bluuebunny/crossref_metadata_2025_split 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

ABSTRACTSystemic 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

AbstractMaternally 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

AbstractBackgroundThe 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.ResultsEvaluation 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.ConclusionsWe 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

SummaryAerobic 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

AbstractHuman 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.ImportanceHuman 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

SummaryPlaque 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

SUMMARYUnderstanding 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

ABSTRACTLiver 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

AbstractThe 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

ABSTRACTThe 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

AbstractAs 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 class92D30, 92-10, 37N25, 34A34