bluuebunny/crossref_metadata_2025 huggingface dataset:
The forkhead transcription factor FKH-7/FOXP acts in chemosensory neurons to regulate developmental decision-making
Authors: Chai Cynthia M. , Taylor Seth R. , Tischbirek Carsten H. , Wong Wan-Rong , Cai Long , Miller David M. , Sternberg Paul W.
Published: February 2025

Autism is a complex neurodevelopmental disorder with many associated genetic factors, including the forkhead transcription factor FOXP1. Although FOXP1’s neuronal role is well-studied, the specific molecular consequences of different FOXP1 pathogenic variants in physiologically-relevant contexts are unknown. Here we ascribe the first function to Caenorhabditis elegans FKH-7/FOXP, which acts in two chemosensory neuron classes to promote the larval decision to enter the alternative, developmentally-arrested dauer life stage. We demonstrate that human FOXP1 can functionally substitute for C. elegans FKH-7 in these neurons and that engineering analogous FOXP1 hypomorphic missense mutations in the endogenous fkh-7 locus also impairs developmental decision-making. In a fkh-7/FOXP1 missense variant, single-cell transcriptomics identifies downregulated expression of autism-associated kcnl-2/KCNN2 calcium-activated potassium channel in a serotonergic sensory neuron. Our findings establish a novel framework linking two evolutionarily-conserved autism-associated genes for deeper characterization of variant-specific molecular pathology at single neuron resolution in the context of a developmental decision-making paradigm.
Covariate Adjusted Logit Model (CALM) for Generating Dose-Response Curves from Observational Data with Applications to Vaccine Effectiveness Trials
Authors: Shang Nong , Schrag Stephanie , Kahn Rebecca , Rhodes Julia
Published: February 2025

Establishing dose-response relationships with observational data is challenging due to confounding covariates and selection bias, particularly when the bias causes marginal distributions of confounding covariates to differ between the sample and the target population. In this scenario, standard causal analysis approaches like g-formula are not applicable without further modeling of the dose-response relationship. To address this limitation, we extend the log-linear structure mean model for binary treatments into a Covariate Adjusted Logit Model (CALM) for continuous treatments, introducing a new causal estimand that measures relative dose-response relationship. Based on one interpretation of vaccine effectiveness, the relative dose response curve can be described as a function that reduces susceptibility to disease, making the adjustment for confounding covariates equivalent to revealing latent susceptibility status. Accordingly, we leverage a Gibbs sampler called the All-or-Nothing (AoN) algorithm for Bayesian and non-parametric estimation of the relative response curve, providing new options beyond regular causal techniques, such as those based on generalized propensity scores. In the context of vaccine effectiveness (VE) clinical trials, CALM addresses the issue of confounding covariates that affect dose-response relationships differently in placebo and vaccine arms. While deriving a common absolute dose-response curve for both arms to evaluate VE is generally infeasible, our model provides a common relative dose-response curve for this purpose. Simulation studies confirm that CALM outperforms alternative methods in scenarios with confounding factors, making it a valuable tool for future immunological response-based vaccine trials.
Earlier Detection of Brain Injury Using Optical Brain Pulse Monitoring in Critically Ill Patients Following Cardiac Arrest
Authors: Teo Elliot J. , Petautschnig Sigrid , Hellerstedt Jack , Chung Sung W , Udy Andrew , Smith Paul , Haydon Tim , Dixon Barry
Published: February 2025

IMPORTANCE

Point-of-care, non-invasive brain monitoring in critically ill patients following cardiac arrest could provide earlier detection of neurological injury and, when combined with earlier treatments, limit brain injury. Point-of-care monitoring could also enable better neuro-prognostication.

OBJECTIVES

The study assessed the time to detection of brain injury using optical brain pulse monitoring (OBPM) compared to routine brain monitoring. The association of OBPM signals with more severe forms of brain injury was also assessed.

DESIGN

Retrospective analysis of patients enrolled in an observational study.

SETTING

Critical care unit of a tertiary academic hospital.

PARTICIPANTS

Adult patients requiring mechanical ventilation in a critical care unit following a cardiac arrest.

MAIN OUTCOMES AND MEASURES

OBPM uses red and infrared light to capture brain pulse waveforms whose morphology reflects the relative arteriole and venous pressure levels driving microvascular blood flow in the brain. The OBPM sensors were placed bilaterally on the anterior temporal region of the scalp, over the middle cerebral artery territories. Time to brain injury detection was defined as the period from cardiac arrest to the first detection of brain injury by OBPM or routine monitoring.

RESULTS

Twelve patients were enrolled, three required veno-arterial extra-corporeal membrane oxygenator support. In-hospital mortality was 83% and eight patients developed global hypoxic-ischemic brain injury. The median time to detection of brain injury was 57 hours earlier using OBPM compared to routine monitoring (P < 0.01). In brain injured patients OBPM brain pulse morphologies changed over time and were often different between hemispheres, high amplitude respiratory waves were also present. Known poor prognostic brain pulse waveform morphologies were present in some patients with severe brain injury.

CONCLUSIONS AND RELEVANCE

OBPM detected brain injury earlier compared to routine brain monitoring. Earlier detection of neurological injury could improve patient outcomes through earlier treatment and better neuro-prognostication.

KEY POINTS

Question

Can point-of-care non-invasive optical brain pulse monitoring (OBPM) in critically ill patients following cardiac arrest provide earlier detection of brain injury compared to routine monitoring?

Findings

In this observational study of 12 patients the median time to detection of brain injury was 57 hours earlier using OBPM compared to routine monitoring.

Meaning

Earlier detection of brain injury could improve patient outcomes through earlier treatment and better neuro-prognostication.
Effects of Socioeconomic Status in Colorectal Cancer Incidence and Clinical Outcome Differences Among Asian American Populations: A Systematic Review
Authors: Sakazaki Amy , Lui Austin , Wang Melody , Ngo Katherine , Lugue Maria Theresa , Aligireddy Himani , Nguyen Maria , Murakami Shin
Published: February 2025

Introduction

Colorectal cancer (CRC) is the second leading cause of cancer death in the Asian American and Pacific Islander (API) population, a diverse and rapidly growing minority group in the US. Race, ethnicity, and socioeconomic status (SES) are known to impact outcomes of CRC, but the relationship is unclear in the context of the Asian American cohort and its diverse subgroups. This systemic review aims to gain insight into the relationship between the incidence and clinical outcomes of CRC in the Asian American community.

Methods

A systematic literature search was conducted per PRISMA protocol using PubMed, Scopus, EMBASE, Cochrane, CINAHL, and Web of Science databases, accessed on August 13, 2023.

Results

Of the 2225 studies identified, a total of 14 studies were included in the analysis. Four studies concluded that there was no association or variable response to SES measurements in CRC incidence in the Asian American population. However, there was evidence that the incidence of CRC varies among Asian American subgroups, using varying measures of SES. In the eight studies that measured mortality or survival as the primary outcome, seven found decreased mortality and increased survival in the API population despite changes in SES. Out of the six studies that measured incidence, four studies found no association with SES. A study found that Chinese Americans experienced a significant decrease in every socioeconomic status (SES) category. Japanese Americans experienced a significant decrease in the lowest SES category, while Koreans and Filipinos experienced a significant increase in both the lowest and highest SES categories. Therefore, grouping various Asian American ethnicities as a single monolithic “Asian” category is misleading.

Conclusion

Although the incidence of CRC was thought to be low and decreasing, this review found various trends in different Asian American subset groups. For example, there was a decrease in CRC rates in two ethnic groups and an increase in the other two ethnic groups. The potential causes of these varying CRC incidence rates are likely multifactorial and may include inadequate screening rates, lack of CRC education, and cultural barriers. Further studies are needed to understand these mechanisms. This review recommends a more detailed classification of the API ethnic population but not as a single monolithic entity as Asian. It also emphasizes preventative CRC screening within the API communities due to lower rates of CRC screening among them.
Specific neuroblast-derived signals control both cell migration and fate in the rostral migratory stream
Authors: Zhou Wei , Munoz James R. , Ho Hsin-Yi Henry , Hanamura Kenji , Dalva Matthew B.
Published: February 2025

Functional neuronal circuits require neuroblasts migrate to appropriate locations and then differentiate into neuronal subtypes. However, it remains unknown how neuroblasts in the subventricular zone (SVZ) are guided through the rostral migratory stream (RMS) to the olfactory bulb (OB). Here we define EphB2 as a neuroblast-derived cue that controls migration along the RMS and helps to determine cell fate. Within the RMS, EphB2 is expressed selectively in, kinase-active in, and required for the migration of neuroblasts. As neuroblasts enter the OB and differentiate, EphB kinase activity is down-regulated, and in the granule cell layer (GCL), EphB2 expression is down-regulated. Blocking EphB kinase activity or knocking down EphB2 results in defects in migration and premature cellular differentiation in the RMS. Unexpectedly, premature loss of EphB2 expression causes neuroblasts to stop migrating and differentiate into astrocyte-like cells. Thus, EphB2 kinase activity and expression are linked to migration and specification of neuroblast fate.
A screen to identify antifungal antagonists reveals a variety of pharmacotherapies induce echinocandin tolerance inCandida albicans
Authors: Reitler Parker , DeJarnette Christian A. , Kumar Ravinder , Tucker Katie M. , Peters Tracy L. , Twarog Nathaniel R , Shelat Anang A. , Palmer Glen E.
Published: February 2025

Through screening a comprehensive collection of drugs approved for human use, we identified over 20 that oppose the antifungal activity of the echinocandins upon the infectious yeast,Candida albicans. More detailed evaluation of five such drugs, including the atypical antipsychotic aripiprazole and the tyrosine kinase inhibitor ponatinib, indicated they promoteC. albicanssurvival following exposure to the echinocandin antifungals. The activity of the five selected antagonists was dependent upon the Mkc1p MAPK pathway, however, ponatinib was paradoxically shown to suppress phosphorylation and therefore activation of Mkc1p itself. Components of several other signaling pathways are also required, including those of calcineurin and casein kinase-2, suggesting the observed antagonism required much of the cell wall stress responses previously described forC. albicans. Transcriptome analysis revealed that the antagonists stimulated the expression of genes involved in xenobiotic and antifungal resistance, and suppressed the expression of genes associated with hyphal growth. Thus, the echinocandin antagonistic drugs modulateC. albicansphysiology in ways that could impact its pathogenicity and/or response to therapeutic intervention. Finally, a mutant lacking the Efg1p transcription factor, which has a central role in the activation ofC. albicanshyphal growth was found to have intrinsically high levels of echinocandin tolerance, suggesting a link between modulation of morphogenesis related signaling and echinocandin tolerance.

Importance

We report a substantial number of previously unknown drug interactions that modulate the echinocandin sensitivity of one of the most prevalent human fungal pathogens,Candida albicans. The echinocandins are the first line therapy for treating disseminated and often lethalCandidainfections, that account for >75% of invasive fungal infections in the U.S.. For largely unknown reasons, a substantial number of patients with invasive candidiasis fail to respond to treatment with these drugs. The finding of this study suggest that co-administered medications have the potential to influence the therapeutic outcomes of invasive fungal infections through modulating antifungal drug tolerance and/or fungal pathogenicity. The potential for echinocandin antagonistic medications to influence therapeutic outcomes is discussed.
Glissandra oviformisn. sp.: a novel predatory flagellate illuminates the character evolution within the eukaryotic clade CRuMs
Authors: Yazaki Euki , Harada Ryo , Isogai Ryu , Bamba Kohei , Ishida Ken-ichiro , Inagaki Yuji , Shiratori Takashi
Published: February 2025

Culturing protists offers a powerful approach to exploring eukaryotic diversity, especially for deep-branching lineages. In this study, we cultured and described a novel protist species, namedGlissan-dra oviformisn sp., within the poorly studied and unclassified genusGlissandra. While an SSU rDNA gene phylogeny failed to resolve its phylogenetic placement in the eukaryotic tree, a phylogenomic analysis of 340 proteins indicatedG. oviformisas a deep-branching member of the CRuMs clade. Prior to this study, this clade consisted of diverse het-erotrophic amoeba and flagellates and lacks clear synapomorphies. Ultrastructural observations re-vealed thatG. oviformisshares the characteristics with some CRuMs members, including the pellicle underlying the plasma membrane and an internal sleeve surrounding the central pair of the axoneme at the flagellar transitional region. Our findings suggest potential shared characteristics and synapomorphies for CRuMs and contribute to a deeper understanding of the character evolution within CRuMs.
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

The 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 Statement

Genetic 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

Background

Common 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.

Objective

This 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.

Methods

The 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.

Results

There 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).

Conclusions

This 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

Background and hypothesis

In 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.

Methods

Observational 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.

Results

Among 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.

Conclusion

The 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 points

What was known

With 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 adds

By continuously following CKD patients with a close collaboration between nephrologists and General Practitioners, hospitalizations can be reduced.

Potential impact

The 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

Personalized, 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

Background

Previous 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.

Methods

In 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.

Results

After 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.

Conclusions

MASLD 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
Genome-wide transcriptome analysis reveals sex-specific biological differences in the early phase of an acute myocardial infarction.
Authors: Shulkin Aaron , Pandal Perman , Vazquez Eliseo , Cortez-Toledo Elizabeth Jasmin , Atsina Kwame , Mersha Tesfaye , Lopez Javier E.
Published: February 2025

Background: Clinical outcomes of acute myocardial infarction (AMI) are known to vary between females and males; however, the nature of this sex dimorphism remains controversial. Most AMI transcriptomic studies have not considered differences between females and males, and combined sexes in their analysis to increase sample size and gain power (canonical approach). Our objective was to (1) use a sex-specific differentially expressed gene meta-analysis (ss-DEGma) in blood and (2) identify sex-specific pathways related to the early phase of AMI. Methods: Gene expression data (7 sets) for sex-combined (canonical) and sex-specific analysis (ss-DEGma) were obtained from the publicly-available GEO database. Datasets from whole blood and peripheral blood cells sampled within 3 days post-AMI were analyzed using GEO2R. The massiR tool identified sex in 72% of samples. The top-ranking DEGs were used to identify significant sex-specific biological pathways in the KEGG database (FDR <0.05). Results: We performed this meta-analysis in 291 women and 452 men and > 20,000 genes (see Table for identified DEGs). Sex-combined DEGs yielded 100 significant KEGG pathways. Sex-specific DEGs yielded 8/61 (13%) additional new pathways not identified by the sex-combined analysis. Sex-combined pathways were predominantly immunological (35%), while male- and female-specific pathways were 43% and 18% immunological, respectively. Proliferative and metabolic pathways were the next most represented pathways in females, which were not present in males at all. Conclusion: We present 8 new sex-specific AMI-related transcriptional pathways not identified in the canonical sex-combined analysis. Furthermore, we find that 53% of pathways identified in the canonical sex-combined analysis are not shared between sexes. This data underscores an urgent need for prospective sex-specific transcriptomic analysis to define the sex-specific biological difference post-AMI.
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

The 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 statement

We 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

Dynamin 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

The 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

Identifying 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

Type 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

Background

Diabetes 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).

Objectives

To investigate the association of FokI, TaqI, BsmI, and ApaI polymorphisms with susceptibility to T1DM, T2DM, and GDM.

Methods

A 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.

Results

Significant 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.

Conclusion

The 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.
Identification and validation of aging-related genes in IgA nephropathy
Authors: Shu Jinlian , Li He , Li Hairong , Xing Airong , Yao Shaofeng
Published: February 2025

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Aging is a major risk factor for progression of IgAN to end stage renal disease. The purpose of this study was to identify and verify aging-related genes associated with IgAN through bioinformatics analysis. Microarray datasets of GSE93798 and GSE37460 were downloaded from the Gene Expression Omnibus (GEO) database. The aging-related DEGs (AR-DEGs) associated IgAN was analyzed by R programming software, and then genome ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed. The PPI network of AR-DEGs was then contructed, and hub genes were ranked using five methods of the cytoHubba plugin in Cytoscape software. CIBERSORT algorithm was used to evaluate the infiltrating immune cells and their relationship with hub genes. Next, Nephroseq V5 online platform was used to verify and analyze the mRNA expression patterns of hub genes in IgAN patients and normal controls.A total of 372 DEGs were identified, of which the expression of 158 were upregulated and 214 were downregulated. GO and KEGG enrichment pathway analysis mainly focused on regulation of macrophage derived foam cell differentiation, PI3K-Akt signaling pathway. Based on the results of PPI network analysis, the eight hub genes were identified, includingAGT,ALB,CD36,EGF,KDR,LPL,MYC,PPARGC1A. Immunoinfiltration analysis indicated thatCD36were closely related to immune cell infiltration. Furthermore, the expression levels of these hub genes were validated using the Nephroseq V5 online platform. Further clinical sample studies confirmed thatCD36was highly expressed in renal tissues of IgAN patients. These findings provide new insights into potential aging-related genes associated with IgAN, which may better contribute to understanding the pathogenesis of IgAN.CD36may have diagnostic value for aging-related IgAN.
AI for Mortality Prediction from Head Trauma Narratives
Authors: Pham Tuan D. , Marks Katya , Hughes Declan , Chatzopoulou Domniki , Coulthard Paul , Holmes Simon
Published: February 2025

Head injuries are a leading global cause of mortality and disability, highlighting the critical need for advanced prognostic tools to inform clinical decision-making and optimize healthcare resource utilization. For the first time, this study introduces a cutting-edge artificial intelligence (AI) framework designed to predict mortality outcomes from head injury narratives. Leveraging deep learning-based natural language processing techniques, the framework identifies and extracts key features from unstructured text describing injury mechanisms and patient conditions to train predictive models. Validation was conducted on a diverse dataset of 1,500 head injury cases using a stratified holdout approach, with 90% allocated for training and 10% for testing. The one-dimensional convolutional neural network model demonstrated strong performance, achieving averagely 85% accuracy, 74% correct mortality prediction, 88% correct survival prediction, and an impressive area under the receiver operating characteristic curve of 0.91. This work highlights the transformative potential of AI in harnessing narrative clinical data to enhance prognostic accuracy, paving the way for more effective, evidence-based management of head injury patients.
Lifetime air pollution exposure from prenatal to 18 years and cardiovascular health in young adulthood: findings from a UK birth cohort
Authors: Soares Ana Goncalves , Tilling Kate , Makanvand Maryam , Kerckhoffs Jules , Hansell Anna L , Timpson Nicholas J , Elhakeem Ahmed
Published: February 2025

Aims

We assessed the association between air pollution from pregnancy (in utero) to 18 years and cardiovascular health markers in early adulthood.

Methods

Data from 3,767 individuals from a UK birth cohort were used. We explored the associations between modelled fine particulate matter (PM2.5), nitrogen dioxide (NO2) and black carbon (BC) across an 18-year period and eight cardiovascular health markers measured at 18 year of age. Long-term exposure to air pollution was assessed by averaging the air pollutants over time and by creating air pollutant trajectories. Linear regressions were used to assess the associations between air pollutants and cardiovascular health markers. Possible sensitive periods of exposure and sex differences in these associations were also explored.

Results

Higher average levels of PM2.5and NO2were associated with higher peripheral (pDBP) and central diastolic blood pressure (cDBP); e.g., an interquartile range increase in PM2.5was associated with 0.46 mmHg (95%CI 0.14, 0.78) higher pDBP and 0.50 mmHg (95%CI 0.17, 0.83) higher cDBP. Higher average PM2.5levels were also associated with lower carotid intima-media thickness and higher BC levels were associated with higher heart rate (HR). Latent classes showed the same overall patterns of association, with the trajectory classes with the highest levels of air pollution exposure tending to have higher pDBP, cDBP and HR. There was little evidence of sensitive periods of exposure and sex differences in the associations.

Conclusions

Higher lifetime exposure to air pollution up to 18 years was associated with markers of poorer cardiovascular health in early adulthood.
A semiparametric method to test for correlated evolution in a phylogenetic context
Authors: Harmon Luke J. , Revell Liam J.
Published: February 2025

Phylogenetic comparative methods are a broad suite of approaches for studying trait and species diversification using evolutionary trees. In spite of their substantial growth in sophistication and complexity in recent years, among the most commonly-employed phylogenetic comparative method continues to be a simple measure of the evolutionary correlation between variables, while accounting for the statistical non-independence in our data that arises from common descent. The standard parametric phylogenetic approach for measuring the evolutionary correlation between continuously valued characters assumes a model called Brownian motion for the evolution of our traits. Here, we introduce a new semiparametric method that relaxes this assumption by testing for the evolutionary correlation between variables based on contrast ranks, and then obtains a null distribution on the test statistic via random permutation. We show that this approach has reasonable statistical properties: type I error close to the nominal level, and power that is similar to fully parametric methods. We conclude by comparing our new method to related approaches.
Microbial succession at weaning is guided by microbial metabolism of host glycans
Authors: Lubin Jean-Bernard , Planet Paul J. , Silverman Michael A.
Published: February 2025

The weaning transition from a milk-based to a solid-food diet supports critical developmental changes to the intestinal microbiome and immune system. However, the specific microbial and host features that influence microbial succession at weaning are not well understood. Here, we developed a simple approach to investigate the complex dynamics of microbial succession during weaning by co-housing gnotobiotic mice colonized with the defined pre-weaning community PedsCom and the adult-derived consortium OMM12. As expected, co-housing PedsCom mice with OMM12 recapitulated microbial succession at weaning and induced immune system maturation in PedsCom mice. Unexpectedly, we found that the OMM12 microbes with the highest host glycan utilization profiles were the most adept colonizers of PedsCom mice. Genomic analysis confirmed that PedsCom is deficient in the carbohydrate-active enzymes responsible for degrading host-derived glycans, including mucins, compared to adult-derived consortia. We validated a role for glycan utilizationin vivoby demonstrating that the mucus-degrading commensal microbeAkkermansia muciniphilacritically depends on the metabolism of mucin glycans for colonization of PedsCom mice. These findings highlight the importance of host-derived glycans in shaping microbial communities during the weaning transition and suggest host glycans as novel targets to modulate intestinal microbial populations, introduce beneficial probiotics, and enhance immune system development during weaning.