bluuebunny/crossref_metadata_2025 huggingface dataset:
Sociodemographic Inequalities in Heat-Related Mortality across Summer Seasons from 2022 to 2024 in Peru
Authors: Intimayta-Escalante Claudio
Published: February 2025

Aim

To assess sociodemographic inequalities in Heat-Related Mortality (HRM) across Peruvian departments during the summer seasons from 2022 to 2024.

Methods

An ecological study was conducted to analyze excess mortality during the summers of 2022–2023 and 2023–2024 in relation to maximum temperature records across 24 Peruvian departments. Sociodemographic factors, including sex, age group (<60 years or≥60 years), and educational level (elementary or lower vs. higher education), were considered. HRM was estimated for the overall population and stratified by sociodemographic characteristics using Poisson regression models. Inequality in HRM was quantified using the GINI index, where values near 1 indicate absolute inequality, while values closer to 0 suggest greater equality.

Results

A total of 70,832 deaths were analyzed, with 35,268 occurring in the summer of 2022–2023 and 35,564 in 2023–2024. The mean HRM was 29.24%, ranging from 2.26% to 166.67% across 10 departments. Higher HRM values were observed among females (HRM=51.90%), individuals<60 years (HRM=68.63%), and those with higher educational attainment (HRM=62.20%). The overall GINI index for HRM was 0.64, with greater inequality observed among females (GINI=0.38), individuals<60 years (GINI=0.51), and those with higher education levels (GINI=0.47).

Conclusion

Significant sociodemographic inequalities in HRM were observed across Peruvian departments during the summer seasons from 2022 to 2024. The highest inequalities were found among females, individuals<60 years, and those with higher educational attainment.
Long-term survival after invasive pneumococcal disease – a matched cohort study using electronic health records in England
Authors: Suffel Anne , Abdullahi Fariyo , Barry Eleanor , Walker Jemma , Andrews Nick , Amin-Chowdhury Zahin , Ladhani Shamez N , Grint Daniel , McDonald Helen I. , Douglas Ian , Mansfield Kathryn E. , Parker Edward P.K.
Published: February 2025

Background

Invasive pneumococcal disease (IPD) is associated with increased long-term mortality, but it is unclear if this can be explained by pre-existing comorbidities that predispose individuals to pneumococcal infection.

Methods

We conducted a matched cohort study comparing long-term survival (beyond 120 days after infection) in individuals with IPD and comparators without IPD. Cases were individuals in England aged ≥65+ years with laboratory-confirmed IPD (2012–2019) identified through enhanced national surveillance. Comparators matched on age, sex, and calendar date were drawn from primary care electronic health records in Clinical Practice Research Datalink GOLD. We used Cox regression (stratified by matched set) to compare mortality in people with and without IPD, adjusting for relevant comorbidities, deprivation, and ethnicity.

Results

We included 13,401 IPD cases and 67,005 comparators. After adjusting for comorbidities, deprivation, and ethnicity, we found increased all-cause mortality in IPD cases compared to comparators (hazard ratio 3.74, 95% CI: 3.50–3.99). The predicted median survival from adjusted models was 4.7 years (IQR: 2.9-7.4) for IPD cases and >11.9 (IQR : 8.7->11.9) for comparators. This increased mortality was consistent across subgroups defined by age, vaccination history, and comorbidity status (including diabetes, chronic respiratory disease, and chronic heart disease).

Conclusions

IPD was associated with increased mortality at least 5 years after infection. These findings demonstrate the long-term consequences of IPD, emphasising the value of IPD prevention and the need for more research into clinical management of IPD survivors. Long-term mortality should be incorporated in cost–effectiveness analyses for pneumococcal vaccines.

Article summary

Compared to people without infection, people who survived invasive pneumococcal disease in England had a 3.7-fold increase in mortality up to 10 years after infection. This increased mortality remained after accounting for age, sex, underlying comorbidities, deprivation, and ethnicity.
Profiling and Predicting Faculty Assessment Behavior in Surgical Education
Authors: Patel Ranish K. , Jenkins Phillip D , Lee Emily , Nitzkorwski James , Seshadri Ramanathan , Rhee Rebecca , Cook Mackenzie , Shelton Julia , Doberne Julie , Jesneck Jonathan , Thanawala Ruchi
Published: February 2025

Objective

To study and profile the digital assessment behaviors of surgical faculty and residents, and to build a classifier to predict assessment completion, enhancing formative feedback initiatives.

Background

As competency-based paradigms are integrated into surgical training, developing digital education tools for measuring competency and providing rapid feedback is crucial. Simply making assessments available is inadequate and results in disappointingly low user participation. To optimize engagement and efficacy of these tools, user assessment behaviors need to be studied.

Methods

User data was aggregated from a HIPAA-compliant electronic health record (EHR)-integrated medical education platform. Faculty and resident behaviors were analyzed with respect to factors, such as time, day, device type, automated reminders, and EHR integration. A graphical convolutional neural network (GCN) model was trained to predict faculty participation in completing assessments.

Results

10,729 assessments were completed by 254 attendings for 428 residents across 22 institutions, from 2022 to 2024. 86% of assessments were completed by faculty on weekdays, were significantly influenced by automated platform triggers and EHR integration, and distinct faculty behavior profiles contingent upon time to completion and comment length were established. Residents opened assessments at a median of 1.5 hours of faculty assessment completion, with 96% of assessments viewed by 24 hours. The GCN model successfully predicted faculty assessment completion with 93.5% accuracy and an area under the ROC curve of 0.97.

Conclusions

Faculty assessment behaviors represent an actionable bottleneck which can be leveraged to optimize and tailor the design of digital education tools, to enhance formative feedback.
Sexual Initiation and the Timing of First Union among women in Uganda
Authors: Lwanga Charles , Nsimbe Dick , kalule-Sabiti Ishmael , Mangombe Kudzaishe , Otim Jude
Published: February 2025

Summary (Abstract)

The aim of this paper was to examine the socioeconomic correlates of the length of the gap between onset of sex initiation and the age at first union, and also estimate the waiting time to first union after sexual debut. Self-reported data from the individual record file were extracted from the 2016 Uganda Demographic and Health Survey (UDHS), comprising of a subsample of 4293 women aged 15-25. Chi-square tests and the logistic regression of multivariable event history analysis were used to investigate the relationship between socioeconomic factors and the length of the gap. Descriptive findings show that the average and mean waiting time in years is about 5.6 and 5.5 respectively. Age at sexual initiation and current age of the woman were the only significant factors. Women who had their sexual debut before age 15 would take longer to transit to first union and this is perhaps attributed to serial monogamy, and having multiple and concurrent partners which leads to a failure in subsequent union formation. Women aged 20-25 had a disproportionally lower risk of transiting to first union, which is attributed to social development aspects, diverging from earlier thinking that a woman is supposed to either be one’s wife or one’s mother. In conclusion, efforts to address what might influence the length of the gap between sexual union and first union need to take into account the age at sexual debut and the current age of the women.
A within-host birth–death and time–dose–response model for Legionnaires’ disease
Authors: Jamieson Nyall , Charalambous Christiana , Schultz David M. , Hall Ian
Published: February 2025

Understanding the dose–response relationship for infectious diseases is important for quantitative microbial risk assessment studies to mitigate risk. To capture the dose–response dynamics, understanding the pathogenesis of the infectious agent is desirable. Typically, attempting to understand the dose–response dynamics would involve within-host mathematical modelling and fitting dose–response curves to experimental data. No mathematical model exists that describes the within-host dynamics that occur within an individual infected with Legionnaires’ disease. Further, most dose–response models are based either on a single-hit or threshold hypothesis for the cause of illness. Here, we derive a model to explain within-host dynamics post-infection with Legionnaires’ disease that incorporates heterogeneity at the cellular and population levels. We develop a new dose–response model that allows for either of two hypotheses for the cause of illness, adding a new level of flexibility not currently seen in the literature. We extend the dose–response model to incorporate time as we develop a dose-dependent incubation-period model that is based on biological mechanisms. Our within-host models provide an ID50 of between eight and nineLegionellaand median incubation periods close to four days, which is consistent with evidence obtained from animal experiments and human outbreaks in the literature.
GWAS linksAPOEto neuropsychiatric symptoms in mild cognitive impairment and dementia
Authors: Vattathil Selina M. , Blostein Freida , Miller-Fleming Tyne W. , Davis Lea K. ,   Alzheimer’s Disease Genetics Consortium (ADGC),   Alzheimer’s Disease Neuroimaging Initiative, Wingo Thomas S. , Wingo Aliza P.
Published: February 2025

INTRODUCTION

Neuropsychiatric symptoms in dementia (NPS) collectively refer to behavioral and psychological symptoms affecting individuals with mild cognitive impairment (MCI) or Alzheimer’s disease or related dementia (ADRD). NPS are among the most troubling aspects of living with dementia and their treatments have limited efficacy. We aim to investigate genetic variants contributing to NPS to identify new therapeutic targets.

METHODS

We performed a genome-wide association study (GWAS) for nine NPS domains measured by the NPI-Q in 12,800 participants of European ancestry with MCI or ADRD recruited by Alzheimer’s disease research centers across the U.S.

RESULTS

We found genome-wide significant signals for agitation, anxiety, apathy, delusions, and hallucinations in theAPOElocus that were driven by theAPOEε4 allele. We replicated these findings in two independent datasets. Mediation analyses revealed that MCI/ADRD severity only partially mediated the GWAS signals, except for apathy.

DISCUSSION

These findings suggest theAPOEε4 allele influences NPS independently of and beyond its effect on ADRD.
Mammo-Bench: A Large-scale Benchmark Dataset of Mammography Images
Authors: Bhole Gaurav , Suba S , Parekh Nita
Published: February 2025

Breast cancer remains a significant global health concern, and machine learning algorithms and computer-aided detection systems have shown great promise in enhancing the accuracy and efficiency of mammography image analysis. However, there is a critical need for large, benchmark datasets for training deep learning models for breast cancer detection. In this work we developed Mammo-Bench, a large-scale benchmark dataset of mammography images, by collating data from seven well-curated resources,viz., DDSM, INbreast, KAU-BCMD, CMMD, CDD-CESM, DMID, and RSNA Screening Dataset. To ensure consistency across images from diverse sources while preserving clinically relevant features, a preprocessing pipeline that includes breast segmentation, pectoral muscle removal, and intelligent cropping is proposed. The dataset consists of 74,436 high-quality mammographic images from 26,500 patients across 7 countries and is one of the largest open-source mammography databases to the best of our knowledge. To show the efficacy of training on the large dataset, performance of ResNet101 architecture was evaluated on Mammo-Bench and the results compared by training independently on a few member datasets and an external dataset, VinDr-Mammo. An accuracy of 78.8% (with data augmentation of the minority classes) and 77.8% (without data augmentation) was achieved on the proposed benchmark dataset, compared to the other datasets for which accuracy varied from 25 – 69%. Noticeably, improved prediction of the minority classes is observed with the Mammo-Bench dataset. These results establish baseline performance and demonstrate Mammo-Bench's utility as a comprehensive resource for developing and evaluating mammography analysis systems.
A Sensitive Soma-localized Red Fluorescent Calcium Indicator for Multi-Modality Imaging of Neuronal Populations In Vivo
Authors: Zhou Shihao , Zhu Qiyu , Eom Minho , Fang Shilin , Subach Oksana M. , Ran Chen , Alvarado Jonnathan Singh , Sunkavalli Praneel S. , Dong Yuanping , Wang Yangdong , Hu Jiewen , Zhang Hanbin , Wang Zhiyuan , Sun Xiaoting , Yang Tao , Mu Yu , Yoon Young-Gyu , Guo Zengcai V. , Subach Fedor V. , Piatkevich Kiryl D.
Published: February 2025

Recent advancements in genetically encoded calcium indicators, particularly those based on green fluorescent proteins, have optimized their performance for monitoring neuronal activities in a variety of model organisms. However, progress in developing red-shifted GECIs, despite their advantages over green indicators, has been slower, resulting in fewer options for end-users. In this study, we explored topological inversion and soma-targeting strategies, which are complementary to conventional mutagenesis, to re-engineer a red genetically encoded calcium indicator, FRCaMP, for enhancedin vivoperformance. The resulting sensors, FRCaMPi and soma-targeted FRCaMPi (SomaFRCaMPi), exhibit up to 2-fold higher dynamic range and peak ΔF/F0per single AP compared to widely used jRGECO1a in neurons in culture andin vivo. Compared to jRGECO1a and FRCaMPi, SomaFRCaMPi reduces erroneous correlation of neuronal activity in the brains of mice and zebrafish by two- to four-fold due to diminished neuropil contamination without compromising the signal-to-noise ratio. Under wide-field imaging in primary somatosensory and visual cortex in mice with high labeling density (80-90%), SomaFRCaMPi exhibits up to 40% higher SNR and decreased artifactual correlation across neurons. Altogether, SomaFRCaMPi improves the accuracy and scale of neuronal activity imaging at single-neuron resolution in densely labeled brain tissues due to a 2-3-fold enhanced automated neuronal segmentation, 50% higher fraction of responsive cells, up to 2-fold higher SNR compared to jRGECO1a. Our findings highlight the potential of SomaFRCaMPi, comparable to the most sensitive soma-targeted GCaMP, for precise spatial recording of neuronal populations using popular imaging modalities in model organisms such as zebrafish and mice.
Low relative air humidity leads to smaller, denser stomata and higher stomatal ratios in Arabidopsis
Authors: Tulva Ingmar , Jalakas Pirko , Ivandi Elena , Wierzchula Alexander , Obinwanne Patricia Kika , Hõrak Hanna
Published: February 2025

Atmospheric dryness is increasing, bringing about decreases in plant productivity. Stomatal pores mediate plant gas-exchange with the environment, balancing CO2uptake with water loss. Stomatal anatomical and physiological traits respond to changes in environment, potentially affecting plant growth and yield under future environments. Designing stomatal patterns to suit future climate conditions has the potential to improve plant water use efficiency or productivity. By combining mutations in signaling pathways that control stomatal development and apertures, we designed plants that combine high stomatal densities with more open stomata and show that respective mutations independently affect stomatal conductance and density. Analyses of adaxial and abaxial stomatal conductances showed that in Arabidopsis, adaxial stomata are responsible for a significant proportion of leaf gas-exchange. Adaxial and abaxial stomatal physiology were largely similarly affected by mutations in stomatal regulation pathways but adaxial stomata tended to be relatively more closed than abaxial stomata. We show that growth under low relative air humidity leads to higher stomatal densities and smaller stomata. Stomatal development in the adaxial and abaxial leaf surface responded differently to dry air conditions: adaxial stomatal index increased, whereas abaxial stomatal index decreased. Stomatal ratio increased under dry air conditions, leading to a higher degree of amphistomaty. Plant growth was independently suppressed by dry air and high stomatal density and index. Our results suggest that acclimation to decreasing air humidity leads to stomatal anatomical adjustments that help to maximize plant gas-exchange potential under conditions where water supply may be limited and sporadic.
Lack ofAtMC1 catalytic activity triggers autoimmunity dependent on NLR stability
Authors: Salguero-Linares Jose , Armengot Laia , Ayet Joel , Ruiz-Solaní Nerea , Saile Svenja C. , Salas-Gómez Marta , Fernandez Esperanza , Denolf Lode , Navarrete Fernando , Krumbach Jenna , Kaiser Markus , Stael Simon , Breusegem Frank Van , Gevaert Kris , Kaschani Farnusch , Petersen Morten , El Kasmi Farid , Valls Marc , Coll Núria S.
Published: February 2025

Plants utilize cell surface-localized pattern recognition receptors (PRRs) and intracellular nucleotide-binding leucine-rich repeat (NLR) receptors to detect non-self and elicit robust immune responses. Fine-tuning the homeostasis of these receptors is critical to prevent their hyperactivation. Here, we show that Arabidopsis plants lacking metacaspase 1 (AtMC1) display autoimmunity dependent on immune signalling components downstream of NLR and PRR activation. Overexpression of a catalytically inactiveAtMC1 in anatmc1background triggers severe autoimmunity partially dependent on the same immune signalling components. Overexpression of the E3 ligase SNIPER1, a master regulator of NLR homeostasis, fully reverts the AtMC1-dependent autoimmunity phenotype, inferring that a broad defect in NLR turnover may underlie the severe phenotype observed. Catalytically inactiveAtMC1 localizes to punctate structures that are degraded through autophagy. Altogether and considering previous evidence on the proteostatic functions ofAtMC1, we speculate that WtAtMC1 may either directly or indirectly control NLR protein levels, thereby preventing autoimmunity.
DiversePseudomonasspecies engage in beneficial and suppressive interactions with the kiwifruit pathogenPsaacrossActinidiagermplasm
Authors: Patterson Haileigh R. , Hemara Lauren M. , Templeton Matthew D. , Jayaraman Jay
Published: February 2025

In 2010, aPseudomonas syringaepv.actinidiaebiovar 3 (Psa3) incursion into New Zealand kiwifruit orchards devastated susceptibleActinidia chinensiscultivars. In contrast, manyActinidiaspecies maintained in germplasm collections were resistant to Psa3 and showed limited symptoms. Recent genome biosurveillance revealed the emergence of widespread leaf spot symptoms in Psa3-resistantActinidiagermplasm. Surprisingly, few Psa3 isolates were recovered from symptomatic tissues, despite the frequent isolation of phenotypicalPseudomonasisolates on selective agar. Despite the poor recovery of Psa3 isolates, Psa3 was found in all symptomatic leaf tissue through qPCR and metabarcoding analysis. Metabarcoding revealed stark differences in bacterial community composition from samples taken from lesion-carrying or lesion-free material from the same leaf. Host genotype also appeared to influence community composition but to a lesser extent. Whole genome sequencing of diversePseudomonasspp. isolates revealed that many belonged to theP. syringaespecies complex. Curiously, the kiwifruit-associatedP. syringaepv.actinidifoliorum(Pfm), was never recovered, nor were any other phylogroup 1 pathovars. Pathogenicity and competitive assays revealed that while individually diversePseudomonasisolates were not more pathogenic than Pfm or Psa3 on resistantActinidiahosts, they could interact with Psa to sometimes improve their growth, suggesting that these isolates may form pathogenic consortia in these disease-associated phyllosphere communities on typically Psa3-resistant hosts.

Graphical Abstract
Unique Behavior Profiles that Specify Mental Distress in Autism
Authors: Strobl Eric V.
Published: February 2025

Objective

Patients with autism spectrum disorder (ASD) often have difficulty describing their emotions, leaving clinicians to infer mental distress from aberrant behaviors. Unfortunately, aberrant behaviors are non-specific and can differ from those of typically developing peers. However, aberrant behavior profiles (ABPs), or weighted combinations ofmultipleaberrant behaviors, may be specific and recognizable. We thus sought to identify ABPs that correlate with distinct types of mental distress, and also correlate differently in ASD than in typical development (TD).

Method

We integrated three studies that measured diagnostic symptom severity using the Child and Adolescent Symptom Inventory, and aberrant behaviors using the Aberrant Behavior Checklist. We then performed a component analysis to identify maximally non-overlapping severity scores that correlate with ABPs differently in ASD than in TD.

Results

Behaviors associated with impulsivity and distractibility correlated more positively with the severity of specific phobia and social anxiety in ASD than in TD. Hyperactivity and tantrums correlated more positively with attention-deficit hyperactivity disorder and oppositional defiant disorder in ASD than in TD. Emotional reactivity correlated more positively with obsessions and somatization, but social withdrawal and self-injurious behaviors correlated more negatively; the opposite pattern held in a second phenotype of social anxiety. Finally, preoccupation correlated positively with schizophrenia, but depression and inactivity correlated negatively; the opposite pattern held with the severity of post-traumatic stress disorder and a second phenotype of specific phobia.

Conclusion

Patients with ASD (1) externalize more in attention-deficit hyperactivity disorder and oppositional defiant disorder, (2) exhibit unique signs of internal distress in post-traumatic stress and psychosis, and (3) display highly distinct ABPs in specific forms of anxiety.
Increasing severity, importance of viral transmission, and environmental exposures for pediatric asthma in a large urban health system, 2018-2023
Authors: McCuskee Sarah , Kowalski Rishi , Mei Cindy , Zebrowski Alexis , Patel Aman , Zajac Lauren , Zikry Hashem , Ayyash Ali , DeFelice Nicholas
Published: February 2025

Objective

Pediatric asthma is multifactorial: social, environmental, and infectious exposures trigger exacerbations. Policies adopted to mitigate COVID-19 transmission in schools including school closures, mask mandates, and full reopening, provide a natural experiment to investigate the importance of socially-driven exposures, including viral transmission, in pediatric asthma.

Methods

This observational study used retrospective review of all electronic health records from the largest urban health system in New York City over five school years from 2018-2023. We investigated the epidemiology of acute, unscheduled care for pediatric asthma in children ages 5-17 years, including emergency department (ED) visits, hospital admissions, intensive care unit (ICU) stays, and viral testing. Comparison groups were drawn from citywide surveillance data and all-cause visits. We investigated population-level exposures: COVID-19 mitigation policies and wildfire smoke events.

Results

In the post-pandemic period, ED volume for pediatric asthma dropped (p<0.0001); however, children who presented were significantly more likely to require hospital admission and ICU care (p<0.001). Viral testing was employed more frequently, and more frequently positive, in the post-pandemic period (p<0.0001), with rhinovirus driving a greater proportion of pediatric asthma than all-cause adult or pediatric visits (p=0.02). After mask mandates were dropped in early 2022, pediatric asthma peaked during the immediate return-to-school fall period, slightly preceding the winter 2022 peak in viral illnesses. Wildfire smoke events were not significantly associated with pediatric asthma visits.

Conclusions

Socially-driven factors including viral transmission and school policies were important in driving pediatric asthma during and after the COVID-19 pandemic. Increased acuity despite lower volumes may help guide health systems as they strive to increase readiness to care for pediatric populations.
FUS post-transcriptional splicing is autoregulated via RNA condensation with therapeutic potential for ALS-FUS
Authors: Huang Wan-Ping , Kumar Vedanth , Yap Karen , An Haiyan , John Sabin J. , Hodgson Rachel E. , Avila Anna Sanchez , Day Emily , Ellis Brittany C.S. , Chung Tek Hong , Lord Jenny , Müller-McNicoll Michaela , Makeyev Eugene V. , Shelkovnikova Tatyana A.
Published: February 2025

Mutations in theFUSgene cause aggressive and often juvenile forms of amyotrophic lateral sclerosis (ALS-FUS). In addition to mRNA, theFUSgene gives rise to a partially processed RNA with retained introns 6 and 7. We demonstrate that these FUSint6&7-RNAs form nuclear condensates scaffolded by the highly structured intron 7 and associated with nuclear speckles. Using hybridization-proximity labelling proteomics, we show that the FUSint6&7-RNA condensates are enriched in splicing factors and the m6A reader YTHDC1. These ribonucleoprotein structures facilitate post-transcriptional FUS splicing and depend on m6A/YTHDC1 for their maintenance. FUSint6&7-RNAs become hypermethylated in cells expressing mutant FUS, leading to their enhanced condensation and consequently, splicing. We further demonstrate that FUS protein is repelled by m6A. Thus, ALS-FUS mutations may cause an abnormal activation of FUS post-transcriptional splicing via altered RNA methylation. Strikingly, ectopic expression of FUS intron 6&7 sequences dissolves the endogenous FUSint6&7-RNA condensates, downregulating FUS mRNA and protein. Overall, we describe an RNA condensation-dependent mechanism regulating FUS splicing that can be harnessed for developing new therapies.
The 3’ Region of the ZPA Regulatory Sequence (ZRS) is required for activity and contains a critical E-box
Authors: Ball Kathryn F. , Manu Stephen , Underhill Abbie K. , Rudd Sarah R. , Malone Madison M. , Amoah Japhet , Cooper Allen M. , Pira Charmaine U. , Oberg Kerby C.
Published: February 2025

1

Background

During development, Hand2 and Hoxd13 transcription factors (TFs) regulate Sonic hedgehog (Shh) expression in the zone of polarizing activity (ZPA) in the distal posterior limb mesoderm. The ZPA regulatory sequence (ZRS) is a conserved, limb-specific enhancer that controls Shh expression. The ZRS can be divided into 5’, central, and 3’ subdomains, each with an E-box site that can bind basic helix-loop-helix (bHLH) TFs like Hand2. In addition, two Hoxd13 sites are present in the 5’ and central subdomains. Hand2 purportedly binds the ZRS through the central E-box, and both Hand2 and Hoxd13 have been shown to activate the ZRSin vitro. We hypothesized that the central E-box was required for activity, while the other E-boxes and Hoxd13 sites localize ZRS activity to the distal posterior limb mesoderm.

Methods

To identify the functional role of each subdomain, we generated three ZRS fragments (5’, central, and 3’) and combined fragment constructs to test subdomain collective contributions. Additionally, we disrupted the five binding sites, alone or in concert, using site-directed mutagenesis. All ZRS constructs were cloned into a GFP reporter and evaluated in anin vivochicken limb bioassay. We validated our findings using select ZRS constructs in transgenic mice.

Results

We found that the 3’ fragment was necessary for ZRS activity, while the 5’ and central fragments had no activity alone or when combined. However, combining the 3’ fragment with the 5’ fragment restored robust activity. Further, mutation of all five binding sites markedly reduced ZRS activity. Reinstating each of the Hoxd13 sites restored focal activity, while restoring the 5’ and central E-boxes had little effect. However, the 3’ E-box proved sufficient for robust activity even in the absence of the other four binding sites.

Conclusions

Our data indicate that the ZRS 3’, not the central, subdomain is necessary for activity and contains the 3’ E-box that Hand2 likely uses to induce Shh expression, while the 5’ and central E-boxes appear to be inhibitory. Our data also suggest that the Hoxd13 binding sites promote localized activity within the ZPA.
Aerobic exercise decreases the number and transcript expression of inflammatory M1 macrophages and CD8+ T cells in the epicardial adipose tissue of female pigs
Authors: Ahmad Irshad , Gupta Shreyan , Thomas Micah , Cai James J. , Heaps Cristine L. , Newell-Fugate Annie E.
Published: February 2025

Background

Epicardial adipose tissue (EAT) regulates coronary artery function via lipid metabolism and immune cell recruitment. Increased EAT is a risk factor for coronary artery disease (CAD), but aerobic exercise mitigates CAD. The effect of aerobic exercise on immune cells in EAT is unknown. We hypothesized that aerobic exercise creates an anti-inflammatory environment characterized by increased M2 macrophages and up-regulation of anti-inflammatory cytokine transcripts in EAT.

Methods

Female Yucatan pigs (n=7) were allocated to sedentary or exercised groups. To mimic CAD, a coronary artery was chronically occluded or remained non-occluded. EAT samples were processed for bulk and single nuclei transcriptomic sequencing.

Results

Sub-clustering identified immune, endothelial, smooth muscle, adipocytes, adipocyte progenitor cells (APSCs), and neuronal cells, with adipocytes and APSCs being dominant. Non-occluded sedentary EAT had the largest percentage of M1 macrophages and CD8+ T cells. Irrespective of occlusion, sedentary EAT had the largest fraction of cells expressing genes in the tumor necrosis factor (TNF) superfamily. Irrespective of occlusion, exercise upregulated peroxisome proliferator-activated receptor (PPAR) gamma (G) expression and enriched PPAR signaling pathways in adipocytes, macrophages, and T cells. However,PPARGexpression was lowest in CD8+ T cells from non-occluded exercised EAT. The greatest number of significant cell-cell communications between adipocytes and immune cells via growth factors and adhesion molecules occurred in occluded sedentary EAT.

Conclusion

Aerobic exercise mitigates the proinflammatory nature of EAT in CAD via modulation of immune cell subpopulations, decreased TNF superfamily and increasedPPARGgene expression, and decreased growth factor communication between adipocytes and immune cells.
Fmr1KO causes delayed rebound spike timing in mediodorsal thalamocortical neurons through regulation of HCN channel activity
Authors: Ordemann Gregory J. , Lyuboslavsky Polina , Kizimenko Alena , Brumback Audrey C.
Published: February 2025

Background

The neurodevelopmental disorder Fragile X syndrome (FXS) results from hypermethylation of theFMR1gene which prevents FMRP production. FMRP modulates the expression and function of a wide variety of proteins, including voltage-gated ion channels such as Hyperpolarization-Activated Cyclic Nucleotide gated (HCN) channels, which are integral to rhythmic activity in thalamic structures. Thalamocortical pathology, particularly involving the mediodorsal thalamus (MD), has been implicated in neurodevelopmental disorders. MD connectivity with mPFC is integral to executive functions like working memory and social behaviors that are disrupted in FXS.

Methods

We used a combination of retrograde labeling andex vivobrain slice whole cell electrophysiology in 40 wild type and 42Fmr1KO male mice to investigate how a lack ofFmr1affects intrinsic cellular properties in lateral (MD-L) and medial (MD-M) MD neurons that project to the medial prefrontal cortex (MD→mPFC neurons).

Results

In MD-L neurons,Fmr1knockout caused a decrease in HCN-mediated membrane properties such as voltage sag and membrane afterhyperpolarization. These changes in subthreshold properties were accompanied by changes in suprathreshold neuron properties such as the variability of action potential burst timing.

Conclusions

InFmr1knockout mice, reduced HCN channel activity in MD→mPFC neurons impairs both the timing and magnitude of HCN-mediated membrane potential regulation. Changes in response timing may adversely affect rhythm propagation inFmr1KO thalamocortical circuitry. MD thalamic neurons are critical for maintaining rhythmic activity involved in cognitive and affective functions. Understanding specific mechanisms of thalamocortical circuit activity may lead to therapeutic interventions for individuals with FXS.
Characterisation of facial expressions and behaviours of horses in response to positive and negative emotional anticipation using network analysis
Authors: Phelipon Romane , Bertrand Léa , Jardat Plotine , Reigner Fabrice , Lewis Kate , Micheletta Jérôme , Lansade Léa
Published: February 2025

The welfare of an animal is closely linked to their emotional experiences, making it essential to identify reliable indicators of these emotions. This study aimed to identify behaviours and facial movements in horses experiencing contrasting emotional valence, triggered by the anticipation of a positive condition (going to pasture) or a negative condition (going alone to a novel environment). Twenty horses were daily trained to wait in a starting box before being exposed to these two conditions. After one week of positive training or negative training, we analysed horses’ behaviours, cortisol variations, and facial movements while they waited in their starting box. First, we confirmed that the two conditions induced contrasting emotional valence, as evidenced by the shorter time taken to approach in the positive condition compared to the negative, and by the higher maximal heart rate and cortisol variation in the negative condition. Then using the Equine Facial Action Coding System (EquiFACS) and network analysis (NetFACS) we revealed distinct behaviours and facial expression profiles. In positive anticipation, the horses exhibited a greater range of behaviours, including shaking their heads from side to side, stepping back, sniffing, and pawing at the ground. Additionally, two distinct facial expression profiles were identified as specific to positive and negative anticipation. In positive anticipation, the horses displayed a higher neck, accompanied by a greater frequency of half-blinks and mouth movements. Conversely, in negative anticipation, the horses exhibited a medium neck, with ears backward accompanied by more flattened ears and expressed more nostril movements. The findings highlight the importance of these indicators in characterising horses’ emotions and emphasise their significance for assessing equine welfare.
Protein-Like Polymer for Inhibition of Tau Fibril Propagation in Human-Derived Models of Neurodegeneration
Authors: Longhini Andrew P. , Fattah Mara , Sala-Jarque Julia , DuBose Austin , Rivera Erica Keane , Sclafani Olivia R , Zhou Jessica , Anatot Jacqueline E. , Thompson Matthew P. , Unger Matthew T. , Beckett Emily R. , Fagan Colby , Nakamura Dylan , Morimoto Richard I. , Han Songi , Qiao Baofu , Gianneschi Nathan C. , Kosik Kenneth S.
Published: February 2025

The misfolding, aggregation, and spread of tau protein fibrils underlie tauopathies, a diverse class of neurodegenerative diseases for which effective treatments remain elusive. Among these are corticobasal dementia (CBD) and progressive supranuclear palsy (PSP), canonical examples of 4-repeat (4R) tauopathies characterized by tau isoforms exclusively with four microtubule-binding repeat domains. We target this 4R tau isoform-specific mechanism by focusing on misfolded tau’s distinctive stem-loop-stem structural motif formed by the junction of the 4R-defining alternatively spliced exon and the adjacent constitutive exon. A synthetic peptide based on this stem-loop-stem sequence can induce aggregation and spread in an isoform-specific manner. Here, we develop a protein-like polymer (PLP) in which multiple copies of this synthetic peptide form a brush-like structure capable of preventing tau aggregation by binding and capping fibril endsin vitro, in human brain organoids, and in cellular models with an EC50 of 105 ± 14 nM. PLPs demonstrate robust activity against fibrils derived from CBD and PSP patient brains and a PS19 mouse tauopathy model. Previous tau-targeted treatments have primarily focused on broad tau clearance, aggregation inhibition, or microtubule stabilization, often lacking isoform specificity and precision. In contrast, this approach targets the 4R tau isoform’s unique structural motif, offering a tailored therapeutic intervention for diseases like CBD and PSP. Supported by prior studies showing blood-brain barrier penetrance and safety profiles, this tau-binding PLP offers a promising translational path toward clinical applications in tauopathy treatment.
Electric field driven domain wall dynamics in
BaTiO3
nanoparticles
Authors: Liu Jialun , Yang David , Suzana Ana F. , Leake Steven J. , Robinson Ian K.
Published: February 2025

We report a detailed investigation into the response of single BaTiO3 (BTO) nanocrystals under applied electric fields (E-field) using Bragg coherent diffraction imaging. Our study reveals pronounced domain wall migration and expansion of a sample measure under applied electric field. The changes are most prominent at the surface of the nanocrystal, where the lack of external strain allows greater domain wall mobility. The observed domain shifts are correlated to the strength and orientation of the applied E-field, following a side-by-side domain model from Suzana []. Notably, we identified a critical electric field strength of 3 MV/m, which leads to irreversible structural changes, suggesting plastic deformation. The findings highlight how surface effects and intrinsic defects contribute to the enhanced dielectric properties of BTO at the nanoscale, in contrast to bulk materials, where strain limits domain mobility. These findings deepen our understanding of nanoscale dielectric behavior and inform the design of advanced nanoelectronic devices.

Published by the American Physical Society
2025
Atom-wise formulation of the many-body dispersion problem for linear-scaling van der Waals corrections
Authors: Muhli Heikki , Ala-Nissila Tapio , Caro Miguel A.
Published: February 2025

A common approach to modeling dispersion interactions and overcoming the inaccurate description of long-range correlation effects in electronic structure calculations is the use of pairwise-additive potentials, as in the Tkatchenko-Scheffler [] method. In previous work [H. Muhli , ], we have shown how these are amenable to highly efficient atomistic simulation by machine learning their local parametrization. However, the atomic polarizability and the electron correlation energy have a complex and nonlocal many-body character and some of the dispersion effects in complex systems are not sufficiently described by these types of pairwise-additive potentials. Currently, one of the most widely used rigorous descriptions of the many-body effects is based on the many-body dispersion (MBD) model [A. Tkatchenko , ]. In this work, we show that the MBD model can also be locally parametrized to derive a local approximation for the highly nonlocal many-body effects. With this local parametrization, we develop an atomwise formulation of MBD that we refer to as linear MBD (lMBD), as this decomposition enables linear scaling with system size. This model provides a transparent and controllable approximation to the full MBD model with tunable convergence parameters for a fraction of the computational cost observed in electronic structure calculations with popular density-functional theory codes. We show that our model scales linearly with the number of atoms in the system and is easily parallelizable. Furthermore, we show how using the same machinery already established in previous work for predicting Hirshfeld volumes with machine learning enables access to large-scale simulations with MBD-level corrections.

Published by the American Physical Society
2025
Origin of the anomalous Hall effect in Cr-doped
RuO2
Authors: Smolyanyuk Andriy , Šmejkal Libor , Mazin Igor I.
Published: February 2025

RuO2 is one of the most highlighted candidates for altermagnetism. However, the most recent muon spin spectroscopy and neutron studies demonstrated the absence of magnetic order in this system. The electronic structure of RuO2 hints at a possibility of realizing a magnetically ordered state upon hole doping, and such a possibility was explored experimentally in Cr-doped RuO2, where it was suggested that this system exhibits the anomalous Hall effect (AHE) due to altermagnetism. In this paper, based on our density functional calculations, we revise the results obtained for this system and propose a different interpretation of experimental results. Our calculations suggest that extra holes are bound to Cr impurity and do not dope Ru bands, which remain nonmagnetic. Thus, the observed AHE is not due to the altermagnetism but stems entirely from magnetic Cr ions.

Published by the American Physical Society
2025
Variational neural and tensor network approximations of thermal states
Authors: Lu Sirui , Giudice Giacomo , Cirac J. Ignacio
Published: February 2025

We introduce a variational Monte Carlo algorithm for approximating finite-temperature quantum many-body systems, based on the minimization of a modified free energy. This approach directly approximates the state at a fixed temperature, allowing for systematic improvement of the expressiveness without accumulating errors from iterative imaginary-time evolution. We employ a variety of trial states—both tensor networks as well as neural networks—as variational for our numerical optimization. We benchmark and compare different constructions in the above classes, both for one- and two-dimensional problems, with systems made of up to N=100 spins. Our results demonstrate that while restricted Boltzmann machines show limitations, string bond tensor network states exhibit systematic improvements with increasing bond dimensions and the number of strings.

Published by the American Physical Society
2025
Saturable absorption in highly excited laser-irradiated silicon and its suppression at the surface
Authors: Yamada Shunsuke , Otobe Tomohito
Published: February 2025

Nonlinear electronic excitation in laser-irradiated silicon at finite electron temperatures is numerically investigated by first-principles calculations based on the time-dependent density functional theory. In bulk silicon at finite temperatures under near-infrared laser irradiation, we found that the absorbed energy is saturated when using a certain laser intensity even with a few-cycle pulse. Although one-photon processes of conduction-to-conduction and valence-to-valence transitions are dominant at such a laser intensity, the Pauli blocking inhibits further one-photon transition. With higher intensities, multiphoton excitation across the bandgap overwhelms the one-photon excitation and the saturable absorption disappears. At the surface of finite-temperature silicon, the Pauli blocking is suppressed by the symmetry breaking and the absorbed energy is relatively enhanced from the energy of the saturable absorption in the bulk region.

Published by the American Physical Society
2025
T
-odd parton distribution functions and azimuthal anisotropy at high transverse momentum in
p−p
and
p−A
collisions
Authors: Soudi Ismail , Majumder Abhijit
Published: February 2025

Various azimuthal anisotropies (v1,v2,v3,v4), at high transverse momentum (high pT), are shown to arise from the asymmetric scattering of transverse polarized quarks and gluons, arising from unpolarized nucleons (the Boer-Mulders effect) and resulting in unpolarized hadrons (the Collins effect). Combined with the asymmetric scattering of partons from polarization independent but transverse momentum dependent (TMD) distributions, we obtain a possible mechanism to understand the azimuthal anisotropy of hadrons at large transverse momentum observed in p−p collisions. Constraining the ratio of polarization dependent TMD distributions to polarization independent distributions by comparing with the data from p−p collisions, we find that scaling the acquired transverse momentum of the initial state partons from the proton, due to prescattering before the hard interaction, with the length of the nucleus (k⊥2∝A1/3), straightforwardly yields the azimuthal anisotropy at high pT in p−A collisions.

Published by the American Physical Society
2025
Relaxation times for disoriented isospin condensates in high energy heavy ion collisions
Authors: Chabowski Olivia , Kapusta Joseph I. , Singh Mayank
Published: February 2025

Fluctuations between charged and neutral kaons measured by the ALICE Collaboration in Pb-Pb collisions at the CERN Large Hadron Collider (LHC) exceed conventional explanations. Previously it was shown that if the scalar condensate is accompanied by an electrically neutral isospin-1 field then the combination can produce large equilibrium fluctuations where 〈u¯u〉≠〈d¯d〉. Hadronizing strange and antistrange quarks might then strongly fluctuate between charged (us¯ or su¯) and neutral (ds¯ or sd¯) kaons. Here, we estimate the times for the condensates to achieve their equilibrium probability distributions within causal volumes in high energy heavy ion collisions. This is achieved by modeling the temperature dependence of the condensates, mesonic collective excitations, decay rates of the associated fields, and employing the Langevin and Fokker-Planck equations. Within this model, we find that the equilibration times are short compared with the expansion time, making disoriented isospin condensates a viable explanation for the anomalous fluctuations observed at the LHC.

Published by the American Physical Society
2025
Implication of a negative effective range on the
DD¯*
interaction and the nature of
X(3872)
Authors: Shen Yi-Bo , Liu Ming-Zhu , Liu Zhi-Wei , Geng Li-Sheng
Published: February 2025

A recent analysis of the LHCb data [Esposito , ] obtained a sizable negative effective range for the X(3872). This has attracted intensive discussions on whether X(3872) can be deemed as a DD¯* molecular state. This work explicitly demonstrates that the negative effective range of the X(3872) does not contradict the molecular picture, adopting an effective field theory formulation of the DD¯* interaction that can simultaneously reproduce the binding energy and effective range of the X(3872). We elaborate on the implications of the large negative effective range of X(3872) and the small binding energy on the underlying DD¯* interaction. Such results are relevant for a better understanding of hadronic molecules and their binding mechanism.

Published by the American Physical Society
2025
Appraising constrained second-order power corrections in HQET with
Λb→Λclν
Authors: Bernlochner Florian U. , Papucci Michele , Robinson Dean J.
Published: February 2025

We derive the Λb→Λc form factors for the Standard Model and beyond at second order in heavy quark effective theory, applying the recently proposed residual chiral expansion to reduce the set of unknown subsubleading hadronic functions to a single, highly constrained function, that is fully determined by hadron mass parameters at zero recoil. We fit a form factor parametrization based on these results to all available lattice QCD predictions and experimental data. We find that the constrained and predictive structure of the form factors under the residual chiral expansion is in excellent agreement with lattice QCD predictions and experimental data, as well as prior heavy-quark-effective-theory-based fits.

Published by the American Physical Society
2025