bluuebunny/crossref_metadata_2025 huggingface dataset:
IFN-associated B cell hyperactivity is highly enriched in SLE patients harboring Sm/RNP antibodies
Authors: van Dooren H.J. , Atisha-Fregoso Y. , Dorjée A.L. , Huizinga T.W.J. , Mackay M. , Aranow C. , Toes R.E.M. , Diamond B. , Suurmond J.
Published: November 2024

Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by an array of autoantibodies, in particular anti-nuclear antibodies (ANA). The disease is also hallmarked by an expansion of plasmablasts (PB) in peripheral blood. How these relate to autoantibody production is not clear. Here, we aimed to understand B cell alterations in SLE and their relationship to immunoglobulin levels and autoantibody production.

We demonstrate that a subgroup of SLE patients is characterized by a high frequency of PB relative to memory B cells (high PB/M). Patients with this phenotype more frequently had high disease activity. Despite low overall frequencies of memory B cells, these patients exhibited an increased activation in the switched CD27+ memory compartment and a strong IFN signature in PB. Repertoire analysis revealed a highly polyclonal expansion and enrichment for IgG1 expressing PB in patients with a high PB/M ratio which was reflected in increased serum IgG levels. Importantly, the hyperactive B cell phenotype was highly enriched in patients harboring Sm/RNP autoantibodies (OR: 9.17 (2.97-26.0)). In summary, we show for the first time a direct relationship between IFN and PB expansion in a subgroup of SLE patients, highly enriched in those harboring Sm/RNP antibodies. These results provide insight into the pathways leading to B cell hyperactivity and autoantibody production which may guide the tailoring of B cell- and IFN-targeted therapies.

Graphical abstract
Reciprocal host-Wolbachiainteractions shape infection persistence upon loss of cytoplasmic incompatibility in haplodiploids
Authors: Kauai Felipe , Wybouw Nicky
Published: November 2024

Maternally transmitted symbionts such asWolbachiaspread within host populations by mediating reproductive phenotypes. Cytoplasmic incompatibility (CI) is a reproductive phenotype that interferes with embryonal development when infected males fertilize uninfected females.Wolbachia-based pest control relies on strong CI to suppress or replace pest populations. Host modifier systems have been identified that suppress CI strength, threatening the efficacy ofWolbachia-based pest control programs. In haplodiploids, CI embryos either die (Female Mortality, FM-CI) or develop into uninfected males (Male Development, MD-CI). The reciprocal spread of host suppressors and infection as well as the interaction with the two CI outcomes in haplodiploids remains poorly understood. The contribution of sex allocation distortion (Sd), an independentWolbachia-mediated reproductive phenotype that causes a female-biased sex ratio, to infection persistency in haplodiploids is also poorly understood, especially with imperfect maternal transmission. To address these issues, we developed individual-based simulations grounded in the haplodiploidTetranychus urticaepest system. We validated our simulations by trackingWolbachiaspread in experimentalT. urticaepopulations and by contrasting the predictions of deterministic models. Within ∼15 host generations, we found that deterministic models inflate final infection frequencies by ∼8.1%, and significantly overestimate the driving potential of CI, particularly under low initial infection frequencies. Compared to MD-CI, we show that FM-CI strongly extends infection persistency when suppressors are segregating in the population. We also quantify how maternal transmission and CI outcome modulate the reciprocal spread of suppressors and infection. Upon loss of CI, we show that hypomorphic expression of Sd (∼5%) is sufficient for a stable persistence of infection. We derive a closed-form expression that approximates the stable polymorphic infection frequencies that can be maintained by Sd. Collectively, our results advance our understanding of how symbiosis with CI-inducingWolbachiamight evolve and inform CI-based pest control programs of potential future risks.
Preparing high-quality chromosome spreads fromCrocusspecies for karyotyping and FISH
Authors: El-nagish Abdullah , Liedtke Susan , Breitenbach Sarah , Heitkam Tony
Published: November 2024

Background

The saffron-producingCrocus sativusand its wild relativeC. cartwrightianusare key species for understanding genetic evolution in this genus. Molecular-cytogenetic methods, especially fluorescentin situhybridization (FISH), are essential for exploring the genetic relationships in this genus. Yet, preparing high-quality chromosomes for FISH analysis acrossCrocusspecies remains difficult. A standardized protocol for achieving clear and well-separated mitotic chromosomes is still lacking. This study assesses the effectiveness of four chromosome fixation methods for optimal chromosome spread preparation inCrocus. Root tips of differentCrocusspecies were treated with four chromosome preparation methods namely hydroxyurea-colchicine (HC), nitrous oxide (NO), hydroxyquinoline (HQ), and ice water (IW) pretreatments to investigate their effectiveness in producing high-quality mitotic chromosome spreads. Metaphases obtained by the four methods were analyzed to assess their quality and metaphase index.

Results

Evaluation of 22,507 nuclei allowed us to confidently recommend a protocol forCrocuschromosome preparation. Among the methods, ice water pretreatment yielded the highest metaphase index (2.05%), more than doubling the results of HC (1.08%), NO (1.15%), and HQ (1.16%). Ice water-treated chromosomes exhibited better chromosome morphology, with relatively proper size, and non-overlapping chromosomes that were optimal for FISH analysis. Ice water pretreatment was also applied toC. cartwrightianus, the diploid progenitor ofC. sativus, where it demonstrated similar efficacy. DAPI staining of chromosomes in both species allowed for clear visualization of intercalary and terminal heterochromatin. FISH analysis using 18S-5.8S-25S and 5S rDNA probes confirmed the utility of IW-prepared chromosome spreads for cytogenetic studies.

Conclusions

We strongly recommend ice water pretreatment as a suitable and effective method for obtaining many metaphase spreads of high-quality inC. sativusand related species, particularly for applications involving a detailed cytogenetic analysis.
A synthetic potassium channel reduces oxidative stress via cellular adaptronics
Authors: Russo Alberto , Saponaro Andrea , Trini Simone , Nelson Tyler S. , Allen Heather N. , Oddone Rebecca , Villa Chiara , Torrente Yvan , Khanna Rajesh , Porro Alessandro , Thiel Gerhard , Moroni Anna
Published: November 2024

Aerobic metabolism is crucial for human life but reactive oxygen species (ROS) byproducts cause cellular toxicity. Although antioxidant defenses usually maintain ROS levels within a safe range, ROS production can exceed the buffering capacity of cells, causing oxidative stress and disease. Inspired by the principle of adaptronics, we created a synthetic potassium channel that senses cellular ROS levels and mitigates oxidative stress by modulating membrane potential. Engineered from TASK1 channel, ROSTASK1 is sensitive to supraphysiological ROS levels, imposing restorative membrane potential changes on cells or organelles under oxidative stress. We also engineered a blue-light sensitive ROSTASK1 to achieve optogenetic control. In proof-of-concept experiments, mitochondrially-delivered ROSTASK1 rescued ROS overproduction in myoblasts from a Leigh syndrome patient and ROSTASK1 abolished chronic pain-like behavior in mouse models of inflammation and nerve injury. Thus, by functioning as both a sensor and modulator of ROS levels, ROSTASK1 provides a self-healing system during oxidative stress.
YTHDF1 and YTHDC1 m6A reader proteins regulate HTLV-1taxandhbzactivity
Authors: King Emily M. , Midkiff Amanda , McClain Karsyn , Kim Sanggu , Panfil Amanda R.
Published: November 2024

Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus responsible for adult T-cell leukemia/lymphoma (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a progressive neurodegenerative disease. Regulation of viral gene expression plays a key role in viral persistence and pathogenesis. However, the molecular mechanisms underlying this fine-tuned regulation remain poorly understood. Little is known regarding RNA chemical modifications of HTLV-1 RNA and how these affect viral biology and disease development. Posttranscriptional chemical modification of RNA is common in eukaryotes, with N6-methyladenosine (m6A) being the most prevalent. In this study, we investigated the role of m6A RNA modifications on HTLV-1 gene expression. Using MeRIP-Seq, we mapped sites of m6A modification to the 3’ end of the viral genome. We found HTLV-1 RNA, as well as viral oncogene transcriptstaxandhbz, contained m6A modifications. m6A-depletion in HTLV-1-transformed cells decreased sense-derived viral genes (Tax, Gag, Env) and increased antisense-derivedHbzexpression.Taxandhbztranscripts were bound by reader proteins YTHDF1 and YTHDC1 in a panel of HTLV-1 T-cell lines. Using expression vectors and shRNA-mediated knockdown, we found YTHDF1 had opposing effects on viral gene expression – decreasing sense-derived viral genes and increasing antisense-derivedHbz. Upon further study, the YTHDF1 effects ontaxabundance were dependent ontaxm6A deposition. The nuclear m6A reader protein YTHDC1 affected the abundance of both sense- and antisense-derived viral transcripts and specifically enhanced the nuclear export oftaxtranscript. Collectively, our results demonstrate global m6A levels and m6A reader proteins YTHDF1 and YTHDC1 regulate HTLV-1 gene expression.

Importance

Human T-cell leukemia virus type 1 (HTLV-1) persistence and pathogenesis are controlled through tight regulation of viral gene expression. The fate of RNA can be controlled by epigenetic modifications which impact gene expression without altering the DNA sequence. Our study details the impact of N6-methyladenosine (m6A) RNA chemical modifications on HTLV-1 gene expression. We found reductions in global m6A levels affected viral gene expression, decreasingTaxand other sense-derived viral genes, while increasing the antisense-derivedHbz. Our results suggest the oncogenic viral transcripts,taxandhbz, are m6A-modified in cells. We found these viral RNA modifications are interpreted by reader proteins YTHDF1 and YTHDC1, which dictate the fate of the viral RNA. Understanding HTLV-1 RNA chemical modifications offers potential insights into novel therapeutic strategies for HTLV-1-associated diseases.
Large scale semi-automated quantification of viral spread reveals multi-phasic structure of plaque formation
Authors: Howell Liam M. , Newsome Timothy P
Published: November 2024

Plaque assays are typically quantified at an endpoint and fail to capture the temporal dynamics of viral infection and spread. In this study we introduce a high-throughput method utilising live-cell imaging and a recombinant vaccinia virus (VACV) engineered to express two fluorescent transgenes linked to distinct replication phases. This novel approach allows for real-time tracking of VACV plaques from their inception at a single infected cell through to multicellular expansion, enabling detailed kinetic analysis of plaque development. Using this analysis pipeline we categorise VACV plaque formation into three distinct phases: Establishment, Expansion, and Exhaustion, and quantitatively describe their dynamics. Our findings reveal significant variability in the initiation time of plaque spread (from single-cell to multicellular stages) and the growth rate of plaques, both between individual plaques and across different cell lines. This variability underscores the influence of host cellular factors on the kinetics of viral replication. Additionally, we reveal that the viral replication cycle dramatically accelerates through the early phases of plaque formation, which we hypothesise is driven by the changing multiplicity of cellular infection at the plaque edge. Finally, we demonstrate that differences in plaque sizes between two cell lines (BS-C-1 and HaCaT) can be largely attributed to variations in viral replication rate. This research reinforces the value of live-cell fluorescence microscopy in elucidating the complex spatiotemporal dynamics of viral infections, and contributes to a deeper understanding of the mechanisms driving viral spread and replication kinetics.
Towards Multimodal Longitudinal Analysis for Predicting Cognitive Decline
Authors: Ashish Rayan M. , Turner Jessica A.
Published: November 2024

Understanding and predicting cognitive decline in Alzheimer’s disease (AD) is crucial for timely intervention and management. While neuroimaging biomarkers and clinical assessments are valuable individually, their combined predictive power and interaction with demographic and cognitive variables remain underexplored. This study lays the groundwork for comprehensive longitudinal analyses by integrating neuroimaging markers and clinical data to predict cognitive changes over time. Using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), we applied feature-driven supervised machine learning techniques for assessing cognitive decline predictability. We hypothesize that combining neuroimaging biomarkers with demographic and clinical assessment variables significantly improves the prediction of cognitive decline in Alzheimer’s disease. Our results show that while imaging biomarkers alone offer moderate predictive capabilities, including key clinical assessment and demographic variables in conjunction with imaging biomarkers significantly improves the model performance. Furthermore, our results indicate that non-imaging variablesalonecan serve as effective and cost-efficient predictors of cognitive decline. This study underscores the need for integrating multi-dimensional data in future longitudinal research to capture time-dependent patterns in cognitive decline and guide the development of targeted intervention strategies. We also introduce NeuroLAMA - an open and extensible data engineering and machine-learning system, to support the continued investigation by the community
DynaMELD: A Dynamic Model of End-Stage Liver Disease for Equitable Prioritization
Authors: Cooper Michael J. , Gao Xiang , Zhao Xun , Khoroshchuk Dariia , Wang Yingke , Azhie Amirhossein , Naghibzadeh Maryam , Holdsworth Sandra , Gross Jed Adam , Brudno Michael , Feld Jordan J. , Jaeckel Elmar , Hirschfield Gideon , Krishnan Rahul G. , Bhat Mamatha
Published: November 2024

Liver transplantation (LT) is a life-saving intervention for patients with end-stage liver disease (ESLD). However, 12–20% of patients listed for LT will die on the waitlist. Modern risk scores used for transplant prioritization cannot encompass the full statistical heterogeneity of patients awaiting LT, disadvantaging women and patients with cholestatic liver disease.

Our study objective was to implement more equitable LT prioritization via a more expressive class of statistical models to individualize risk prediction.

To do so, we created DynaMELD, a deep machine learning-based model of waitlist prioritization. DynaMELD leverages a neural network to model complex interactions between covariates, and leverages the rate-of-change (velocity) of time-varying laboratory biomarkers to predict a more personalized risk of mortality or dropout. Our study cohort comprised 53,046 patients with ESLD listed for LT from 2016– 2023 from the U.S. Scientific Registry of Transplant Recipients.

Using 90-day concordance to measure risk discrimination, DynaMELD achieves 90-day concordance 0.5% higher than MELD 3.0 (p< 0.001). Using pooled group concordance (PGCI) as a measure of fairness, DynaMELD achieves a PGCI 1.2% higher for female patients (p< 0.001), 8.3% higher for patients with primary biliary cholangitis (p< 0.001), 7.2% higher for patients with primary sclerosing cholangitis (p< 0.001), and 1.5% higher for patients with acute-on-chronic liver failure Grade 1 (p< 0.001) compared to MELD 3.0. DynaMELD reclassifies members of these sub-groups into higher risk tiers, suggesting it would improve their access to organ offers. Introspecting upon DynaMELD using the method of SHapley Additive exPlanations (SHAP) values provides an individualized degree of model interpretability.

Overall, DynaMELD may provide more accurate, individualized predictions of waitlist mortality or dropout to reduce inequities and fairly prioritize patients for liver transplant.
Unveiling the Hidden Syndrome: The Enigma of Anti-Transcobalamin Receptor Autoantibodies
Authors: Matsuda Kazuki M. , Kotani Hirohito , Sato Shinichi , Yoshizaki Ayumi
Published: November 2024

The transcobalamin receptor (CD320) functions as a critical mediator for vitamin B12 uptake in cells, with emerging evidence linking autoantibodies against CD320 to various autoimmune conditions. Pluvinageet al.’s recent study identified anti-CD320 autoantibodies as a cause of autoimmune vitamin B12 central deficiency, specifically affecting the central nervous system while sparing peripheral nerves. Their findings align with our previous work showing anti-CD320’s role in cutaneous arteritis. Both studies identified overlapping CD320 epitopes targeted by autoantibodies and demonstrated the therapeutic efficacy of high-dose vitamin B12 supplementation in mitigating symptoms by reducing CD320 expression on the surface of vascular endothelial cells. Expanding on these findings, we observed anti-CD320 autoantibodies in systemic sclerosis, systemic lupus erythematosus, and other inflammatory disorders, suggesting a broader clinical relevance. The work by Pluvinageet al.and our group supports the concept of an "anti-CD320-associated syndrome," with high-dose B12 supplementation as a promising treatment strategy. Further research is needed to fully elucidate the tissue-specific mechanisms and pathophysiology underlying these autoimmune conditions.
Genetically predicted plasma erythropoietin levels and clonal haematopoiesis risk: a Mendelian randomisation study
Authors: Richenberg George , Carter Paul , Gaunt Tom R. , Kar Siddhartha P.
Published: November 2024

The aetiology of clonal haematopoiesis (CH) and its progression to haematological malignancies is poorly understood. Erythropoietin (EPO) has been linked to favourable haematopoietic stem and progenitor cell clonal compositions in mice and humans, but a direct large-scale assessment of its role in CH is lacking. We evaluated the association between plasma EPO levels and overall,DNMT3A- andTET2-mutant CH risks using Mendelian randomisation (MR). Germline variants in the EPO gene (common promoter variant rs1617640 and rare missense mutation rs11976235) from a genome-wide association study (GWAS) of plasma EPO levels in 33,657 individuals were used to genetically predict EPO levels. CH associations were obtained from a European ancestry GWAS of 25,657 CH cases, including 16,219DNMT3A- and 3,918TET2-mutant CH cases, and 342,869 “controls” without detectable CH. MR analyses using the Wald ratio revealed that higher plasma EPO levels proxied by rs1617640 were associated with reduced risks of overall (odds ratio/OR (95% confidence interval/CI)=0.68 (0.50-0.93); P=0.01),DNMT3A- (OR (95% CI)=0.68 (0.48-0.96); P=0.03) andTET2-mutant (OR (95% CI)=0.48 (0.24-0.97); P=0.04) CH. These point estimates were directionally consistent with those obtained using the rare variant rs11976235, and in analyses of overall CH in African, East Asian and South Asian ancestry individuals. Bayesian evaluation also indicated that elevated plasma EPO levels were protective forDNMT3A- andTET2-mutant CH with probabilities ≥92% and 73%, respectively. Thus, increased genetically predicted plasma EPO levels are protective for overall CH and its two most common subtypes. Our findings suggest that pharmacologically raising EPO may be a promising strategy worth further investigating for the prevention of CH and possibly to prevent its progression to haematological malignancies in high-risk individuals.
The impact of human behavioral adaptation stratified by immune status on COVID-19 spread with application to South Korea
Authors: Sharbayta Sileshi Sintayehu , Jo Youngji , Jung Jaehun , Buonomo Bruno
Published: November 2024

As the COVID-19 pandemic continues with ongoing variant waves and vaccination efforts, population-level immunity and public risk perceptions have shifted. This study presents a behavioral transmission model to assess how virus spread and care-seeking behavior differ based on individuals’ immunity status. We categorized the population into two groups: “partially immune” and “susceptible,” which influenced their response to vaccination and testing, as well as their prioritization of information related to disease prevalence and severity. Using COVID-19 data from South Korea (February 1, 2022 - May 31, 2022), we calibrated our model to explore these dynamics. Simulation results suggest that increasing reactivity to information among partially immune individuals to the same level as susceptible individuals could reduce peak active cases by 16%. Conversely, if partially immune individuals shift their risk perception focus from prevalence (90% prevalence vs. 10% severity) to severity (90% severity vs. 10% prevalence), the peak in active cases could increase by 50%. These findings highlight the need for adaptive vaccination and testing strategies as public risk perceptions evolve due to prior exposures and vaccinations. As new variant waves emerge in the post-pandemic endemic era, our study offers insights into how immunity-based behavioral differences can shape future infection peaks.

Subject class

92D30, 92-10, 37N25, 34A34
Evaluating the health impact, health-system costs and cost-effectiveness of using TrueNat on stool samples compared to usual care for the diagnosis of paediatric tuberculosis in primary care settings: a modelling analysis
Authors: Mafirakureva Nyashadzaishe , Daniel Olugbenga Kayode , Olayinka Jamiu Olabamiji , Ochei Kingsley Chinedum , Klinkenberg Eveline , Ihesie Austin , Nongo Debby , Eneogu Rupert Amanze , Mwansasu Andwele , Elom Emeka Uga , Aderonke Agbaje Vivian , Dakum Patrick Patrick Sunday , Mensah Charles Olalekan , Odola Oluwafemi Christopher , Olayemi Abiola Oladotun , Faleye Emily Yemisi , Makinde Adekunle Omotoso , Dodd Peter J.
Published: November 2024

The World Health Organisation (WHO) recommends rapid molecular diagnostics to improve bacteriological confirmation of tuberculosis in children. TrueNat MTB, MTB Plus and MTB-RIF Dx assays (Molbio Diagnostics, India), recommended by WHO, hold potential as point-of-care tests in resource-limited settings. Using stool samples with these assays could enhance testing access, improve linkage to care, reduce costs, and increase cost-effectiveness over traditional methods. However, evidence on their costs and cost-effectiveness is limited and needed for informed policy decisions on adoption and scale up. We used a decision-tree analytic modelling approach, time-and-motion study, and routine data to estimate the potential impact of implementing stool-based TrueNat testing for the diagnosis of pulmonary tuberculosis in children within Nigerian primary healthcare settings on healthcare outcomes, resource use, health system costs, and cost-effectiveness relative to the standard of care (SoC). The cost per test was $13.06 (standard deviation; $0.77) for TrueNat and $16.25 (standard deviation; $1.34) for Xpert. For every 100 children with presumptive tuberculosis, the stool-based TrueNat testing intervention was projected to increase case detection rate by 29% (95% uncertainty interval [UI 9-48]) and bacteriological confirmation by 6% (95% UI 3-8). Diagnoses at primary health centres (PHC) would increase by 34% (95% UI 20-46), averting 7 (95% UI 2-12) deaths and 182 (95% UI 59-311) discounted DALYs. Although resource use and health system costs increased by $6,172 (95% UI -2,427-10,455) per 100 children, the incremental cost-effectiveness ratio of $34 per DALY averted suggests cost-effectiveness at thresholds of 0.5×GDP per capita. Implementing stool-based TrueNat testing has potential to increase access and reduce direct health system costs associated with the diagnosis of pulmonary tuberculosis in children in routine health care settings. Such an approach is likely to represent a good value for money compared to SoC.

Funding

USAID
The ClinGen Syndromic Disorders Gene Curation Expert Panel: Assessing the Clinical Validity of 111 Gene-Disease Relationships
Authors: Broeren Eleanor C , Gitau Vanessa N , Byrne Alicia B , Ajuyah Pamela , Balzotti Marie B , Berg Jonathan S , Bluske Krista , Bowen Beatrice Monica , Brown Matthew P , Buchanan Amanda , Burns Brendan T , Burns Nicole J , Chandrasekhar Anjana , Chawla Aditi , Chong Jessica X , Chopra Maya , Clause Amanda R , DiStefano Marina T , DiTroia Stephanie , Elnagheeb Marwa A , Girod Amanda N , Goel Himanshu , Golden-Grant Katie L , Ha Thuong , Hamosh Ada , Huang Jennifer M , Hughes Madeline Y , Jamuar Saumya S , Kam Sylvia , Kesari Akanchha , Koh Ai Ling , Lassiter Rhonda N.T. , Leigh Sarah E. , Lemire Gabrielle , Lim Jiin Ying , Malhotra Alka , McCurry Hannah R , Milewski Becky , Moosa Shahida , Murray Stephen A , Owens Emma H , Palmer Elizabeth E , Palus Brooke C , Patel Mayher J , Rajkumar Revathi , Ratliff Julie C , Raymond F Lucy , Assis Bruno D.R.R. , Sajan Samin A , Schlachetzki Zinayida , Schmidt Sarah A , Stark Zornitza , Samuel Strom P , Taylor Julie P , Thaxton Courtney , Thrush Devon L , Toro Sabrina , Tshering Kezang , Vasilevsky Nicole A , Wayburn Bess , Webb Ryan F , O'Donnell-Luria Anne , Coffey Alison J
Published: November 2024

Purpose: The Clinical Genome Resource (ClinGen) Gene Curation Expert Panels (GCEPs) have historically focused on specific organ systems or phenotypes; thus, the ClinGen Syndromic Disorders GCEP (SD-GCEP) was formed to address an unmet need. Methods: The SD-GCEP applied the ClinGen framework to evaluate the clinical validity of genes associated with rare syndromic disorders. 111 Gene-Disease Relationships (GDRs) associated with 100 genes spanning the clinical spectrum of syndromic disorders were curated. Results: From April 2020 through March 2024, 38 precurations were performed on genes with multiple disease relationships and were reviewed to determine if the disorders were part of a spectrum or distinct entities. 14 genes were lumped into a single disease entity and 24 were split into separate entities, of which 11 were curated by the SD-GCEP. A full review of 111 GDRs for 100 genes followed, with 78 classified as Definitive, 9 as Strong, 15 as Moderate, and 9 as Limited highlighting where further data are needed. All diseases involved two or more organ systems, while the majority (88/111 GDRs, 79.2%) had five or more organ systems affected. Conclusion: The SD-GCEP addresses a critical gap in gene curation efforts, enabling inclusion of genes for syndromic disorders in clinical testing and contributing to keeping pace with the rapid discovery of new genetic syndromes.
Global Lipidomic and Metabolomic Uncovers Blood Signatures of Left Ventricular Assist Devices for Heart Failure
Authors: Zhang Na , Chen Hao , Li Heping , Xu XiaoYu , Zhang Xuman , Hou Haitao , Han Zhifu , He Guowei , Zhang Yu
Published: November 2024

Background

The left ventricular assist device (LVAD) significantly improves the health of patients with chronic advanced heart failure (HF); however, its underlying molecular mechanisms remain unclear. This study aimed to develop an integrated plasma pseudo-targeted lipidomic and untargeted metabolomic strategy to provide insight into the early postoperative changes that occur in the global blood metabolome profile and determine whether these changes can be used to screen patients for LVAD installation.

Methods

Data was collected from 20 pairs of patients with HF before and after LVAD surgery and compared with 36 healthy subjects. Plasma metabolomic and lipidomic profiles were established by liquid chromatography-mass spectrometry and analyzed by multivariate statistics.

Results

A total of 49 lipids showed significant recovery after LVAD pump loading compared with before pump loading. Moreover, 144 differential metabolites and 21 pathways were identified from healthy control and patients with HF. Among which, 33 metabolites were differentially regulated between pre and post-LVAD samples (p < 0.05, FC > 2). Further analysis revealed differential regulation in two key pathways: fatty acid metabolism and methionine metabolism. Simultaneously, we identified S-adenosylmethionine, L-methionine, FFA (14:1), and FFA (16:1) as potential diagnostic markers for the prediction of LVAD efficacy in HF. In three postLVAD patients who died within one year, we observed a decrease in SM (24:0) and SM (22:0) immediately before LVAD implantation, indicating that these metabolites may predict a poor outcome. Furthermore, we demonstrated that PS (18:1/20:4) and canavaninosuccinate were significantly attenuated in postLVAD patients.

Conclusions

Our findings provide preliminary evidence that LVAD therapy is associated with changes in the metabolomic and lipidomic profiles of patients with HF. It highlights the potential use of metabolomics as a tool to stratify LVAD patients based on the risk of adverse events. These findings may help to guide patient selection for advanced HF therapies and identify new HF therapeutic targets.

Graphical Abstract
Supervised and self-directed technology-based dual-task exercise training programme for older adults at risk of falling – Protocol for a feasibility study
Authors: Mathur Prerna , Thomas Helen , Cooper Angela , Chechlacz Magdalena , Stathi Afroditi , Goodyear Victoria , Miller Caroline , Krauss Taylor , Ives Natalie , Magill Laura , Kinghorn Philip , Wilson Daisy , Chiou Shin-Yi
Published: November 2024

Falls among older adults pose a significant public health challenge, as they lead to severe outcomes such as fractures and loss of independence. Research has shown that training cognitive function and balance simultaneously, termed Dual-Task (DT) training, improves mobility and reduces fall risks in older adults. This study aims to evaluate the feasibility and acceptability of a blended supervised and self-directed technology-based DT training programme for older adults who have high risk of falling. This is a single-arm, non-randomised feasibility study employing quantitative and qualitative methods. Fifty healthy adults aged 65 years or above will be recruited from the NHS primary and secondary care pathways and from the community. Participants will undergo supervised cognitive and balance DT training for 12 weeks, followed by self-directed DT training for an additional 12 weeks. The cognitive training will be delivered using a commercial mobile application (app) available from the AppStore or Google Play. The balance training will involve static (Marching on the spot, Tandem Stand, Hip Abduction & Extension, Squats, Tiptoe Stand, and Pendulum/Sideways Sway) and dynamic (Figure of Eight Walk, Walking Forwards and Backwards, Lunges, Functional Reach, Toe Tapping, Upper Limb Strength Exercises, and Side-Steps/Simple Grapevine) exercises focused on improving balance, postural stability and strength. Feasibility outcomes will be recruitment, adherence, usage of the app, and attrition. Outcomes measure data, that will be collected at baseline and at 24 weeks, includes the Timed-Up and Go (TUG) test (likely primary outcome in any future trial), along with self-reported questionnaires assessing cognition, fear of falling, quality of life, healthcare service usage, and the self-reported number of falls. Focus group interviews will be conducted with thirty participants and thirty healthcare professionals for in-depth exploration of the feasibility and acceptability of the DT training programme.

Trial registration number

ISRCTN15123197
Polygyny among men in Ghana: a population based cross-sectional study
Authors: Quartey Gladys , Padi Abigail , Dadzie Louis Kobina , Dzirasah King David , Aboagye Richard Gyan , Ahinkorah Bright Opoku , Seidu Abdul-Aziz
Published: November 2024

Background

Polygyny has been practiced in many cultures around the world over the past couple of decades. Available evidence indicates that polygyny is practiced in more than 83% of the 849 cultures globally. Therefore, this study seeks to assess the prevalence and determinants of polygyny among men in Ghana.

Methods

This research is based on 1,892 married men using the 2014 Ghana Demographic and Health Survey (GDHS) data. Polygyny was the outcome variable. Multilevel mixed-effects logistic regression models were fitted to examine the factors associated with polygyny. The results were presented as adjusted odds ratio with 95% confidence interval.

Results

The prevalence of polygyny was 8.8[7.5%-10.5%]. Men aged 45-59[aOR=7.01; 95%CI= [2.87,17.15] and 30-44 [aOR=4.36; 95%CI= [1.81,10.53] were more likely to engage in polygyny compared to those aged 15-29. Men in communities with high wealth status had higher odds of polygyny compared to those in communities with low wealth status [aOR=2.49; 95%CI= [1.22,5.09]. On the other hand, men with a secondary level of education [aOR=0.53;95%CI= [0.29,0.95] and those with comprehensive knowledge of HIV and AIDS [aOR=0.59;95%CI= [0.37,0.94] were less likely to engage in polygyny compared to those with no formal education and those without comprehensive HIV and AIDS knowledge.

Conclusion

The study has contributed to knowledge on the prevalence and determinants of polygyny among men in Ghana. In Ghana, age, education, community wealth status, and knowledge of comprehensive HIV/AIDS are determinants of polygyny among men. Interventions to improve universal access to education and social protection policies are critical to reshaping socio-cultural practices and views that engender polygyny among men in Ghana. In addition, strengthening existing laws and policies is important in addressing the social challenges caused by polygamous unions. Furthermore, explorative studies must be conducted to identify the possible impact of polygamy on those who practice it.
Post-Critical Period Transcriptional and Physiological Adaptations of Thalamocortical Connections after Sensory Loss
Authors: Iyer Laxmi , Johnson Kory , Collier Sean , Koretsky Alan P. , Petrus Emily
Published: November 2024

Abstract Figure

Graphical Abstract

Unilateral whisker denervation activates plasticity mechanisms and circuit adaptations in adults. Single nucleus RNA sequencing and multiplex fluorescence in situ hybridization revealed differentially expressed genes related to altered glutamate receptor distributions and synaptogenesis in thalamocortical (TC) recipient layer 4 (L4) neurons of the sensory cortex, specifically those receiving input from the intact whiskers after whisker denervation.

Electrophysiology detected increased spontaneous excitatory events at L4 neurons, confirming an increase in synaptic connections. Elevated expression levels of Gria2 mRNA and functional GluA2 subunit of AMPA receptors at the TC synapse indicate the presence of stabilized and potentiated TC synapses to L4 excitatory neurons along the intact pathway after unilateral whisker denervation. These adaptations likely underlie the increased cortical activity observed in rodents during intact whisker sensation after unilateral whisker denervation. Our findings provide new insights into the mechanisms by which the adult brain supports recovery after unilateral sensory loss.
Viral susceptibility and innate immune competency ofCarollia perspicillatabat cells produced for virological studies
Authors: Gonzalez Victoria , Word Cierra , Guerra-Pilaquinga Nahomi , Mazinani Mitra , Fawcett Stephen , Portfors Christine , Falzarano Darryl , Kell Alison M. , Jangra Rohit K. , Banerjee Arinjay , Seifert Stephanie N. , Letko Michael
Published: November 2024

Multiple viruses that are highly pathogenic in humans are known to have evolved in bats. How bats tolerate infection with these viruses, however, is poorly understood. As viruses engage in a wide range of interactions with their hosts, it is essential to study bat viruses in a system that resembles their natural environment like bat-derivedin vitrocellular models. However, stable and accessible bat cell lines are not widely available for the broader scientific community. Here, we generatedin vitroreagents for the Seba’s short-tailed bat (Carollia perspicillata), tested multiple methods of immortalization, and characterized their susceptibility to virus infection and response to immune stimulation. Using a pseudotyped virus library and authentic virus infections, we show that theseC. perspicillatacell lines derived from a diverse array of tissues are susceptible to viruses bearing the glycoprotein of numerous orthohantaviruses, including Andes and Hantaan virus and are also susceptible to live hantavirus infection. Furthermore, stimulation with synthetic double-stranded RNA prior to infection with VSV and MERS-CoV induced a protective antiviral response, demonstrating the suitability of our cell lines to study the bat antiviral immune response. Taken together, the approaches outlined here will inform future efforts to developin vitrotools for virology from non-model organisms and theseC. perspicillatacell lines will enable studies on virus-host interactions in bats.
Early-Life Systemic Inflammation Modulate Microglia Phenotype to Slow Down Aβ Pathology in the 5xFAD Mouse Model of Alzheimer’s Disease
Authors: Yang Yiyi , García-Cruzado Marta , Zeng Hairuo , Wang Xinrui , Bachiller Sara , Camprubí-Ferrer Lluís , Bahatyrevich-Kharitonik Bazhena , Fernández-Calle Rosalía , Deierborg Tomas
Published: November 2024

Early infection in life has been implicated in increasing the risk for neurological disorders. Here we performed single-cell sequencing of microglia and monocytes from 6-month-old WT and 5xFAD mice subjected to one dose of LPS (1mg/kg) at postnatal day 9. We successfully mapped disease-associated microglia (DAM) and perivascular macrophages in our data and demonstrated a subpopulation of microglia that adopted a monocyte-like profile, marked by Lyz2, Tmsb10, Lgals1and Lgals3. This unique subset appeared in response to early systemic LPS challenge and AD pathology but diminished in the presence of double stimulus. Different cytokines were altered in the brain and periphery as seen using mesoscale plates. GM-CSF and MIP-1α levels were altered in an amyloid-β(Aβ)-dependent manner in hippocampus. MIP-1β and IFN-γ were altered upon early LPS stimulation. In the periphery, we found MMP-9 was significantly increased in serum samples from 5xFAD mice. Interestingly, early LPS stimulation significantly elevated TNF-α in serum from WT and 5xFAD mice, but was reduced in the hippocampus due to Aβ pathology. The LPS treatment in 5xFAD mice had a tendency to improve the short-term memory deficit. Taken together, we observed long-lasting effects from early life stress, including activation of inflammation in the periphery and brain through modulation of different signaling cascades.
Scents Modulate Anxiety Levels, but Electroencephalographic and Electrocardiographic Assessments Could Diverge from Subjective Reports
Authors: Morozova Marina , Gabrielyan Irina , Kleeva Daria , Efimova Victoria , Lebedev Mikhail
Published: November 2024

Scents could modulate anxiety levels, such as anxiety in a medical office. Here we investigated the impact of two scents on the subjective and physiological anxiety markers in the dental office environment, utilizing self-reported anxiety assessments alongside physiological assessment with electroencephalographic (EEG) and electrocardiographic (ECG) measurements. Lavender was the first tested scent with the previously reported calming effect. African stone was the second stimulus with a musky scent. Twenty healthy participants took part in scent exposure sessions. Anxiety levels were assessed using the State-Trait Anxiety Inventory (STAI), EEG-based theta, alpha, and beta power ratios, and heart rate variability (HRV) indices derived from ECG data. Lavender exposure significantly decreased self-reported anxiety whereas African stone reduced physiological indicators of anxiety. Namely, African stone exposure led to decreased theta and increased alpha power in the parietal-occipital EEG signals. Additionally, decreases were observed in low-frequency (LF) HRV power and total HRV power, reflecting lowered autonomic arousal. These findings support the potential effectiveness for olfactory interventions to aid in anxiety management within clinical environments, but draw attention to the issue of proper evaluation of anxiety. In particular, the difference between the subjective reports and traditional EEG and HRV markers indicates that anxiety involves a complexity of factors, which makes its treatment by scents challenging.
Iso-orientation bias of layer 2/3 connections: the unifying mechanism of spontaneous, visually and optogenetically driven V1 dynamics
Authors: Rózsa Tibor , Cagnol Remy , Antolík Ján
Published: November 2024

Functionally specific long-range lateral connectivity in layer 2/3 of the primary visual cortex (V1) supports the integration of visual information across visual space and shapes spontaneous, visual and optogenetically driven V1 activity. However, a comprehensive understanding of how these diverse cortical regimes emerge from this underlying cortical circuitry remains elusive. Here we address this gap by showing how the same model assuming moderately iso-orientation biassed long-range cortical connectivity architecture explains diverse phenomena, including (i) range of visually driven phenomena, (ii) modular spontaneous activity, (iii) the propagation of spontaneous cortical waves, and (iv) neural responses to patterned optogenetic stimulation. The model offers testable predictions, including presence of slower and iso-tropic spontaneous wave propagation in layer 4 and non-monotonicity of optogenetically driven cortical response to increasingly larger disk of illumination. We thus offer a holistic framework for studying how cortical circuitry governs information integration across multiple operating regimes.
Anatomical characterisation of somatostatin-expressing neurons belonging to the anterolateral system
Authors: Ma Wenhui , Polgár Erika , Dickie Allen C. , Hajer Mai Abu , Quillet Raphaëlle , Gutierrez-Mecinas Maria , Yadav Mansi , Hachisuka Junichi , Todd Andrew J , Bell Andrew M.
Published: November 2024

Anterolateral system (ALS) spinal projection neurons are essential for pain perception. However, these cells are heterogeneous, and there has been extensive debate about the roles of ALS populations in the different pain dimensions. We recently performed single-nucleus RNA sequencing on a developmentally-defined subset of ALS neurons, and identified 5 transcriptomic populations. One of these, ALS4, consists of cells that expressSst, the gene coding for somatostatin, and we reported that these were located in the lateral part of lamina V. Here we use a SstCremouse line to characterise these cells and define their axonal projections. We find that their axons ascend mainly on the ipsilateral side, giving off collaterals throughout their course in the spinal cord. They target various brainstem nuclei, including the parabrachial internal lateral nucleus, and the posterior triangular and medial dorsal thalamic nuclei. We also show that in the L4 segmentSstis expressed by ∼75% of ALS neurons in lateral lamina V and that there are around 120Sst-positive lateral lamina V cells on each side. Our findings indicate that this is a relatively large population, and based on projection targets we conclude that they are likely to contribute to the affective-motivational dimension of pain.
An antibiotic-free antimicrobial combination of bacteriocins and a peptidoglycan hydrolase:in vitroandin vivoassessment of its efficacy
Authors: Kranjec Christian , Oftedal Thomas F. , Ovchinnikov Kirill V. , da Silva Duarte Vinicius , Hermansen Simen , Kaus-Drobek Magdalena , Sabała Izabela , Porcellato Davide , Carlsen Harald , Kjos Morten
Published: November 2024

Mastitis is an inflammatory disease of the mammary gland commonly brought about by bac-terial pathogens that gain physical access to the glandular epithelium through the teat canal. In bovines, common mastitis-causing agents are environmental or pathogenic bacterial spe-cies, including staphylococci, streptococci, enterococci, and Gram-negative bacteria such asEscherichia coli. Current therapeutic strategies for bovine mastitis typically involve the ad-ministration of antibiotic formulations within the infected udder, possibly resulting in in-creased selection of antibiotic resistance and the accumulation of antibiotic residues within the milk. In this study, we sought to design an antibiotic-free antimicrobial formulation to treat bovine mastitis based on bacterial antimicrobial peptides (bacteriocins) and proteins (pepti-doglycan hydrolases). Using a combination ofin vitroassays with a range of bacteriocins, we show that the combination of the thiopeptide micrococcin P1 (MP1) and the lantibiotic nisin A (NisA) is a robust antimicrobial formulation that effectively inhibits the growth of bo-vine mastitis-derived bacteria, both in planktonic and biofilm-associated growth modes. The addition of AuresinePlus (Aur, a staphylococcus-specific PGH) further increased the antimi-crobial potency againstS. aureus. Furthermore, using two mouse models, a skin infection model and a mastitis model, we show that the combination MP1-NisA-Aur effectively inhibits methicillin-resistantS. aureus(MRSA)in vivo. We discuss the potential and challenges of using antibiotic-free antimicrobial combinations in the treatment of bacterial infections.
Body Size Variation and Sexual Dimorphism in Eleven Species of Venezuelan Anurans
Authors: Cañizales Israel
Published: November 2024

This study investigates intra- and interspecific variation in snout–vent length (SVL) and abdominal width (AW) across 11 anuran species in Venezuela, revealing significant patterns of sexual size dimorphism (SSD) in seven species. Females exhibited larger SVL than males in most species (e.g.,Atelopus cruciger,Leptodactylus fuscus, and Phyllomedusa trinitatis), with mean SVL differences ranging from 4 to 15 mm (p< 0.05). This study provides the first reference AW values for these species, contributing novel data for morphometric studies. Four species (Boana punctata,Leptodactylus fuscus,Rhinella marina, andScinax rostratus) showed no significant differences in SVL or AW (p> 0.05), indicating limited SSD or monomorphism. Statistical analyses highlighted geographic variation in SVL, with female-biased SSD more pronounced in arboreal species and male-biased SSD associated with territorial, burrow-digging behaviors in terrestrial species (p< 0.05). These findings support Rensch’s rule, where SSD scales with body size: SSD decreases with increasing female size and increases with male-biased size. InL. fuscus, for instance, SVL values (males: 54.5 mm; females: 61.56 mm) exceeded reported ranges but lacked statistical significance (p= 0.595), highlighting substantial geographic and ecological influences. Directional asymmetry was evident in arboreal species, linked to their ecological adaptations for locomotion. Conversely, terrestrial species displayed larger size variation associated with competition and reproductive strategies. Statistical tests demonstrated the role of ecological traits, activity patterns, and reproductive pressures in shaping SSD (e.g.,p< 0.01 for differences in tree vs. ground-dwelling species). This study underscores the complexity of SSD, influenced by ecological, behavioral, and geographic factors. Morphometric indices validated here offer practical tools for future studies, requiring careful application across species, populations, and developmental stages. The results emphasize the ecological and evolutionary importance of body size variation and provide critical data for conservation efforts in Venezuelan anurans.