bluuebunny/crossref_metadata_2025 huggingface dataset:
Glucocerebrosidase Deficiency Dysregulates Human Astrocyte Lipid Metabolism
Authors: Tahanis Aboud , Nguyen Thao , Oji Suki , Martinez de Kraatz Marisela , Jayasi Jazmine , Anderson Morgan , Krencik Robert
Published: January 2025

Background: Deficiency in the lysosomal enzyme, glucocerebrosidase (GCase), caused by mutations in the GBA1 gene, is the most common genetic risk factor for Parkinson's disease (PD). However, the consequence of reduced enzyme activity within neural cell sub-types remains ambiguous. Thus, the purpose of this study was to define the effect of GCase deficiency specifically in human astrocytes and test their non-cell autonomous influence upon dopaminergic neurons in a midbrain organoid model of PD. Methods: Wild-type (GBA+/+), N370S mutant (GBA+/N370), and GBA1 knockout (GBA-/-) astrocytes were rapidly and directly induced from human pluripotent stem cells (hPSCs) via transcription factor-based differentiation. These astrocytes were extensively characterized for GCase-dependent phenotypes using immunocytochemistry, organoid coculture, enzymatic assays, lipid tracers, transcriptomics, and lipidomics. Results: hPSC lines were rapidly induced into astrocytes and enzymatic assays confirmed that GBA-/- astrocytes completely lacked GCase activity, while GBA+/N370 preserved partial activity. GBA-/-, but not GBA+/N370S, exhibited lysosomal alterations, with enlarged lysosomes and glucosylceramide (GlcCer) accumulation. GCase deficiency also exacerbated TNF-alpha-induced secretion of the inflammatory biomarker, CCL2. In midbrain organoids, GCase activity did not modulate the ability of astrocytes to support dopamine neuron production and survival. Lipidomics revealed a GBA-/--specific increase in sphingomyelin, and a decrease of triglycerides. Direct rescue of GCase activity with GBA1 mRNA treatment reduced GlcCer accumulation. Astrocytes exhibited a relatively high uptake and storage of fatty acid analogs as lipid droplets, in comparison to neurons, and this process was impaired in GBA-/- astrocytes. Lastly, GBA-/- astrocytes accumulate neuronal membrane-derived GlcCer. These findings highlight the critical role of astrocytic GCase in lipid metabolism and its neuronal influence. Conclusion: GCase deficiency does not inhibit human astrocyte differentiation nor cause a non-cell autonomous neurotoxic effect upon dopaminergic neurons within midbrain organoids. However, it does elicit enhanced inflammatory reactivity, accumulation of GlcCer, and a distinct lipidomic profile, indicating impaired lipid metabolism in astrocytes that can dysregulate neuron-astrocyte intercellular signaling. Overall, these insights underscore dysfunctional astrocyte lipid metabolism as a high priority therapeutic target in Parkinson's disease and related neurodegenerative disorders.
Evaluating Genetic Regulators of MicroRNAs Using Machine Learning Models
Authors: Cihan Mert , Anyaegbunam Uchenna Alex , Albrecht Steffen , Andrade-Navarro Miguel A , Sprang Maximilian
Published: January 2025

This study explores the genetic regulators of microRNAs (miRNAs) using an ensemble of machine learning models to predict miRNA expression levels from gene expression data. Employing ridge regression, we accurately predicted the expression of 353 human miRNAs (R2> 0.5), revealing robust miRNA-gene regulatory relationships. By analyzing the coefficients of these predictive models, we identified genetic regulators for each miRNA and highlighted the multifactorial nature of miRNA regulation.

Further network analysis uncovered that miRNAs with higher predictive accuracy are more densely connected to their top predictive genes, reflecting strong regulatory control within miRNA-gene networks. To refine these insights, we filtered the gene-miRNA interaction networks to identify miRNAs specifically associated with enriched pathways, such as synaptic function and cardiovascular processes. From this pathway-centric analysis, we present a curated list of miRNAs and their genetic regulators, pinpointing their activity within distinct biological contexts.

Additionally, our study provides a comprehensive set of metrics and coefficients for the genes most predictive of miRNA expression, along with a filtered subnetwork of miRNAs linked to specific pathways and phenotypes. By integrating miRNA expression predictors with network analysis and pathway enrichment, this work advances our understanding of miRNA regulatory mechanisms and their roles across distinct biological systems.
Self-supervision deep learning models are better models of human high-level visual cortex: The roles of multi-modality and dataset training size
Authors: Grosbard Idan Daniel , Yovel Galit
Published: January 2025

With the rapid development of Artificial Neural Network based visual models, many studies have shown that these models show unprecedented potence in predicting neural responses to images in visual cortex. Lately, advances in computer vision have introduced self-supervised models, where a model is trained using supervision from natural properties of the training set. This has led to examination of their neural prediction performance, which revealed better prediction of self-supervised than supervised models for models trained with language supervision or with image-only supervision. In this work, we delve deeper into the models’ ability to explain neural representations of object categories. We compare models that differed in their training objectives to examine where they diverge in their ability to predict fMRI and MEG recordings while participants are presented with images of different object categories. Results from both fMRI and MEG show that self-supervision was advantageous in comparison to classification training. In addition, language supervision is a better predictor for later stages of visual perception, while image-only supervision shows a consistent advantage over a longer duration, beginning from 80ms after exposure. Examination of the effect of data size training revealed that large dataset did not necessarily improve neural predictions, in particular in visual self-supervised models. Finally, examination of the correspondence of the hierarchy of each model to visual cortex showed that image-only self-supervision led to better correspondence than image only models. We conclude that while self-supervision shows consistently better prediction of fMRI and MEG recordings, each type of supervision reveals a different property of neural activity, with language-supervision explaining later onsets, while image-only self-supervision explains long and very early latencies of the neural response, with the model hierarchy naturally sharing corresponding hierarchical structure as the brain.
MiRNA-501-3p and MiRNA-502-3p: A Promising Biomarker Panel for Alzheimer’s Disease
Authors: Devara Davin , Sharma Bhupender , Goyal Gunjan , Rodarte Daniela , Kulkarni Aditi , Tinu Nathan , Pai Ayana , Kumar Subodh
Published: January 2025

INTRODUCTION

Alzheimer’s disease (AD) lacks a less invasive and early detectable biomarker. Here, we investigated the biomarker potential of miR-501-3p and miR-502-3p using different AD sources.

METHODS

MiR-501-3p and miR-502-3p expressions were evaluated in AD CSF exosomes, serum exosomes, familial and sporadic AD fibroblasts and B-lymphocytes by qRT-PCR analysis. Further, miR-501-3p and miR-502-3p expressions were analyzed in APP, Tau cells and media exosomes.

RESULTS

MiR-501-3p and miR-502-3p expressions were significantly upregulated in AD CSF exosomes relative to controls. MiRNA levels were high in accordance with amyloid plaque and NFT density in multiple brain regions. Similarly, both miRNAs were elevated in AD and MCI serum exosomes compared to controls. MiR-502-3p expression was high in fAD and sAD B-lymphocytes. Finally, miR-501-3p and miR-502-3p expression were elevated intracellularly and secreted extracellularly in response to APP and Tau pathology.

DISCUSSION

These results suggest that miR-501-3p and miR-502-3p could be promising biomarkers for AD.
Dimerization and dynamics of angiotensin-I converting enzyme revealed by cryoEM and MD simulations
Authors: Mancl Jordan M. , Wu Xiaoyang , Zhao Minglei , Tang Wei-Jen
Published: January 2025

Angiotensin-I converting enzyme (ACE) regulates the levels of disparate bioactive peptides, notably converting angiotensin-I to angiotensin-II and degrading amyloid beta. ACE is a heavily glycosylated dimer, containing 4 analogous catalytic sites, and exists in membrane bound and soluble (sACE) forms. ACE inhibition is a frontline, FDA-approved, therapy for cardiovascular diseases yet is associated with significant side effects, including higher rates of lung cancer. To date, structural studies have been confined to individual domains or partially denatured cryoEM structures. Here we report the cryoEM structure of the full-length, glycosylated, sACE dimer. We resolved four structural states at 2.99 to 3.65 Å resolution which are primarily differentiated by varying degrees of solvent accessibility to the active sites and reveal the full dimerization interface. We also employed all-atom molecular dynamics (MD) simulations and heterogeneity analysis in cryoSPARC, cryoDRGN, and RECOVAR to elucidate the conformational dynamics of sACE and identify key regions mediating conformational change. We identify differences in the mechanisms governing the conformational dynamics of individual domains that have implications for the design of domain-specific sACE modulators.
The extracellular matrix drives guanylate production and protects pancreatic cancer cells from oxaliplatin-induced DNA damage
Authors: Efthymiou Georgios , Compare Coralie , Lohmann Eugénie , Kousteridou Paraskevi , Bertrand Pierre , Carr Heather S. , Ben-Sahra Issam , Nemazanyy Ivan , Tubiana Sarah Simha , Hussain Zainab , Finetti Pascal , Bertucci François , Bidaut Ghislain , Lachaud Christophe , Guillaumond Fabienne , Tomasini Richard , Vasseur Sophie
Published: January 2025

The excessive production of extracellular matrix (ECM) and the metabolic adaptations in pancreatic ductal adenocarcinoma (PDAC) contribute individually to enhanced chemoresistance, dramatic tumor progression and dismal patient survival. However, ECM-driven metabolic alterations that promote chemoresistance in PDAC are so far unexplored. Here, we usein-vitro-generated ECM bio-scaffolds that recapitulate cell-ECM interactions and induce broad metabolic alterations in PDAC cells. High-throughput integration of multi-omics datasets coupled with metabolic tracing showed that the ECM enhances the generation of guanylates in PDAC cells, the accumulation of which alleviates oxaliplatin-induced DNA damage, and boosts PDAC cell proliferation. These events are guided by the guanosine monophosphate (GMP)-producing enzymes Impdh and Gmps, the expression of which correlated with that of matrisomal and DNA repair genes in PDAC patient samples. We propose that targeting ECM-driven metabolic processes, like the enhanced Impdh activity, may be an effective therapeutic approach for PDAC patients that bypasses the negative side effects of direct targeting of the ECM itself.
Interleukin 10 controls the balance between tolerance, pathogen elimination and immunopathology in birds
Authors: Meunier Dominique , Corona-Torres Ricardo , Boulton Kay , Wu Zhiguang , Ballantyne Maeve , Glendinning Laura , Ahmad Anum Ali , Borowska Dominika , Taylor Lorna , Vervelde Lonneke , del Pozo Jorge , Vasilogianni Marili , Jaramillo-Ortiz José , Sanchez-Arsuaga Gonzalo , Psifidi Androniki , Tomley Fiona , Watson Kellie A. , McGrew Michael J. , Stevens Mark P. , Blake Damer P. , Hume David A.
Published: January 2025

Effective mucosal immunity in the intestine involves a fine balance between tolerance of the microbiome, recognition and elimination of pathogens, and inflammatory tissue injury. The anti-inflammatory cytokine IL10 regulates these processes in the intestines of mice and humans; the anti-inflammatory activity of IL10 is also conserved in birds. To determine the function of IL10 in avian mucosal immunity, we generated germ line modifications of the chickenIL10locus to abolish or reduce IL10 expression.In vitroanalysis of macrophage response to lipopolysaccharide confirmed the loss of IL10 protein expression, the lack of dosage compensation in heterozygotes, and prevention of autocrine inhibition of nitric oxide production in homozygous IL10 knockout macrophages. IL10-deficiency significantly altered the composition of the caecal microbiome, but unlike IL10-deficient mice and humans, IL10-deficient chickens did not exhibit spontaneous colitis. Following experimental challenge withSalmonella entericaserovar Typhimurium orCampylobacter jejuniin IL10-deficient chickens, enhanced clearance of the pathogens was associated with elevated transcription of pro-inflammatory genes and increased infiltration of inflammatory cells into gut mucosa. In IL10-deficient chickens challenged with the parasiteEimeria tenella,pathogen clearance was accelerated but caecal lesions were more severe and weight gain was compromised. Neither the heterozygous IL10 knockout nor a homozygous IL10 enhancer mutation had a major effect on pathogen clearance or inflammation in any of the challenge models. Our findings highlight the intrinsic compromise in mucosal immune response and have important implications for the development of strategies to combat avian and zoonotic pathogens in poultry.
Small molecule promoters of endogenous lipid droplet accumulation drive lysophagy
Authors: Vechalapu Sai Kumari , Duraisamy Santhosh , Senthil Sathyapriya , Kumar Rakesh , Ajnar Deepa , Draksharapu Apparao , Kumar Suresh , Allimuthu Dharmaraja
Published: January 2025

Lipid droplets (LDs) play a central role in regulating metabolism in stress-induced conditions, including one triggered by nutrient deprivation. Unravelling the protein networks involved in the biogenesis of LDs and their causative and functional roles in health and disease continue to evolve. To this cause, genetic manipulation of the lipid metabolic network or supplementation of high fat diet/ oleic acid (OA) are the traditional routes for voluntarily triggering LDs formation in cells and animals. We developed a screening platform for the identification of new LDs inducers, and our primary screening of various fatty acids identified linoleic acid (LOA, DUFA) as a better tool than OA (MUFA) in promoting LDs formation. The screening and validation discovered new small molecule-based tools for promoting a rapid organization of endogenous lipids into droplets in multiple cell types. Notably, our mass spectral lipidomics analysis presented the overproduction of phosphatidylcholines and small triglycerides, a hallmark of LDs. Mechanistic investigations of our lead molecules highlighted lipid peroxidation and ATP depletion through mitochondrial impairment in cells, which could serve as chemical cues for driving the fusion of cellular lipids into LDs. Finally, we uncovered the abrupt levels of LDs formation induced by our molecules promoted lysophagy in cancer cells to prevent their proliferation. Collectively, our work introduces new small molecules as powerful tools for reliably promoting LDs accumulation for studying their roles in biology, and we demonstrate the over accumulation of LDs prevent cancer cell proliferation, movement, and colonization.
Interleukin-34 and debris clearance by mononuclear phagocytes drive retinal pigment epithelium regeneration in zebrafish
Authors: Leach Lyndsay L. , Gonzalez Rebecca G. , Jayawardena Sayuri U. , Gross Jeffrey M.
Published: January 2025

The retinal pigment epithelium (RPE) surrounds the posterior eye and maintains the health and function of the photoreceptors. Consequently, RPE dysfunction or damage has a devastating impact on vision. Due to complex etiologies, there are currently no cures for patients with RPE degenerative diseases, which remain some of the most prevalent causes of vision loss worldwide. Further, owing to a limited capacity for mammalian tissue repair, we know little about how the RPE regenerates. Here, we utilize zebrafish as a model to uncover novel mechanisms driving intrinsic RPE regeneration. We show that interleukin-34 signaling from damaged RPE is required for precisely timed recruitment of mononuclear phagocytes (MNPs) to the injury site. Additionally, we find that cellular debris clearance by MNPs is indispensable for regeneration, as microglia-deficient zebrafish fail to regenerate RPE and photoreceptor tissues. Together, our results establish specific pro-regenerative functions of MNPs after RPE damage.
Tracking the phenology of riverine insect communities using environmental DNA
Authors: Cereghetti Eva , Ajvazi Xhesida , Keck François , Patrignani Andrea , Tartini Nicolò , Altermatt Florian , Carraro Luca
Published: January 2025

Aquatic insects are iconic and ecologically highly relevant inhabitants of riverine ecosystems. They are also often the target of monitoring programs to assess the ecological status of these lotic habitats. Environmental DNA (eDNA) techniques have been widely and successfully implemented to investigate freshwater insects and other macroinvertebrates. Commonly, such monitoring is conducted at one or two timepoints per year, despite the known strong seasonality and phenology of aquatic insects. Here, we assessed if and how eDNA can capture the temporal changes of the orders Ephemeroptera (mayflies), Plecoptera (stoneflies), Trichoptera (caddisflies) and Diptera (true flies). We carried out eDNA sampling at roughly monthly intervals from April to October at 25 sites across a whole river catchment in the northeastern part of Switzerland. We found pronounced, cyclic phenological trends in all orders but Trichoptera: the communities diverged from spring to summer and then in fall gradually returned closer to the spring state. The four orders exhibited different predominance in gains or losses of species detection throughout this time interval. Lastly, we found that field replicates, despite showing a relatively high local stochasticity, were able to provide a more complete assessment of aquatic communities and could thus be used as a proxy for the frequency of observation of a species through the seasons. In fact, this approach yielded comparable temporal patterns to the ones extracted from the Global Biodiversity Information Facility (GBIF). Overall, our findings demonstrate that eDNA techniques can be used to reveal intra-annual dynamics of aquatic insects. Given the current necessity to assess and monitor the biodiversity status of ecosystems, we therefore show that eDNA methods are a viable option to obtain a deeper understanding of the structuring of freshwater communities over time.
Optimization of a maize rapid cycle breeding scheme using the Modular Breeding Program Simulator (MoBPS)
Authors: Pook Torsten , Tost Mila Leonie , Simianer Henner
Published: January 2025

In recent years, the turnover of plant breeding has substantially increased as the use of genomic information allows for earlier selection and the integration of controlled growing environments reduces time to reach a particular growing stage. However, high generation turnover and intensive selection of lines before own yield trials are performed come at the risk of a drastic reduction of genetic diversity paired with lower prediction accuracies. To this end, we investigate strategies to cope with these challenges in a maize rapid cycle breeding scheme using stochastic simulations using the software MoBPS. We find that genetic gains soon reach a plateau when only the original breeding material is phenotyped. Updating the training data set via additional phenotyping of crosses or doubled haploid lines ensures long-term progress with a gain of 6.80 / 6.95 genetic standard deviations for the performance as a cross /per seafter 30 cycles of breeding compared to 3.40 / 4.28 without additional phenotyping. Adding genetic material with comparable genetic level and novel diversity from outside the breeding material led to a further increase to 9.34 / 7.89 genetic standard deviations. In particular, for the management of genetic diversity, further additions to the breeding scheme are analyzed to optimize the number of selected lines per cycle and to account for the relatedness of F2 plants in the selection using the software AlphaMate. Finding a balance between genetic gains and diversity is important for a given time frame. MoBPS provides a tool for the quantification of these effects and provides solutions specific to the respective breeding program.
Gibberellin enhances germination ofNolana mollisandHeliotropium pycnophyllumseeds
Authors: van den Brink Liesbeth , Mai Melissa H , Henneberg Lorenz , Ecke Margret , Canessa Rafaella
Published: January 2025

Desert plants often exhibit seed dormancy, which enables seeds to wait out unfavorable conditions and germinate when there is enough water for the seedling to establish securely. Here, we tested several dormancy-breaking mechanisms forNolana mollisandHeliotropium pycnophyllum, including storage temperature, scarification, hormones, germination temperature, and light cycles during germination. For both species, gibberellin enhanced germination significantly. All other treatments, or combinations of treatments, had no significant effect. Our results can be applied to restoration efforts in arid areas, or in urban areas in arid climates, where the use of native species reduces watering necessities.
Separate, Separated and Together: the Transcriptional Program of theClostridium acetobutylicum- Clostridium ljungdahliisyntrophy leading to interspecies cell fusion
Authors: Willis Noah B. , Papoutsakis Eleftherios T.
Published: January 2025

Syntrophic cocultures (hitherto assumed to be commensalistic) ofClostridium acetobutylicumandClostridium ljungdahlii, whereby CO2and H2produced by the former feeds the latter, result in interspecies cell fusion involving large scale exchange of protein, RNA and DNA between the two organisms. Although mammalian cell fusion is mechanistically dissected, the mechanism for such microbial-cell fusions is unknown. To start exploring this mechanism, we used RNA sequencing to identify genes differentially expressed in this coculture using two types of comparisons. One type compared coculture to the two monocultures, capturing the combined impact of interactions through soluble signals in the medium and through direct cell-to-cell interactions. The second type compared membrane separated versus unseparated cocultures, isolating the impact of interspecies physical contact. While we could not firmly identify specific genes that might drive cell fusion, consistent with our hypothesized model for this interspecies microbial cell fusion, we observed differential regulation of genes involved inC. ljungdahlii’sautotrophic Wood-Ljungdahl-Pathway metabolism and genes of the motility machinery. Unexpectedly, we also identified differential regulation of biosynthetic genes of several amino acids, and notably of arginine and histidine. We verified that they are produced byC. acetobutylicumand are metabolized byC. ljungdahliito its growth advantage. These and other findings, and notably upregulation ofC. acetobutylicumribosomal-protein genes, paint a more complex syntrophic picture and suggest a mutualistic relationship, whereby beyond CO2and H2,C. acetobutylicumfeedsC. ljungdahliiwith growth boosting amino acids, while benefiting from the H2utilization byC. ljungdahlii.

IMPORTANCE

The construction and study of synthetic microbial cocultures is a growing research area due to the untapped potential of defined multi-species industrial bioprocesses and the utility of defined cocultures for generating insight into complex, undefined, natural microbial consortia. Our previous work showed that coculturingC. acetobutylicumandC. ljungdahliileads to a unique metabolic phenotype (production of isopropanol) and heterologous cell fusion events. Here, we used RNAseq to explore genes involved in and impacted by these fusions. First, we compared gene expression in coculture to each individual monoculture. Second, we utilized a transwell system to compare gene expression in mixed cocultures to cocultures with both species physically separated by a permeable membrane, isolating the impact of interspecies “touching” on the transcriptome. This study deepens our mechanistic understanding of theC. acetobutylicum-C. ljungdahliicoculture phenotype, laying the groundwork for reverse genetic studies of heterologous cell fusion inClostridiumcocultures.
Cryo-EM captures early intermediate steps in dynein activation by LIS1
Authors: Nguyen Kendrick H. V. , Karasmanis Eva P. , Kendrick Agnieszka A. , Reck-Peterson Samara L. , Leschziner Andres E.
Published: January 2025

Cytoplasmic dynein-1 (dynein) is an essential molecular motor in eukaryotic cells. Dynein primarily exists in an autoinhibited “Phi” state and requires conformational changes to assemble with its cofactors and form active transport complexes. LIS1, a key dynein regulator, enhances dynein activation and assembly. Using cryo-EM and a human dynein-LIS1 sample incubated with ATP, we mapped the conformational landscape of dynein activation by LIS1. We discovered a novel early intermediate state that we propose precedes our previously identified dynein-LIS1 “Chi” state. Mutations that disrupt this species, which we termed “Pre-Chi”, led to motility defects in vitro, emphasizing its functional importance. Together, our findings provide new insights into how LIS1 relieves dynein autoinhibition during the activation pathway.
Association between TG/HDL-C and depression: Results from the NHANES, 2005-2020
Authors: Tang Xuemiao , He Qiuhua , Yang Na , Fu Qiang
Published: January 2025

Lipid profile disturbances are frequently observed in depressive patients. Triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) can be reflective of the level of blood lipids. However, it remains unclear whether higher TG/HDL-C increases the risk of depression. This study aimed to investigate the association between TG/HDL-C and depression. In this cross-sectional study, 19,297 participants were analyzed from the National Health and Nutrition Examination Survey (NHANES) between 2005 and 2020. A weighted multivariable logistic regression model, restricted cubic spline regression model and threshold effect analysis were used to explore the association and dose-response relationship of TG/HDL-C with depression risk in the total population and subgroups. A total of 19,297 participants who had complete data on TG/HDL-C and depression measurement were included in this study (mean age 50 years, 51% female). Participants with depression had higher TG/HDL-C than those without depression. TG/HDL-C was associated with an increased risk of depression after adjusting for all covariates (in model 3: OR = 1.12, 95% CI: 1.03-1.21,P= 0.005). Moreover, a nonlinear J-shaped relationship was observed between TG/HDL-C ratio and the risk of depression, with an inflection point of 0.402 by threshold effect analysis. These findings indicate that TG/HDL-C has a J-shaped association with the risk of depression.
Improving Diagnostic Accuracy of Routine EEG for Epilepsy using Deep Learning
Authors: Lemoine Émile , Toffa Denahin , Xu An Qi , Tessier Jean-Daniel , Jemel Mezen , Lesage Frédéric , Nguyen Dang K. , Bou Assi Elie
Published: January 2025

Background and Objectives

The diagnostic yield of routine EEG in epilepsy is limited by low sensitivity and the potential for misinterpretation of interictal epileptiform discharges (IEDs). Our objective is to develop, train, and validate a deep learning model that can identify epilepsy from routine EEG recordings, complementing traditional IED-based interpretation.

Methods

This is a retrospective cohort study of diagnostic accuracy. All consecutive patients undergoing routine EEG at our tertiary care center between January 2018 and September 2019 were included. EEGs recorded between July 2019 and September 2019 constituted a temporally shifted testing cohort. The diagnosis of epilepsy was established by the treating neurologist at the end of the available follow-up period, based on clinical file review. Original EEG reports were reviewed for IEDs. We developed seven novel deep learning models based on Vision Transformers (ViT) and Convolutional Neural Networks (CNN), training them to classify raw EEG recordings. We compared their performance to IED-based interpretation and two previously proposed machine learning methods.

Results

The study included 948 EEGs from 846 patients (820 EEGs/728 patients in training/validation, 128 EEGs/118 patients in testing). Median follow-up was 2.2 years and 1.7 years in each cohort, respectively. Our flagship ViT model, DeepEpilepsy, achieved an area under the receiver operating characteristic curve (AUROC) of 0.76 (95% CI: 0.69–0.83), outperforming IED-based interpretation (0.69; 0.64–0.73) and previous methods. Combining DeepEpilepsy with IEDs increased the AUROC to 0.83 (0.77–0.89).

Discussion

DeepEpilepsy can identify epilepsy on routine EEG independently of IEDs, suggesting that deep learning can detect novel EEG patterns relevant to epilepsy diagnosis. Further research is needed to understand the exact nature of these patterns and evaluate the clinical impact of this increased diagnostic yield in specific settings.
Wearable-based digital biomarker provides a valid alternative to traditional clinical measures for post-stroke upper-limb motor recovery
Authors: Wang Ryan , Lang Catherine E. , Stoykov Mary E. , Bonato Paolo , Lee Sunghoon I.
Published: January 2025

Existing clinical assessments for upper-limb motor rehabilitation post-stroke pose limitations as endpoints for clinical trials. This study aims to develop a wearable-based digital biomarker for assessing motor recovery using accelerometer data collected in naturalistic environments. The study analyzed approximately 23,000 hours of data from 215 participants, including subacute and chronic stroke survivors and healthy individuals. A novel analytical approach decomposed continuous accelerometer data into a lower-level unit of motor behaviors called movement segments, from which key features were extracted and aggregated using a linear mixed-effects model to produce a composite biomarker. The resulting digital biomarker demonstrated excellent interpretability, reliability, concurrent validity, discriminant validity, known-group validity, and responsiveness, enabling a nearly 66% reduction in the required sample size for clinical trials compared to traditional measures. These findings highlight its potential as a low-burden, scalable assessment tool for upper-limb motor recovery, with applications in both clinical trials and routine clinical practice.
Estradiol-based Menopausal Hormone Therapy is associated with improved episodic and prospective memory scores in the Canadian Longitudinal Study of Aging
Authors: Puri Tanvi A. , Gravelsins Laura , Alexander Madeline Wood , McGovern Andrew J. , Duarte-Guterman Paula , Rabin Jennifer S. , Murphy Kelly J. , Galea Liisa A.M.
Published: January 2025

Introduction

Menopause and menopausal hormone therapy (MHT) can influence cognition in postmenopausal women, but previous literature remains equivocal about their effects. MHT varies based on formulation and route of administration, both of which influence dose of estradiol (E2), the estrogen with the greatest affinity to the estrogen receptor. Transdermal E2 avoids hepatic conversion and results in higher plasma levels of E2 than oral E2 formulations. The cognitive domains of executive functions, episodic memory and prospective memory are diminished with age, but may be differentially sensitive to MHT, dependent on the brain regions recruited during the task. There is a lack of research investigating the effects of the age of menopause and estradiol (E2)-based MHT on different cognitive domains.

Methods

Using baseline data from the Canadian Longitudinal Study of Aging, we examined the associations between age of menopause and E2 based MHT on performance in three cognitive domains: episodic memory, prospective memory, and executive functions. Our cohort included 7,251 postmenopausal women who were cognitively healthy, with models adjusted for age, education, and body mass index.

Results

Earlier age at menopause was significantly associated with lower scores across all cognitive domains. However, for the executive functions domain, an earlier age of menopause was associated with lower scores only in those with grand parity (4 or more children) and there was a greater effect size among APOE ε4 carriers. We found that transdermal E2 was associated with higher episodic memory scores, whereas oral E2 was associated with higher prospective memory scores compared to no MHT. Neither administration route significantly affected executive function.

Conclusion

These results highlight the differential effects of E2-based MHT depending on route of administration and cognitive domain, and underscore the importance of considering age of menopause and individual characteristics such as reproductive history and genotype status. This work provides clarity to inconsistencies in the literature and informs the development of precision medicine approaches for cognitive aging in postmenopausal people.
VZV gE Promotes STING Degradation via Midnolin-Proteasome Pathway to Inhibit cGAS-STING Signaling
Authors: Chen Lumiao , Dai Lingao , Nie Shenghao , Zhao Yue , Li Fanyuan , Deng Xiujiao , Liu Chunlin , Li Moran , Luo Zewei , Liu Yuqing , Ge Weiwei , Liu Xiaofei , Yi Qian , Li Yongkui , Pan Pan , Wang Xiaoping
Published: January 2025

Varicella-zoster virus (VZV) infects 85 million individuals annually and it is known for its intricate interplay with host cellular mechanisms, significantly impacting antiviral immune responses. Previous studies have highlighted the critical role of VZV glycoprotein E (gE) in virus-host interactions, but the precise mechanisms remain to be elucidated. Our results demonstrate that VZV gE interacts with STING, specifically through the gE (350-480aa) and STING (151-160aa) regions. This interaction predominantly involves incompletely glycosylated gE. Functional assays revealed that gE inhibits the cGAS-STING signaling pathway. gE enhances VZV proliferation and promotes STING degradation via the proteasome pathway, without affecting STING ubiquitination. We identified Midnolin as a mediator in this degradation process, with gE facilitating the interaction between STING and Midnolin. In vivo, gE expression in mice led to diminished antiviral responses upon HSV-1 infection, highlighting gE’s role in modulating immune signaling. Our findings provide significant insights into VZV’s evasion of host immune responses. By promoting STING degradation through an unconventional Midnolin-proteasome pathway, VZV gE effectively suppresses antiviral signaling, facilitating enhanced viral proliferation. The findings contribute significantly to the understanding of VZV pathogenesis and provide new therapeutic strategies against VZV.
A starvation-triggered AAA+ ATPase halts chromosome replication progression by disassembling the bacterial DNA sliding clamp
Authors: Surbhi  , Shau Arnab Kumar , Chacko Feby Mariam , Radhakrishnan Sunish Kumar
Published: January 2025

Living cells should coordinate vital events such as DNA replication with the availability of nutrients. For example, when cells encounter starvation, to maintain genomic integrity they should harbour robust mechanisms to stop DNA replication. Mechanisms regulating the progression of DNA replication when bacterial cells encounter starvation remain largely unclear. Herein, we identify the role of IncA –a AAA+ ATPase homologous to the prokaryotic RarA and eukaryotic WRNIP1/Mgs1– in inhibiting the progression of chromosome replication in nutrient-starved stationary phase cells ofCaulobacter crescentus. We show that the starvation-induced alarmone (p)ppGpp ensures the confinement of IncA production to the stationary phase cells. At the mechanistic level, IncA directly interacts with the β-sliding clamp protein DnaN and disassembles DnaN from the replisome, thereby stalling the progression of DNA replication. Furthermore, we reveal the requirement of IncA’s ATPase activity for disassembling DnaN. Remarkably, we demonstrate that the IncA homolog fromE. coliis capable of inhibiting DNA replication inCaulobacter. We propose that IncA homologs serve a stress-dependent role in inhibiting DNA replication across diverse domains of life.
Audiovisual gamma stimulation enhances hippocampal neurogenesis and neural circuit plasticity in aging mice
Authors: Trinchero Mariela F. , Herrero Magalí , Mugnaini Matías , Aguilar-Arredondo Andrea , Benas Sabrina , Satorre Ignacio G. , Kropff Emilio , Schinder Alejandro F.
Published: January 2025

Gamma oscillations are disrupted in various neurological disorders, including Alzheimer’s disease (AD). In AD mouse models, non-invasive audiovisual stimulation (AuViS) at 40 Hz enhances gamma oscillations, clears amyloid-beta, and improves cognition. We investigated mechanisms of circuit remodeling underlying these restorative effects by leveraging the sensitivity of hippocampal neurogenesis to activity in middle-aged wild-type mice. AuViS increased progenitor cell proliferation, neuronal differentiation and morphological maturation of newborn granule cells, promoting their synaptic integration. While visual or auditory stimuli alone induced dendritic growth, axonal changes required combined audiovisual stimulation. The actions of AuViS involved neurotrophin pathways, as shown by the lack of effect upon TrkB signaling blockade. These results reveal widespread plasticity mechanisms triggered by AuViS, a therapeutic approach currently proposed for treating neurological disorders in humans.
Burnout among hospital doctors working at a West Midlands Major Trauma Centre: a cross-sectional study
Authors: Basso Alexandro , Attwater Amy
Published: January 2025

Introduction

Worryingly, burnout is becoming increasingly common among the doctor cohort across the United Kingdom (UK) according to the General Medical Council (GMC), which has also seen an increasing desire to leave the UK profession. The main aims of this study were to: 1) determine the prevalence of burnout among doctors; 2) investigate the association between socio-demographic variables, including thoughts on leaving the profession or the NHS, and both burnout and its two dimensions; 3) examine the potentially predictive relationship between socio-demographic variables and burnout.

Method

This cross-sectional study employed the Oldenburg Burnout Inventory (OLBI) to determine the prevalence of burnout as measured across its two core dimensions, exhaustion and disengagement, among doctors working at University Hospital Coventry, a major trauma centre located within the West Midlands. In total, 156 doctors took part in a completed anonymised online questionnaire which also gathered socio-demographic information.

Results

111 (71%) participants were categorised as experiencing burnout, 22 (14%) and 7 (4%) were categorised as exhausted or disengaged, and 16 (10%) were categorised as non-burnout. Whilst there were no associations found between burnout group and socio-demographic variables, there were significant associations found between the exhaustion and disengagement scores and professional grade (p< 0.05 andp< 0.001, respectively). Doctors who were in the earlier stages of their career, particularly resident doctors in lower training, were found to have significantly higher exhaustion and disengagement scores, and this finding was supported by correlation analysis. There was significant association between burnout group and thoughts on leaving the profession or the NHS (p< 0.001). The predictive relationship between socio-demographic variables and burnout groups was found to be poor.

Conclusion

At University Hospital Coventry, burnout is a persistent and prevalent issue that affects doctors across all societal and demographic groups. Given the current workforce crisis, more targeted interventions need to be done by organisations to minimise burnout across its two core dimensions to ensure current workforce trends are reversed.
Features of strangeness production in
pp
and heavy-ion collisions
Authors: Pop A. , Petrovici M.
Published: January 2025

Based on existing experimental data for A−A collisions starting from the Alternating Gradient Synchrotron energies to those of the CERN Large Hadron Collider, various systematics related to strange hadrons and antihadrons are presented. As in the case of pions, kaons, and protons, the ratio between the average transverse momentum and the square root of the total particle multiplicity per unit rapidity and unit transverse overlap area (〈pT〉/〈dN/dy〉/S⊥) decreases with collision energy and centrality supporting the predictions of the color glass condensate and percolation approaches. The dependencies on 〈dN/dy〉/S⊥ of the slope and offset extracted from the 〈pT〉-particle mass correlation and of the average transverse expansion velocity and kinetic freeze-out temperature, parameters obtained from Boltzmann-Gibbs Blast-Wave fits of pT spectra for strange hadrons, are compared with those for pions, kaons, and protons. The detailed study of the entropy density (〈dN/dy〉/S⊥) dependence of the ratio of strange hadron yields per unit rapidity to the total particle multiplicity per unit rapidity (YS/〈dN/dy〉) at different collision energies and centralities reveals the necessity to study strange hadrons and antihadrons separately. The correlations YS/〈dN/dy〉−〈dN/dy〉/S⊥ for single- and multistrange antihadron yields, as a function of the fireball size, are discussed. The YS/〈dN/dy〉−〈dN/dy〉/S⊥ correlations for combined and separated strange hadron species, at different centralities, clearly show a maximum in the region where a transition from baryon-dominated matter to meson-dominated matter occurs. Comparison with pp experimental data reveals another similarity between pp and Pb-Pb collisions at CERN Large Hadron Collider energies. To facilitate a possible comparison with theoretical approaches, the different correlations are either fitted with suitable functions or the corresponding experimental data are provided.

Published by the American Physical Society
2025
Multiparticle collision framework for active polar fluids
Authors: Baziei Oleksandr , Loewe Benjamín , Shendruk Tyler N.
Published: January 2025

Sufficiently dense intrinsically out-of-equilibrium suspensions, such as those observed in biological systems, can be modeled as active fluids characterized by their orientational symmetry. While mesoscale numerical approaches to active nematic fluids have been developed, polar fluids are simulated as either ensembles of microscopic self-propelled particles or continuous hydrodynamic-scale equations of motion. To better simulate active polar fluids in complex geometries or as a solvent for suspensions, mesoscale numerical approaches are needed. In this work, the coarse-graining multiparticle collision dynamics (MPCD) framework is applied to three active particle models to produce mesoscale simulations of polar active fluids. The first active-polar MPCD (AP-MPCD) is a variant of the Vicsek model, while the second and third variants allow the speed of the particles to relax towards a self-propulsion speed subject to Andersen and Langevin thermostats, respectively. Each of these AP-MPCD variants exhibits a flocking transition at a critical activity and banding in the vicinity of the transition point. We leverage the mesoscale nature of AP-MPCD to explore flocking in the presence of external fields, which destroys banding, and anisotropic obstacles, which act as a ratchet that biases the flocking direction. These results demonstrate the capacity of AP-MPCD to capture the known phenomenology of polar active suspensions and its versatility to study active polar fluids in complex scenarios.

Published by the American Physical Society
2025
Distinguishing Dirac from Majorana Heavy Neutrino at Future Lepton Colliders
Authors: Cao Qing-Hong , Cheng Kun , Liu Yandong
Published: January 2025

We propose to identify whether a sterile neutrino is Dirac-type or Majorana-type by counting the peak of the rapidity distribution at lepton colliders. Our method requires only one charged-lepton tagging, and the nature of sterile neutrinos can be pinned down once they are confirmed.

Published by the American Physical Society
2025
Systematic coarse-graining of sequence-dependent structure and elasticity of double-stranded DNA
Authors: Skoruppa Enrico , Schiessel Helmut
Published: January 2025

Coarse-grained models have played an important role in the study of the behavior of DNA at length scales beyond a few hundred base pairs. Traditionally, these models have relied on structurally featureless and sequence-independent approaches, such as the twistable wormlike chain. However, research over the past decade has highlighted the substantial impact of DNA sequence even at the kilobase pair scale. Several robust sequence-dependent models have emerged, capturing intricacies at the base pair-step level. Here we introduce an analytical framework for coarse-graining such models to lower resolution representations while preserving essential structural and dynamic features, enabling the efficient sampling of large molecules. When considering both rotational and translational degrees of freedom, coarse-graining is shown to yield excellent results up to about one helical repeat. For scenarios where the local stretch modulus is inconsequential, this range can be significantly increased by only considering the rotational degrees of freedom, which permits faithful coarse-grained representation up to several helical repeats. Rather than providing a fully parametrized model, we present the methodology and software necessary for mapping any base pair-step model to the desired level of coarse-graining. Finally, we provide application examples of our method, including estimates of the persistence length and effective torsional stiffness of DNA in a setup mimicking a freely orbiting tweezer, as well as simulations of helically curved DNA.

Published by the American Physical Society
2025
Superconducting Quantum Oscillations and Anomalous Negative Magnetoresistance in a Honeycomb Nanopatterned Oxide Interface Superconductor
Authors: Wang Yishuai , Hong Siyuan , Pan Wenze , Zhou Yi , Xie Yanwu
Published: January 2025

The extremely low superfluid density and unprecedented tunability of oxide interface superconductors provide an ideal platform for studying fluctuations in two-dimensional superconductors. In this work, we fabricate an LaAlO3/KTaO3 interface superconductor patterned with a nanohoneycomb array of insulating islands. Little-Parks-like magnetoresistance oscillations are observed, which are dictated by the superconducting flux quantum h/2e. Moreover, an anomalous negative magnetoresistance (ANMR) appears under a weak magnetic field, suggesting magnetic-field-enhanced superconductivity. By examining their dependences on temperature, measurement current, and electrical gating, we conclude that both phenomena are associated with superconducting order parameter: The h/2e oscillations provide direct evidence of Cooper-pair transport, and the ANMR is interpreted as a consequence of multiple connected narrow superconducting paths with strong fluctuations.

Published by the American Physical Society
2025