bluuebunny/crossref_metadata_2025 huggingface dataset:
Depression and Low Social Support Mediate the Association of Marital Stress and 12-Month Cardiac-Specific Quality of Life in Young Adults With Acute Myocardial Infarction
Authors: Zhu Cenjing , Dreyer Rachel P. , Li Fan , Spatz Erica S. , Caraballo César , Mahajan Shiwani , Raparelli Valeria , Leifheit Erica C. , Lu Yuan , Krumholz Harlan M. , Spertus John A. , D’Onofrio Gail , Pilote Louise , Lichtman Judith H.
Published: February 2025

Objective

This study explored whether and how depression and low social support mediate the association between marital stress and cardiac-specific quality of life (QoL) in young adults (≤55 years) with acute myocardial infarction (AMI).

Methods

Data were obtained from 1593 married/partnered AMI survivors aged 18–55 years enrolled in the VIRGO study (2008–2012). Marital stress (Stockholm Marital Stress Scale) was self-reported at 1 month post-AMI and categorized as absent/moderate or severe. Significant depressive symptoms (Patient Health Questionnaire-9 score ≥10), low social support (ENRICHD Social Support Instrument score ≤3 on ≥2 items and total score ≤18), and cardiac-specific QoL (Seattle Angina Questionnaire) were assessed at 12 months post-AMI. Natural direct effect (NDE) of marital stress and indirect effects (NIE) through depression or low social support and the proportion mediated (PM) were estimated by causal mediation methods with adjustment for baseline QoL and sociodemographic factors.

Results

There was a significant direct effect from severe marital stress to lower cardiac-specific QoL after covariate adjustment (NDE = −4.83, 95% CI = −6.98 to −2.49, p < .001). Categorized depression and low social support mediated 11.5% (NIE = −0.63, 95% CI = −1.15 to −0.10, p = .014) and 13.5% (NIE = −0.69, 95% CI = −1.10 to −0.29, p < .001) of the total effect between marital stress and QoL, respectively. When examined as continuous scores, both mediator effects were of borderline significance (PHQ-9: PM = 38.2%, p = .086; social support: PM = 46.1%, p = .051).

Conclusions

Depression and low social support partially mediated the relationship between marital stress and cardiac-specific QoL, underscoring the need for further exploration of additional mediators to inform more comprehensive secondary prevention strategies.
Adverse Childhood Experiences Influence Longitudinal Changes in Leptin But Not Adiponectin
Authors: Matovic Sara , Rummel Christoph , Neumann Elena , McGrath Jennifer , Gouin Jean-Philippe
Published: February 2025

Objective

Adverse childhood experiences (ACEs) are associated with a greater risk of obesity and cardiometabolic disease. Adipokines, including leptin and adiponectin, play vital roles in biological processes linked to obesity and cardiometabolic risk. The adiponectin/leptin ratio may represent a marker of impaired hormonal regulation of adipose tissue. Prior cross-sectional studies suggest patterns of higher plasma leptin and lower adiponectin among adults who have experienced ACEs. This study addresses whether ACEs influence longitudinal changes in leptin, adiponectin, and the adiponectin/leptin ratio, after accounting for current chronic stress and adiposity.

Methods

This longitudinal study included 192 middle-aged mothers (mean age = 46.78 years) experiencing higher (n = 108) and lower (n = 84) chronic caregiving stress. Adipokines and adiposity were measured at three timepoints: T1 (baseline), T2 (15 months later), and T3 (30 months after T1). ACEs were assessed retrospectively using the Childhood Trauma Questionnaire.

Results

Mixed-effect models showed that leptin and adiponectin increased over time. Greater ACEs exposure was associated with larger increases in leptin over time, but it was not related to adiponectin or the adiponectin/leptin ratio. Current caregiving stress was not related to leptin and adiponectin levels and did not interact with ACEs in predicting adipokine levels. Mediation analyses revealed that increases in waist circumference partially mediated the association between ACEs and increases in leptin over time.

Conclusions

ACEs may increase vulnerability to cardiometabolic risk in midlife caregiving mothers through its influence on longitudinal changes in leptin and central adiposity.
Prognostic Impacts of Depression and Inflammatory Factors in Pancreatic Cancer Patients
Authors: Chen Po See , Shen Yang-Chen , Lin Cheng-Feng , Liu Ping-Yen , Lin Peng-Chan , Su Pei-Fang , Yen Chia-Jui , Shan Yan-Shen
Published: February 2025

Objective

This study explores the potential connections between clinical depression, inflammation, and cancer progression in pancreatic cancer patients.

Methods

Conducted from May 2021 to May 2023 at the National Cheng Kung University Hospital Clinical Data Warehouse, this prospective study involved 279 pancreatic cancer patients. The nine-item self-reported Patient Health Questionnaire (PHQ-9) was used to assess depressive symptoms. The study focused on the correlation between clinically significant depression (PHQ-9 scores >10), levels of inflammatory factors, and patient survival rates.

Results

At the time of diagnosis, 34.0% of the patients exhibited clinically significant depression. Analysis using Fixed Effects in Generalized Linear Mixed Models (GLMM) revealed a notable link between log-transformed C-reactive protein (ln CRP) levels with occurrence of depression (odds ratio [OR] = 1.274, p = .010). Furthermore, a univariate Cox proportional hazard model with time-varying covariates indicated a correlation between clinically significant depression and decreased overall survival (hazard ratio [HR] = 6.245, p < .001). A multivariate Cox model also showed significant associations of both ln CRP levels (HR = 1.966, p = .030) and clinically significant depression (HR = 3.611, p = .028) with survival outcomes.

Conclusions

The findings highlight a complex interplay between inflammation, depression, and survival in pancreatic cancer patients. However, the study is limited by the lack of control over all potential confounders, such as chronic conditions, which could independently influence both depression and inflammatory biomarkers.
Epilepsy Surgery Education: A Survey of US Epilepsy Fellowship Program Directors
Authors: Katyal Roohi , Sheikh Irfan S. , Gutierrez Camilo , Sinha Saurabh R. , Day B. Keith , Gavvala Jay R. , Sheth Sameer A. , Wirrell Elaine , Beniczky Sándor , Nascimento Fábio A.
Published: February 2025

Purpose:

To understand the current state of epilepsy surgery education delivered to epilepsy fellows in the United States.

Methods:

An online survey focused on characteristics of epilepsy surgery education was distributed to all 93 epilepsy fellowship program directors listed on the ACGME website (accessed in May 2022). Programs were stratified per the number of fellows currently enrolled: 0 to 3 (group A) and ≥4 (group B).

Results:

Forty-one of 93 (44%) epilepsy fellowship programs were included in the study. The average number of resective surgeries, ablations, or corpus callosotomies per year was mostly 0 to 30 (54%) in group A and mostly >30 (80%) in group B (P = 0.05). The average number of intracranial implantations per year was mostly 0 to 20 (58%) in group A and mostly >20 (80%) in group B (P < 0.05). The average number of neurostimulation implantations per year was 15 (range 0–90; vagal nerve stimulation), 7 (range 0–25; responsive neurostimulation), and 4 (range 0–10; deep brain stimulation). In 78% of programs, fellows are not required to present a minimum number of epilepsy surgery cases in multidisciplinary conference before graduation. Roughly half of programs (51%) reported not using objective measures to assess fellow competency in epilepsy surgery.

Conclusions:

Our results suggest significant variability in epilepsy surgery volume and, consequently, fellow exposure to surgical cases and lack of standardized, objective measures in fellow teaching and assessment in the field of epilepsy surgery across programs in the United States. We advocate development of a core epilepsy surgery curriculum including minimum standards at the national level.
The combined effects of elevated predation risk and anthropogenic noise on dwarf mongoose vigilance behaviour
Authors: Westover Lucy , Morris-Drake Amy , Layton Megan , Kern Julie M. , Arbon Josh J. , Radford Andrew N.
Published: February 2025

Anthropogenic noise is a pervasive pollutant in the world’s ecosystems, with numerous studies demonstrating negative physiological, developmental and behavioural impacts across taxa. However, research has tended to focus on anthropogenic noise in isolation; many species often experience this pollutant in conjunction with other anthropogenic and natural stressors. Here, we used a field experiment to investigate the combined effects of a sequential elevation in perceived predation risk followed by exposure to road noise on the vigilance behaviour of dwarf mongooses (
Helogale parvula
). As expected, both alarm-call playback (simulating a greater predation risk) and road-noise playback independently led to more vigilance compared to close-call and ambient-sound (control) playbacks, respectively. The two stressors had an equivalent effect on total vigilance, lending support to the risk-disturbance hypothesis. The combination of the two stressors did not, however, generate a significantly different amount of vigilance compared to road-noise playback alone. Thus, our experiment provides further evidence that anthropogenic noise can influence the vigilance–foraging trade-off but no indication of an additive or synergistic effect when combined with the natural stressor of elevated predation risk. Further investigation of combined-stressor effects is critical if we are to understand the true impacts of anthropogenic disturbances on species and communities.
Model-guided gene circuit design for engineering genetically stable cell populations in diverse applications
Authors: Sechkar Kirill , Steel Harrison
Published: February 2025

Maintaining engineered cell populations’ genetic stability is a key challenge in synthetic biology. Synthetic genetic constructs compete with a host cell’s native genes for expression resources, burdening the cell and impairing its growth. This creates a selective pressure favouring mutations which alleviate this growth defect by removing synthetic gene expression. Non-functional mutants thus spread in cell populations, eventually making them lose engineered functions. Past work has attempted to limit mutation spread by coupling synthetic gene expression to survival. However, these approaches are highly context-dependent and must be tailor-made for each particular synthetic gene circuit to be retained. By contrast, we develop and analyse a biomolecular controller which depresses mutant cell growth independently of the mutated synthetic gene’s identity. Modelling shows how our design can be deployed alongside various synthetic circuits without any re-engineering of its genetic components, outperforming extant gene-specific mutation spread mitigation strategies. Our controller’s performance is evaluated using a novel simulation approach which leverages resource-aware cell modelling to directly link a circuit’s design parameters to its population-level behaviour. Our design’s adaptability promises to mitigate mutation spread in an expanded range of applications, while our analyses provide a blueprint for using resource-aware cell models in circuit design.
Mechanics of pressurized cellular sheets
Authors: Chandler Thomas G. J. , Ferria Jordan , Shorthose Oliver , Allain Jean-Marc , Maiolino Perla , Boudaoud Arezki , Vella Dominic
Published: February 2025

Everyday experience shows that cellular sheets are stiffened by the presence of a pressurized gas: from bicycle inner tubes to bubble wrap, the presence of an internal pressure increases the stiffness of otherwise floppy structures. The same is true of plants, with turgor pressure (due to the presence of water) taking the place of gas pressure; indeed, in the absence of water, many plants wilt. However, the mechanical basis of this stiffening is somewhat opaque: simple attempts to rationalize it suggest that the stiffness should be independent of the pressure, at odds with everyday experience. Here, we study the mechanics of sheets that are a single-cell thick and show how a pressure-dependent bending stiffness may arise. Our model rationalizes observations of turgor-driven shrinkage in plant cells and also suggests that turgor is unlikely to provide significant structural support in many monolayer leaves, such as those found in mosses. However, for such systems, turgor does provide a way to control leaf shape, in accordance with observations of curling upon drying of moss leaves. Guided by our results, we also present a biomimetic actuator that uncurls upon pressurization.
Bottom-up robust modelling for the foraging behaviour of
Physarum polycephalum
Authors: Reginato Damiano , Proverbio Daniele , Giordano Giulia
Published: February 2025

The true slime mould
Physarum polycephalum
has the remarkable capability to perform self-organized activities such as network formation among food sources. Despite well reproducing the emergence of slime networks, existing models are limited in the investigation of the minimal mechanisms, at the microscopic scale, that ensure robust problem-solving capabilities at the macroscopic scale. To this end, we develop three progressively more complex multi-agent models to provide a flexible framework to understand the self-organized foraging and network formation behaviours of
Physarum
. The hierarchy of models allows for a stepwise investigation of the minimal set of rules that allow bio-inspired computing agents to achieve the desired behaviours on nutrient-poor substrates. By introducing a quantitative measure of connectedness among food sources, we assess the sensitivity of the model to user-defined and bio-inspired parameters, as well as the robustness of the model to parameter heterogeneity across agents. We ultimately observe the robust emergence of pattern formation, in line with experimental evidence. Overall, our study sheds light on the basic mechanisms of self-organization and paves the way towards the development of decentralized strategies for network formation in engineered systems, focusing on trade-offs between biological fidelity and computational efficiency.
Multiple factors contribute to female dominance in migratory bioflows
Authors: Doyle Toby D. , Poole Oliver M. , Barnes Jaimie Christopher , Hawkes Will Leo S. , Jimenez Guri Eva , Wotton Karl R.
Published: February 2025

Migration is a widely observed phenomenon supported by morphological, physiological and behavioural traits that vary with season and sex in many species. Recently, the genetic components underpinning migration in the marmalade hoverfly (Diptera: Syrphidae) have been unpacked through detection of differentially expressed genes between migrant and non-migrant females. Males also migrate, but changing sex ratios during autumn migration, from around 50% female in northern Europe to around 90% in southern Europe, suggests males are poor long-distance fliers. To elucidate the mechanisms underpinning this sex difference, we performed morphological, physiological and transcriptomic characterization of actively migrating females and males. Both sexes show similar physiological adaptations including hyperphagia and starvation resistance, but females display higher tolerance to cold, have lower wing loading values and display a greater flight capacity. In addition, females modulate the expression of genes involved in immunity, hypoxia and longevity while suppressing hormonal pathways involved in maintaining reproductive diapause. These traits contribute to the success of female migrants and underlie the diminishing pool of males, influencing population dynamics across huge geographic areas and through the whole migratory and overwintering period.
An odorant-binding protein functions in fire ant social immunity interfacing with innate immunity
Authors: Zhang Wei , Chen Xuanyu , Tian Jiaxin , Schal Coby , Mohamed Amr , Zang Lian-Sheng , Xia Yuxian , Keyhani Nemat O.
Published: February 2025

Social immunity-mediated sanitation behaviours occur in insects when microbially killed corpses are removed and/or dismembered by healthy nestmates. However, little is known concerning the chemical signals or receptor proteins that mediate these responses. Here, we identify cuticular components in the eusocial red important fire ant,
Solenopsis invicta
: behenic acid, which induces dismemberment behaviour, and oleic and
cis
,
cis
-9,12-linoleic acids, which inhibit dismemberment in a process mediated by
S. invicta
odorant-binding protein-15 (SiOBP15). Yeast two-hybrid screening and protein–protein interaction analyses identified the ant immunity-related proteins apolipophorin-III (SiApoLp-III) and fatty acid binding protein-5 (SiFABP5) as SiOBP15 interacting partners. SiOBP15 and SiFABP5 bound all three dismemberment-related compounds, whereas interactions between SiOBP15 and SiApoLp-III narrowed binding to behenic acid. RNAi-mediated gene expression knockdown of
SiOBP15
,
SiApoLp-III
or
SiFABP5
revealed that behenic acid chemoreception determines dismemberment behaviour via SiApoLp-III/SiOBP15, whereas SiOBP15 or SiOBP15/SiFABP5 recognition of linoleic acid inhibits dismemberment behaviour. These data identify a host circuit linking olfactory proteins and proteins involved in innate immunity to control the degree of sanitation behaviour elicited in response to microbial infection. We identify specific chemical cues transduced by these proteins, providing a mechanism connecting olfaction-related processes to innate immunity, host–pathogen interactions and social immunity.
Experimental assessment of dry water materials for inhibiting explosion under the coal gasification atmosphere
Authors: Liang Guangqian , Luo Peikai
Published: February 2025

This study focused on the inhibitory effects of dry water materials on the coal dust explosion characteristics in the coal hydrogenation process by adopting a 20 l explosion device. Additionally, the inhibitory effects of dry water material were compared with SiO
2
and NH
4
H
2
PO
4
. The results showed that 10 wt% dry water materials notably delay the arrival time of the peak explosion pressure, significantly inhibiting the initial energy release during the explosion, resulting in the maximum rate of explosion pressure rise decreasing by 61.96%. As the dry water material adds up to 50 wt%, the maximum explosion pressure significantly reduced to 0.258 MPa and delayed by 431.1 ms. The flame propagation velocity reduced from 2.19 to 0.33 m s
-1
. In addition, dry water material, with its excellent heat absorption and adsorption and isolation properties, had more significant inhibitory effects than SiO
2
and NH
4
H
2
PO
4
.
Does biofluorescence enhance visual signals in birds-of-paradise?
Authors: Martin Rene P. , Carr Emily M. , Sparks John S.
Published: February 2025

Visual signals are important for mediating numerous behaviours in organisms. Frequently, brightly coloured feathers are used in signalling during reproductive behaviours in birds. Furthermore, an increasing number of studies have documented the additional use of biofluorescence as a visual cue. We investigate the presence of fluorescence in all 45 species of birds-of-paradise (Paradisaeidae), a group where males exhibit elaborate feather morphology, coloration, and mating displays. We show that all core birds-of-paradise are biofluorescent (37 species representing 14 of 17 genera); all genera except
Lycocorax
,
Manucodia
and
Phonygammus
, which comprise the sister group to the core birds-of-paradise. In males, biofluorescence occurs on plumage and skin used in reproductive displays. Biofluorescent regions vary among species but include the inner mouth and bill, as well as feathers on the head, neck, belly and plumes. In females, biofluorescence is usually restricted to plumage on the chest and belly. Emitted biofluorescent wavelengths are green and green-yellow, with emission peaks around 520 and 560 nm. Using an established framework of criteria for determining the functional role of biofluorescence in communication, our results provide evidence that within core birds-of-paradise, males likely utilize biofluorescence to enhance visual cues used during male hierarchy and mating displays.
Using mobile eye tracking to study dogs’ understanding of human referential communication
Authors: Völter Christoph J. , Gerwisch Karoline , Berg Paula , Virányi Zsófia , Huber Ludwig
Published: February 2025

The extent to which dogs understand human referential communication is among the most studied questions in canine cognition research. While it is widely accepted that dogs follow (some) human referential signals, the way they understand them remains controversial. Here, we applied mobile eye tracking with dogs to investigate during real-world interactions how ostensive pointing and gaze cues direct dogs’ visual attention and bias their subsequent choices in an object-choice task. We addressed the question of whether dogs would exhibit a greater response to referential communication compared with other directional cues. Five conditions were tested (pointing, pointing + gazing, gazing, fake throwing and no-cue control), each cue condition indicating the location of a hidden food reward. Results demonstrated that the combination of pointing and gazing significantly increased dogs’ attention towards the designated referent. In pointing + gazing, dogs maintained longer attention on the referent compared with other conditions and they approached it significantly above chance levels. While the alternative cue (fake throwing) moved the dogs’ gaze to the indicated direction, it did not increase the frequency of gaze shifts to the precise referent location. Our findings highlight that the joint use of pointing and gazing is a particularly effective method for directing dogs’ attention to a referent.
Resting calcium ion fluxes protect cells from fast mitochondrial fragmentation, cell stress responses, and immediate transcriptional reprogramming
Authors: Fecher Caroline , Sodmann Annemarie , Schlott Felicitas , Jaepel Juliane , Schmitt Franziska , Lengfelder Isabella , Bischler Thorsten , Nieswandt Bernhard , Winklhofer Konstanze F. , Blum Robert
Published: February 2025

Homeostatic calcium ion (Ca2+) fluxes between the endoplasmic reticulum, cytosol, and extracellular space occur not only in response to cell stimulation but also in unstimulated cells. Using murine astrocytes as a model, we asked whether there is a signaling function of these resting Ca2+-fluxes. The data showed that endoplasmic reticulum (ER) Ca²⁺ depletion, induced by sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase (SERCA) inhibition, resulted to prolonged Ca²⁺ influx and mitochondrial fragmentation within 10 to 30 minutes. This mitochondrial fragmentation could be prevented in Ca2+- free medium or by inhibiting store-operated Ca2+entry (SOCE). Similarly, attenuation of STIM proteins, which are vital ER Ca2+sensors, protected mitochondrial morphology. On the molecular level, ER Ca2+depletion, achieved either by removing extracellular Ca2+or through acute SERCA inhibition, led to changes in gene expression of about 13% and 41% of the transcriptome within an hour, respectively. Transcriptome changes were associated with universal biological processes such as transcription, differentiation, or cell stress. Strong increase in expression was observed for the transcription factor ATF4, which is under control of the kinase PERK (EIF2AK3), a key protein involved in ER stress. Corroborating these findings, PERK was rapidly phosphorylated in Ca2+-free medium or after acute pharmacological inhibition of SOCE. In summary, resting, homeostatic Ca2+fluxes prevent immediate- early cell stress and transcriptional reprogramming.
Short- and long-term effects of uterine disease on oocyte developmental capacity in postpartum dairy cows
Authors: Caldeira M. O. , McDonald K. S. , Martinez E. S. M. , Moraes J. G. N. , Sellmer Ramos I. , Poock S. E. , Ortega M. S. , Lucy M. C.
Published: February 2025

The hypothesis was that early postpartum uterine disease would reduce the developmental capacity of oocytes thus contributing to the reduced fertility of dairy cows with uterine disease. Dairy cows were diagnosed healthy or with metritis at 7 to 10 d postpartum. The reproductive tract was collected at approximately 1 mo (Exp. 1) or approximately 80 or 165 d (Exp. 2) postpartum for the collection of cumulus-oocyte complexes (COC). The COC were matured, co- incubated with sperm for fertilization, and cultured to the blastocyst stage (8 d) in vitro. For Exp.1, the disease diagnosis (healthy or metritis) did not affect the number of collected COC or the subsequent embryo development to the blastocyst stage. The presence of purulent material in the uterine lumen (endometritis) at time of oocyte collection, however, was associated with a reduced cleavage rate evaluated 3 d following fertilization. For Exp. 2, there was no effect of disease diagnosis (healthy or metritis) on the number of COC or their subsequent development. Reduced cleavage rates were observed in COC retrieved from cows slaughtered at 80 d postpartum, but not at 165 d postpartum, and this reduction was associated with a vaginal microbiome indicative of uterine disease at 4 to 5 wk postpartum. Regression analyses that included plasma haptoglobin or energy metabolite concentrations or uterine bacterial genera abundance did not explain a large percentage of the variation in oocyte development in vitro. We conclude that there is an effect of uterine disease at one month postpartum on the oocyte and its capacity for development (Exp. 1) and this effect may be present at 80 d postpartum (Exp. 2). In later postpartum cows (165 d postpartum; Exp. 2) there was no effect of uterine disease on in vitro oocyte development.

GRAPHICAL ABSTRACT

HIGHLIGHTS

Oocytes collected at 1 month postpartum from dairy cows with endometritis (purulent uterine lumen) had a lower cleavage rate following in vitro fertilization when compared with oocytes collected from healthy cows (Exp. 1).

Oocytes collected at approximately 80 d postpartum from dairy cows with evidence of uterine disease at 4 to 5 wk postpartum had a lower cleavage rate following in vitro fertilization but this disease-associated difference was not observed when oocytes were collected from cows later postpartum (approximately 165 d postpartum; Exp. 2).

Regardless of the study (Exp. 1 or 2), uterine disease primarily affected the percentage of oocytes that cleaved after fertilization.

Statistical associations between circulating metabolites or relative abundance of uterine bacteria were either not significant or explained only a small percentage of the variation in the in vitro embryo development in either experiment.
Unravelling Sex Differences in the Genetic Architecture of Anxiety: A Genome-Wide Association Study in the UK Biobank
Authors: Hu Jihua , Lupton Michelle K. , Byrne Enda M. , Martin Nicholas G. , Whiteman David C. , Olsen Catherine M. , Thomas Jodi T. , Medland Sarah E. , Grasby Katrina L. , Mitchell Brittany L.
Published: February 2025

Background

Anxiety disorders show striking sex differences in prevalence, symptoms, and clinical characteristics, shaping how they manifest and are experienced.

Methods

This study investigated the genetic basis of these differences using sex-specific genome-wide association studies (GWAS). GWAS were conducted separately in females (47,054 cases, 57,027 controls) and males (23,819 cases, 55,030 controls) within the UK Biobank. Functional annotation, sex-specific polygenic scores (PGS), and genetic correlations were performed to assess genetic differences and functional implications.

Results

In females, 10 lead SNPs were significantly associated with anxiety, compared to four in males. Among these, three lead SNPs in females and two in males demonstrated significantly different effect sizes across sexes. In addition, SNP-based heritability estimates were significantly different and gene-based tests and functional prioritization identified different genes associated with anxiety in females and males. However, whole-genome analyses, including genetic correlations across sexes and PGS predictions, revealed no significant genetic differences between the sexes. Sex combined GWAS of several traits showed a trend toward sex differences with anxiety in genetic correlation analysis. Sex-specific GWAS on waist-to-hip ratio (WHR) adjusted for BMI enabled separate genetic correlation analyses with anxiety, revealing significant sex differences that were not observed in the combined GWAS.

Conclusions

This study is the first sex-specific GWAS of anxiety. While the overall genetic architecture of anxiety is largely shared between sexes, our findings reveal distinct sex-specific genetic associations and correlations, highlighting the value of analysing the sexes separately to uncover genetic signals that may be masked in sex-combined samples.
MilkOligoCorpus: a semantically annotated resource for knowledge extraction on mammalian milk oligosaccharides
Authors: Rumeau Mathilde , Courtin Marine , Bossy Robert , Sauvion Clara , Loux Valentin , Ba Mouhamadou , Knudsen Christelle , Combes Sylvie , Nédellec Claire , Deléger Louise
Published: February 2025

Milk oligosaccharides are bioactive components that regulate the composition of the neonatal microbiota and exert immunomodulatory functions. Their beneficial effects depend on their structure. Numerous studies have shown intra- and inter-species variation in the structural composition and concentration of these compounds in mammalian milk, yet the biological significance of such variation remains poorly understood. Automated natural language processing methods are promising tools for extracting and gathering structured data from unstructured texts to get insight into the biological significance of milk oligosaccharide variation across mammals. These methods require training and evaluation on manually annotated text corpora. While annotated corpora exist for chemical substances, none are specifically designed for training natural language processing models to extract information on milk oligosaccharides.

To this end, we propose MilkOligoCorpus, a new gold standard for milk oligosaccharide composition in mammalian species. MilkOligoCorpus’ annotation scheme is a rich entity/relation model designed to describe the diversity pattern of milk oligosaccharides according to female factor variability and to help better understand the structure-related function of milk oligosaccharides. MilkOligoCorpus consists of 30 PubMed texts fully annotated with entities related to individuals, samples, oligosaccharides and oligosaccharide quantification linked by binary and n-ary relationships. To address data interoperability across disparate publications and databases, four terminological resources were also developed to assign unique identifiers to the entities, supported by external ontologies.

This paper presents the creation of the MilkOligoCorpus and its associated schema, along with the development of annotation guidelines and terminological resources. We also present experimental results obtained by baseline information extraction models on the corpus.
Integrating Natural Language Processing to Assess Effect of Loneliness and Social isolation on Cognitive Decline in Dementia: A Retrospective Cohort Analysis
Authors: Myers James , Stafford Tom , Koychev Ivan , Perneczky Robert , Bandmann Oliver , Vaci Nemanja
Published: February 2025

INTRODUCTION

The study aimed to compare cognitive trajectories between patients with reports of social isolation and loneliness and those without.

METHODS

Reports of social isolation, loneliness, and Montreal Cognitive Assessment (MoCA) scores were extracted from dementia patients’ medical records using Natural Language Processing models and analysed using mixed-effects models.

RESULTS

Lonely patients (n = 382) showed lower MoCA scores throughout the disease (B = - 0.83, t = −2.64, p = 0.008). Socially isolated patients (n = 523) experienced faster cognitive decline six months before diagnosis (B = −0.21, t = −2.18, p = 0.029), but were comparable to controls (n = 3912) before this period. This led to lower MoCA scores at diagnosis (B = −0.69, t = −2.53, p = 0.011) and in later stages.

DISCUSSION

Lower cognitive levels in lonely and socially isolated patients suggest that these factors may contribute to dementia progression.
Ethical and Social Considerations of Applying Artificial Intelligence in Healthcare; a Two-Pronged Scoping Review
Authors: Ratti Emanuele
Published: February 2025

Background

Artificial Intelligence (AI) is being designed, tested, and in many cases actively employed in almost every aspect of healthcare from primary care to public health. It is by now well established that any application of AI carries an attendant responsibility to consider the ethical and societal aspects of its development, deployment and impact. However, in the rapidly developing field of AI, developments such as machine learning, neural networks, generative AI, and large language models have the potential to raise new and distinct ethical and social issues compared to, for example, automated data processing or more ‘basic’ algorithms.

Methods

This article presents a scoping review of the ethical and social issues pertaining to AI in healthcare, with a novel two-pronged design. One strand of the review (SR1) consists of a broad review of the academic literature restricted to a recent timeframe (2021-23), to better capture up to date developments and debates. The second strand (SR2) consists of a narrow review, limited to prior systematic and scoping reviews on the ethics of AI in healthcare, but extended over a longer timeframe (2014-2024) to capture longstanding and recurring themes and issues in the debate. This strategy provides a practical way to deal with an increasingly voluminous literature on the ethics of AI in healthcare in a way that accounts for both the depth and evolution of the literature.

Results

SR1 captures the heterogeneity of audience, medical fields, and ethical and societal themes (and their tradeoffs) raised by AI systems. SR2 provides a comprehensive picture of the way scoping reviews on ethical and societal issues in AI in healthcare have been conceptualized, as well as the trends and gaps identified.

Conclusion

Our analysis shows that the typical approach to ethical issues in AI, which is based on the appeal to general principles, becomes increasingly unlikely to do justice to the nuances and specificities of the ethical and societal issues raised by AI in healthcare, as the technology moves from abstract debate and discussion to real world situated applications and concerns in healthcare settings.
Human genomic regions of systemic interindividual epigenetic variation are implicated in neurodevelopmental and metabolic disorders
Authors: Chang Wen-Jou , Maduranga Uditha , Gunasekara Chathura J. , Yang Alan , Hirschtritt Matthew , Rodriguez Katrina , Coarfa Cristian , Jun Goo , Hanis Craig L. , Flanagan James M. , Gorlov Ivan P. , Amos Christopher I. , Wiemels Joseph L. , Schaefer Catherine A. , Susser Ezra S. , Waterland Robert A.
Published: February 2025

Abstract

Epigenome-wide association studies (EWAS) profile DNA methylation across the human genome to identify associations with diseases and exposures. Most employ Illumina methylation arrays; this platform, however, under-samples interindividual epigenetic variation. The systemic and stable nature of epigenetic variation at correlated regions of systemic interindividual variation (CoRSIVs) should be advantageous to EWAS. Here, we analyze 2,203 published EWAS to determine whether Illumina probes within CoRSIVs are over-represented in the literature. Enrichment of CoRSIV-overlapping probes was observed for most classes of disease, particularly for neurodevelopmental disorders and type 2 diabetes, indicating an opportunity to improve the power of EWAS by over 200- and over 100-fold, respectively. EWAS targeting all known CoRSIVs should accelerate discovery of associations between individual epigenetic variation and risk of disease.
High Tau Expression Correlates with Reduced Invasion and Prolonged Survival in Ewing Sarcoma
Authors: Cidre-Aranaz Florencia , Magrin Claudia , Zimmermann Malenka , Li Jing , Baffa Anna Lisa , Ciccaldo Matteo , Hartmann Wolfgang , Dirksen Uta , Sola Martina , Paganetti Paolo , Grünewald Thomas G P , Papin Stéphanie
Published: February 2025

The microtubule-associated protein Tau (encoded by theMAPTgene) is linked to a family of neurodegenerative disorders defined as tauopathies, which are characterized by its brain accumulation in neurofibrillary tangles and neuropil threads. Newly described Tau functions comprise DNA protection, chromatin remodeling, p53 regulation and cell fate modulation, suggesting a role of Tau in oncogenesis. Bioinformatic-supported characterization of Tau in cancer reveals robust expression in bone cancer cells, in particular Ewing sarcoma (EwS) cell lines. EwS is an aggressive cancer caused by a fusion of members of theFETandETSgene families, primarilyEWSR1::FLI1. Here we found thatMAPTis a EWSR1::ETS target gene and that higher Tau expression in EwS cells inhibited their migratory and invasive behavior, consistent with a more immobile and proliferative phenotype observed in EwS. Indeed, we report that high Tau expression is associated with improved overall survival of EwS patients. We also show that the sessile but proliferative phenotype of EWSR1::ETS-high cells may result from a modulatory role of Tau on focal adhesion to extracellular matrix proteins. Our data highlight the utility of determining Tau expression as a prognostic factor in EwS as well as the opportunity to target Tau expression as an innovative EwS therapy.
Precise engineering of chimeric antigen receptor expression levels defines T cell identity and function
Authors: Ramos Andrew S. , Simon Sylvain , Siller-Farfan Jesus , Rajan Anusha , Revale Santiago , Zanchini di Castiglionchio Elena , Pelea Oana , Fulga Tudor A. , Riddell Stanley , Dushek Omer , Michaels Yale S. , Sauka-Spengler Tatjana
Published: February 2025

Chimeric Antigen Receptor (CAR) T therapy is a potent treatment for haematological malignancies, but T cell exhaustion reduces its efficacy in many patients. Although high CAR transgene levels appear to drive T cell exhaustion, the relationship between CAR expression levels, T cell function, and transcriptional identity is yet to be mapped at high resolution. Here, we harness a high-resolution microRNA-based control system to precisely modulate CAR transgene expression levels and assess the impact on T cell activation, gene expression and function. By post-transcriptionally modulating CAR abundance, we show that differential CAR levels significantly impact T cell proliferation, cytokine production and tonic signalling. T cells with high CAR expression become strongly activated even at low target antigen densities, while those with low CAR expression are triggered only by high concentrations of their target. Single-cell RNA sequencing of primary T cells expressing a broad range of CAR transcript levels revealed global transcriptional programmes that become dysfunctional with increased CAR abundance, expanding our understanding of T cell exhaustion. Notably, we identified a narrow CAR expression range where the exhaustion transcriptional state is not triggered, demonstrating that T cell exhaustion can be controlled by fine-tuning CAR levels. This work demonstrates that CAR expression levels are key determinants of T cell transcriptional identity and function and introduces a tractable method to precisely tune CAR expression and T cell activity.
High density probes reveal medullary seizure and rapid medullary shutdown in a model of fatal apnea in seizure
Authors: Budde Ryan , RoaFiore Laura , Irazoqui Pedro
Published: February 2025

Objective

Sudden unexpected death in epilepsy (SUDEP) is suggested to be a cardiorespiratory collapse that occurs shortly after a seizure. Prior work in rats suggests that reflexive apneas (produced by stimulation of trigeminal or vagal peripheral sensory targets) is highly fatal during seizure but well tolerated otherwise. These reflexes share network connectivity in the medulla, particularly the caudal solitary nucleus (NTS) and ventral respiratory column (VRC), and possibly other intermediate structures. We sought to observe the electrographic activity in these regions.

Methods

We use urethane anesthetized long evans rats. We utilized either 125μm silver wire in the caudal NTS or a Neuropixel 1.0 probe along a dorsoventral trajectory that spanned the caudal NTS to the VRC. We additionally recorded cardiorespiratory activity via several methods. We induced a reflexive apnea – the diving reflex – by nasal irrigation of cold water for several seconds, which produces a period of apnea, then gasping, and then a gradual return to eupnea. We repeated several trials while the animal was healthy and subsequently induced continuous seizure activity with kainate and repeated the reflexes, which are ultimately fatal during seizure.

Results

Seizure activity confounds many established methods of analyzing high-density single unit data such as provided by Neuropixels probes, and so our analyses focus on averaging responses over larger anatomical regions (120μm) covering small populations of neurons. Seizure produces broad increases in neuronal activity across the medullary tract, which by itself is not dangerous. Ictal reflexive apneas were broadly more inhibitory (producing a reduction in firing rate) than they were preictally, and fatal ictal responses resulted in a very rapid shutdown of all medullary activity. We only rarely observed ictal central apneas (apneas with no apparent stimuli), but when we did they were apparently safe, always survived, and produced no significant change in network activity (neither increase nor decrease).

Conclusions

These data support the theory that central apnea events in seizure are relatively safe as we observed they produce little change in the medullary tract network, while stimuli-induced-reflexive-apneas are dangerous because they produce profound quieting across respiratory centers. Our data suggest that seizure spreads to this medullary tract at approximately the same rate and intensity as forebrain, as previously described in this model. These data are supportive of SUDEP mechanisms involving brainstem inhibition as a primary cause, such as spreading depolarization waves. These findings likely extend beyond nasal irrigation to any sensory reflexive apnea caused by airway irritation of any kind, and may bear relevance to similar deaths seen in infants.
Genome-wide association study of susceptibility to acute respiratory distress syndrome
Authors: Guillen-Guio Beatriz , Suarez-Pajes Eva , Tosco-Herrera Eva , Hernandez-Beeftink Tamara , Lorenzo-Salazar Jose Miguel , Chang Diana , González-Montelongo Rafaela , Rubio-Rodríguez Luis A. , Leavy Olivia C. , Allen Richard J. , Corrales Almudena , Cruz Raquel , Bardají-Carrillo Miguel , Carracedo Angel , Tamayo Eduardo , Kerchberger V. Eric , Ware Lorraine B. , Yaspan Brian L. , Scholz Markus , Scherag André , Villar Jesús , Wain Louise V. , Flores Carlos
Published: February 2025

Introduction

Acute respiratory distress syndrome (ARDS) is a severe inflammatory process of the lung, often due to sepsis, and poses significant mortality burden in intensive care units. Here we conducted the largest genome-wide association study (GWAS) of sepsis-associated ARDS to identify novel genetic risk loci that can help guide the development of new therapeutic options.

Methods

We performed a case-control GWAS in 716 patients with sepsis-associated ARDS and 4,399 at-risk sepsis controls from three independent studies. Results were meta-analysed across the three studies, with significance set atp<5×10-8. Suggestive associations were declared for variants exhibiting consistent effects, likely to replicate and nominal significance (p<0.05) in all three studies. Prioritised loci were subjected to Bayesian fine mapping,in-silicofunctional assessments, and gene-based rare variant collapsing analysis using whole exome sequencing (WES) data. Two independent studies with 430 ARDS cases and 1,398 controls served as replication samples.

Results

We identified a variant showing genome-wide significant association with sepsis-associated ARDS risk intergenic toANKRD31andHMGCR, previously linked to cholesterol metabolism. Suggestive associations were found for eight other variants. The rare exonic variant analysis showed associations betweenHMGCRandPOC5and sepsis-associated ARDS at nominal level (p<0.05). While no nominal significance was achieved in the two additional validation cohorts, three variants exhibited a consistent direction of effects across all 5 studies.

Conclusion

A common variant intergenic toANKRD31andHMGCRwas associated with sepsis-associated ARDS risk, suggesting a link between cholesterol metabolism and ARDS risk. Validation in independent studies is needed.
The Link to Oxidative Metabolism Varies across rs-fMRI Metrics: A Whole-Brain Assessment Using Macrovascular Correction
Authors: Zhong Xiaole Z. , Van Lankveld Hannah , Chen J. Jean
Published: February 2025

One of the major obstacles to the clinical application of resting-state functional magnetic resonance imaging (rs-fMRI) is the complex nature of its measurements, which limits interpretability. An approach to enhance the interpretability of the rs-fMRI metrics is to link them to more fundamental brain physiology, especially cerebral metabolism. Previous studies have established associations between glucose metabolism (CMRglu) and rs-fMRI measurements. In spite of this, oxidative metabolism (CMRO2) is more closely related to cerebral blood flow (CBF) and thus the BOLD signal, and its relationship with CMRgluis complex. Additionally, most currently published rs-fMRI metrics are uncorrected for macrovascular contribution, which may obscure the neuronal contributions. In this study, we measured resting CMRO2(along with the oxygen extraction fraction, OEF and cerebral blood flow, CBF) using gas-free calibrated fMRI. We used linear mixed-effects (LME) models to examine associations between CMRO2and various rs-fMRI metrics before and after macrovascular correction. We found that: 1) significant associations exist between CMRO2and multiple rs-fMRI metrics, with the strongest association found for the global functional density (gFCD) and the weakest for seed-based functional connectivity (FC); 2) associations with rs-fMRI metrics also varied for OEF and CBF; 3) significant sex differences were observed in the above associations; 4) the use of macrovascular correction substantially strengthened the goodness fit of all LME models examined. This latter improvement further validates the use of macrovascular correction in rs-fMRI. These results provide a framework for linking rs-fMRI metrics to fundamental brain physiology, thus improving interpretability of rs-fMRI measurements. This is the first study to formally link whole-brain MRI-based baseline CMRO2and rs-fMRI metrics, and helps to push the envelope for rs-fMRI in future clinical applications.