bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation between the NRS-2002 score and PD-1/CTLA-4 levels in patients with CAP
Authors: Zhang Chenguang , Zhang Mingqiang , Wu Sheng , Mu Xiangdong
Published: February 2025

Objective

To investigated the relationship between nutritional status and PD-1/CTLA-4 in CAP patients to determine whether the nutritional status is associated with the immunosuppression generated by T cells.

Methods

According the enrollment strategy, we enrolled 60 patients and collected their medical records.Take their blood samples and analyzed the distribution of PD-1 and CTLA-4 in different T cell subgroups.

Results

The level of PD-1 and CTLA-4 in the CD4+, CD8+and Tregs were inclusive with the SCAP occurrence, mortality and PSI score.The malnutrition risk group suffered higher percentage of SAP, longer hospital-stay days and higher mortality when compared with the no-risk group.The higher the PD-1/CTLA-4 levels were, the higher the NRS-2002 score was.

Conclusion

A high NRS-2002 score may increase the length of hospital stay and the occurrence of SCAP. Higher PD-1 and CTLA-4 levels were associated with a higher PSI grade. Nutritional status influenced the occurrence of immunosuppression. Malnutrition status may increase the risk of immunosuppression, which is regulated by PD-1 and CTLA-4.
A Climate-Driven Mechanistic Transmission Model to Characterize Dengue Epidemiology in Dhaka, Bangladesh
Authors: Paul Kishor K , Regan David G , Green Donna , Macadam Ian , Gray Richard T
Published: February 2025

Dengue is a major public health concern in tropical and sub-tropical areas of the world. Dengue virus is transmitted to humans primarily by femaleAedes aegyptimosquitoes and its epidemiology is heavily influenced by the climate. We developed a mechanistic compartmental model to characterize how climate and the evolution of population-level immunity influence changes in the epidemiology of dengue. The model explicitly incorporates aquatic and adult stages of the mosquito vector and cross-immunity (to another serotype) to better represent the transmission of dengue compared to previous models. It incorporates parameters related to mosquito development, behaviour, and mortality that are dependent on temperature, rainfall, and humidity. We calibrated the model to available dengue seroprevalence estimates for Dhaka, Bangladesh as it is a well-observed densely populated endemic area for dengue and will be strongly impacted by climate change. We then simulated dengue epidemiology for the period of 1995-2014 and compared the simulation output with available epidemiologic data. The model produced repeating annual outbreaks of dengue with strong seasonality, as observed in the dengue case reports for Dhaka. The median number of annual dengue infections produced by the model was 1.6 million cases (IQR: 0.6-2.3 million) and the median of the annual daily peak size of dengue infections was 24,121 (IQR: 7,807-39,308) across the simulations. These figures while exceeding reported cases in Dhaka, which do not include asymptomatic infections or cases not seeking healthcare, align with previous estimates. The modelled seroprevalence of 62% (IQR: 58– 75%) aligned with survey results from Dhaka. In most model simulations, dengue infections occurred during August to December with the median peak occurring in October. The model outputs demonstrated a high degree of conformity to the reported data in terms of seasonality, and seroprevalence, indicating that the model provides a good representation of overall dengue epidemiology in Dhaka. By accounting for climate variables, host immunity, and their interplay, our model is well-suited for evaluating the long-term impact of climate change on dengue transmission in Dhaka and other settings where climate and epidemiological data are available.
A multistage, multitask transformer-based framework for multi-disease diagnosis and prediction using personal proteomes
Authors: Li Han , Li Yongkang , Liu Yukuan , Cooper-Knock Johnathan , Gao Peng , Shen Xiaotao , Chen Shengquan , Xing Xudong , Zhang Sai
Published: February 2025

Recent advances in cohort-level proteomic profiling have offered unprecedented opportunities for discovering novel biomarkers and developing diagnostic and predictive tools for complex human diseases. However, the inherent complexity of proteomics data and the scarcity of phenotypic labels, particularly for rare diseases, pose significant challenges in modeling proteome-phenome relationships. Utilizing proteomics data from 2,924 plasma proteins measured in 53,014 UK Biobank participants, we introduce Prophet, an interpretable deep learning framework that combines transformer architecture with a multistage, multitask training strategy to improve disease prediction and biological discovery from personal proteomic profiles. Prophet begins with self-supervised pretraining to model protein interactions, followed by prompt-based fine-tuning for disease diagnosis, and concludes with continuous fine-tuning for disease prediction. Extensive benchmarking across more than 100 diseases demonstrates Prophet’s superior performance over multiple baseline methods, achieving the highest increase in the area under the precision-recall curve (AUPRC) by 132.71% for disease diagnosis and 60.29% for disease prediction. Specifically, Prophet enhances diagnostic accuracy for 95.83% of diseases and boosts predictive accuracy for 94.02% of diseases. Through model interpretation, Prophet identifies 21,549 and 25,915 protein-disease associations for prevalent and incident diseases, respectively, and uncovers prevailing proteomics-based similarities among diseases. Our work provides a powerful framework for proteomics-based disease diagnosis, prediction, and biomarker discovery.
Co-production of informal settlement health: A community based participatory research program for building healthy communities in urban informal settlements of Salvador, Brazil
Authors: Mogaji Hammed , Yeimi Alexandra Alzate Lopez , Almeida Figuerêdo Lívia , Araujo Virgens João Henrique , Aliaga Marie Agnes , Argibay Hernan D , Salles Inajara , Pereira Moreira Andreane , Lima e Silva Terezinha de Jesus , Cristina dos Santos Suzana , Batista Rita , Cardoso Elizete , Cardoso Neves Santos Elenilda , Leal dos Santos Edlane , Rodrigues dos Santos Edlana , Barreto Thiago da Mata , Auxiliadora dos Santos Mattos Thais , Nery Júnior Nivison , Cruz Jaqueline , Carneiro Ianei , Lustosa Ricardo , Dedavid Ferreira Victoria C. , Reis Mitermayer , Ko Albert I , Costa Federico , Begon Mike , Khalil Hussein
Published: February 2025

More than 15% of Brazil’s urban population lives in slums characterized by limited access to essential urban services, heightened vulnerability to infectious pathogens and environmental hazards, and deprivation of citizenship rights. These conditions exacerbate social inequality, perpetuate cycles of poverty, and fuel violence, underscoring the urgent need for sustainable interventions. Following a social justice framework, we developed a community development program rooted in participatory research methods and popular health education to foster collaboration between university researchers and communities. The aim was to identify priorities and co-create locally driven, cost-effective, and sustainable solutions. This article describes our ongoing project in three prominent urban slums of Salvador, Brazil (Alto do Cabrito, Pau da Lima and Marechal Rondon), detailing the methodologies employed, activities initiated, and interventions developed. We conducted ethnographic, eco-epidemiological, and collaborative mapping surveys to contextualize diverse health and well-being challenges. Furthermore, we organized consultative and socialization events with dynamic community groups identified local priorities, leading to the design of 13 interventions targeting citizenship rights, social cohesion, environmental restoration, waste management, and unemployment. Here, we described how our interdisciplinary approach leveraged social capital and fostered inter-sectoral partnerships to empower marginalized urban communities towards addressing their health and environmental challenges through sustainable, locally tailored solutions. While the program has strengthened community trust, facilitated partnerships, and achieved notable environmental improvements, further evaluation is needed to assess the long-term impacts of these interventions on broader social health determinants.
Genetics of cardiovascular outcomes in individuals with chronic kidney disease: the Chronic Renal Insufficiency Cohort (CRIC) study
Authors: Wen Jia , Lin Bridget M , Sun Quan , Jiang Min-Zhi , Linchangco Greg , Li Gang , Chen Ruochen , Go Alan S. , Miller-Fleming Tyne W. , Shuey Megan M. , Cohen Debbie L. , Rao Panduranga S. , Rahman Mahboob , Cox Nancy J. , Lash James P. , Guan Wyliena , Posner Daniel C. , Hui Qin , Houghton Serena C. , Hung Adriana M. , Cho Kelly , Wilson Peter W.F. , Zhou Haibo , Sun Yan V. , Li Yun , Franceschini Nora ,   Million Veteran Program and the CRIC Study Investigators
Published: February 2025

Genome-wide association studies (GWAS) identified multiple loci for cardiovascular disease, but their relevance to individuals with chronic kidney disease (CKD), who are at higher risk of cardiovascular disease, is unknown. In this study, we performed GWAS analyses of coronary heart disease (CHD) or all-cause stroke in African (AFR) and European (EUR) American participants with CKD of the Chronic Renal Insufficiency Cohort (CRIC). Mixed- effect logistic regression models were race-stratified and adjusted for age, sex, site of recruitment, estimated glomerular filtration rate (eGFR), and principal components, followed by meta-analysis. We attempted replication in participants from two biobanks with biomarker or ICD-10 (International Classification of Diseases, 10th Revision) diagnostic codes for CKD. We assessed the association of single nucleotide variants (SNVs) at known CHD and stroke loci in CRIC and tested the genetic correlation among CRIC, a biobank-based cohort and published GWAS of cardiovascular disease. Among 3,588 CRIC participants, 1,203 had CHD and 535 had all-cause stroke. We identified six SNVs across three loci (LINC02744,AZIN1- AS1, andATP6V0A4) associated with all-cause stroke, and two intronic SNVs at thePPARGlocus associated with CHD. However, SNV associations were not significant in replication studies. Published SNVs for CHD or stroke were not associated with cardiovascular outcomes in CRIC. When testing the genetic correlations between published GWAS and CRIC GWAS, they were significant for CHD (genetic correlations (rg) range of 0.39 to 0.51,p-value<0.007). These findings suggest some differences in the genetic architecture of CHD and stroke among individuals with CKD compared to those from the general population, although large numbers of CKD participants are needed to assess if findings are related to participant selection and CKD severity, or non-traditional risk factors in people with CKD.
Identifying the genetic constraint characteristics and biological correlates of sudden unexplained death susceptibility genes
Authors: Lin Junyi , Xu Chenyang , Shen Qi , Tao Ruiyang , Wang Shouyu
Published: February 2025

Sudden unexplained death (SUD) refers to sudden death in which the cause of death could not be established after a comprehensive medico-legal investigation, including pathological/toxicological assessment and forensic investigation of the circumstances of death. In the past decade, molecular autopsy has proved to be an efficient diagnostic tool in the multidisciplinary management of SUD. Though numerous pathogenic/likely pathogenic (P/LP) variants have been identified, there is still a large proportion of SUD cases without clear molecular autopsy findings, suggesting that the genetic predisposition contributing to SUD might be more complicated than expected. In this study, we analyzed published datasets to characterize the distribution pattern of rare P/LP variants. Enrichment analyses were subsequently conducted to identify the most affected canonical pathways/biological processes and phenotypes/cell types with strongest correlation to SUD. In addition, the constraint metrics of genes harboring P/LP variants were also assessed to investigate the role of selective pressure in shaping the genetic features of SUD.
Impact of multiple phosphorylations on the tau-R2/tubulin interface
Authors: Marien Jules , Prévost Chantal , Sacquin-Mora Sophie
Published: February 2025

The phosphorylation of the microtubule-associated tau protein plays a key role in the regulation of its physiological function. In particular, tau hyperphosphorylation affects its binding on the tubulin surface, destabilizing the tau-microtubule interface and leading to the accumulation of fibrillar aggregates in the brain. In this work, we performed classical Molecular Dynamics simulations for the tau-R2/tubulin assembly with various phosphorylations states of serines 285, 289 and 293. We analyze the resulting trajectories to obtain a detailed view of the protein interface in the complex, and the impact of tau phosphorylations on the stability of this assembly, and on the tubulin disordered C-Terminal tails (CTTs) mobility. We show how the tubulin CTTs help maintaining the tau-R2 fragment on the tubulin surface despite the destabilizing effect induced by phosphorylations. Conversely, tau phosphorylation affects the CTTs flexibility and their potential activity as MAP recruiting hooks. Furthermore, counterion mediated bridges between the phosphate groups and tubulin glutamates also contribute to the binding of tau-R2 on the MT.
Comparative analysis of novelPseudobdellovibrionaceaegenera and species yields insights into the genomics and evolution of bacterial predation mode
Authors: Maher Rebecca L. , Wülbern Janna , Zimmermann Johannes , Yeh Emily , Benda Liesl , Repnik Urska , Fuß Janina , Künzel Sven , Schulenburg Hinrich , Bohannan Brendan J.M. , Adair Karen L. , Johnke Julia
Published: February 2025

Bacteria of the familyPseudobdellovibrionaceaebelong to a group of bacteria that kill and feed on other bacteria. The diversity of predation strategies, habitats, and genome characteristics of these bacteria are largely unexplored, despite their ecological and evolutionary importance in microbial communities. Therefore, we characterized newPseudobdellovibrionaceaestrains isolated from the direct environments of three animal hosts: the zebrafish (Danio rerio), the threespine stickleback fish (Gasterosteus aculeatus), and the nematodeCaenorhabditis elegans. We used transmission electron microscopy (TEM) and genomic analyses to characterize the morphology and predation modes of our isolates. While most of our isolates exhibited periplasmic (i.e. endoparasitic) predation, one isolate clearly exhibited epibiotic (i.e. exoparasitic) predation and represents only the third confirmed epibiotic strain within its clade. Of our isolates, six are members of five new species in the genusBdellovibrioand two strains likely represent new genera within the familyPseudobdellovibrionaceae. From metabarcoding data, we found indications thatPseudobdellovibrionaceaeare widespread among our three animal hosts. Genomic analyses showed that epibiotic predators lack genes involved in host independence (i.e. prey-independent feeding) and peptidoglycan modification. However, genes unique to epibiotic predators may underlie this predation mode, particularly those involved in cell wall remodeling and recycling. With robust phylogenomic analyses, we show that our novel isolates cluster with previously describedPseudobdellovibrionaceaeisolates according to predation mode. Further, by placingPseudobdellovibrionaceaepredators within a wider evolutionary history including other predatory and non-predatory bacteria, we postulate periplasmic predation as the ancestral mode, with more derived epibiotic predators exhibiting genome streamlining.
Beta-Hydroxybutyrate Attenuates Bronchial Smooth Muscle Pro-Inflammatory Cytokine Production
Authors: Fastiggi V. Amanda , Mank Madeleine M. , Poynter Matthew E.
Published: February 2025

Asthma is a common airway condition causing breathing difficulties due to reversible airflow obstruction. It often affects obese individuals, with symptoms triggered by environmental factors that induce immune responses, leading to inflammation and bronchoconstriction. Bronchial smooth muscle (BSM) plays a central role in airway narrowing, driven by type 2 immune responses involving cytokines like IL-4, IL-5, and IL-13, along with leukocytes including eosinophils and type 2 T-helper cells. These responses cause structural changes such as fibrosis and airway thickening, while BSM cells worsen asthma by releasing pro-inflammatory cytokines in response to allergens, microbial signals, or inflammatory cytokines from other cells. While current treatments manage asthma in most patients, alternative therapies are needed for difficult-to-treat cases, particularly prevalent in obese, allergic individuals. Emerging research suggests that therapeutic ketosis, induced by dietary changes or ketone supplementation, may reduce airway hyperresponsiveness and inflammation. The primary ketone body, β-hydroxybutyrate (BHB), produced during carbohydrate scarcity, acts via cell-surface receptors and transporters, potentially mitigating asthma symptoms. Weight loss and caloric restriction increase ketone levels, correlating with reduced inflammation and improved asthma outcomes. We hypothesized that β-hydroxybutyrate (BHB) reduces bronchoconstriction and inflammation in asthma by targeting bronchial smooth muscle. Using human bronchial smooth muscle cells (HBSMC)in vitro,we demonstrate herein that BHB suppresses IL-1β-induced pro-inflammatory cytokine production through Free Fatty Acid Receptor 3 (FFAR3) activation. These findings suggest that bronchial smooth muscle is a key target of therapeutic ketosis, supporting BHB’s potential benefits in preclinical asthma models.
Alternate dyes for image-based profiling assays
Authors: Sivagurunathan Suganya , Byrne Patrick , Muñoz Alán F. , Arevalo John , Carpenter Anne E. , Singh Shantanu , Kost-Alimova Maria , Cimini Beth A.
Published: February 2025

Background

Cell Painting, the leading image-based profiling assay, involves staining plated cells with six dyes that mark the different compartments in a cell. Such profiles can then be used to discover connections between samples (whether different cell lines, different genetic treatments, or different compound treatments) as well as to assess particular features impacted by each treatment. Researchers may wish to vary the standard dye panel to assess particular phenotypes, or image cells live while maintaining the ability to cluster profiles overall.

Methods

In this study, we evaluate the performance of dyes that can either replace or augment the traditional Cell Painting dyes or enable tracking live cell dynamics. We perturbed U2OS cells with 90 different compounds and subsequently stained them with either standard Cell Painting dyes (Revvity), or with MitoBrilliant (Tocris) replacing MitoTracker or Phenovue phalloidin 400LS (Revvity) replacing phalloidin. We also tested the live-cell compatible ChromaLive dye (Saguaro).

Results

All dye sets effectively separated biological replicates of the same sample vs. negative controls (phenotypic activity), although separating from replicates of all other compounds (phenotypic distinctiveness) proved challenging for all dye sets. While individual dye substitutions within the standard Cell Painting panel had minimal impact on assay performance, the live cell dye exhibited distinct performance profiles across different compound classes compared to the standard panel, with later time points more distinct than earlier ones.

Discussion

Substituting MitoBrilliant or Phenovue phalloidin 400LS for standard mitochondrial or actin dyes minimally impacted Cell Painting assay performance. Phenovue phalloidin 400LS offers the advantage of isolating actin features from Golgi or plasma membrane while accommodating an additional 568nm dye. Live cell imaging, enabled by ChromaLive dye, provides real-time assessment of compound-induced morphological changes. Combining this with the standard Cell Painting assay significantly expands the feature space for enhanced cellular profiling. Our findings provide data-driven options for researchers selecting dye sets for image-based profiling.
Fatty acid synthesis supports tumor progression through keeping TORC1 receptive for Insulin/PI3K signaling
Authors: Károlyi Dorottya , Bótor Sólyom Bálint , Neuhauser Natali , Péter Mária , Balogh Gábor , O’Farrell Fergal , Takáts Szabolcs
Published: February 2025

Biosynthesis of lipids and fatty acids (FAs) is a tightly regulated and complex process essential for the normal functioning of various cellular processes as is sufficient lipid availability for the progression of several malignant tumor types. Despite its importance, the roles of the individual steps in lipid biosynthesis during tumor growth and their subsequent interaction with intracellular signaling pathways are still not well understood. In our study, we used the RasV12, Scribble deficient carcinoma model inDrosophilato demonstrate that upregulation of de novo FA and lipid synthesis is a conserved characteristic of malignant tumors. Performing a small-scale genetic screen by tumor cell specific silencing of components of neutral lipid biosynthetic apparatus revealed that the loss of several enzymes involved in FA and diacylglycerol synthesis significantly inhibited tumor growth. Further characterization of the role of acetyl-CoA carboxylase (ACC), the enzyme responsible for the first step of FA synthesis, revealed that loss of ACC significantly reduced late-stage tumor growth due to increased apoptotic activity. However, early tumor development was unaffected. This correlated with our observation that perturbation of FA synthesis led to inactivation of TORC1 (Target of Rapamycin Complex 1) – the master regulator of cell growth and survival – accompanied by activation of the catabolic process autophagy. Moreover, we also demonstrated that TORC1 activity cannot be restored by hyperactivation of upstream Insulin/PI3K signaling or inhibition of AMP-activated kinase (AMPK) in ACC deficient tumor cells but supplementation of ACC deficient tumors with ectopically added oleic acid alone could improve TORC1 activity and thereby tumor progression. Hence, our findings highlight a new role of FAs in regulating TORC1, rendering it receptive to upstream activatory signals, explaining why cancer cells are extremely dependent on de novo FA synthesis.
Mitochondrial accumulation and lysosomal dysfunction result in mitochondrial plaques in Alzheimer’s disease
Authors: Dan Xiuli , Croteau Deborah L. , Liu Wenlong , Chu Xixia , Robbins Paul D , Bohr Vilhelm A.
Published: February 2025

Dysfunctional mitophagy is a key component of Alzheimer’s disease (AD) pathology, yet directin vivoevidence and mechanistic insights remain limited. Using a mitophagy reporter in an AD mouse model (APP/PSEN1/mt-Keima), we identified mitochondrial plaques (MPs) composed of accumulated mitochondria within or outside lysosomes in AD, but not normal mouse brains. Similar structures were also found in AD human brains, but not in healthy controls. Abnormal mitochondrial accumulation in dystrophic neurites, defective mitophagy, and impaired lysosomal function disrupted proper mitochondrial degradation, resulting in excessive mitochondria accumulation both within and outside autophagic vesicles. The resulting intensive mitochondria-containing neurites coalesce into MPs, which co-develop with amyloid plaques to form mixed plaques. These findings establish MPs as novel pathological entity and a promising therapeutic target in AD.
Evolution of Eukaryotic Specific DNA Binding Sites in Asgard Archaeal RecA Recombinases
Authors: Ferlez Bryan , Huang Peter Towei , Hu Jingyi , Brooks Crickard J.
Published: February 2025

RecA-type recombinases are essential for genome maintenance in all domains of life, promoting homologous recombination (HR). While the general reaction catalyzed by recombinases is the same in all domains, key differences at the amino acid level can lead to the specialization of this family of proteins. A key example of this is in the domain of Eukarya, which can utilize two different RecA homologs depending on the life cycle stage of the organism, with the activity of Rad51 utilized during mitotic growth and the activity of Dmc1 used during meiosis. Why most eukaryotes utilize two RecA homologs is an open question. A missing piece of information in this story is the identity of RecA homologs before the divergence of Rad51 and Dmc1, which occurred in early eukaryotes. We analyzed sequence data from the Archaeal homolog, RadA, in the Asgard Archaea superphyla. Our findings include evidence for the evolution of a eukaryotic-specific DNA binding site II within the Asgard lineage. We also identify sequence variants within DNA binding loops L1 and L2, part of binding site I, that imply higher mismatch tolerance within the Asgard and DPANN superphylum. These loops are also observed in the meiosis-specific recombinase Dmc1 within Eukarya. Our phylogenetic analysis suggests the last Archaeal ancestor of Rad51 and Dmc1 was more Dmc1-like in character and likely of lower fidelity.
Examination of germline and somatic intercellular bridges inHydra vulgarisreveals insights into the evolutionarily conserved mechanism of intercellular bridge formation
Authors: Price Kari L. , Tharakan Dyuthi M. , Salvenmoser Willi , Ayers Kathleen , Mah Jasmine , Dunn Casey , Hobmayer Bert , Cooley Lynn
Published: February 2025

Incomplete cytokinesis results in the formation of stable intercellular bridges that have been extensively studied in bilaterians, where they play essential roles in cell-cell communication and coordination of differentiation. However, little is known about their structure and molecular composition in non-bilaterian animals. This study characterizes germline and somatic intercellular bridges in the cnidarianHydra vulgaris, providing insights into their evolutionary origins and functional significance. We identified key conserved components, including KIF23, F-actin, and phosphotyrosine. Notably, we observed microtubule localization withinHydraring canals, suggesting previously unrecognized functions for this cytoskeletal component in intercellular bridge formation. Bioinformatic analyses confirmed the conserved expression ofKif23and suggested its role as a molecular marker for identifying ring canal-associated components. EdU incorporation during DNA replication demonstrated that cells connected by ring canals exhibit synchronized cell cycles, which may be critical for the coordination of division and differentiation. Our findings reveal that the molecular and structural features of intercellular bridges inHydraare conserved across evolutionary lineages, highlighting their ancient origins and functional significance in cellular connectivity. The presence of synchronized cell cycles in ring canal-connected cells underscores their role in promoting coordinated cellular behaviors, processes fundamental to multicellular organization. This study provides new perspectives on the evolution of incomplete cytokinesis and establishes a framework for comparative investigations into the diversity and conservation of intercellular bridge mechanisms across metazoans.
Inborn errors of immunity: manifestation, treatment, and outcome – an ESID registry 1994-2024 report on 30,628 patients
Authors: Kindle Gerhard , Alligon Mickaël , Albert Michael H. , Buckland Matthew , Edgar J. David , Gathmann Benjamin , Ghosh Sujal , Gkantaras Antonios , Nieters Alexandra , Pignata Claudio , Robinson Peter , Rusch Stephan , Schuetz Catharina , Sharapova Svetlana , Shillitoe Benjamin , Candotti Fabio , Cant Andrew J. , Casanova Jean-Laurent , Etzioni Amos , Fischer Alain , Meyts Isabelle , Notarangelo Luigi D. , Pergent Martine , Smith C. I. Edvard ,   ESID Registry Working Party, Hammarström Lennart , Grimbacher Bodo , Seppänen Mikko , Mahlaoui Nizar , Ehl Stephan , Seidel Markus G.
Published: February 2025

TheEuropean Society for Immunodeficienciespatient registry (ESID-R), established in 1994, is one of the world’s largest databases on inborn errors of immunity (IEI). IEI are genetic disorders predisposing patients to infections, autoimmunity, inflammation, allergies and malignancies. Treatments include antimicrobial therapy, immunoglobulin replacement, immune modulation, stem cell transplantation and gene therapy. Data from 194 centers in 33 countries capture clinical manifestations and treatments from birth onward, with annually expected updates. This report reviews the ESID-R’s structure, data content, and impact.

The registry includes 30,628 patient datasets (aged 0–97.9 years; median follow-up: 7.2 years; total 825,568.2 patient-years), with 13,550 cases in 15 sub-studies. It has produced 84 peer-reviewed publications (mean citation rate: 95). Findings highlight real-world observations of IEI diagnoses, genetic causes, treatments, and survival trends. The ESID-R fosters global collaboration, advancing IEI research and patient care. Early declining survival probabilities for many IEI subcategories suggest expanding newborn screening beyond severe combined immune deficiencies. This report highlights the key role of the multi-national ESID-R, led by an independent medical society, in evidence-based discovery.

Worldwide, most patient registries for inborn errors of immunity are national, with limited geographical and temporal scope. This 30-year ESID registry analysis of 30,628 patients’ longitudinal datasets enables robust epidemiological studies on natural disease courses including diagnosis, treatment, and survival, supporting expanded newborn screening and future AI applications in IEI research.
Exploration of Key Markers Driving Ferroptosis in the Progression of Non-Alcoholic Fatty Liver Disease
Authors: Zhang Jiyong , Li Weiyan , Qiu Xiaoying , Wang Yuanyuan , Zeng Yongmei
Published: February 2025

Non-alcoholic fatty liver disease (NAFLD) is a prevalent condition strongly linked to obesity, diabetes, and metabolic syndrome. Its global incidence is steadily increasing, placing a significant health burden on both patients and society. Despite existing treatments, such as lifestyle changes and medications, the lack of effective biomarkers and therapeutic strategies leaves many patients at risk for disease progression. This study aims to identify ferroptosis-related differentially expressed genes (DEGs) through bioinformatics analysis and to explore their roles in NAFLD. By comparing samples from NAFLD patients and healthy controls, we identified 1,770 significant DEGs, with 1,073 being upregulated and 697 downregulated. Pathway analysis revealed a marked decrease in expression within certain key metabolic pathways (such as the one-carbon pool by folate) in the NAFLD group, while expression in DNA repair-related pathways (such as non-homologous end joining) was significantly increased. Additionally, immune cell infiltration analysis showed significant differences in 19 immune cell types between the NAFLD and control groups, with 12 types exhibiting increased infiltration in the NAFLD group. Through protein-protein interaction (PPI) network analysis, we identified 41 critical intersecting genes, and ROC curve validation demonstrated that 25 of these genes had an AUC value exceeding 0.85, highlighting their potential as biomarkers for NAFLD. In conclusion, this study sheds light on the underlying molecular mechanisms of NAFLD and identifies promising genes as potential biomarkers, providing a crucial foundation for future early diagnosis and personalized treatment.
Mendelian randomization analyses uncover causal relationships between brain structural connectome and risk of psychiatric disorders
Authors: Xiao Kanwei , Chang Xinle , Ye Chenfei , Zhang Zhiguo , Ma Ting , Su Jingyong
Published: February 2025

Growing evidence suggests abnormalities of brain structural connectome in psychiatric disorders, but the causal relationships remain underexplored. We conducted bidirectional two-sample Mendelian randomization (MR) analyses to investigate the causal links between 206 white-matter connectivity phenotypes (n = 26,333, UK Biobank) and 13 major psychiatric disorders (n = 14,307 to 1,222,882). Forward MR analyses identified causal effects of genetically predicted five white-matter structural connectivity phenotypes on six psychiatric disorders, with associations being significant or suggestive. For instance, structural connectivity between the left-hemisphere frontoparietal control network and right-hemisphere default mode network was significantly negatively associated with autism spectrum disorder risk, while increased structural connectivity between the right-hemisphere frontoparietal control network and hippocampus was significantly linked to decreased anorexia nervosa and cannabis use disorder risk. Reverse MR analyses revealed significantly or suggestively causal relationships between the risk of two psychiatric disorders and four different white-matter structural connectivity phenotypes. For example, the susceptibility of anorexia nervosa was found to be significantly negatively associated with structural connectivity between the left-hemisphere visual network and pallidum. These findings offer new insights into the etiology of psychiatric disorders and highlight potential biomarkers for early detection and prevention at the brain structural connectome level.
Characterization of perceptual and electrophysiological responses to high-speed robot-controlled pinprick stimulation
Authors: Poux Sofía , Youssif Abed , Van Den Broeke Emanuel N. , Baumgärtner Ulf , Biurrun Manresa José A. , Mista Christian A.
Published: February 2025

Objective

Mechanical pinprick stimuli delivered via robotic systems have been applied using parameters derived from studies using handheld stimulators. This work evaluates the effects of stimulus force and duration on neurophysiological responses and subjective perception.

Methods

Twenty-seven healthy volunteers received pinprick stimuli on the right volar forearm using different combinations of force and duration that configured three stimulus intensities: low, medium and high impulse. The robotic system recorded stimulus force and duration in real-time, and participants rated the perceived intensity after each stimulus on a numerical rating scale (NRS). The peak amplitudes and latencies of the pinprick evoked potentials (PEPs) were compared for the stimulation impulse intensities. The NRS ratings were analysed using linear mixed models, and the PEP features were evaluated through spatio-temporal cluster permutation tests.

Results

The NRS ratings were 2.5 [7.0] for low, 16.4 [18.0] for medium, and 28.5 [31.1] for high impulse stimuli. Differences in brain activity were found when comparing all impulse intensities. Peak N2 latency was longer for high compared to low and for medium compared to low. P2 latency showed no differences across impulse intensities. N2 was more negative for high vs. low and for medium vs. low, with no significant difference between high and medium impulses.

Conclusions

Both cortical and subjective responses depend on the applied impulse intensity. Stimulation parameters should be selected based on the specific effect under investigation, as a range of peripheral afferents may be activated by mechanical stimuli.
Open-Source Retrieval Augmented Generation Framework for Retrieving Accurate Medication Insights from Formularies for African Healthcare Workers
Authors: Owoyemi Joshua , Abubakar Shamsudeen , Owoyemi Ayomide , Togunwa Taofeeq Oluwatosin , Madubuko Favour Chiemerie , Oyatoye Samuel , Oyetolu Zeenat , Akyea Kelvin , Mohammed Afeez Olamilekan , Adebakin Abimbola
Published: February 2025

Accessing accurate medication insights is vital for enhancing patient safety, minimizing errors, and supporting clinical decision-making. However, healthcare professionals in Africa often rely on manual and time-consuming processes to retrieve drug information, exacerbated by limited access to pharmacists due to brain drain and healthcare disparities. This paper presents “Drug Insights,” an open-source Retrieval-Augmented Generation (RAG) chatbot designed to streamline medication lookup for healthcare workers in Africa. By leveraging a corpus of Nigerian pharmaceutical data and advanced AI technologies, including Pinecone databases and GPT models, the system delivers accurate, context-specific responses with minimal hallucination. The chatbot integrates prompt engineering and S-BERT evaluation to optimize retrieval and response generation. Preliminary tests, including pharmacist feedback, affirm the tool’s potential to improve drug information access while highlighting areas for enhancement, such as UI/UX refinement and extended corpus integration.
VDAC isoforms play distinct roles in modulating metabolism and maintaining mitochondrial function
Authors: Rajendran Megha , Rosencrans William M. , Fitzgerald Wendy , Huynh Diana , Beyene Bethel G. , Quan Baiyi , Hwang Julie , Bautista Nina , Chou Tsui-Fen , Bezrukov Sergey M. , Rostovtseva Tatiana K.
Published: February 2025

The Voltage Dependent Anion Channel (VDAC) is the most ubiquitous protein in the mitochondrial outer membrane. This channel facilitates the flux of water-soluble metabolites and ions like calcium across the mitochondrial outer membrane. Beyond this canonical role, VDAC has been implicated, through interactions with protein partners, in several cellular processes such as apoptosis, calcium signaling, and lipid metabolism. There are three VDAC isoforms in mammalian cells, VDAC 1, 2, and 3, with varying tissue-specific expression profiles. From a biophysical standpoint, all three isoforms can conduct metabolites and ions with similar efficiency. However, isoform knockouts (KOs) in mice lead to distinct phenotypes, which may be due to differences in VDAC isoform interactions with partner proteins. To understand the functional role of each VDAC isoform within a single cell type, we created functional KOs of each isoform in HeLa cells and performed a comparative study of their metabolic activity and proteomics. We found that each isoform KO alters the proteome in distinctly different manners, with VDAC3 KO dramatically downregulating key members of the electron transport chain (ETC) while shifting the mitochondria into a glutamine-dependent state. Importantly, this unexpected dependence of mitochondrial function on the VDAC3 isoform is not compensated by the more ubiquitously expressed VDAC1 and VDAC2 isoforms. In contrast, VDAC2 KO did not affect respiration but upregulated ETC components and decreased key enzymes in the glutamine metabolic pathway. VDAC1 KO specifically reduced glycolytic activity linked to decreased hexokinase localization to mitochondria. These results reveal non-redundant roles of VDAC isoforms in cancer cell metabolic adaptability.
Contrasting responses of control and fibrotic lung fibroblasts to fibrotic stimuli: the role of osteoprotegerin in extracellular matrix remodeling
Authors: Liu Yanzhe , Nizamoglu Mehmet , Zhao Fenghua , Borghuis Theo , Koster Taco , Sharma Prashant K. , Harmsen Martin C. , Thomas Matthew J. , White Eric S. , El Kasmi Karim C. , Heijink Irene H , Melgert Barbro N. , Burgess Janette K.
Published: February 2025

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease characterized by dysregulated wound healing, leading to excessive production of extracellular matrix (ECM) proteins, particularly collagen, by activated fibroblasts. Osteoprotegerin (OPG), a soluble protein associated with ECM remodeling in bone, has been found in higher levels in serum and lung tissue of IPF patients compared to controls. However, whether OPG is associated with ECM remodeling by fibroblasts in lung fibrosis remains poorly understood. In this study we assessed differences in OPG levels in ECM-derived hydrogels from non-disease controls and patients with IPF encapsulated with primary human lung fibroblasts from control and patients with IPF (7 days). OPG levels were assessed in a collected culture medium and stained lung tissue sections, and related to biomechanical properties.

Fibrotic human lung fibroblasts secreted and deposited more OPG compared to controls, which was observed in both non-diseased and IPF ECM hydrogels. OPG levels correlated significantly with matrix stiffness and collagen fiber structural properties, but only in IPF hydrogels, independent of fibroblast source. Strikingly, we also observed opposite correlations for control and fibrotic fibroblasts in fibrotic hydrogels. Control fibroblasts within a fibrotic microenvironment, secreted less OPG when hydrogel stiffness increased and deposited more OPG when collagen fibers were more aligned. Interestingly, fibrotic fibroblasts secreted more OPG when collagen fiber length increased and when collagen fiber curvature increased. Overall, our findings suggest that control and fibrotic lung fibroblasts exhibited opposite behavior with respect to OPG and ECM remodeling under fibrotic conditions and this may have consequences for matrix stiffness
Dora, a key component of target-directed miRNA degradation, is essential for local genomic amplification inDrosophilaovarian follicle cells
Authors: Akulenko Natalia , Olenkina Oxana , Mikhaleva Elena , Marfina Sofya , Krylova Anastasia , Toshchakov Stepan , Ryazansky Sergei
Published: February 2025

The ubiquitin ligase receptor Dora, theDrosophilahomolog of ZSWIM8, is a key component of the target-directed microRNA degradation (TDMD) pathway. Previous studies have implicated TDMD – and, consequently, ZSWIM8/Dora – in various developmental processes. Here, we investigate the role of Dora inDrosophilaoogenesis, focusing on its function in ovarian somatic cells. We generated a fly strain with an endogenously tagged Dora protein and observed its presence in both germline and somatic follicular cells of the ovaries. Somatic knockdown ofdorarevealed its essential role in normal eggshell formation. Specifically, its loss led to reduced chorion and vitelline transcript levels and decreased chorion gene amplification, both of which are critical for eggshell protein production. Somatic depletion of Dora did not affect the abundance of other known regulators of eggshell formation, including Ttk69, Cut, miR-7 or miR-318 indicating that Dora functions independently of these pathways. Although a direct link between TDMD and chorion eggshell development remains to be confirmed, our findings clearly highlight Dora as a critical regulator in this process. These results pave the way for further investigation into the specific role of TDMD and provide new insights into the regulatory mechanisms underlying animal oogenesis.
Making friends in an asymmetric game: the establishment of male-female grooming exchanges in vervet monkeys
Authors: Tankink Josefien A. , Granell Ruiz Maria , van de Waal Erica , van Schaik Carel , Bshary Redouan
Published: February 2025

Various concepts have been developed to explain cooperation among unrelated individuals, but linking proposed strategies to empirical evidence remains a challenge, especially for variable reciprocal investments. One famous strategy is “raise-the-stakes”, proposing low initial investments but a steady increase if the partner matches the other’s investments or increases their own investments in a series of exchanges. Contrarily, the “making-friends” strategy predicts high investment between strangers that may either be kept up or downregulated if not fully matched. We tested these predictions on grooming exchanges between wild male-female vervet monkeys, a species with regular male dispersal. Contrary to both predictions, females had a consistently high initial investment and groomed immigrants for longer than was reciprocated, showing no adaptation to the formation of debts. However, females gradually reduced grooming over the first 6 months. Males, on the other hand, did not alter grooming investments over time. Thus, grooming exchanges eventually almost evened out. We present various potential explanations for these results, which are overall more consistent with the “making friends” strategy. Most importantly, this study highlights the complexity of real-life cooperation, emphasizing the need for models that explicitly incorporate life history parameters into cooperative strategies.

Significance statement

This study demonstrates the importance of considering life-history differences between interaction partners when applying theoretical cooperation models to empirical cases. We examined the development of grooming relationships – a behaviour serving both hygiene and social functions in primates – between newly immigrated male and resident female vervet monkeys. We did not observe a slow building up of exchanges, as predicted by a “raise-the-stakes” strategy. Instead, we found that socially established females heavily invest into grooming immigrant males, without receiving matching returns. These results suggest that female core groups compete with neighboring female core groups over males and the services those provide. Our data highlight avenues for future data-informed theoretical models on cooperation.
Cell-type-specific DNA methylation dynamics in the prenatal and postnatal human cortex
Authors: Franklin Alice , Davies Jonathan P. , Clifton Nicholas E , Blake Georgina E T , Bamford Rosemary , Walker Emma M , Chioza Barry , Frith Martyn , Burrage Joe , Owens Nick , Prabhakar Shyam , Dempster Emma , Hannon Eilis , Mill Jonathan
Published: February 2025

The human cortex undergoes extensive epigenetic remodelling during development, although the precise temporal and cell-type-specific dynamics of DNA methylation remain incompletely understood. In this study, we profiled genome-wide DNA methylation across human cortex tissue from donors aged 6 post-conception weeks (pcw) to 108 years of age. We observed widespread, developmentally regulated, changes in DNA methylation, with pronounced shifts occurring during early- and mid-gestation that were distinct from age-associated modifications in the postnatal cortex. Using fluorescence-activated nuclei sorting (FANS), we optimized a protocol for the isolation of SATB2-positive neuronal nuclei, enabling the identification of cell-type-specific DNA methylation trajectories in developing neuronal and non-neuronal populations. Developmentally dynamic DNA methylation sites were significantly enriched near genes implicated in autism and schizophrenia, supporting a role for epigenetic dysregulation in neurodevelopmental disorders. Our findings underscore the prenatal period as a critical window of epigenomic plasticity in the central nervous system with important implications for understanding the genetic basis of neurodevelopmental phenotypes.
Interplay of magnetocrystalline and magnetoelastic anisotropy in epitaxial
Co(101¯0)
films
Authors: Patel Gauravkumar , Ganss Fabian , Fallarino Lorenzo , Sellge Gabriel , Quintana Mikel , Hübner René , Sander Dirk , Hellwig Olav , Lenz Kilian , Lindner Jürgen
Published: February 2025

With the goal of creating an in-plane (IP) uniaxial anisotropy system, we deposited a thickness series of epitaxial Co(101¯0) films grown on Si(110) substrates with Ag(110) and Cr(211) buffer layers by magnetron sputtering. However, quantifying the IP magnetic anisotropy using ferromagnetic resonance measurements revealed a much more complex behavior than expected for a simple uniaxial system like hexagonally close-packed (hcp) Co. To understand the experimental results, an in-depth x-ray diffraction analysis of the film structure was performed. Even at a thickness of 100 nm, it revealed an anisotropic strain in the Co films, mainly within the Co basal plane, while the c axis remained mostly unaffected. Calculations show that such unrelaxed strain induces a significant magnetoelastic anisotropy, which counteracts the magnetocrystalline one and, as a result, reduces the overall effective anisotropy. A detailed analysis revealed that mainly the compressive strain along the Co[101¯0] out-of-plane direction is responsible for the observed magnetoelastic anisotropy, while the tensile strain along the Co[1¯21¯0] IP direction only plays a minor role.

Published by the American Physical Society
2025