bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploring the role of transposable elements to sex gap in longevity in Drosophila species
Authors: Merenciano Miriam , Janillon Sonia , Mermet-Bouvier Camille , Burlet Nelly , Rodriguez-Rada Valentina , Ronget Victor , Gibert Patricia , Gaillard Jean-Michel , Lemaitre Jean-François , Marais Gabriel AB , Boulesteix Matthieu , Fablet Marie , Vieira Cristina
Published: January 2025

In Drosophila, like in many other animal species, females tend to live longer than males, a phenomenon known as sex gap in longevity (SGL). One of the possible causes underlying this phenomenon could be related to the high content of transposable elements (TE) in the Y chromosome (toxic Y hypothesis). TE activity is normally repressed by epigenetic mechanisms, but this regulation weakens with age. Since the Y chromosome is rich in TEs, age-related TE activity should be more pronounced in old males than in old females, likely affecting longevity patterns. In this work, we studied the natural variation in SGL in wild-type populations of three different Drosophila species that vary in their TE content:Drosophila melanogaster,Drosophila simulans, andDrosophila suzukii. Transcriptomic data revealed increased copy-specific TE expression inD. melanogasterandD. suzukiiolder flies. Moreover, we observed a higher number of upregulated TEs in old males compared to old females across all the three species tested. Additionally, we detected an increase in TE-chimeric transcript generation in some aged samples, particularly inD. suzukiimales. Finally, the replacement of the Y chromosome between strains with different SGL led to a progressive reduction in male lifespan and increased TE transcriptional release over generations, suggesting a Y chromosome important role in male longevity. Our work contributes to a better understanding of the genomic differences that lead to variation in longevity patterns between sexes in several species, and emphasizes the importance of studying the role of TEs in male longevity.
17β-Estradiol Counteracts Pathological Microtubule Remodeling To Enhance Cardiac Function
Authors: Moon Ryan , Vogel Neal T. , Mendelson Jenna B. , Hartweck Lynn M. , Carney John P. , Kim Minwoo , Gardner Melissa K. , Prisco Sasha , Prins Kurt W.
Published: January 2025

The female-predominate sex hormone 17β-estradiol exerts cardioprotective effects via multiple mechanisms. Available data demonstrate 17β-estradiol modulates microtubule dynamicsin vitro, but its effects on pathogenic microtubule remodeling in pressure-overloaded cardiomyocytes are unexplored. Here, we show 17β-estradiol directly blunts microtubule polymerizationin vitro, counteracts endothelin-mediated microtubule remodeling in iPSC-cardiomyocytes, and mitigates microtubule stabilization in pulmonary artery banded right ventricular cardiomyocytes. 17β-estradiol treatment blunts cardiomyocyte and nuclear hypertrophy, restores t-tubule architecture, and prevents mislocalization of connexin-43 in RV cardiomyocytes of pulmonary artery banded rats. These cellular phenotypes are paired with significant improvements in RV function. Thus, we propose 17β-estradiol exerts cardioprotective effects via direct modulation of microtubules in addition to its well ascribed signaling functions.
ChemBERTaDDI: Transforming Drug-Drug Interaction Prediction with Transformers and Clinical Insights
Authors: Gromova Anastasiya A. , Maida Anthony S.
Published: January 2025

The problem of polypharmacy arises when two or more drugs taken in combination cause adverse side effects, even when the use of the drugs individually causes no harm. Drug-drug interactions (DDIs) are a major cause of these reactions, contributing to increased morbidity and mortality. As the potential for harmful DDI grows exponentially, the prediction of drug-drug interactions is increasingly critical for patient safety and effective healthcare management. In this paper, we develop theChemBERTaDDIframework, which effectively combines clinical domain data, represented by the mono side-effect features with the enriched chemical molecular representations derived fromChemBERTa-77M-MLM, a transformer-based language model. Experiments performed on a benchmark data set show superior performance compared with five state-of-the-art methods: Decagon, DeepWalk, DEDICOM, NNPS, and RESCAL. The evaluation demonstrates thatChemBERTaDDIachieves an F1 score of 0.94 and an AUROC of 0.97 outperforming the baseline architectures and generalizing to new introduced drug compounds.
A strong relationship between environmental DNA metabarcoding and rank-based abundance of fish
Authors: Littlefair Joanne E , Hayhurst Lauren D , Yates Matthew C , Rennie Michael D , Cristescu Melania E
Published: January 2025

Increasingly, molecular methods of species monitoring are integrated into freshwater biodiversity surveys and fisheries management. Inferring organism abundance or biomass from sequence counts derived from metabarcoding data has been an exciting but contentious concept in the biomonitoring community for some time. Although demonstrating a strong correlation with abundance has proven difficult, many researchers have assumed that quantitative metabarcoding data can at least provide broad-scale ranking of abundance. However, robust field validations of this widely-held assumption remain scarce.

Here, we analyse metabarcoding read counts of fish eDNA data derived from 20 lakes and use betabinomial mixed effects models to compare this to rank abundance generated from long-term fish survey data. Rank abundance data for 18 species was generated within-species across-sites, meaning that ranks compare the abundance of the same species in different lakes. We also investigated a possible allometric effect on eDNA production by analysing a subset of data for effects of fish body mass on the amount of eDNA sequences.

We found a good relationship between species-specific eDNA sequences and within-species rank abundance categories for fishes, with rare fish producing 3% of sequences in a library, moderately abundant producing 7% and abundant fish producing 29%, according to model predictions.

We found a small negative effect of body mass on the amount of eDNA sequences, where the proportion of reads recovered significantly decreased with increased mean body mass of the population.

Synthesis and applications:The benefit of this approach is the potential for rapid assessment of rank abundance for multiple species, including smaller species which are often missed by conventional methods such as gillnetting, with relatively low amounts of additional effort. This approach will assist practitioners taking a species-based approach to freshwater habitat management in lakes worldwide.
Ligand Binding Effects on Activation of Type-2 Angiotensin II Receptor
Authors: YASAR EKREM , DOGRU SEGUN , EROGLU EROL , YARAS NAZMI
Published: January 2025

The Angiotensin II type-2 receptor (AGTR2) is a G-protein coupled receptor (GPCR) in the Renin-Angiotensin System (RAS), mediating essential roles in cardiovascular regulation. Overactivation of AGTR2 causes to cardiovascular pathologies, ranging from hypertension to cancer. Despite its physiological importance, the molecular mechanisms driving AGTR2 activation remain poorly understood. Using long-timescale molecular dynamics (MD) simulations, we investigated the ligand binding effects of Angiotensin II (Ang II) and Angiotensin 1-7 (Ang 1-7) on AGTR2 in inactive and active states. Our results demonstrate that Ang II stabilizes the active-state of AGTR2 by reducing fluctuations in TM6 and Helix8, thereby promoting receptor activation. In contrast, Ang 1-7 modulates the inactive-state by enhancing flexibility in intracellular loops and Helix8, suggesting may a preparatory role for receptor activation. Key interactions, including hydrogen bonds (e.g., PRO7-THR1253.33 for Ang 1-7 and PHE8-LYS2155.42 for Ang II), salt bridges (e.g., ARG2-ASP2796.58 and ARG2-ASP2977.32), and hydrophobic contacts (e.g., TRP1002.60, MET1283.36), were identified as critical for receptor stability and ligand-specific dynamics. Analyses of conserved micro-switch motifs (CWxP, PIF, E/DRY, NPxxY) and intracellular distances revealed additional details about ligand-specific pathways contributing to AGTR2 activation and signal propagation. In addition, Dynamic Residue Interaction Network (DRIN) findings, aligned with micro-switch motif analyses, revealed that ligand binding impacts conserved regions, advancing our knowledge of AGTR2 activation mechanisms. These findings highlight the distinct yet complementary roles of Ang II and Ang 1-7 in regulating AGTR2 dynamics, offering new insights into GPCR activation and therapeutic opportunities for cardiovascular diseases.
The Type IV Secretion System of Patescibacteria is homologous to the bacterial monoderm conjugation machinery
Authors: Quinonero-Coronel Maria del Mar , Cabello-Yeves Pedro J , Haro-Moreno Jose M , Rodriguez-Valera Francisco , Garcillan-Barcia M. Pilar
Published: January 2025

The Candidate Phyla Radiation, also known as Patescibacteria, represents a vast and diverse division of bacteria that has come to light via culture-independent "omics" technologies. Their limited biosynthetic capacity, along with evidence of their growth as obligate epibionts on other bacteria, suggests a broad reliance on host organisms for their survival. Nevertheless, our understanding of the molecular mechanisms governing their metabolism and lifestyle remains limited. The Type IV Secretion System (T4SS) represents a superfamily of translocation systems with a wide range of functional roles. T4SS genes have been identified in the CPR group Saccharibacteria as essential for their epibiotic growth. In this study, we used a comprehensive bioinformatics approach to investigate the diversity and distribution of T4SS within the Patescibacteria lineage. The phylogenetic analysis of the T4SS signature protein VirB4 suggests that most of these proteins cluster into a distinct monophyletic group with a shared ancestry to the MPFFATA class of T4SS. This class is found in the conjugative elements of Firmicutes, Actinobacteria, Tenericutes, and Archaea, indicating a possible horizontal gene transfer from these monoderm microorganisms to CPR bacteria. We identified additional T4SS components near virB4, particularly those associated with the MPFFATA class, as well as homologs of other T4SS classes, such as VirB2-like pilins, and observed their varied arrangements across different CPR phyla. The absence of a relaxase in most of these T4SS clusters suggests that the system has been co-opted for other functions in CPR bacteria. The proximity of T4SS components to the origin of replication (gene dnaA) in some CPR suggests a potential mechanism for increased expression. The broad ubiquity of a phylogenetically distinct T4SS in CPR, combined with its chromosomal location, underscores the significance of T4SS in the biology of Patescibacteria.
VPS13Dmutations affect mitochondrial homeostasis and locomotion inCaenorhabditis elegans
Authors: Yin Xiaomeng , Wang Ruoxi , Thackeray Andrea , Baehrecke Eric H. , Alkema Mark J.
Published: January 2025

Mitochondria control cellular metabolism, serve as hubs for signaling and organelle communication, and are important for the health and survival of cells.VPS13Dencodes a cytoplasmic lipid transfer protein that regulates mitochondrial morphology, mitochondria and endoplasmic reticulum (ER) contact, quality control of mitochondria.VPS13Dmutations have been reported in patients displaying ataxic and spastic gait disorders with variable age of onset. Here we used CRISPR/Cas9 gene editing to createVPS13Drelated-spinocerebellar ataxia-4 (SCAR4) missense mutations and C-terminal deletion inVPS13D’s orthologuevps-13DinC. elegans. Consistent with SCAR4 patient movement disorders and mitochondrial dysfunction,vps-13Dmutant worms exhibit locomotion defects and abnormal mitochondrial morphology. Importantly, animals with avps-13Ddeletion or a N3017I missense mutation exhibited an increase in mitochondrial unfolded protein response (UPRmt). The cellular and behavioral changes caused byVPS13Dmutations inC. elegansadvance the development of animal models that are needed to study SCAR4 pathogenesis.
Creating a General-Purpose Generative Model for Healthcare Data based on Multiple Clinical Studies
Authors: Maruyama Hiroshi , Bito Kotatsu , Saito Yuki , Hibi Masanobu , Katada Shun , Kawakami Aya , Oono Kenta , Charoenphakdee Nontawat , Gao Zhengyan , Igata Hideyoshi , Yoshikawa Masashi , Ota Yoshiaki , Okui Hiroki , Akita Kei , Yamaguchi Shoichiro , Sugawara Yohei , Maeda Shin-ichi
Published: January 2025

Data for healthcare applications are typically customized for specific purposes but are often difficult to access due to high costs and privacy concerns. Rather than prepare separate datasets for individual applications, we propose a novel approach: building a general-purpose generative model applicable to virtually any type of healthcare application. This generative model encompasses a broad range of human attributes, including age, sex, anthropometric measurements, blood components, physical performance metrics, and numerous healthcare-related questionnaire responses. To achieve this goal, we integrated the results of multiple clinical studies into a unified training dataset and developed a generative model to replicate its characteristics. The model can estimate missing attribute values from known attribute values and generate synthetic datasets for various applications. Our analysis confirmed that the model captures key statistical properties of the training dataset, including univariate distributions and bivariate relationships. We demonstrate the model’s practical utility through multiple real-world applications, illustrating its potential impact on predictive, preventive, and personalized medicine.
Patterns of reporting of influenza and pertussis vaccination during pregnancy to the Australian Immunisation Register, 2022
Authors: Sonneveld Nicole , Wilson Elizabeth , Ennis Sonya , McRae Jocelynne , Macartney Kristine , Liu Bette
Published: January 2025

Objectives

Timely, accurate reporting of pregnancy vaccination coverage is key to evaluating pregnancy immunisation programs. We compared influenza and pertussis vaccination reporting on the New South Wales (NSW) Perinatal Data Collection (PDC) and the Australian Immunisation Register (AIR), to understand coverage, reporting, timing of vaccination and provider type.

Design

Retrospective population-based cohort study.

Setting

People giving birth at ≥20-weeks gestation (2017–2022) in the NSW PDC, linked to AIR-reported influenza and pertussis vaccinations.

Main outcome measures

Influenza and pertussis coverage according to 1) the PDC and 2) linked AIR records, and agreement between data sources by year (influenza: 2021–2022, pertussis: 2017–2022) and selected characteristics (2022). Description of provider type and timing for vaccinations reported to the AIR (2022).

Results

PDC-reported influenza and pertussis coverage peaked in 2020 (influenza: 58.8% (52,940/90,091), pertussis: 79.0% (71,169/90,091)), decreasing thereafter (influenza: 49.1% (43,744/89,112), pertussis: 77.6% (69,129/89,112) in 2022). Influenza and pertussis vaccination coverage as reported to the AIR increased from 34.7% (33,611/96,789) in 2021 to 44.8% (39,935/89,112) in 2022 and 24.4% (22,857/93,582) in 2017 to 51.6% (46,009/89,112) in 2022, respectively. Agreement between AIR and PDC improved over time, but remained suboptimal (influenza: 75.5%, pertussis: 56.6% in 2022). AIR and PDC agreement differed most by antenatal care model, particularly for pertussis vaccinations. In 2022, of pregnancy vaccinations reported to the AIR, >75% were provided in general practices. Co- administration occurred infrequently (8.8%).

Conclusions

Despite mandated reporting to the AIR, there was significant underreporting of pregnancy vaccinations to the AIR as compared with the NSW PDC. National collection of accurate and timely data on pregnancy vaccination coverage is needed to monitor vaccine uptake, and identify and monitor strategies to improve uptake, particularly with the new pregnancy RSV vaccine program in 2025. We identified co-administration as a potential strategy to improve influenza vaccination coverage during pregnancy.
The association of umbilical cord blood neurofilament light with non-reassuring fetal status: a prospective observational study
Authors: Zalcberg David , Kramer Kaitlin , Payne Emma , Payne Thomas , Marathe Shreeya , Mahajan Neha , Liu Ashly , Barry Jessica , Duckworth Andrew , Brookes Mitchell , de Vries Bradley , Gonzalez-Ortiz Fernando , Blennow Kaj , Zetterberg Henrik , Gordon Adrienne , Moran Benjamin , Manning Helen , Sanders Robert D.
Published: January 2025

Objective

Early detection of hypoxic–ischaemic encephalopathy (HIE) in neonates is critical. We conducted a pilot cohort study to determine the feasibility of collecting umbilical cord blood samples for neurofilament light (NfL) and to assess the association of NfL with non-reassuring fetal status and other cord biomarkers.

Design

Prospective cohort study.

Setting

A single, large tertiary and quaternary referral hospital.

Patients

108 maternal participants consenting to donate cord blood.

Intervention

Umbilical cord venous blood plasma NfL levels.

Main outcome measures

(1) Feasibility of cord NfL sample collection and analysis; (2) Association of NfL with non-reassuring fetal status (CTG changes and/or documented non-reassuring fetal status), NICU admission and length of stay; (3) Correlation of NfL with other cord biomarkers.

Results

Cord NfL was higher in preterm neonates, and was correlated with cord lactate, pH, and base excess. After controlling for mode of delivery and gestational age, NfL (OR = 2.29, 95%CI: 1.15 to 5.57), but not pH (OR = 0.78, 95%CI: 0.42 to 1.41), base excess (OR = 0.83, 95%CI: 0.37 to 1.86), or lactate (OR = 1.06, 95%CI: 0.51 to 2.12) was associated with non-reassuring fetal status. NfL levels were higher in neonates admitted to NICU (median (IQR): 11.3 (7) versus 8.5 (5.1)).

Conclusions

Cord blood NfL analysis was feasible and provided correlates of adverse outcomes. Higher venous cord blood NfL levels were associated with non-reassuring fetal status. Further research is needed to validate these findings and establish the role of NfL, if any, in clinical practice.
Development and Validation of the Children’s Medication Self-Efficacy Scale
Authors: Yu Ziying , Yu Jin , Gao Yongqiang , Wang Ting , Wang Xinyu , Liu Pan , Meng Qinghui , Wu Yibo
Published: January 2025

Aims

This study aims to develop a tool to assess medication self-efficacy in children and validate the reliability and validity of the Children’s Medication Self-Efficacy Scale (CMSES).

Methods

Based on Bandura’s theory of self-efficacy and expert recommendations, four items were developed for the scale. Data were collected from 2,258 Chinese children between May and November 2023. Exploratory factor analysis was performed to determine the scale’s structure, followed by confirmatory factor analysis to validate it. Both convergent and discriminant validity were assessed. The internal consistency reliability of the scale was evaluated using Cronbach’s alpha coefficient. Additionally, latent profile analysis (LPA) and receiver operating characteristic (ROC) curve analysis were employed to determine the optimal cut-off point for the scale.

Results

The Cronbach’s alpha coefficient for the CMSES was 0.92. Exploratory factor analysis revealed that the four items could be decomposed into two factors, namely magnitude and strength, which explained 76% of the total variance. Additionally, the scale demonstrated good convergent and discriminant validity. LPA identified three categories of medication self-efficacy among participating children: low (6.9%), medium (40.5%), and high (52.6%). Setting the cut-off point at 16, ROC analysis successfully distinguished children with low medication self-efficacy from others, yielding an area under the curve (AUC) of 88.5% (95% CI: 86.8%-90.2%).

Conclusion

The CMSES is an effective and reliable tool for assessing medication self-efficacy in children.
Molecular profiling of neuronal extracellular vesicles reveals brain tissue specific signals
Authors: Kalia Vrinda , Jackson Gabriela , Dominguez Regina J. , Pinto-Pacheco Brismar , Bloomquist Tessa , Furnari Julia , Banu Matei , Volpert Olga , Manz Katherine E. , Walker Douglas I. , Pennell Kurt D. , Canoll Peter D. , Bruce Jeffrey N. , Eitan Erez , Wu Haotian , Baccarelli Andrea A.
Published: January 2025

Extracellular vesicles (EVs) released by neurons (nEVs) provide an opportunity to measure biomarkers from the brain circulating in the periphery. No study yet has directly compared molecular cargo in brain tissue to nEVs found in circulation in humans. We compared the levels microRNAs and environmental chemicals because microRNAs are one of the most studied nEV cargoes and offer great potential as biomarkers and environmental chemical load in nEVs is understudied and could reveal levels of chemicals in the brain. To do so, we leveraged matched sets of brain tissue and serum, and isolated serum total EVs and serum nEVs. We also generated and compared metabolomic profiles in a different set of matched serum, serum total EVs, and serum nEVs since metabolite cargo in nEVs is also understudied but could offer potential biomarkers. Highly expressed brain tissue miRNAs showed stronger correlations with nEVs than serum or total EVs. We detected several environmental chemical pollutant classes in nEVs. The chemical pollutant concentrations in nEVs were more strongly correlated with brain tissue levels than those observed between brain tissue and serum or total EVs. We also detected several endogenous metabolite classes in nEVs. Compared to serum and total EVs, there was enrichment of metabolites with known signaling roles, such as bile acids, oleic acid, phosphatidylserine, and isoprenoids. We provide evidence that nEV cargo is closely correlated to brain tissue content, further supporting their utility as a brain liquid biopsy.
Is it time for the neurologist to use Large Language Models in everyday practice?
Authors: Maiorana N. V. , Marceglia S. , Treddenti M. , Tosi M. , Guidetti M. , Creta M.F. , Bocci T. , Oliveri S. , Martinelli-Boneschi F. , Priori A.
Published: January 2025

Large Language Models (LLMs) such as ChatGPT and Gemini are gaining momentum in healthcare for their diagnostic potential. However, their real-world applicability in specialized medical fields like neurology remains inadequately explored. The possibility to use these tools in everyday diagnostic practice relies on the evaluation of their ability to serve as support for the clinician in assessing the patient, understanding the possible diagnosis and design the diagnostic pathway. To this end, in this study we (1) examined the available literature on the evaluation of LLMs in neurology diagnosis in order to understand whether the methodologies applied were adequate to translate the use of LLMs in everyday practice, and (2) designed and performed an experiment to evaluate the diagnostic accuracy and clinical recommendations of ChatGPT-3.5 and Gemini compared to neurologists using real-world clinical cases presented following the everyday diagnostic practice. In the vast literature of LLMs application in neurology, only 24 studies reported experiences using LLMs in clinical neurology. The experiments reported showed a heterogeneous scenario of prompt engineering and input formats. At present, while responses using structured prompts were well documented, there is a lack of studies using real-world clinical scenarios, and everyday workflows and practice. We therefore conducted a real-world experiment using a cohort of 28 anonymized patient records from the neurology department of the ASST Santi Paolo e Carlo Hospital (Milan, Italy). Cases were presented to ChatGPT-3.5 and Gemini replicating the typical clinical workflows. Diagnostic accuracy and appropriateness of recommended diagnostic tests were assessed against discharge diagnoses and neurologists’ performance.

Neurologists achieved a diagnostic accuracy of 75%, outperforming ChatGPT-3.5 (54%) and Gemini (46%). Both LLMs exhibited difficulties in nuanced clinical reasoning and over-prescribed diagnostic tests in 17–25% of cases. Despite their ability to generate structured recommendations, they struggled with complex or ambiguous presentations, requiring additional prompts in some cases. We can therefore conclude that LLMs have potential as supportive tools in neurology but they currently lack the depth required for nuanced clinical decision-making. The findings emphasize the need for further refinement of LLMs and the development of evaluation methodologies that reflect the complexities of real-world neurology practice.
Leveraging Hand-Crafted Radiomics on Multicenter FLAIR MRI for Predicting Disability Progression in People with Multiple Sclerosis
Authors: Khan Hamza , Woodruff Henry C , Giraldo Diana L. , Werthen-Brabants Lorin , Mali Shruti Atul , Amirrajab Sina , Brouwer Edward De , Popescu Veronica , Wijmeersch Bart Van , Gerlach Oliver , Sijbers Jan , Peeters Liesbet M. , Lambin Philippe
Published: January 2025

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system that results in varying degrees of functional impairment. Conventional tools, such as the Expanded Disability Status Scale (EDSS), lack sensitivity to subtle changes in disease progression. Radiomics offers a quantitative imaging approach to address this limitation. This study used machine learning (ML) and radiomics features derived from T2-weighted Fluid-Attenuated Inversion Recovery (FLAIR) magnetic resonance images (MRI) to predict disability progression in people with MS (PwMS).

A retrospective analysis was performed on real-world data from 247 PwMS across two centers. Disability progression was defined using EDSS changes over two years. FLAIR MRIs were preprocessed using bias-field correction, intensity normalisation, and super-resolution reconstruction for low-resolution images. White matter lesions (WML) were segmented using the Lesion Segmentation Toolbox (LST), and MRI tissue segmentation was performed using sequence Adaptive Multimodal SEGmentation. Radiomics features from WML and normal-appearing white matter (NAWM) were extracted using PyRadiomics, harmonised with Longitudinal ComBat, and reduced via Spearman correlation and recursive feature elimination. Elastic Net, Balanced Random Forest (BRFC), and Light Gradient-Boosting Machine (LGBM) models were evaluated on validation data and subsequently tested on unseen data.

The LGBM model with harmonised radiomics and clinical features outperformed the clinical only model by achieving a test performance of PR AUC of 0.20 and a ROC AUC of 0.64. Key predictive features, among others, included GLCM maximum probability (WML), GLDM dependence non uniformity (NAWM). Short-term changes (longitudinal imaging approach) showed limited predictive power by achieving a PR AUC of 0.11 and a ROC AUC of 0.69.

These findings support the use of ML models trained on radiomics features integrated with clinical data for predicting disability progression in PwMS. Future studies should validate these findings in larger, balanced datasets and explore advanced approaches, such as deep learning and foundation models, to enhance predictive performance.
Effect of antihypertensive drugs on glaucoma: a Mendelian randomization and triangulation analysis
Authors: Huang Yu , Liu Yiliang , Guo Jingze , Niu Yongyi , Lin Hongliang , Liu Jing , Chen Shuilian , Zhu Zhuoting , Qin Yongjie , Shang Xianwen , Plotnikov Denis , Zhang Hongyang , Wang Huan
Published: January 2025

Importance

Glaucoma is one of the world’s leading causes of irreversible blindness and effective interventions with less side effect and less cost were still in need.

Objective

To investigate the potential of repurposing antihypertensive drugs to glaucoma treatment and intra ocular pressure (IOP) lowering in cost effective manners.

Design, Setting and Participants

Two sample Mendelian Randomization (MR) was used to investigate the genetic effect of antihypertensive drugs on glaucoma protection or IOP lowering. Two strategies (biomarker or eQTL approach) were applied to define the instrumental variable (IV). Genome-wide association study (GWAS) results on systolic blood pressure (SBP) of 526,001 European participants were used as exposure and GWAS on primary open angle glaucoma (POAG, 15,229 cases and 177,473 controls) and on IOP compromising 70832 participants in the UK Biobank were used as the outcome. All analyses were performed between April 2022 and December 2022.

Exposures

The SBP lowering effect of the antihypertensive drug targets.

Main Outcomes and Measures

POAG or IOP measurements.

Results

Using IVs defined by the biomarker approach, genetically-proxied lower SBP through diuretics targets was causally associated with a reduced risk of glaucoma (OR per mmHg reduction in SBP 0.87, 95% CI: 0.97-0.78, p = 0.009 for potassium-sparing diuretics [PSD] and OR=0.86, 95% CI: 0.92-0.81,p =2.67e-05 for loop diuretics [LD]). When using eQTL as IVs, the IVW-MR yielded a causal effect estimate on POAG of 0.88 (95% CI 0.79 -0.97, P = 0.011) per 1 mmHg decrease in blood pressure via PSD targets and 0.92 (95% CI 0.85 – 1, P=0.052) via LD. No consistence effects were observed among different MR methods for other antihypertensive drugs on glaucoma or IOP. After triangulation genetic evidence from MR, epidemiological evidence from observational studies and experimental evidence, the protective effect of PSD/LD on POAG was suggested.

Conclusions and Relevance

We found PSD and LD drugs hold promise as potential therapeutic agents to reduce the risk of POAG

Key Points

Question

Can antihypertensive drugs be repurposed to the treatment of ocular hypertension?

Findings

Different Mendelian Randomization (MR) analysis strategies identified that diuretics (potassium-sparing diuretics [PSD) and loop diuretics [LD] might have a protective effect on primary open angle glaucoma (POAG). Furthermore, the triangulation analysis compared the genetic evidence from MR, epidemiological evidence from observational studies and experimental evidence and found a consistent protective effect of PSD/LD on POAG.

Meaning

PSD/LD may be repurposed to the treatment of POAG and they may also benefit patients with hypertension as well as POAG.
Activin A-activated ALK4 induces pathogenic Th17 involvement in endothelial–mesenchymal transition in systemic lupus erythematosus-associated pulmonary arterial hypertension
Authors: Jing Shuliang , Qian Junyan , Yao Mingxin , Mao Pei , Zhang Jingyuan , Wu Zhihong , Ying Hongjie , Wang Lie , Li Mengtao , Yang Jun
Published: January 2025

Objective

Autoimmune diseases, such as systemic lupus erythematosus (SLE), are associated with pulmonary arterial hypertension (PAH), a condition that can lead to heart failure. However, whether T cells also contribute to the occurrence of PAH in SLE, has not been clarified. The objective of this study was to elucidate the role of Activin A signaling in the effector cells mainly involved in SLE-PAH.

Methods

CyTOF analysis was performed to identify the major affected immune cell population after the treatment in SLE-PAH patients. ELISA showed the serum Activin A and IL-17 levels were significantly higher in patients with SLE-PAH compared to SLE alone and healthy donors. We also conducted Th17 cells coculturing with pulmonary microvascular endothelial cells(PMECs) and constructed a SLE-PH mouse model and CD4+T cells depletion mice together with two rat models to identify the converged target.

Results

The reduced CD4+T cell number was detected in SLE-PAH patients after treatment. Activin A signals via ALK4 in both Th17 cells and PMECs. When ALK4 was overexpressed in Th17 cells, IL-6 and CTGF gene expression was significantly increased in cocultured PMECs. We found severe SLE-PH in mice by overexpression ALK4, and alleviated hemodynamic changes in CD4+T cells depletion mice. ALK4 inhibitor TEW is effective to treat PAH by repressing CTGF transcription, which was facilitated by synergistic increases in pSmad2 and pSTAT3 levels downstream of ALK4 activation.

Conclusion

Our findings suggest that Activin A activates ALK4 in Th17 cells to induce IL-17 secretion, meanwhile activated ALK4 via Smad2 phosphorylation to induce EndoMT in hPMECs, indicating that ALK4 is a promising therapeutic target for SLE-PAH.
Anaemia among mother-child dyads in India: trends, drivers, and future projections
Authors: Pedgaonker Sarang , Meher Trupti , Gupta Monali , Chakrabarti Suman , Nguyen Phuong Hong , Singh Shri Kant , Avula Rasmi , Dwivedi Laxmi Kant , Aditi  , Scott Samuel
Published: January 2025

Anaemia among mothers and their children is a widespread public health challenge with profound consequences for individuals and societies. While anaemia has been studied separately in women and children, there remains a literature gap examining anaemia in mother-child dyads, limiting insights on interventions that may simultaneously address anaemia in both groups. Our study examines trends and drivers of anaemia among mother-child dyads (N=408,342) in India using nationally-representative data from 2006 to 2021 and estimates the potential future reduction in anaemia based on changes in selected drivers. We employed descriptive statistics, multivariable logistic regression and population attributable fraction (PAF) analysis. The co-occurrence of anaemia among mothers-child dyads decreased from 35% in 2006 to 33% in 2016, but increased to 37% in 2021. Subnational analyses revealed varying trends by states, with Delhi showing the highest increase (17% to 32%) and Sikkim the largest decrease (29% to 16%) between 2006 and 2021. Maternal education, regular consumption of non-vegetarian food and green leafy vegetables, consumption of iron folic acid supplements, utilization of government health services, and improved sanitation at both household and community levels were associated with lower likelihood of anaemia among mother-child dyads. The cumulative PAF suggested that addressing these factors collectively could reduce anaemia prevalence among mother-child dyads by 18% to 28% (under different scenarios) by 2030. The study underscores the need for comprehensive, multi-sectoral interventions targeting both maternal and child health to effectively combat anaemia in mother-child dyads.

Key messages

The co-occurrence of anaemia among mother-child dyads in India increased from 33% in 2016 to 37% in 2021. More effective strategies and interventions to combat anaemia are needed.

Realistic improvements in maternal education, dietary practices, toilet facilities and reduction in community open defecation could reduce anaemia prevalence among mother-child dyads by 18% by 2030.

More optimistic scenarios could reduce anaemia burden by 28% by 2030, with improvements in education and sanitation being critical.
Sympathetic nerve activity recovery from the skin recording using the modern optimal shrinkage technique
Authors: Su Pei-Chun , Chen Chao-Yi , Kuo Chia-Hao , Tsai Wei-Chung , Wu Hau-Tieng
Published: January 2025

Objective

The widely used bandpass filter (BPF)-based algorithm for recovering sympathetic nerve activity (SNA) from the skin sympathetic nerve activity (SKNA-I) signal, recorded via electrocardiogram electrodes or subcutaneous sympathetic nerve activity (SCNA-I) in a lead I setup, has limitations. It excludes spectral information outside the BPF range and may retain artifacts, such as cardiac activity or pacemaker interference, in the recovered SNA (rSNA) signal. This study aims to develop an algorithm that recovers the full spectral SNA information as comprehensively as possible for evaluating the autonomic nervous system (ANS).

Methods

We propose a novel algorithm, S3 (SNA from Shrink and Subtraction), which integrates the optimal shrinkage algorithm (eOptShrink) with the template subtraction (TS) method. The performance of S3 was evaluated against other algorithms using semi-real simulated SKNA-I data, a human SKNA-I database including subjects with pacemakers or atrial fibrillation, and a mouse SCNA-I database.

Results

The S3 algorithm demonstrated numerical efficiency and outperformed existing approaches, including traditional TS, BPF and other methods, in both time and frequency domains. Notably, in addition to the traditional 500-1000Hz spectral band, S3 effectively recovers spectral information across the 50-300Hz and 300-500Hz frequency bands, making it suitable for homecare ANS evaluation. All quantitative results are supported by the rSNA tracing for visual inspections.

Conclusion

S3 accurately recovers the full-spectrum SNA.

Significance

By enabling the exploration of the entire SNA spectrum, S3 offers a promising tool for ANS evaluation and applications in homecare environments.
Specificity of a polygenic score for aggressive prostate cancer
Authors: Dornisch Anna M , Xu George J , Karunamuni Roshan , Brunette Charles A , Danowski Morgan E , Teerlink Craig C , Gaziano J. Michael , Garraway Isla P , Hauger Richard L , Kibel Adam S , Lynch Julie A , Maxwell Kara N , Rose Brent S , Andreassen Ole A , Dale Anders M , Donovan Jenny L , Hamdy Freddie , Lane Athene , Mills Ian G , Martin Richard M , Neal David E , Turner Emma L , Wolk Alicja ,   PRACTICAL Consortium,   VA Million Veteran Program, Vassy Jason L , Seibert Tyler
Published: January 2025

To address the concern that polygenic hazard scores for prostate cancer (PCa) might not distinguish between indolent and aggressive disease, we performedcase-onlyanalyses using a 601-variant polygenic score (PHS601). We hypothesized that among men who eventually developed PCa, those with higher PHS were more likely to develop aggressive disease.

We analyzed genetic and phenotypic data from a diverse, national cohort of men diagnosed with PCa (Million Veteran Program, n = 69,901, 6413 metastatic). We used Cox proportional hazards models to examine the association of PHS601 with both age at onset of metastatic PCa (birth-to-met) and time from localized to metastatic diagnosis (localized-to-met). We performed an external validation of the case-only birth-to-met analysis in two population-based cohorts from the PRACTICAL Consortium.

PHS601 was associated with both birth-to-met and localized-to-met within MVP. The HRs for men in the highest quintile of PHS601 vs. those in the lowest quintile (HR80/20) were 1.74 [1.65-1.84] and 1.41 [1.31-1.41] for birth-to-met and localized-to-met, respectively. These findings were validated in two external cohorts (COSM and ProtecT). PHS601 was also associated with earlier development of metastasis. Men with high PHS601 are diagnosed with prostate cancer at a younger age and are more likely to develop metastasis.
The effects of cryptic diversity on diversification dynamics analyses in Crocodylia
Authors: Darlim Gustavo , Höhna Sebastian
Published: January 2025

Incomplete taxon sampling due to underestimation of present-day biodiversity biases diversification analysis by favouring slowdowns in speciation rates towards recent time. For instance, in diversification dynamics studies in Crocodylia, long-term low net-diversification rates and slowdowns in speciation rates have been suggested to characterise crocodylian evolution. However, crocodylian cryptic diversity has never been considered. Here, we explore the effects of incorporating cryptic diversity into a diversification dynamics analysis of extant crocodylians. We inferred a time-calibrated cryptic-species-level phylogeny using cytochromebsequences of 45 lineages compared with the formally recognized 26 crocodylian species. Diversification rate estimates using the cryptic-species-level phylogeny show increasing speciation and net-diversification rates towards the present time, which is contrasting to previous findings. Cryptic diversity should be considered in future macroevolutionary analyses, however representation of cryptic extinct taxa represents a major challenge. Additionally, further investigation of crocodylian diversification dynamics under different underlying genomic data is encouraged upon advances in population genetics. Our case study adds to diversification dynamics knowledge of extant taxa and demonstrates that cryptic species and robust taxonomic assessment are essential to study recent biodiversity dynamics with broad implications for evolutionary biology and ecology.
Lipid nanoparticle delivery of siRNA to dorsal root ganglion neurons to treat pain
Authors: Han Xiangfei , Petrova Veselina , Song Yudong , Cheng Yu-Ting , Jiang Xingya , Zhou Hui , Hu Caleb , Chen Dean Shuailin , Yong Hyo Jeong , Kim Hyoung Woo , Zhang Biyao , Barkai Omer , Jain Aakanksha , Renthal William , Lirk Philipp , Woolf Clifford J. , Shi Jinjun
Published: January 2025

Sensory neurons within the dorsal root ganglion (DRG) are the primary trigger of pain, relaying activity about noxious stimuli from the periphery to the central nervous system; however, targeting DRG neurons for pain management has remained a clinical challenge. Here, we demonstrate the use of lipid nanoparticles (LNPs) for effective intrathecal delivery of small interfering RNA (siRNA) to DRG neurons, achieving potent silencing of the transient receptor potential vanilloid 1 (TRPV1) ion channel that is predominantly expressed in nociceptor sensory neurons. This leads to a reversible interruption of heat-, capsaicin-, and inflammation-induced nociceptive conduction, as observed by behavioral outputs. Our work provides a proof-of-concept for intrathecal siRNA therapy as a novel and selective analgesic modality.
An improved gray whale assembly highlights how allospecific reference-genome choice can affect genomic diversity estimates
Authors: Brüniche-Olsen Anna , Black Andrew , Walden Kimberly K. O. , Fields Christopher , Bickham John W. , Dewoody J. Andrew
Published: January 2025

Gray whales (Eschrichtius robustus) are unique as bottom feeding baleen whales and they have long been a conservation concern on both sides of the Pacific, in part because they migrate and disperse farther than any other species on earth. They experienced drastic population size declines due to environmental changes and commercial whaling. Here, we present an improved genome assembly for the gray whale. This genome assembly covers 2.4 Gb divided across 2689 contigs with an N50 of 15Mb. From the new assembly, we identify 75Mb sex-linked contigs and a identify 94.6% of searched genes based on Benchmarking Universal Single-Copy Ortholog score. We use the gray whale assembly to explore the effects of mapping to conspecific vs allospecific reference genomes when estimating genome-wide heterozygosity (H) and runs of homozygosity (ROH). The use of allospecific genomes significantly underestimate bothHand ROH burden regardless of genomic distance and assembly quality. Our analyses highlight the importance of using contiguous conspecific assemblies in whale genomics and conservation.

Significance

Gray whales are unique in their behavior, morphology and ecology. The novel and contiguous genome assembly presented here will serve as a valuable resource for studies of their population and comparative genomics, as well as for identifying key adaptations that have evolved in this clade. Finally, our results demonstrate that biases can arise when using allopatric assemblies to evaluate diversity metrics, so they should be used and interpreted with caution.
Sterile- or pathogen-induced endolysosomal damage activate the NLRP6 inflammasome in human intestinal epithelial cells
Authors: Boegli Alexandra , Bernard Elliott M. , Lacante Louise , Majeux Gaël , Mack Vanessa , Broz Petr
Published: January 2025

NLRP6 controls host defense against bacteria and viruses in the gastrointestinal tract by a poorly understood mechanism. Here, we report that NLRP6 forms an inflammasome upon endolysosomal damage caused by sterile triggers or bacterial pathogens such asListeria monocytogenesin human intestinal epithelial cells (IECs). NLRP6 activation required Listeriolysin O-dependent cytosolic invasion ofL. monocytogenesand drove IEC pyroptosis via ASC/Caspase-1-mediated GSDMD cleavage. NLRP6 inflammasome formation was independent of bacterial PAMPs, such as lipoteichoic acid or dsRNA, which were previously reported to activate NLRP6.L. monocytogenesmutants deficient in cell-to-cell spread or escape from secondary vacuoles induced less cell death, linking bacteria-induced endolysosomal damage to NLRP6 activation. Finally, sterile endolysosomal damage recapitulated pathogen-induced NLRP6 activation and drove IEC pyroptosis. In summary, our study reveals that NLRP6 allows IECs to detect endolysosomal damage, thereby not only making it responsive to pathogens but more generally to wide-ranging sources of pathological endolysosomal damage.
ASK1 overexpression protects from HFD-induced body weight gain via FGF21
Authors: Goergen Anne , Challa Tenagne Delessa , Borsigova Marcela , Villarroel-Vicente Carlos Villarroel-Vicente , Van Krieken Pim , Wueest Stephan , Konrad Daniel
Published: January 2025

People with obesity are at high risk to develop metabolic complications such as type 2 diabetes and metabolic dysfunction-associated fatty liver disease (MAFLD). We previously reported that the apoptosis signal-regulating kinase 1 (ASK1) regulates the development of MAFLD, since high fat diet (HFD)-fed mice with liver-specific ASK1 depletion and overexpression revealed increased and blunted development of MAFLD, respectively. Herein we identify a protective role of liver-expressed ASK1 in the context of diet-induced obesity. When fed a HFD for 20 weeks, liver-specific ASK1 overexpressing mice (ASK1+hep) were resistant to obesity and showed improved glucose metabolism as well as increased energy expenditure compared to control animals. Moreover, HFD-fed ASK1+hep mice had higher BAT activity as well as increased browning of inguinal WAT, as suggested by increased UCP1 levels. The latter may be induced by the hepatokine fibroblast growth factor (FGF21), a hormone that is mainly produced in the liver and is known to reduce body weight via increasing energy expenditure. In line with an important role of FGF21, its plasma levels were significantly increased in HFD-fed ASK1+hep mice and they negatively correlated with body weight. Mechanistically, we propose that the transcription factor ATF4 is activated via HFD-induced ASK1-p38 signaling in hepatocytes, subsequently promoting hepatic Fgf21 gene expression. Supporting this hypothesis, p38 inhibition resulted in a more pronounced reduction in Fgf21 expression in ASK1+hep hepatocytes compared to controls, while silencing of ATF4 in primary hepatocytes significantly decreased Fgf21 transcript levels in ASK1+hep hepatocytes but not in hepatocytes derived from control mice. In conclusion, we have uncovered a yet undescribed axis between hepatic ASK1 and FGF21 which positively affects body weight and glucose metabolism.