Coach text-based interventions encouraging physical activity. Among messages matched to an individual’s stage of change, 68.0% (N=430) preferred MHC-Coach-generated messages (P <0.001). Blinded behavioral science experts (N=2) rated MHC-Coach messages higher than human-expert messages for perceived effectiveness (4.4 vs. 2.8) and Transtheoretical Model alignment (4.1 vs. 3.5) on a 5-point Likert scale. This work demonstrates how language models can operationalize behavioral science frameworks for personalized health coaching, promoting long-term physical activity and potentially reducing cardiovascular disease risk at scale.
Metabolic dysfunction-associated steatotic liver disease status modifies risks of in-stent restenosis in coronary atherosclerosis: A long-term longitudinal study
Authors: Lai Jiaming , Ye Junzhao , Luo Ling , Teng Long , Shao Congxiang , Dong Zhi , Mai Weiyi , Zhuang Xiaodong , Zhong Bihui 
Published: February 2025

AbstractBackgroundPrevious studies have verified that metabolic dysfunction-associated steatotic liver disease (MASLD) confered higher risk of coronary atherosclerosis development. However, whether MASLD influence prognosis after drug-eluting stent (DES) implantation treatment remain not known.MethodsIn this retrospective observational study, 301 included cardiovascular disease (CVD) patients who underwent re-coronary angiography after the first successful DES-based percutaneous coronary intervention. All the patients received computerized tomography (CT) to estimate liver steatosis (65.8% of MASLD). The primary outcome was in-stent restenosis (ISR) determined by intravenous ultrasound. Liver fibrosis was assessed with Fibrosis-4 (FIB-4) index.ResultsAfter a median follow-up of 27 (range from 12 to 144) months, subjects with MASLD over presented ISR than those without (30.3% vs. 8.7 %, P < 0.001). The Cox proportional hazard model confirmed that, MASLD [HR (95%CI): 2.64 (1.14– 6.11), P = 0.024], FIB-4 index [HR (95%CI): 2.05 (1.50–2.82), P < 0.001] were independently associated with ISR. The hazard model’s area under the receiver operating characteristic curves (AUROC) of 1, 3, 5 and 10 years prediction for ISR were respectively 0.620, 0.801, 0.830 and 0.721. Kaplan-Meier survival analysis demonstrated that ISR increased progressively with the FIB-4 index (log-rank, P<0.001). Additionally, after low-density lipoprotein (LDL) cholesterol reached control standard, FIB-4 index [HR (95%CI): 2.72 (1.43–5.16), P = 0.002] and liver CT attenuation [HR (95%CI): 0.94 (0.88–0.99), P = 0.048] remained independently associated with ISR.ConclusionsMASLD and related liver fibrosis are associated with the ISR in CVD patients after DES implantation, and management of MASLD might attenuate the risks of ISR.Graphical abstract
Age-related Inhibitory Decline: Examining Inhibition Sub-Components and their Impact on Sustained Attention in Healthy Ageing
Authors: Treacy Ciara , Andrews Sophie C. , Levenstein Jacob M. 
Published: February 2025

AbstractThe inhibition deficit hypothesis postulates that inhibitory functioning declines with age, which negatively impacts other cognitive abilities. Yet still, the influence of healthy ageing on inhibitory functioning remains unclear, with the multifaceted nature of inhibition often an overlooked factor. Moreover, no prior study has empirically tested whether inhibition explains differential age-effects in sustained attention. Thus, we cross-sectionally investigated the inhibition deficit hypothesis in eighty healthy older adults (mean age = 67.78 years, 44f) administering three inhibition tasks (i.e., flanker, Stroop, and go/no-go), each measuring a distinct sub-component process, and one sustained attention task (i.e., SART) via the PsyToolkit platform. No significant bivariate relationships were identified among the inhibition measures. Semi-partial correlations (rho) of the three inhibition sub-component measures (correcting for gender and education) with age resulted in significant positive relationships with task performance on the Stroop and go/no-go, such that older individuals had more pronounced Stroop effects and worse go/no-go accuracy, respectively. Lastly, go/no-go performance completely mediated the relationship between ageing and sustained attention performance, whilst Stroop effects partially mediated this association. The lack of significant inter-task correlations supports the independence of these sub-component processes of inhibition and cautions against conflating these sub-components into a generalised concept of inhibition. Further, age-related declines were observed in specific inhibition tasks, which speaks against ageneralinhibition deficit in healthy ageing. The mediation findings demonstrate that inhibitory sub-components account for age-related declines in sustained attention, over and beyond ageing itself via an indirect path, representing an important cognitive domain to maintain throughout ageing.Public significance statementWe identify that three commonly used inhibition tasks are indeed measuring different sub-component processes, underlining the importance of considering the non-unitary nature of inhibition. Age-related decrements in inhibition were identified among a subset of inhibitory measures, challenging the notion of global inhibitory decline during healthy. Our mediation results provide evidence that inhibition can explain differential age-effects in sustained attention in healthy older adults, lending support for the inhibition deficit hypothesis.
Self-assembly is important for the target membrane recruitment of a nuclear dynamin-related protein
Authors: Rout Sakti Ranjan , Alam Faiyaz , Sahoo Swapnil , Rahaman Abdur 
Published: February 2025

AbstractDynamin superfamily proteins are large GTPases that perform their cellular functions by self-assembling on their target membranes. Dynamin-related protein 6 (Drp6) associates with the nuclear membrane and performs nuclear remodeling. However, the mechanism of its recruitment to the target membrane is not known. Here, we discover that self-assembly of Drp6 is essential for its nuclear membrane recruitment. We identified four residues, 411-GKFR-414 to be essential for its self-assembly. We also demonstrated that the mutant Drp6 (Drp6GKFR-AAAA) failed to recruit to the nuclear membrane. This loss of nuclear membrane recruitment is not due to the lack of membrane binding capability, since the mutated protein was able to bind membrane preparedin vitro. Together, our results suggest that in addition to membrane binding, self-assembly of a nuclear dynamin-related protein is also important for the target membrane recruitment.
A model for background selection in non-equilibrium populations
Authors: Barroso Gustavo V. , Ragsdale Aaron P. 
Published: February 2025

AbstractThe magnitude of negative selection varies across the genome, affecting local levels of diversity by virtue of linked selection. Predicting patterns of diversity under such background selection has received considerable attention, and recent applications were able to explain a large portion of the variation in diversity across the human genome. However, current models have yielded conflicting results, stemming from two key limitations. First, they display inaccuracies in the most critical region of parameter space (Nes∼ −1), where the reduction in diversity is sharpest; second, they assume a constant population size over time. Here, we develop predictions for diversity under background selection based on the Hill-Robertson system of two-locus statistics allowing for population size changes. We treat the joint effect of multiple selected loci independently, but we show that interference among them is well captured through local rescaling of mutation, recombination and selection in an iterative procedure that converges quickly. We further accommodate existing background selection theory to population size changes, bridging the gap between weak and strong selection. Simulations show that our predictions are accurate over the entire distribution of selection coefficients. We characterize the temporal dynamics of linked selection under non-equilibrium demography and demonstrate that patterns of diversity can be misinterpreted by other models. Specifically, neglecting population size changes bias predictions of diversity, which then carry over to downstream inferences of the distribution of fitness effects and deleterious mutation rate. Jointly modeling demography and linked selection therefore improves our understanding of the genomic landscape of diversity, which will help refine inferences of linked selection in humans and other species.
Uncovering the Signatures of Cellular Senescence in the Human Dorsolateral Prefrontal Cortex
Authors: Sloan Nicholas , Mares Jason , Daly Aidan , Coie Lilian , Grier Shaunice , Barretto Natalie , Casel Obadele , Kang Kristy , Jackson Chris , Pedersen Maria , Khiste Shruti , Fullerton Ben , Petrescu Joana , Mattison Courteney , Smith Colin , Suh Yousin , Menon Vilas , Phatnani Hemali 
Published: February 2025

SummaryIdentifying senescent cells poses challenges due to their rarity, heterogeneity, and lack of a definitive marker. We performed Visium spatial transcriptomics (ST) and single nucleus RNA sequencing (snRNA-seq) on non-pathological human tissue to build a transcriptomic atlas of aging and senescence in the dorsolateral prefrontal cortex (dlPFC). We identified markers characteristic of aging dlPFC cortical layers and cell types. We also observed an increase in astrocyte abundance and decrease in somatostatin expressing inhibitory neurons. Overall, the senescence profile in the dlPFC was highly heterogeneous and heavily influenced by cell type identity and cortical layer. Combined unbiased analysis of ST and snRNA-seq datasets revealed gene expression modules encoding for communities of microglia and endothelial cells in the white matter and regional astrocytes programs that were strongly enriched with age and for senescence-related genes. These findings will help facilitate future studies exploring the function of senescent cell subpopulations in the aging brain.
IFN-α Induces Heterogenous ROS Production in Human β-Cells
Authors: Wagner Leslie E. , Melnyk Olha , Turner Abigail , Duffett Bryce E. , Muralidharan Charanya , Martinez-Irizarry Michelle M. , Arvin Matthew C. , Orr Kara S. , Manduchi Elisabetta , Kaestner Klaus H. , Brozinick Joseph T. , Linnemann Amelia K. 
Published: February 2025

ABSTRACTType 1 diabetes (T1D) is a multifactorial disease involving genetic and environmental factors, including viral infection. We investigated the impact of interferon alpha (IFN-α), a cytokine produced during the immune response to viral infection or the presence of un-edited endogenous double-stranded RNAs, on human β-cell physiology. Intravital microscopy on transplanted human islets using a β-cell-selective reactive oxygen species (ROS) biosensor (RIP1-GRX1-roGFP2), revealed a subset of human β-cells that acutely produce ROS in response to IFN-α. Comparison to Integrated Islet Distribution Program (IIDP) phenotypic data revealed that healthier donors had more ROS accumulating cells. In vitroIFN-α treatment of human islets similarly elicited a heterogenous increase in superoxide production that originated in the mitochondria. To determine the unique molecular signature predisposing cells to IFN-α stimulated ROS production, we flow sorted human islets treated with IFN-α. RNA sequencing identified genes involved in inflammatory and immune response in the ROS-producing cells. Comparison with single cell RNA-Seq datasets available through the Human Pancreas Analysis Program (HPAP) showed that genes upregulated in ROS-producing cells are enriched in control β-cells rather than T1D donors. Combined, these data suggest that IFN-α stimulates mitochondrial ROS production in healthy human β-cells, potentially predicting a more efficient antiviral response.
Vitamin D Receptor Gene Polymorphisms in Type 1, Type 2, and Gestational Diabetes Mellitus: A Comprehensive Meta-Analysis and Meta-Regression of 154 Studies
Authors: Alnaji Haider Ali , Abdul Jaleel Al-Karrar Kais , Normatov Muslimbek G. , Abo Algon Ali Abbas , Ali Hanaa Addai , Almulla Abbas F. 
Published: February 2025

AbstractBackgroundDiabetes mellitus (DM) includes metabolic disorders marked by chronic hyperglycemia. Vitamin D and its receptor (VDR) play crucial roles in DM pathophysiology. Four single nucleotide polymorphisms (SNPs) in the VDR gene, namely FokI, TaqI, BsmI, and ApaI, have been implicated in DM risk. However, no prior meta-analysis has systematically assessed their associations across type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), and gestational diabetes mellitus (GDM).ObjectivesTo investigate the association of FokI, TaqI, BsmI, and ApaI polymorphisms with susceptibility to T1DM, T2DM, and GDM.MethodsA systematic search of PubMed, Google Scholar, and SciFinder identified 154 studies (49,675 participants: 23,225 DM patients and 26,450 controls). Meta-analyses assessed genetic associations, and subgroup analyses were performed by ethnicity and DM subtype.ResultsSignificant associations were observed between T1DM and FokI, BsmI, and ApaI polymorphisms, while TaqI showed no association. For T2DM, FokI, BsmI, and TaqI polymorphisms were associated with risk in specific ethnic groups. GDM analysis revealed no overall associations, though the FokI SNP showed significance in one ethnic subgroup. Comparative analysis across DM types revealed no differences in VDR polymorphisms except for the BsmI SNP, which increased T2DM risk in certain genetic models.ConclusionThe G allele of the BsmI SNP significantly increases T2DM risk, while the T allele of the FokI SNP is protective in T1DM. These findings highlight the importance of VDR polymorphisms in DM susceptibility across diverse populations.