bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multi-Omics Analysis of Red Blood Cells Reveals Molecular Pathways Underlying Thalassemia Severity Beyond Globin Gene Mutations
Authors: Mitra Nibedita , Bhattacharyya Upasana , Chowdhury Prosanto , Pal Arijit , Korwar Arvind , Bhattacharjee Samsidhhi , Basu Anupam 
Published: February 2025

ABSTRACTBackgroundHemoglobinopathies are the most common monogenic genetic disorders, primarily managed through blood transfusions or bone marrow transplantation. Clinical severity other than mutational effect not well investigated and still unknown. This study aims to identify dysregulated molecular pathways in red blood cells contributing to thalassemia severity.MethodFrom a cohort of 285 hemoglobinopathy patients, 10 age-matched individuals with identical compound heterozygous mutations (IVS 1-5 G>C and CD 26 G>A) were screened. Five had severe thalassemia requiring regular transfusions, while five had a non-severe form requiring fewer transfusions. RNA sequencing and proteome analysis were conducted on isolated RBCs, through Novaseq and Orbitrap MS platform respectively. Bioconductor-R and different bioinformatics tools were utilized subsequently.ResultsTranscriptome analysis revealed an increased percentage of snRNA transcripts in all over thalassemia group. Pathways related to autophagy, mitophagy, and chaperone-mediated folding were enriched in the severe group. Thus, dysregulated genes, linked to ineffective erythropoiesis were fished out also.ConclusionIn this this study, thalassemia subjects were of same mutational genotype, but clinically opposite severity. Accordingly, first time identified six pathways which are responsible for thalassemia severity independent of mutational burden. These dysregulated pathways can be further be explored and targeted experimentally for drug development.
Spatially resolved proteomic signatures of atherosclerotic carotid artery disease
Authors: Sinha Ankit , Sachs Nadja , Kratz Elena , Pauli Jessica , Steigerwald Sophia , Albrecht Vincent , Nordmann Thierry , Ugur Enes , Rodriguez Edwin H , Engl Marie-Luise , Skowronek Patricia , von Scheidt Moritz , Winter Hanna , Branzan Daniela , Schunkert Heribert , Maegdefessel Lars , Mann Matthias 
Published: February 2025

AbstractAtherosclerotic plaque rupture remains a leading cause of adverse cardiovascular events, yet the molecular drivers of plaque vulnerability are incompletely understood. To address this challenge, we developed an integrated approach that combines histomorphology-guided spatial proteomics with machine learning to map protein signatures across spatially distinct plaque subregions. Our analysis revealed that vulnerability signatures concentrate in the necrotic core and fibrous cap subregions, and are significantly enriched for ossification, inflammation, cholesterol metabolism, and extracellular matrix degradation pathways. When comparing the vulnerability status across subregions, we found that the necrotic core has the most distinctive vulnerability-associated proteome, with 454 proteins significantly altered between stable and vulnerable states. We identified a mechanistic link between inflammation and oxidative stress, PCSK9 upregulation, and vascular smooth muscle cell dysfunction in vulnerable plaques. This finding suggests arterial PCSK9 as a therapeutic target beyond its established role in hepatic lipid metabolism. By employing machine learning, we developed and independently validated a seven-protein tissue panel (receiver operating characteristic– area under the curve = 0.86) and found a 12-protein serum panel to predict plaque vulnerability status. Thus, plaque vulnerability signatures are spatially concentrated in specific subregions and highlight actionable biomarkers and therapeutic targets for advanced carotid artery disease.
The impact of medication reconciliation on discrepancies and all-cause readmission among hospitalized patients with chronic kidney disease: A quasi-experimental study
Authors: Altawalbeh Shoroq M. , Sallam Nahlah M. , Alshogran Osama Y. , Al-Khatib Minas , Bani Amer Mohammad S. , Tahaineh Linda , Albsoul-Younes Abla 
Published: February 2025

AbstractIntroductionChronic kidney disease (CKD) with its associated comorbidities and pill burden can expose patients to a heightened risk of drug-related problems, including medication discrepancies.This study aimed to evaluate the impact of medication reconciliation supplemented with medication review on the number of medication discrepancies at discharge and all-cause readmission among CKD patients.MethodsThis was a quasi-experimental trial among adult CKD patients admitted into two major referral hospitals in northern Jordan. Patients in the intervention group received medication reconciliation supplemented with medication review by a clinical pharmacist, while those in the control group received the usual care. The recognized discrepancies were evaluated at admission and at discharge in both groups. Participants were followed for 90-day readmission.ResultsAmong patients in the intervention group, the average number of discrepancies was 2.5±2.2 per CKD patient. Compared to the control group, the reduction in discrepancy numbers between admission and discharge was higher in the intervention group by 1.66 discrepancies. The likelihood of 90-day readmission was significantly lower in the intervention group (OR=0.41; P=0.002).ConclusionSupplemented medication reconciliation among CKD patients reveals a favorable impact on medication discrepancies and readmission rates. Optimizing medication management during transitions of care can improve overall health outcomes.Impact of findings on practice statementsActivating the role of clinical pharmacists in providing medication reconciliation can decrease medication discrepancies and enhance clinical outcomes particularly in hospitalized CKD patients.Designing and implementing an effective interprofessional collaborative approach in the hospital settings might boost the benefits achieved from transition-of-care services.
Screening rare genetic diagnoses for amenability to bespoke antisense oligonucleotide therapy development: a retrospective cohort study
Authors: Cheerie David , Lauffer Marlen C. , Newton Logan , Amburgey Kimberly , Beijer Danique , Haque Bushra , Kalish Brian T. , Meserve Margaret , Oh Rachel Y. , Pan Amy Y. , Reuter Miriam , Szego Michael J. , Szuto Anna ,   N=1 Collaborative, Aartsma-Rus Annemieke , Axford Michelle M. , Deshwar Ashish R. , Dowling James J. , Marshall Christian R. , Ivakine Zhenya , Synofzik Matthis , Yu Timothy W. , Costain Gregory 
Published: February 2025

ABSTRACTPurposeTo estimate the proportion of molecular genetic diagnoses in a real-world, phenotypically heterogeneous patient cohort that are amenable to antisense oligonucleotide (ASO) treatment.MethodsWe retrospectively applied the N=1 Collaborative’s VARIANT (VariantAssessments towards Eligibility forAntisense OligonucleotideTreatment) guidelines to all diagnostic variants found by clinical genome-wide sequencing at a single pediatric hospital in 532 patients over a 6-year period. Variants were classified as either “eligible”, “likely eligible”, “unlikely eligible”, or “not eligible” in relation to the different ASO approaches, or “unable to assess”.ResultsIn total, 25 unique variants across 26 patients (4.9% of 532 patients) were eligible or likely eligible for ASO treatment at a molecular genetic level, via canonical exon skipping (4), splice correction (3), or mRNA knockdown (18). Only eight of these molecular genetic diagnoses were made within a year of symptom onset. After considering disease and delivery related factors, 11 diagnoses were still considered candidates for bespoke ASO development.ConclusionA meaningful proportion of genetic diagnoses identified by genome-wide sequencing may be amenable to ASO treatment. These results underscore the importance of timely diagnosis, and the proactive identification and accelerated functional testing of genetic variants amenable to ASO treatments.
MicroRNA Expression in Asymptomatic Welders: Implications for Biomarker Discovery for Environmentally-Linked Neurodegenerative Disorders
Authors: Bargues-Carot Alejandra , Prado-Rico Janina , Kawasawa Yuka Imamura , Cai Jiazhang , Yanosky Jeff D. , Zenitsky Gary , Jin Huajun , Lewis Mechelle , Ma Ping , Anantharam Vellareddy , Kanthasamy Arthi , Rico Andre Luis Garao , Hall Molly A. , Mailman Richard B. , Kanthasamy Anumantha G. , Huang Xuemei 
Published: February 2025

AbstractChronic occupational exposure to metals in welding fumes has been implicated in the etiology of neurodegenerative diseases (NDDs), including Parkinson’s disease (PD) and Alzheimer’s disease (AD). Changes in microRNA (miRNA) expression have been associated with various neurodegenerative conditions. Circulating miRNAs, in particular, have emerged as promising, minimally invasive biomarkers for diagnosing and monitoring disease progression. This study was designed to characterize the expression of miRNAs in neuronally-enriched serum extracellular vesicles (EVs) among welders and non-welders to explore their potential link to metal concentrations and welding exposure measures and their potential as early diagnostic biomarkers for neurodegeneration. Serum samples from 39 welders and 27 healthy individuals were collected, and EV-enclosed miRNAs were extracted and analyzed. Also, whole blood metal concentrations and welding exposure measurements were obtained. Fifty miRNAs were found to be dysregulated in weldersvs.non-welders, of which three (miR-16-5p, miR-93-5p, miR-486-5p) showing reduced expression and two (miR-4281 and miR-4417) exhibiting positive correlations with blood metal concentrations as well as with long- and short-term welding exposure measures. The dysregulation of these miRNAs suggests that exposure to metals could disrupt important biological processes, possibly contributing to an elevated risk of NDDs. These findings highlight the need for further research to validate the causal relationship between exposure to metals in welding fumes, the dysregulation of circulating miRNAs, and their role in neurodegenerative disease development, with implications for miRNA-based biomarkers in early disease detection and prevention.
Identification of the Inducible HIV reservoir in Tonsillar, Intestinal and Cervical Tissue Models of HIV Latency
Authors: Gallego-Cortés A. , Sánchez-Gaona N. , Mancebo-Pérez C. , Ruiz-Isant O. , Benítez-Martínez A. , Landolfi S. , Castellví J. , Pumarola F. , Ortiz N. , Llano I. , Lorente J. , Mañalich-Barrachina L. , Prado JG. , Martín-Gayo E. , Falcó V. , Genescà M. , Buzon MJ. 
Published: February 2025

AbstractHIV persists in diverse tissues, with distinct cellular reservoirs presenting a major barrier to a cure and requiring targeted therapeutic strategies to address this heterogeneity. Here, we developed tissue models of HIV latency using human tonsillar, intestinal and cervicovaginal tissues. These models revealed differential HIV infection across CD4+T cell subpopulations, with ART partially restoring CD4+T cells and reducing intact HIV DNA. T follicular helper cells (TFH CD69+ CCR7-) were the primary inducible reservoir in tonsils, while tissue-resident memory cells (TRM CD69+ CD49a+) dominated in the intestine. Identification of markers for inducible reservoirs revealed that CD69, CD45RO, and PD-1 were shared across tissues, while CXCR5 in the tonsils and CD49a in the intestine served as tissue-specific markers. Furthermore, using different latency reversal agents (LRAs) we found that Histone Deacetylase Inhibitors (HDACis) failed to induce HIV in any tissue, the SMAC mimetic AZD5582 was effective only in a resident-memory CD4+T cell subpopulation in the intestine, and IL15 exhibited the broadest reactivation potential across tissues and CD4+T subsets. These models recapitulate key aspects of HIV infection providing insights into the inducible reservoir’s composition in different tissues and informing strategies for its elimination.
Exposure to rotenone triggers redox driven system-wide lipidome alterations and metabolic trade-offs linked to Parkinson’s disease
Authors: Tiwari Ashutosh Kumar , Rathor Priya , Patel Rajendra P , Jha Pawan Kumar , Birse Nick , Ratnasekhar CH 
Published: February 2025

AbstractWith the global rise in aging populations, the increasing incidence of neurodegenerative diseases underscores concerns about brain health, with pesticides like rotenone, emerging as key environmental hazardous. The precise mechanism by which chronic environmental concentration of rotenone exposure causes Parkinson-like phenotype is not understood. Previous studies showed that rotenone induces depletion of dopaminergic neurons by influencing mitochondrial functions. Mitochondrial dysfunction alters lipid homeostasis; therefore, brain lipids can be potential targets for the early risk assessment and prognosis of Parkinson’s disease (PD). However, the specific lipidome changes and associated biomarkers of chronic rotenone in vivo exposure causing PD are largely unknown. This study investigates the lipid profile disruptions and biomarkers induced by environmentally relevant concentrations of chronic rotenone exposure using the neuro-modelDrosophila melanogaster. An untargeted LC-HRAMS-based lipidomics identified that lipid classes, GP, SP, FA and GL were significantly altered. Furthermore, system-wide loss of cross talk of mitochondrial and peroxisome lipids by altering their redox homeostasis causing PD was observed. Additionally, lipid oxidative stress markers, and behavior abnormalities correlated with altered lipids linked to PD. The findings highlight the rotenone induced complex metabolic trade-offs, prioritizing brain’s neural integrity at the expense of peripheral lipid levels, leading to PD.Environmental implicationThis study highlights the environmental risks of chronic rotenone exposure, commonly used in agriculture. The findings show that even low concentrations of rotenone disrupt lipid metabolism, particularly in the brain, affecting mitochondrial and peroxisomal functions, contributing to depleting dopaminergic neurons, which are linked to neurodegenerative diseases like Parkinson’s. The study also identify lipid markers linked to rotenone induced PD and reveals metabolic trade-offs, where the brain prioritizes neural integrity over peripheral lipid balance. These lipidome changes and redox-driven shifts threaten both individual health and ecosystem stability, emphasizing the need for policies to regulate pesticide use and minimize exposure risks.Graphical abstract
Predictors of brain iron deposition in dementia and Parkinson’s disease-associated subcortical regions: genetic and observational analysis in UK Biobank
Authors: Casanova Francesco , Tian Qu , Williamson Daniel S , Lucas Mitchell R , Zweibaum David , Ding Jun , Atkins Janice L , Melzer David , Ferrucci Luigi , Pilling Luke C 
Published: February 2025

AbstractBackgroundBrain iron in specific subcortical regions increases risk of dementia and Parkinson’s Disease (PD). Genetic and environmental factors affect iron deposition, but the underlying mechanisms are unclear.ObjectiveIdentify risk factors and diseases associated with brain iron, and assess causality using genetics.Methods41,581 UK Biobank participants had MRI-estimated brain iron in four dementia or PD-associated subcortical regions (Caudate, Putamen, Substantia Nigra, Thalamus). We investigated common risk factors (including adiposity, blood pressure, health behaviours, and inflammation) and diseases observationally, using covariate-adjusted regression models, and genetically, with Mendelian randomization.ResultsParticipants diagnosed with Alzheimer’s disease, PD, or other diseases had higher brain iron. Anaemia, osteoporosis, and hyperparathyroidism were associated with lower brain iron. Higher BMI and blood pressure, history of smoking, and self-reported meat consumption, increased brain iron. Haematological parameters, inflammatory and kidney biomarkers, and calcium, were also associated.Genetics support causal effects of depression, type-2 diabetes, and 7 other diseases with increased iron, but not Alzheimer’s disease. Evidence supports a causal effect of osteoporosis on lower iron in the substantia nigra. We found causal associations between adiposity and proteins (such as IL-6 receptor and transferrin receptor) on subcortical brain iron.ConclusionsWe identified causal effects for liability to type-2 diabetes, depression, and other conditions, on subcortical iron deposition, but not to Alzheimer’s disease, supportive of dementia as a consequence of brain iron deposition, not a cause. The role of adiposity reducing interventions on brain iron should be investigated. Relationships between brain iron, osteoporosis, calcium, and hyperparathyroidism warrant further investigation.
Wearable MEG data recorded during human stepping
Authors: Spedden Meaghan E. , O’Neill George C. , West Timothy O. , Tierney Tim M. , Mellor Stephanie , Alexander Nicholas A. , Seymour Robert , Lundbye-Jensen Jesper , Nielsen Jens Bo , Farmer Simon F. , Bestmann Sven , Barnes Gareth R. 
Published: February 2025

AbstractNon-invasive spatiotemporal imaging of brain activity during large-scale, whole body movement is a significant methodological challenge for the field of movement neuroscience. Here, we present a dataset recorded using a new imaging modality – optically-pumped magnetoencephalography (OP-MEG) – to record brain activity during human stepping. Participants (n=3) performed a visually guided stepping task requiring precise foot placement while dual-axis and triaxial OP-MEG and leg muscle activity (electromyography, EMG) were recorded. The dataset also includes a structural MRI for each participant and foot kinematics. We validate the fidelity of the OPM data by showing movement-related beta band desynchronization source localised to the primary motor cortex. This multimodal dataset offers a resource for methodological development and testing for OPM data (e.g., movement-related interference rejection), within-subject analyses, and exploratory analyses to generate hypotheses for further work on the neural control of human stepping.
Rearing conditions bidirectionally modulate cognitive abilities and AP-1 signaling in hippocampal neurons in a cell type-specific manner
Authors: Alaiz-Noya Marta , Miozzo Federico , Fuentes-Ramos Miguel , Machnicka Magdalena , Kurowska Marcelina , Herrera Macarena L. , del Blanco Beatriz , Ninerola Sergio , Bustos-Martínez Isabel , Wilczynski Bartek , Barco Angel 
Published: February 2025

AbstractEnvironmental conditions profoundly influence cognitive development, particularly during early life. Transcriptional and epigenetic mechanisms may serve as molecular substrates for the lasting effects of environmental enrichment (EE) and impoverishment (IE) on cognitive abilities and hippocampal function. However, the specific gene programs driving these changes remain largely unknown. In this study, EE and IE modulated the cognitive abilities of mice in opposing directions. By combining hippocampal microdissection and genetic tagging of neuronal nuclei with genome-wide analyses of gene expression, chromatin accessibility, histone acetylation, and DNA methylation, we uncovered profound differences in the transcriptional and epigenetic profiles of CA1 pyramidal neurons and dentate gyrus (DG) granule neurons. These analyses revealed cell type-specific genomic changes induced by EE and IE, highlighting distinct patterns of neuroadaptation within each population. This multiomic screen pinpointed the activity-regulated transcription factor AP-1 as a crucial mediator of neuroadaptation to conditions during early life in both cell types, albeit through distinct downstream mechanisms. Conditional deletion ofFos, a core AP-1 subunit, in excitatory neurons hampered EE-induced cognitive enhancement, further underscoring the pivotal role of this transcription factor in neuroadaptation.
Identifying Neurobiological Psychosis Biotypes Using Multi-Scale Functional Network Connectivity and its Latent Independent Subspace
Authors: Ballem Ram , Andrés-Camazón Pablo , Jensen Kyle M. , Bajracharya Prerana , Díaz-Caneja Covadonga M. , Bustillo Juan R , Turner Jessica A. , Pearlson Godfrey D. , Chen Jiayu , Calhoun Vince D. , Iraji Armin 
Published: February 2025

ABSTRACTPsychotic disorders present a great amount of biological heterogeneity. We explore this by leveraging multiscale functional network connectivity (msFNC) to identify distinct neurobiological psychosis biotypes. Resting-state fMRI data from 2103 B-SNIP 1&2 participants (1127 with psychosis, 350 relatives, 626 controls) were analyzed to obtain subject-specific multiscale intrinsic connectivity networks (msICNs) and compute msFNCs. A low-dimensional neurobiological subspace of multiscale connectivity features termed Latent Network Connectivity (LNC) was identified, consisting of three components (cognitive-related, typical, psychosis-related). Projections of psychosis participants’ msFNC onto this subspace revealed three distinct biotypes through unsupervised learning. These biotypes, characterized by cognitive, clinical, and connectivity profiles, spanned all DSM diagnoses (Schizophrenia, Bipolar, Schizoaffective disorders), revealing their overlapping connectivity profiles. Biotype-1, the most cognitively impaired compared to other biotypes, showed Cerebellar-Subcortical and Visual-Sensorimotor hypoconnectivity, alongside Visual-Subcortical hyperconnectivity. Biotype-2 was most cognitively preserved and showed Visual-Subcortical, Subcortical-Sensorimotor, and Subcortical-Higher Cognition hypoconnectivity. Biotype-3 exhibited intermediate cognitive function, showing Cerebellar-Subcortical hypoconnectivity alongside Cerebellar-Sensorimotor and Subcortical-Sensorimotor hyperconnectivity. Notably, unaffected relatives displayed intermediate connectivity patterns, with 55% classified into the same biotype group as their affected family member—a significantly higher rate than random chance (p-valueRelatives-to-Biotype-1< 0.001, p-valueRelatives-to-Biotype-2< 0.05, p-valueRelatives-to-Biotype-3< 0.001) compared to a non-significant 37% alignment using DSM-based diagnosis. Cognitive performance reliably aligns with distinct brain connectivity patterns, which are also evident in unaffected relatives, supporting their construct validity. These findings underscore the limitations of DSM-based classifications in capturing the biological complexity of psychotic disorders and highlight the potential of neurobiological biotypes to enhance our understanding of their spectrum.
Evaluating Variants of Uncertain Significance in Adult Knock-in Zebrafish: A Proof of Concept with aCOL1A2Variant
Authors: Vanhooydonck Michiel , Debaenst Sophie , Vanbelleghem Eva , De Saffel Hanna , Syx Delfien , Sips Patrick , Coucke Paul J. , Willaert Andy , Callewaert Bert 
Published: February 2025

ABSTRACTGenomic variants of uncertain significance (VUS) impede clinical decision-making. In this study, we use a knock-in strategy in zebrafish to evaluate theCOL1A2c.2123G>A VUS, identified in a 59-year-old female with recurrent fractures. Using prime editing, we obtained different zebrafish lines respectively harboring the VUS, a known pathogenic variant, or a known benign variant. Comprehensive skeletal phenotyping revealed no significant abnormalities in the zebrafish modeling the benign variant and the VUS, while zebrafish modeling the pathogenic variant showed scoliosis of the vertebral column, vertebral fusions, vertebral compressions, fractures, and increased mineralization of the notochord and intervertebral ligament. Our findings demonstrate for the first time, thatCOL1A2variant modeling in zebrafish models informs functional validation and shows potential for elucidating associated pathogenic mechanisms. This approach can be extended to study VUS in other genes.