bluuebunny/crossref_metadata_2025 huggingface dataset:
MCL-1 as a molecular switch between myofibroblastic and pro-angiogenic features of breast cancer-associated fibroblasts
Authors: Lefebvre Chloé C , Giowachini Philippine , Derrien Jennifer , Naour Maxime , Corre Isabelle , Douillard Elise , Guillonneau François , Campone Mario , Juin Philippe P , Souazé Frédérique
Published: February 2025

Breast cancer-associated fibroblasts (bCAFs) comprise inflammatory CAFs (iCAFs), characterized by the secretion of pro-inflammatory cytokines, and myofibroblastic CAFs (myCAFs), distinguished by their high production of extracellular matrix and their immunosuppressive properties. We previously showed that targeting the anti-apoptotic protein MCL-1 in primary culture of bCAF derived directly from human samples reduces their myofibroblastic characteristics. We herein show by single-cell RNA-sequencing analysis of bCAFs that MCL-1 knock down induces a phenotypic shift from wound-myCAF to IL-iCAF, characterized by the upregulation of genes associated with inflammation as well as angiogenesis-related genes. In vitro, genetic and pharmacologic MCL-1 inhibition increases VEGF secretion by bCAFs, enhancing endothelial cell tubulogenesis. In a chicken chorioallantoic membrane (CAM) model in ovo, co-engraftment of breast cancer cells and bCAFs with reduced MCL-1 expression leads to heightened peritumoral vascular density, driven by VEGF. Mechanistically, the pro-angiogenic phenotype revealed by MCL-1 inhibition is dependent on BAX-BAK activity. It results in NF-κB activation, inhibition of which by a IKKβ inhibitor suppresses the transcription of VEGF and pro-inflammatory factors triggered by MCL-1 inhibition in bCAFs. Chemotherapy induces a downregulation of MCL-1 in bCAFs and it promotes a pro-angiogenic phenotype, counteracted by overexpressed MCL-1. Overall, these findings uncover a novel regulatory function of MCL-1 in determining bCAF subpopulation differentiation and highlight its role in modulating their pro-angiogenic properties, in response to treatment in particular.
Altered mitochondrial respiration is associated with loss of nuclear-encoded OXPHOS genes in parasitic broomrapes
Authors: Cai Liming , Jansen Robert K , Havird Justin C
Published: February 2025

Parasitic plants, characterized by their dependency on host organisms for nutrients, have displayed far-reaching alterations in physiology and genetics. While significant gene losses and relaxed selection have been documented in the nuclear and plastid genomes, how parasitism impacts the molecular evolution and function of mitochondria has remained controversial. One of the main culprits hindering our understanding in this area is the lack of knowledge on nuclear-encoded mitochondrial-targeted genes (N-mt), which encode most mitochondrial oxidative phosphorylation (OXPHOS) proteins. By conducting a comprehensive survey of N-mt genes across angiosperms, we demonstrated significant gene losses and horizontal transfers associated with relaxed selection unique to holoparasitic Orobanchaceae. These putative losses and transfers have the potential to affect mitochondrial function directly and cause mitonuclear incompatibility because of breakdown between co-evolved protein complexes from mitochondrial and nuclear genomes. Our physiological assessments using high-resolution respirometry revealed that despite genetic alterations, holoparasitic Orobanchaceae maintained robust OXPHOS function but relied more on the fully nuclear-encoded succinate dehydrogenase (complex II). Our results document the first example of significant and biased gene loss in nuclear-encoded mitochondrial OXPHOS genes in parasitic plants, expanding on previous studies focused on mitochondrial-encoded genes and elucidating the mechanisms underlying the preservation of OXPHOS function despite genomic reduction.
Helix-8 and Carboxyl Terminal Tail Regulation of Proteinase Activated Receptor-4 (PAR4) signalling
Authors: Thibeault Pierre E. , Mousa Amr A.K. , Mirka Victor M. , Ramachandran Rithwik
Published: February 2025

The 8th-helix (H8) and carboxyl terminal tail (CT) of GPCRs are crucial for interactions with intracellular signaling molecules and regulatory proteins. We investigated how H8 and CT residues influence signaling in PAR4, a tethered-ligand activated GPCR. Our analysis revealed that PAR4 activation by thrombin or AYPGKF-NH2 stimulates β-arrestin-1/-2 recruitment and activates multiple Gα proteins (Gαq, Gα11, Gαz, Gα15, Gα12, Gα13, Gαi1-3, GαoA/B). Mutation of the H8 sequence (R352AGLFQRS359) significantly reduced G protein activation and β-arrestin recruitment, with residues Leu355-Glu357being particularly important. Mutations of specific lysine residues in H8 and CT also impaired signaling. Additionally, we identified a crucial TM7-H8 interaction and found that CT phosphorylation sites regulate β-arrestin recruitment. Finally, using AlphaFold3 we predicted interactions between PAR4, β-arrestins, and G proteins, revealing novel receptor regulatory sites in the intracellular loops, transmembrane domains, H8 and CT.
Adult killifish exposure to crude oil perturbs embryonic gene expression and larval morphology in first- and second-generation offspring
Authors: Park Jane , Adams Chelsea , Brown Charles , Rocke David , Aeppli Christoph , Galvez Fernando , Whitehead Andrew
Published: February 2025

Exposures to environmental toxicants can have both immediate and long-term impacts, including those that persist into the next generation. Using Gulf killifish (Fundulus grandis), we tested whether adult progenitor exposure to crude oil caused perturbations to larval morphology and embryonic genome-wide gene expression in their first- and second-generation descendants raised in clean water. We also tracked responses of additional direct oil exposures in the F1 and F2 embryos. Exposure to oil in progenitor fish caused altered larval morphology in F1 and F2 descendants. Some perturbations were enhanced by additional oil exposure in lineages with progenitors that had been exposed to oil. Progenitor exposures altered embryonic gene expression in F1 and F2 descendants, implicating impacts on neurological and cardiovascular systems. Molecular responses to progenitor exposure were distinct between F1 and F2 offspring, suggesting complex interactions between mechanisms that contribute to the transgenerational transfer of information. In contrast, molecular responses to additional direct oil exposures during early-life development were highly conserved between generations and between progenitor exposure treatments. We conclude that exposure to crude oil causes developmental perturbations that propagate at least two generations, and we present additional hypotheses about underlying molecular mechanisms and emergent health consequences.
Suppression of Ovarian Cancer Cell Proliferation is Associated with Upregulation of Cell-Matrix Adhesion Programs and Integrin-β4-Induced Cell Protection from Cisplatin.
Authors: Farsinejad Sadaf , Centeno Daniel , Carstens Jan-Savas , Polotaye Teagan , Pavlovic Tonja , Babvey Pouria , Muranen Taru , Muranen Taru , Lum Pek Yee , Martin Laura A. , Iwanicki Marcin P.
Published: February 2025

The role of extracellular matrix adhesion components in the modulation of the treatment sensitivity of ovarian cancer (OC) cells is not well understood. Analysis of ovarian cancer TCGA gene expression data sets revealed an inverse correlation between genes involved in cell-cycle progression and extracellular matrix interactions including laminin-binding receptor integrin 4, a major component of extracellular matrix adhesion. Gene ontology analysis also showed that in patient populations with low integrin β4 expression, cell cycle-related programs were activated, while in populations with high expression of integrin β4, the activation of these cell cycle programs was lower. Suppression of proliferation with CDK4/6 inhibitor Palbociclib stimulated integrin β4 expression and induced protection against cisplatin in cells naturally expressing low levels of integrin β4. Additionally, ovarian cancer patient-derived organoids showed reduced cisplatin sensitivity when pretreated with Palbociclib. Our data also showed that integrin β4 overexpression decreased ovarian cancer cell proliferation and at the same time, attenuated cisplatin response. Our investigations reveal that the expression of integrin β4 inversely correlates with cell cycle progression programs, whether observed in expression data of OC patient samples or various OC cell lines. Consistently with these results, the overexpression of the ITGB4 gene in ovarian cancer cell lines correlated with reduced cell proliferation rates and diminished sensitivity to cisplatin, supporting the idea that integrin & β4 and likely its matrix ligands play critical roles in the regulation of cellular growth and chemoresistance of ovarian cancer cells.
Notification and recordkeeping of occupational mesothelioma in India
Authors: Singh Raja , Frank Arthur L
Published: February 2025

This paper studies the number of occupational mesothelioma cases that have been reported as per law to the factories and mines regulators in India. Zero cases of mesothelioma, which is a notified/notifiable disease under the Mines Act 1952, and notified/notifiable under the broad category of occupational cancers under the Factories, Act 1948 have been notified between 2004 to 2024 (with the factory data compiled only for 8 years). This highlights many issues, including the lack of recordkeeping of occupational diseases when there are cases of mesothelioma being reported by hospitals under the National Cancer Registry Program and many being reported in the scientific literature from India. Though lack of data may not mean the lack of disease, these cases of mesothelioma may either point to a non-occupational exposure to asbestos as an aetiology for such cases, or fixing the recordkeeping and notification of cancers, including mesothelioma, as many occupational cases are reported in the scientific literature. This is especially true as India is one of the largest users and processors of imported asbestos, user of talcum powder and has other potential sources of exposure. With mesothelioma being a surrogate for asbestos exposure, this public health hazard needs focussed implementation of regulated safeguards both occupationally or through non occupational exposures.
Identification of DOK2 and PTPN11 as novel interactors of T cell specific adapter protein TSAd
Authors: Chan Hanna , Borowicz Pawel , Gilmour Brian C , Stensland Maria , Garcia-Loza Ivan , Phuyal Santosh , Marone Romina , Jeker Lukas T. , Nyman Tuula A , Spurkland Anne
Published: February 2025

T cells play a crucial role in the adaptive immune system and depend on tightly regulated intracellular signalling pathways to respond in an appropriate manner. Adapter proteins have flexible and dynamic features, which allow them to regulate T cell signal transduction pathways. As adapter proteins are enzymatically inert and may play multiple roles in parallel, it has been a challenge to fully characterise their functions individually. One such protein in T cells, is T cell specific adapter protein (TSAd), which is upregulated following T cell receptor (TCR) stimulation and is believed to mediate Src family tyrosine kinase signalling. However, the functional role remains elusive, possibly due to limited insight into interactors that potentially bind TSAd. The only structurally well-defined feature within TSAd, is the Src homology 2 (SH2) domain. This conserved domain displays prototypic binding of phosphorylated tyrosines, which suggests that the adapter molecule is implicated in phosphotyrosine signalling pathways. Here, we used an unbiased approach to identify ligands of the TSAd SH2 domain, by using affinity-purification mass spectrometry (AP-MS). Several novel ligands, many of which are known to be implicated in negative regulation of T cell intracellular signalling, were identified. More specifically, we showed that TSAd binds DOK2 and PTPN11 and determined the tyrosines responsible for the TSAd SH2 domain-dependent interaction. Ablation of TSAd and DOK2 by CRISPR/Cas9 in Jurkat T cells resulted in altered tyrosine phosphorylation. Taken together, these findings provide new insight into the possible function of TSAd as a negative signalling node in T cells.
UK health and social care use during and after the pandemic: A qualitative study of the experiences of disabled people from minoritised ethnic groups
Authors: Rivas Carol , Anand Kusha , Ball Elizabeth , Begum Samina , Heera Neelam , Shahid Yesmin , Zuzer Lal Zainab , Moore Amanda P
Published: February 2025

The COVID-19 pandemic acted as a “super-catalyst” in accelerating the United Kingdom transition to remote health and social care, while exposing and deepening existing inequities. The 18-month mixed-methods longitudinal CICADA study explored this from the perspective of disabled individuals from minoritised ethnic groups (including undocumented migrants and asylum seekers) during and after the pandemic. Since our aim was to inform improvements, we used an asset and strengths-based approach underpinned by the embodiment model of disability and intersectional theory. Here we report on findings from 271 semi-structured interviews with disabled individuals from minoritised ethnic groups, follow-on workshops with interviewees in April and September 2022, and 4 key informant interviews.

Findings revealed widespread dissatisfaction. Many found the shift to remote care inaccessible and disempowering. Challenges included difficulties in securing appointments, disrupted patient-clinician relationships, little regard for holistic care or comorbidities, and systemic exclusions due to intersecting and discriminating factors of language, accent, disability and complex needs, digital precarity, and undocumented status. Often, service management of expectations would have improved experiences. The increased burden from health and social care support-seeking counter-intuitively worsened once pandemic restrictions eased and led many to give up; others bypassed general practice or raised complaints, or relied on self-management, traditional remedies or informal support networks. Many resorted to costly and unaffordable private care, often specifically from within their communities, and often having never registered with the National Health Service. There is an urgent need for a more inclusive, tailored approach to health and social care that considers intersecting disadvantages of race, disability, citizenship and socioeconomic status, facilitates community connections and empowerment, and provides support for self-care, alternative care and education. By foregrounding community voices, this research offers valuable insights for policymakers and providers aiming to address disparities and improve health and social care outcomes for marginalized populations.
AI-Driven Early Detection of Severe Influenza in Jiangsu, China: A Deep Learning Model Validated Through The Design of Multi-Center Clinical Trials and Prospective Real-World Deployment
Authors: Chen Yifei , Bo Yan
Published: February 2025

Influenza causes about 650,000 deaths worldwide each year, and the high mortality rate of severe cases is closely related to subjective bias in clinical assessment and inconsistent diagnostic and treatment standards. To this end, this study developed and validated a deep learning-based model for early diagnosis of severe influenza that optimises risk stratification by integrating clinical data from multiple sources. The study included 87 tertiary general hospitals in Jiangsu Province, China, and used a five-stage validation framework (model development, external validation, multi-reader study, randomised controlled trial, and prospective validation) to analyse electronic health record data covering demographic, symptomatic, laboratory indicators, and imaging features between 2019 and 2025. Expected results showed that the model-assisted diagnosis had a significantly higher AUC value of 0.18 (95% CI: 0.14-0.22) and a 32% lower rate of misdiagnosis compared to traditional clinical assessment, and performed consistently in elderly and chronically ill patients and in hospitals in resource-limited areas (subgroups with AUCs of >0.82 in all cases). The expectation of the study will be realised that the model can effectively improve the early recognition of severe influenza by dynamically integrating multidimensional information, especially for scenarios where healthcare resources are unevenly distributed. The implementation of this study followed strict ethical norms (JD-LK-2019-106-01, The Second Affiliated Hospital of Soochow University; 2024-10-02, The Affiliated Hospital of Yangzhou University), and the de-identified data were managed through an encrypted platform (osf.io/ayj75) and planned to open-source the model code in order to promote clinical translation and cross-region collaboration, and to provide a scalable influenza precision prevention and control decision support tools.

Trial:ChiCTR2000028883

Registration DOI:https://doi.org/10.17605/OSF.IO/SC93Y
A metagenomic approach to One Health surveillance of antimicrobial resistance in a UK veterinary centre
Authors: Elton Linzy , Mateos Alonso Dupuy , Frosini Siân Marie , Jepson Rosanne , Rofael Sylvia , McHugh Timothy D , Wey Emmanuel Q
Published: February 2025

Introduction

There are currently no standardised guidelines for genomic surveillance of One Health (OH) antimicrobial resistance (AMR). This project aimed to utilise metagenomics to identify AMR genes present in a companion animal hospital and compare these with phenotypic results from bacterial isolates from clinical specimens from the same veterinary hospital.

Methods

Samples were collected from sites around a primary companion animal veterinary hospital in North London. Metagenomic DNA was sequenced using Oxford Nanopore Technologies (ONT) MinION. The sequencing data were analysed for AMR genes, plasmids and clinically relevant pathogen species. These data were compared to phenotypic speciation and antibiotic susceptibility tests (ASTs) of bacteria isolates from patients.

Results

The most common resistance genes identified wereaph(n=101 times genes were isolated across 48 metagenomic samples),sul(84),blaCARB(63),tet(58) andblaTEM(46). In clinical isolates, a high proportion of phenotypic resistance to the β-lactams was identified. Rooms with the greatest mean number of resistance genes identified per swab site were the medical preparation room, dog ward and surgical preparation room. Twenty-four Gram-positive and four enterobacterial plasmids were identified. Sequencing reads matched with 14/22 (64%) of the phenotypically isolated bacterial species.

Discussion

Metagenomics identified AMR genes, plasmids and species of relevance to human and animal medicine. Communal animal-handling areas harboured more AMR genes than areas animals did not frequent. When considering infection prevention and control (IPC) measures, adherence to, and frequency of, cleaning schedules, alongside potentially more comprehensive disinfection of animal-handling areas may reduce the number of potentially harmful bacteria present.

PubMed “veterinary” or “companion” AND “AMR” or “resistan*” NOT (Review[Publication Type]) (2018-2023)

“veterinary” or “companion” AND “AMR” or “resist*” AND “sequencing” or “metagenomic*” “veterinary” or “companion” AND “AMR” or “resistan*” NOT (Review[Publication Type]) (2018-2023)

https://www.iscaid.org/clinical-practice
Scanning Electron Microscopy Study of Bacterial Growth in Mycelial Extracellular Matrices
Authors: Browner Davin , Adamatzky Andrew
Published: February 2025

Fungi and bacteria are found living in a wide variety of environments and their interactions are important in many processes including soil health, human and animal physiology and in biotechnological applications. The specificity of interaction between these microorganisms in co-culture is difficult to establish. For example, differentiation between trivial processes as a result of stochastic mixing compared with mutualistic or antagonistic interactions. Here, we investigate a single morphological feature of co-cultures of planktonic bacterial growth within biofilm-forming liquid cultures of mycelium. Namely, the attachment of bacterial co-habitants of speciesBacillus subtilisto fungal hyphae of speciesHericium erinaceus. The bacteria-in-mycelial-biofilm method was developed and utilised to allow for attachment of bacteria to hyphae via containment within extracellular polymeric substances (EPS) and the overall extracellular matrix (ECM) of the mycelium. Attachment structures appear to result from the hyphal surface as a result of production of EPS. The mean biofilm area across T1-3 was 3.90 (µm2) ± 0.72 (µm2) and the mean percentage coverage was 18.33 (%) ± 5.52 (%). The bacterial biofilm components could not be ruled out as co-contributing to formation of attachment structures due to the structures being present connecting individual bacterium as well as to hyphae.
Identification of polyphosphate-binding proteins inE. coliuncovers targets involved in translation control and ribosome biogenesis
Authors: Baijal Kanchi , Kore Brianna , Abramchuk Iryna , Denoncourt Alix , Han Shauna , Simms Abby , Dagenais Amy , Long Abagail R. , Rudner Adam D. , Lavallée-Adam Mathieu , Gray Michael J. , Downey Michael
Published: February 2025

In many bacteria, polyphosphate kinase (PPK) enzymes use ATP to synthesize polyphosphate (polyP) in response to cellular stress. These chains of inorganic phosphates are joined by high-energy bonds and can reach hundreds of residues in length. PolyP plays diverse functions in helping bacteria adjust to changing environmental conditions. However, the molecular mechanisms underlying these functions are poorly understood. In eukaryotic cells, polyacidic serine- and lysine-rich (PASK) motifs of proteins can mediate binding to polyP chains. Whereas PASK motifs are relatively common in yeast and human cells, we report that these sequences are rare in bacteria commonly used for polyP research. Thus, to identify novel polyP-binding proteins inEscherichia coli,we carried out an untargeted screen and identified 7 novel targets with links to translation control and ribosome biogenesis. For two targets, the GTPase activating protein YihI and the ribonuclease Rnr, we mapped the regions of polyP interaction to non-PASK sequences and identified lysine residues critical for binding. We found that deletion ofrnrsuppressed the slow growth phenotype of Δppkmutants grown on minimal media. Conversely,ppkdeletion resulted in decreased Rnr protein expression. These phenotypes were dependent on the polyP binding region of Rnr but independent of polyP binding itself, suggesting a complex interplay between PPK and Rnr function inE. coli.Overall, our work provides new insights into the scope of polyP binding proteins and extends the connections between polyP and the regulation of protein translation inE. coli.
Donor transcription suppresses D-loops incisand promotes genome stability
Authors: Djeghmoum Yasmina , Piazza Aurèle
Published: February 2025

D-loops are DNA joint molecule intermediates central to DNA break repair by homologous recombination (HR). Priority rules between recombination and transcription at the donor locus have not been investigated. Here, using a controlled break induction system and physical detection of D-loops inS. cerevisiae, we show that donor transcription by RNA polymerase II acutely suppresses D-loops incis, in an orientation-dependent manner. This inhibition does not rely on endogenous transcription factors, the RNA product, RNA:DNA hybrids, or previously characterized D-loop disruption factors. Transcription can be the major D-loop suppression pathway and inhibits the formation of repeat-mediated genome rearrangements. Transcription is therefore a negative regulator of HR at the D-loop level that promotes genome stability. These findings reveal the functional prioritization between two universal DNA-dependent processes.

Highlights

Donor transcription suppresses D-loops acutely and incis

Donor transcription is independent from conservedtransD-loop disruption pathways

Transcription directionality modulates D-loop suppression

Transcription locally enforces HR fidelity
Identification of a multi-omics factor predictive of long COVID in the IMPACC study
Authors: Gabernet Gisela , Maciuch Jessica , Gygi Jeremy P. , Moore John F. , Hoch Annmarie , Syphurs Caitlin , Chu Tianyi , Jayavelu Naresh Doni , Corry David B. , Kheradmand Farrah , Baden Lindsey R. , Sekaly Rafick-Pierre , McComsey Grace A. , Haddad Elias K. , Cairns Charles B. , Rouphael Nadine , Fernandez-Sesma Ana , Simon Viviana , Metcalf Jordan P. , Agudelo Higuita Nelson I , Hough Catherine L. , Messer William B. , Davis Mark M. , Nadeau Kari C. , Pulendran Bali , Kraft Monica , Bime Chris , Reed Elaine F. , Schaenman Joanna , Erle David J. , Calfee Carolyn S. , Atkinson Mark A. , Brackenridge Scott C. , Melamed Esther , Shaw Albert C. , Hafler David A. , Ozonoff Al , Bosinger Steven E. , Eckalbar Walter , Maecker Holden T. , Kim-Schulze Seunghee , Steen Hanno , Krammer Florian , Westendorf Kerstin , Network IMPACC , Peters Bjoern , Fourati Slim , Altman Matthew C. , Levy Ofer , Smolen Kinga K. , Montgomery Ruth R. , Diray-Arce Joann , Kleinstein Steven H. , Guan Leying , Ehrlich Lauren I. R.
Published: February 2025

Following SARS-CoV-2 infection, ∼10-35% of COVID-19 patients experience long COVID (LC), in which often debilitating symptoms persist for at least three months. Elucidating the biologic underpinnings of LC could identify therapeutic opportunities. We utilized machine learning methods on biologic analytes and patient reported outcome surveys provided over 12 months after hospital discharge from >500 hospitalized COVID-19 patients in the IMPACC cohort to identify a multi-omics “recovery factor”. IMPACC participants who experienced LC had lower recovery factor scores compared to participants without LC. Biologic characterization revealed increased levels of plasma proteins associated with inflammation, elevated transcriptional signatures of heme metabolism, and decreased androgenic steroids in LC patients. The recovery factor was also associated with altered circulating immune cell frequencies. Notably, recovery factor scores were predictive of LC occurrence in patients as early as hospital admission, irrespective of acute disease severity. Thus, the recovery factor identifies patients at risk of LC early after SARS-CoV-2 infection and reveals LC biomarkers and potential treatment targets.
Passive sensing with psyche: utilizing data from wearable technology to predict emotion states
Authors: Karim Helmet T. , Matin Ajmail , Goel Mayank
Published: February 2025

Depression and anxiety are some of the most common mental health disorders in the world contributing to significant morbidity and mortality. Past treatments have focused primarily on treating depression and anxiety. However, there is an urgent need to detect chronic stress states and potentially intervene using just-in-time personalized interventions. Modern technology has revolutionized our ability to passively measure various biological and physiological signals. In our daily lives, we generate significant amounts of electronic data from our phones, wearable technology, watches, and even computers and cars. In this analysis, we focus on using wearable data from FitBit to passively predict daily mood states (e.g., sad/tense/anxious vs. happy). We use daily FitBit data from 38 participants and ~1200 days of data to predict mood states (e.g., sad/tense/anxious vs. happy) on a day-to-day basis using an elastic net regression machine learning algorithm. We were able to accurately predict these states using a cross-validated machine learning algorithm and identified features predictive of each of the mood states. In this proof-of-concept analysis, we show that predicting daily mood states is feasible and may help to not only detect daily mood states but also improve passive awareness and deliver just-in-time interventions.
Single-nucleus analysis of thoracic perivascular adipose tissue reveals critical changes in cell composition, communication, and gene regulatory networks induced by a high fat hypertensive diet
Authors: Terrian Leah , Thompson Janice M. , Bowman Derek E. , Panda Vishal , Contreras G. Andres , Rockwell Cheryl , Sather Lisa , Fink Gregory D. , Lauver D. Adam , Nault Rance , Watts Stephanie W. , Bhattacharya Sudin
Published: February 2025

Cardiovascular disease (CVD) is the leading cause of death worldwide, with hypertension being its primary causal factor. Most blood vessels are surrounded by perivascular adipose tissue (PVAT), which regulates blood vessel tone through the secretion of vasoactive factors. PVAT is recognized as a key mediator of vascular function and dysfunction in CVD, although the underlying mechanisms remain poorly understood. To investigate PVAT’s mechanistic role in hypertension, we performed single nucleus RNA-Sequencing analysis of thoracic aortic PVAT from Dahl SS rats fed a high-fat, hypertensive diet. Computational analysis revealed extensive diet-induced changes in cell-type composition, cell-type specific gene expression, cell-cell communication pathways, and intracellular gene regulatory networks within PVAT. Furthermore, we identified key transcription factors mediating these networks and demonstrated through virtual knock-out experiments that these factors could serve as potential therapeutic targets for preventing or reversing PVAT’s hypertensive state.
TrackRefiner: A tool for refinement of bacillus cell tracking data
Authors: Ahmadi Atiyeh , Dostmohammadi Alireza , McLean Rhyan , Ingalls Brian
Published: February 2025

Motivation

Single-cell resolution time-lapse microscopy of bacterial populations is a powerful tool for assessing cellular behavior and interaction dynamics. Realizing the full potential of this approach requires accurate image analysis: segmentation of individual cell objects, tracking of persistent cells from frame to frame, and connecting of mother cells to daughters when division events occur. In particular, accurate tracking is needed to produce longitudinal datasets for analysis of interactions and features that develop through time. Tracking is challenging when populations are densely packed or when cells undergo significant motion between frames. The leading software packages struggle to provide accurate data in such cases.

Result

To address this problem, we present TrackRefiner, a tool for refinement of bacillus cell tracking data. This package was specifically designed to refine the tracking outputs of CellProfiler, a commonly used image processing tool. TrackRefiner is built with a modular and publicly accessible structure, making it adaptable for integration with other image processing software. To assess the package’s performance, we manually determined ground truth tracking results for eight datasets from four research groups, comprising a total of 159,349 object links. This curated dataset, the first of its kind, serves as a valuable benchmark for assessing the performance of bacillus cell tracking algorithms. For timelapses with frequent imaging, TrackRefiner consistently achieved, with one exception, over 98% detection accuracy and corrected 57-100% of tracking errors. Accuracy was reduced for images sampled at lower frequency.

Availability and implementation

For easy access, TrackRefiner has been published on PyPI and Anaconda. Source code and user manuals can be accessed via Github and OSF. The manually curated benchmark dataset is also posted at these sites.
Developing Foundation Models for Predicting Viral Animal Host Range in Intelligent Surveillance
Authors: Guo Jinyuan , Guo Qian , Yin Hengchuang , Han Yilun , Geng Peter X. , Hou Jiaheng , Zhang Haoyu , Tan Jie , Li Mo , Zhang Yan , Jiang Xiaoqing , Zhu Huaiqiu
Published: February 2025

Emerging human infectious viruses originating from animals continue to pose a persistent threat to global public health. Understanding the host range of animal viruses is crucial for identifying potential spillover pathways and mitigating the risk of future pandemics. Here, we present VirHRanger, a prediction method that integrates foundation models trained on viral genome and protein sequences, alongside genomic and protein compositional traits, viral phylogeny, and protein-protein interactions. To systematically predict the animal host range, VirHRanger incorporates host taxonomy-aware neural networks trained on a comprehensive collection of animal-virus associations spanning mammals, birds, and arthropods. Within a dataset of 4,006 virus species spanning 99 viral families, our model achieved robust performance with a micro-averaged AUROC of 0.938 across all host categories, demonstrating its effectiveness in capturing generalizable host signals from viral genetic data. On a dataset of 315 novel viruses, which are associated with key reservoir animal hosts and insect vectors, VirHRanger notably outperformed the homology-based method, exhibiting a strong generalizability to novel viruses. Furthermore, VirHRanger identified host range variations among closely related viruses within theCoronaviridaefamily and successfully predicted the ability of SARS-CoV-2 to infect humans and other animal hosts. These findings highlight the potential of VirHRanger to transform sequencing data into timely insights for disease control during the early stages of zoonotic outbreaks.
Human type-I interferon omega holds potent antiviral properties and promotes cytolytic CD8+T cell responses
Authors: Nguyen Hoang Oanh , Recordon-Pinson Patricia , Andreola Marie-Line , Papagno Laura , Appay Victor
Published: February 2025

The type-I interferon family is well known for its critical role in innate immunity. It comprises several members, among which IFN-α2 and IFN-β are the most extensively studied, with important antiviral and immune-modulatory functions. Recent findings linking autoantibodies against type-I interferons to severe COVID-19 suggest a potential role for IFN-ω in combating SARS-CoV-2 infection. However, little is known about human IFN-ω, as most research on this interferon has been conducted in feline models. Here, we demonstrate that human IFN-ω is secreted at levels comparable to those of IFN-α2 or IFN-β upon stimulation with inflammatory agonists and triggers a robust antiviral response, inhibiting SARS-CoV-2 infectionin vitro. Moreover, IFN-ω enhances the effector functions of antigen-specific CD8+T cells primedde novofrom healthy donor cells, highlighting its capacity to promote strong cellular immunity. Our results position IFN-ω as a key member of the type-I interferon family, with promising potential for therapeutic and vaccine applications.

Author Summary

Type-I interferons are pleiotropic cytokines, including IFN-α and IFN-β, which are well known for their antiviral activities. Here, we report on the functional characteristics of human IFN-ω, a neglected member of the type-I IFN family, which has primarily been studied in feline models. We show here that human IFN-ω induces intense downstream signaling in cells resulting in the upregulation of antiviral genes, and efficient restriction of SARS-CoV-2 replication. IFN-ω also promotes the acquisition of strong cytolytic functions by antigen primed CD8+T cells. Overall, our findings portray human IFN-ω as a major antiviral molecule, similar to the well-studied and highly effective IFN-α2. The secretion of IFN-ω upon infection is likely to be crucial for effective control of multiple viruses, advocating for its use in therapeutic approaches in humans.
Addressing efficacy of everyday hygiene cleansing products in context of sustainable handwashing behaviour in the post-pandemic era
Authors: Pathak Sandip B. , Arora Shafali , Sayyed Jabir , Trivedi Urmi , Sherin Lincy , Kumar Nitish , Jayasekera Harshinie W. , Majumdar Amitabha , Mukherjee Sayandip
Published: February 2025

Simple hygiene behaviour such as washing hands is key to improving health of individuals and reducing community transmission of communicable diseases such as respiratory and enteric infections. Consistent and relentless messaging by global and local health authorities had resulted in heightened hygiene awareness amongst the public during the COVID-19 pandemic. Unfortunately, many of the hygiene behaviours practiced during the pandemic have proven to be unsustainable in the immediate period following the pandemic. While CDC guidelines suggest washing hands with soap for a minimum of 20 seconds to prevent the spread of germs, a hygiene intervention’s effectiveness must be evaluated in context of the prevalent hygiene behaviour. Here we report our findings from an observational study conducted across India, Pakistan, Saudi Arabia, and United Arab Emirates focusing on handwashing habit of individuals in the post-pandemic period. Across all geographies, the time spent for lathering product on skin (contact time) for a significant majority of individuals recruited for the study was found to be 10 seconds and less. To ensure that marketed hygiene formulations such as liquid cleansers and sanitizers are efficacious in inactivating pathogens under conditions practiced by the majority as a part of their daily hand washing practices, we have investigated the in-vitro antimicrobial efficacy of several hygiene cleansing formulations at 10 seconds of contact time. Our results show that well-formulated cleansing solutions can reduce the input titre of both bacterial and viral pathogens by 99.9% or more, even with brief contact. With the global resurgence of both existing and emerging pathogens in the post-pandemic world, promoting sustainable handwashing practices for infection prevention remains a challenge as it is deeply rooted in the socio-economic fabric of many countries. Therefore, it is crucial to conduct regular studies like this to reassure end-users and combat complacency regarding the composition of everyday hygiene products.

Highlights

Studies of handwashing behavior in 4 countries reveals significantly short lathering duration

Antimicrobial efficacy testing of marketed products was conducted against a range of pathogens

Suitably formulated hygiene products can inactivate pathogens at short durations of contact
Nitrous oxide modulates cortical activity, wake-sleep oscillations, and produces antidepressant-like effects in mice
Authors: Kohtala Samuel , Parekh Puja K , Baramaki Iman , Kohtala Piia , Ilkka Liisa , Antila Hanna , Lee Francis S , Liston Conor
Published: February 2025

Emerging evidence suggests that nitrous oxide (N2O), a gaseous NMDA receptor antagonist and dissociative anesthetic, exerts rapid antidepressant effects akin to subanesthetic ketamine. However, its cellular, molecular, and behavioral effects remain poorly understood. Using in vivo two-photon imaging through cortical microprisms, we demonstrate that 50% N2O/O2rapidly increases neuronal calcium activity in the mouse medial prefrontal cortex (mPFC). This was corroborated by elevated c-Fos expression at both protein and mRNA levels in mPFC lysates. Cortical EEG recordings revealed that N2O increased subsequent wake-associated gamma oscillations and enhanced slow-wave activity during sleep, suggestive of cortical activation and synaptic potentiation. In a chronic corticosterone stress model, N2O elicited antidepressant-like behavioral effects in several, though not all, domains. Together, these findings indicate that a single treatment with N2O rapidly enhances cortical activity, modulates sleep and wake EEG oscillations, and produces antidepressant-like effects, paralleling key actions associated with subanesthetic ketamine.
Connectome-seq: High-throughput Mapping of Neuronal Connectivity at Single-Synapse Resolution via Barcode Sequencing
Authors: Chen Danping , Isakova Alina , Zhou Wan Joe , Wu Yunming , Zhao Boxuan Simen
Published: February 2025

Understanding neuronal connectivity at single-cell resolution remains a fundamental challenge in neuroscience, with current methods particularly limited in mapping long-distance circuits and preserving cell type information. Here we present Connectome-seq, a high-throughput method that combines engineered synaptic proteins, RNA barcoding, and parallel single-nucleus and single-synaptosome sequencing to map neuronal connectivity at single-synapse resolution. This AAV-based approach enables simultaneous capture of both synaptic connections and molecular identities of connected neurons. We validated this approach in the mouse pontocerebellar circuit, identifying both established projections and potentially novel synaptic partnerships. Through integrated analysis of connectivity and gene expression, we identified molecular markers enriched in connected neurons, suggesting potential determinants of circuit organization. By enabling systematic mapping of neuronal connectivity across brain regions with single-cell precision and gene expression information, Connectome-seq provides a scalable platform for comprehensive circuit analysis across different experimental conditions and biological states. This advance in connectivity mapping methodology opens new possibilities for understanding circuit organization in complex mammalian brains.
Deep Sound Synthesis Reveals Novel Category-Defining Sound Features in the Human Auditory Cortex
Authors: Xing Lidongsheng , Formisano Elia , Riecke Lars
Published: February 2025

The human auditory system extracts meaning from the environment by transforming acoustic input signals into semantic categories. Specific acoustic features give rise to distinct categorical percepts, such as speech or music, and to spatially distinct preferential responses in the auditory cortex. These responses contain category-relevant information, yet their representational level and role within the acoustic-to-semantic transformation process remain unclear. We combined neuroimaging, a deep neural network, a brain-based sound synthesis, and psychophysics to identify the sound features that are internally represented in the speech- and music-selective human auditory cortex and test their functional role in sound categorization. We found that the synthetized sounds exhibit unnatural features distinct from those normally associated with speech and music, yet they elicit categorical cortical and behavioral responses resembling those of natural speech and music. Our findings provide new insights into the fundamental sound features underlying speech and music categorization in the human auditory cortex.
CHD3 regulates BMP signalling response during cranial neural crest cell specification
Authors: Mitchell Zoe H. , den Hoed Joery , Claassen Willemijn , Demurtas Martina , Deelen Laura , Campeau Philippe M. , Liu Karen , Fisher Simon E. , Trizzino Marco
Published: February 2025

CHD3 is a component of the NuRD chromatin remodeling complex. PathogenicCHD3variants cause Snijders Blok-Campeau Syndrome, a neurodevelopmental disorder with variable features including developmental delays, intellectual disability, speech/language difficulties, and craniofacial anomalies. To unveil the role of CHD3 in craniofacial development, we differentiatedCHD3-KO induced pluripotent stem cells into cranial neural crest cells (CNCCs). CHD3 expression is low in wild-type iPSCs and neuroectoderm, but upregulated during CNCC specification, where it opens the chromatin at BMP-responsive enhancers, to allow binding of DLX5 and other factors. CHD3 loss leads to repression of BMP target genes and an imbalance between BMP and Wnt signalling, ultimately resulting in aberrant mesodermal fate. Consequently, CNCC specification fails, replaced by early-mesoderm identity, which can be partially rescued by titrating Wnt levels. Our findings highlight a novel role for CHD3 as a pivotal regulator of BMP signalling, essential for proper neural crest specification and craniofacial development.
The give and take in photosymbiosis unraveled by metabolomics of Radiolaria
Authors: Nikitashina Vera , Bartels Benjamin , Mansour Joost Samir , LeKieffre Charlotte , Decelle Johan , Hertweck Christian , Not Fabrice , Pohnert Georg
Published: February 2025

Marine planktonic Radiolaria harboring symbiotic microalgae are ubiquitous in the oceans and abundant in oligotrophic areas. In these low-nutrient environments they are among the most important primary producers. Systematic studies of radiolarian biology are limited because Radiolaria are non-culturable and prone to damage during sampling. To obtain insight into the mechanistic basis of radiolarian photosymbiosis we address here the metabolic contributions of the partners to the performance of the holobiont. Therefore, we describe the metabolic inventory of two highly abundant photosymbiotic Radiolaria – colony-forming Collodaria and single-celled Acantharia and compare their metabolomes to metabolomes of respective free-living algae. Most of the metabolites detected in the symbiosis are not present in the free-living algae, suggesting a significant transformation of symbionts’ metabolites by the host. The metabolites identified in both the holobiont and the free-living algae encompass molecules of primary metabolism and a number of osmolytes, including dimethylsulfoniopropionate. Mass spectrometry imaging revealed the presence of dimethylsulfoniopropionate in both the symbionts and host cells, indicating that the algae provide osmolytic protection to the host. Furthermore, our findings suggest a possible dependence of Collodaria on symbiotic vitamin B3. Distinctive differences in phospholipid composition between free-living and symbiotic stages indicate that the algal cell membrane may undergo rearrangement in the symbiosis. Our results demonstrate a strong interdependence and rewiring of the algal metabolism underlying Radiolaria-microalgae photosymbioses.
Implicit Emotional Biases in Anxiety and Depression: A Fast Periodic Visual Stimulation Study
Authors: Vandenheever David , Davidson Haleigh , Kemp Jennifer , Murphy Zack , Kujawa Autumn , Shi Catherine , Nadorff Michael , Bates-Brantley Kayla , Sidwell MacKenzie
Published: February 2025

Anxiety and depression are among the leading global causes of disability, yet their underlying neural mechanisms remain poorly understood. Traditional event-related potential (ERP) studies have shown attentional biases in anxiety and blunted responses to positive stimuli in depression, but limitations in sensitivity and interpretability hinder their clinical application. Fast Periodic Visual Stimulation (FPVS) offers an objective, high signal-to-noise ratio (SNR) approach to measuring neural responses to emotional stimuli. In this study, we applied FPVS with affective images to assess differences in emotional processing between individuals with anxiety and healthy controls across two experimental phases, optimizing stimulus presentation parameters. The results revealed that individuals with anxiety exhibited increased neural responses to negative stimuli compared to positive stimuli, as well as reduced responses to high-arousal stimuli, particularly in occipito-temporal and central-parietal regions. Additionally, individuals with comorbid depression showed blunted responses to high-arousal stimuli across multiple brain regions, consistent with reduced emotional reactivity. These findings support the feasibility of FPVS as a rapid and reliable tool for assessing emotional processing differences in clinical populations, with potential applications in translational research and psychiatric screening