Gene. 2025 Jan 18:149257. doi: 10.1016/j.gene.2025.149257. Online ahead of print.

ABSTRACT

CRISPR-Cas9 technology has revolutionized genetic engineering, offering precise and efficient genome editing capabilities. This review explores the application of CRISPR-Cas9 for cystic fibrosis (CF), particularly targeting mutations in the CFTR gene. CF is a multiorgan disease primarily affecting the lungs, gastrointestinal system (e.g., CF-related diabetes (CFRD), CF-associated liver disease (CFLD)), bones (CF-bone disease), and the reproductive system. CF, a genetic disorder characterized by defective ion transport leading to thick mucus accumulation, is often caused by mutations like ΔF508 in the CFTR gene. This review employs a systematic methodology, incorporating an extensive literature search across multiple academic databases, including PubMed, Web of Science, and ScienceDirect, to identify 40 high-quality studies focused on CRISPR-Cas9 applications for CFTR gene editing. The data collection process involved predefined inclusion criteria targeting experimental approaches, gene-editing outcomes, delivery methods, and verification techniques. Data analysis synthesized findings on editing efficiency, off-target effects, and delivery system optimization to present a comprehensive overview of the field. The review highlights the historical development of CRISPR-Cas9, its mechanism, and its transformative role in genetic engineering and medicine. A detailed examination of CRISPR-Cas9's application in CFTR gene correction emphasizes the potential for therapeutic interventions while addressing challenges such as off-target effects, delivery efficiency, and ethical considerations. Future directions include optimizing delivery systems, integrating advanced editing tools like prime and base editing, and expanding personalized medicine approaches to improve treatment outcomes. By systematically analyzing the current landscape, this review provides a foundation for advancing CRISPR-Cas9 technologies for cystic fibrosis treatment and related disorders.

PMID:39832688 | DOI:10.1016/j.gene.2025.149257

Medicine (Baltimore). 2025 Jan 17;104(3):e41272. doi: 10.1097/MD.0000000000041272.

ABSTRACT

Cystic fibrosis (CF), a historically fatal childhood disease, now became a manageable adulthood disease. The transition of the disease to adulthood and the patients to adult physicians raised a new question: What is the extent of adult physicians' contributions to CF literature? We examined the data of all CF publications from Web of Sciences between 1945 and 2023. We determined the adult CF articles by searching for the term "adult" in titles. We analyzed the data in terms of publication years, study types, countries, and languages. A total of 30,944 articles examined. From 1945 to 2023, both the number of published articles (88-10,460), and the number of publishing journals (31-1770) on CF have increased. The number of articles on adult CF has also increased, from only 3 in the first 3 decades up to 716 between 2010 and 2019. While pediatrics was initially the leading journal with the highest number of articles published on CF, general medicine journals, and finally the Journal of Cystic Fibrosis became the leading publisher. The USA were the most productive country on behalf of publication on CF. The increasing number of annual publications clearly shows the growing interest in CF. The increase in the number of articles on adult CF along with the increase in publishing journals provide evidence that the disease is now acknowledged as a disease concerning adults.

PMID:39833061 | DOI:10.1097/MD.0000000000041272

CMAJ. 2025 Jan 19;197(2):E45-E46. doi: 10.1503/cmaj.241452.

NO ABSTRACT

PMID:39832926 | DOI:10.1503/cmaj.241452

Commun Biol. 2025 Jan 20;8(1):93. doi: 10.1038/s42003-025-07529-7.

ABSTRACT

Invasive lung myofibroblasts are the main cause of tissue remodeling in idiopathic pulmonary fibrosis (IPF). A key mechanism contributing to this important feature is aberrant crosstalk between the abnormal/injured lung epithelium and pulmonary fibroblasts. Here, we demonstrate that lungs from patients with IPF and from mice with bleomycin (BLM)-induced pulmonary fibrosis (PF) are characterized by the induction of human epididymis protein 4 (HE4) overexpression in epithelial cells. HE4 knockdown primarily in epithelial cells attenuates BLM-induced PF in mice, whereas the administration of recombinant mouse HE4 exacerbates fibrosis after BLM stimulation. Mechanistic analysis shows that HE4 and annexin II (ANXA2) specific binding enhances the profibrotic phenotype in epithelial cells, and directly promotes lung fibroblast activation, leading to aberrant epithelial-fibroblast crosstalk and the persistent myofibroblast phenotype. The HE4 and ANXA2 binding site is located after the 30th amino acid at the N terminus of the HE4 molecule. Finally, intratracheal administration of HE4 shRNA lentivirus protects mice against BLM-induced PF. These data suggest that HE4 can serve as a potential therapeutic target in the treatment of IPF.

PMID:39833358 | DOI:10.1038/s42003-025-07529-7

BMJ Open Respir Res. 2025 Jan 19;12(1):e002725. doi: 10.1136/bmjresp-2024-002725.

ABSTRACT

INTRODUCTION: Persistent lung abnormalities following COVID-19 infection are common. Similar parenchymal changes are observed in idiopathic pulmonary fibrosis (IPF). We investigated whether common genetic risk factors in IPF are associated with developing lung parenchymal abnormalities following severe COVID-19 disease.

METHODS: Consecutive adults hospitalised for laboratory-confirmed COVID-19 infection were prospectively recruited from March to May 2020. Three single-nucleotide polymorphisms (SNPs) conferring risk for IPF were genotyped (MUC5B rs35705950, ATP11A rs1278769 and DPP9 rs12610495). High-resolution CT and pulmonary function tests were performed at 3 months postdischarge from hospital. Ground glass opacities and reticulation on imaging were visually quantified by two expert thoracic radiologists. Linear regression was used to evaluate the association between risk alleles at each of the three SNPs and (a) lung parenchymal abnormalities as well as (b) pulmonary function, adjusted for age, sex, smoking history and days spent on supplemental oxygen during acute illness.

RESULTS: 71 patients were included. Mean age was 63±16 years, 62% were male, 31% were ever-smokers and median hospital length of stay was 9±11 days, with 23% requiring mechanical ventilation. The MUC5B risk allele was associated with a significant decrease in ground glass (β=-0.8, 95% CI -1.5 to -0.1, p=0.02) at 3 months, and this finding was paralleled by a concurrent but non-significant trend towards increased diffusion capacity for carbon monoxide (DLCO) (β=8.8, 95% CI -1.2 to 18.8, p=0.08) compared with patients without this risk allele. None of the risk alleles were significantly associated with reticulation at 3 months.

CONCLUSION: In an adjusted analysis controlling for severity of infection, MUC5B was associated with reduced ground glass and a trend towards concordant higher DLCO at 3 months after severe COVID-19 illness. This hypothesis-generating result suggests a possible protective effect of MUC5B in postinfectious lung abnormalities as compared with fibrosis in IPF, highlighting a plausible trade-off between its role in immune defence and epithelial cell function.

PMID:39832890 | DOI:10.1136/bmjresp-2024-002725

Sci Rep. 2025 Jan 17;15(1):2331. doi: 10.1038/s41598-025-86544-4.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disorder of unknown etiology, characterized by interstitial fibrosis of the lungs. Bleomycin-induced pulmonary fibrosis mouse model (BLM model) is a widely used animal model to evaluate therapeutic targets for IPF. Histopathological analysis of lung fibrosis is an important method for evaluating BLM model. However, this method requires expertise in recognizing complex visual patterns and is time-consuming, making the workflow difficult and inefficient. Therefore, we developed a new workflow for BLM model that reduces inter- and intra-observer variations and improves the evaluation process. We generated deep learning models for grading lung fibrosis that were able to achieve accuracy comparable to that of pathologists. These models incorporate complex image patterns and qualitative factors, such as collagen texture and distribution, potentially identifying drug candidates overlooked in evaluations based solely on simple area extraction. This deep learning-based fibrosis grade assessment has the potential to streamline drug development for pulmonary fibrosis by offering higher granularity and reproducibility in evaluating BLM model.

PMID:39833349 | DOI:10.1038/s41598-025-86544-4

J Headache Pain. 2025 Jan 20;26(1):14. doi: 10.1186/s10194-025-01950-3.

ABSTRACT

BACKGROUND: Migraine is a complex neurological disorder characterized by recurrent episodes of severe headaches. Although genetic factors have been implicated, the precise molecular mechanisms, particularly gene expression patterns in migraine-associated brain regions, remain unclear. This study applies machine learning techniques to explore region-specific gene expression profiles and identify critical gene programs and transcription factors linked to migraine pathogenesis.

METHODS: We utilized single-nucleus RNA sequencing (snRNA-seq) data from 43 brain regions, along with genome-wide association study (GWAS) data, to investigate susceptibility to migraine. The cell-type-specific expression (CELLEX) algorithm was employed to calculate specific expression profiles for each region, while non-negative matrix factorization (NMF) was applied to decompose gene programs within the single-cell data from these regions. Following the annotation of brain region expression profiles and gene programs to the genome, we employed stratified linkage disequilibrium score regression (S-LDSC) to assess the associations between brain regions, gene programs, and migraine-related SNPs. Key transcription factors regulating critical gene programs were identified using a random forest model based on regulatory networks derived from the GTEx consortium.

RESULTS: Our analysis revealed significant enrichment of migraine-associated single nucleotide polymorphisms (SNPs) in the posterior nuclear complex-medial geniculate nuclei (PoN_MG) of the thalamus, highlighting this region's crucial role in migraine pathogenesis. Gene program 1, identified through NMF, was enriched in the calcium signaling pathway, a known contributor to migraine pathophysiology. Random forest analysis predicted ARID3A as the top transcription factor regulating gene program 1, suggesting its potential role in modulating calcium-related genes involved in migraine.

CONCLUSION: This study provides new insights into the molecular mechanisms underlying migraine, emphasizing the importance of the PoN_MG thalamic region, calcium signaling pathways, and key transcription factors like ARID3A. These findings offer potential avenues for developing targeted therapeutic strategies for migraine treatment.

PMID:39833696 | DOI:10.1186/s10194-025-01950-3

Mol Biol Evol. 2025 Jan 21:msaf012. doi: 10.1093/molbev/msaf012. Online ahead of print.

ABSTRACT

Loss-of-function alleles are a pertinent source of genetic variation with the potential to contribute to adaptation. Cave-adapted organisms exhibit striking loss of ancestral traits such as eyes and pigment, suggesting that loss-of-function alleles may play an outsized role in these systems. Here, we leverage 141 whole genome sequences to evaluate the evolutionary history and adaptive potential of single nucleotide premature termination codons (PTCs) in Mexican tetra. We find that cave populations contain significantly more PTCs at high frequency than surface populations. We also find that PTCs occur more frequently in genes with inherent relaxed evolutionary constraint relative to the rest of the genome. Using SLiM to simulate PTC evolution in a cavefish population, we show that the smaller population size and increased genetic drift is sufficient to account for the observed increase in PTC frequency in cave populations without positive selection. Using CRISPR-Cas9, we show that mutation of one of these genes, pde6c, produces phenotypes in surface Mexican tetra that mimic cave-derived traits. Finally, we identify a small subset of candidate genes that contain high frequency PTCs in cave populations, occur within selective sweeps, and may contribute to beneficial traits such as reduced energy expenditure, suggesting that a handful of PTCs may be adaptive. Overall, our work provides a rare characterization of PTCs across wild populations and finds that they may have an important role in loss-of-function phenotypes, contributing to a growing body of literature showing genome evolution through relaxed constraint in subterranean organisms.

PMID:39833658 | DOI:10.1093/molbev/msaf012

Sci Rep. 2025 Jan 20;15(1):2587. doi: 10.1038/s41598-025-86740-2.

ABSTRACT

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social communication and interaction problems. The prevalence of ASD is increasing globally, with a higher ratio of males to females. Gastrointestinal symptoms are common in individuals with ASD, and gut microbiota has been implicated in the disorder's development. This study aimed to investigate the gut microbiota alteration in Thai individuals with ASD compared to healthy controls using 16S rRNA gene sequencing. The influence of gender and age on gut microbiota composition and function was also examined. A total of 65 ASD individuals and 30 neurotypical (NT) individuals were included in the analysis. The results revealed notable differences in gut microbiota composition between the ASD and NT groups, with variations observed in microbial richness and the presence of enriched microbial taxa. These differences were influenced by both gender and age. Fusobacteriota, Fusobacteriaceae, and Fusobacterium were found to be enriched in individuals with ASD. Furthermore, the study identified gender-related taxa, such as Bacteroides plebeius, enriched in ASD females. Age-related taxa, including Veillonella, known to be associated with poor oral hygiene, were also observed in ASD children. The analysis of differentially abundant pathways highlighted the enrichment of various metabolic pathways in individuals with ASD, including those related to endocrine-disrupting chemicals. These findings underscore the importance of considering gender and age when studying gut microbiota in ASD. They provide valuable insights into the potential role of gut microbiota dysbiosis in ASD pathogenesis and highlight the influence of environmental factors.

PMID:39833480 | DOI:10.1038/s41598-025-86740-2

Sci Data. 2025 Jan 20;12(1):111. doi: 10.1038/s41597-025-04460-8.

ABSTRACT

Arhopalus unicolor is a carrier of the pine wood nematode (PWN), which causes pine wilt disease, killing pine trees and causing considerable economic and environmental losses. While the A. unicolor mitochondrial genome has been published, a high-quality genome assembly and annotation of A. unicolor is not yet available. To address this, we assembled a chromosome-level reference genome assembly of A. unicolor with a combination of Illumina, PacBio, and Hi-C sequencing technologies. The final genome size was determined to be 1268.11 Mb, with a GC% of 32.44%, and the scaffold N50 value was 19.30 Mb. A total of 98.77% of the assembled sequences mapped to 10 pseudochromosomes, and BUSCO analysis revealed high completeness, with 97.15% gene coverage. Furthermore, the genome contains 71.74% repeat elements and encompasses 16,450 predicted protein-coding genes. This genome sequence of A. unicolor will be a valuable resource for understanding the genetics and evolutionary history of this species and for developing effective management strategies for this PWN carrier.

PMID:39833239 | DOI:10.1038/s41597-025-04460-8

Nat Commun. 2025 Jan 20;16(1):837. doi: 10.1038/s41467-025-56049-9.

ABSTRACT

Accurate gametogenesis requires the establishment of the telomere bouquet, an evolutionarily conserved, 3D chromosomal arrangement. In this spatial configuration, telomeres temporarily aggregate at the nuclear envelope during meiotic prophase, which facilitates chromosome pairing and recombination. The mechanisms governing the assembly of the telomere bouquet remain largely unexplored, primarily due to the challenges in visualizing and manipulating the bouquet. Here, using Schizosaccharomyces pombe as a model system to elucidate telomere bouquet function, we reveal that centromeres, traditionally perceived as playing a passive role in the chromosomal reorganization necessary for bouquet assembly, play a key role in the initiation of telomere bouquet formation. We demonstrate that centromeres are capable to induce telomere mobilization, which is sufficient to trigger the first stages of bouquet assembly and the meiotic transcription program in mitotic cells. This discovery highlights the finely tuned control exerted over long-distance heterochromatic regions and underscores a pivotal step in the mechanism of eukaryotic telomere bouquet formation and meiotic transcriptional rewiring.

PMID:39833200 | DOI:10.1038/s41467-025-56049-9

Nat Commun. 2025 Jan 20;16(1):872. doi: 10.1038/s41467-025-56192-3.

ABSTRACT

Knowledge about how and where proteins interact provides a pillar for cell biology. Protein proximity-labeling has emerged as an important tool to detect protein interactions. Biotin-related proximity labeling approaches are by far the most commonly used but may have labeling-related drawbacks. Here, we use pupylation-based proximity labeling (PUP-IT) as a tool for protein interaction detection in plants. We show that PUP-IT readily confirmed protein interactions for several known protein complexes across different types of plant hosts and that the approach increased detection of specific interactions as compared to biotin-based proximity labeling systems. To further demonstrate the power of PUP-IT, we used the system to identify protein interactions of the protein complex that underpin cellulose synthesis in plants. Apart from known complex components, we identified the ARF-GEF BEN1 (BFA-VISUALIZED ENDOCYTIC TRAFFICKING DEFECTIVE1). We show that BEN1 contributes to cellulose synthesis by regulating both clathrin-dependent and -independent endocytosis of the cellulose synthesis protein complex from the plasma membrane. Our results highlight PUP-IT as a powerful proximity labeling system to identify protein interactions in plant cells.

PMID:39833163 | DOI:10.1038/s41467-025-56192-3

Redox Biol. 2025 Jan 19:103496. doi: 10.1016/j.redox.2025.103496. Online ahead of print.

NO ABSTRACT

PMID:39833011 | DOI:10.1016/j.redox.2025.103496

Acta Pharmacol Sin. 2025 Jan 20. doi: 10.1038/s41401-024-01452-z. Online ahead of print.

ABSTRACT

The bromodomain (BRD) represents a highly conserved structural module that provides BRD proteins with fundamental functionality in modulating protein-protein interactions involved in diverse biological processes such as chromatin-mediated gene transcription, DNA recombination, replication and repair. Consequently, dysregulation of BRD proteins has been implicated in the pathogenesis of numerous human diseases. In recent years, considerable scientific endeavors have focused on unraveling the molecular mechanisms underlying BRDs and developing inhibitors that target these domains. While these inhibitors compete for binding with the acetylated lysine binding site of BRDs, achieving inhibition of BRD proteins via competitive pocket binding has proven challenging due to the conserved nature of these pockets. To address this limitation, the present study employed dynamic simulations for a comprehensive analysis, leading to the identification of a non-conserved pocket in CECR2 for achieving BRD family inhibition through allosteric modulation. Subsequently, the compound BAY 11-7085 was proven capable of covalently binding to C494 of this pocket after covalent docking and biological verification in vitro. The allosteric inhibition strategy of CECR2 was further verified by the structurally optimized compound LC-CE-7, which is an allosteric covalent CECR2 inhibitor with anti-cancer effects in MDA-MB-231 cells.

PMID:39833305 | DOI:10.1038/s41401-024-01452-z

Biosens Bioelectron. 2025 Jan 13;273:117142. doi: 10.1016/j.bios.2025.117142. Online ahead of print.

ABSTRACT

Food allergies affect millions of individuals worldwide, significantly impacting personal health and the economy. While avoiding allergenic foods remains the primary management strategy, consumers lack reliable means for immediate allergen detection in everyday dining settings. Here, we present iEAT2 (integrated Exogenous Allergen Test 2), an advanced electrochemical sensing system for rapid, on-site food allergen detection. Building upon our previous assay system, the iEAT2 features technical breakthroughs: i) a complete kit for sample processing, including a torsion device for food grinding, and ii) a new strategy for multi-electrode measurements, which enables the simultaneous detection of multiple allergens in a simplified electronic architecture. We designed a compact iEAT2 prototype capable of 16 electrochemical reactions. Experimental validation confirmed the independent electrochemical measurements in a simultaneous operation. Furthermore, the entire testing protocol was completed within 15 min, from allergen extraction to detection. The platform detected three common food allergens (gliadin, Ara h1, and ovalbumin) at concentrations below established allergic reaction thresholds. It also effectively identified cross-contamination events in real-world food samples. This technology may empower consumers to monitor food safety and improve its management.

PMID:39832405 | DOI:10.1016/j.bios.2025.117142

BMC Psychiatry. 2025 Jan 20;25(1):52. doi: 10.1186/s12888-025-06493-0.

ABSTRACT

OBJECTIVE: Paliperidone palmitate is a second-generation antipsychotic that has undergone extensive investigation in clinical trials. However, real-world studies assessing its safety in large populations are lacking. As such, this study aimed to comprehensively evaluate real-world adverse drug events (ADEs) linked to paliperidone palmitate by employing data mining techniques on the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database and the Japanese Adverse Drug Event Report (JADER) database.

METHODS: The study retrieved ADE reports from the FAERS database covering the period from 2009 through the third quarter of 2024, and from the JADER database covering the period from 2013 through the second quarter of 2024. Utilizing disproportionality analyses such as the reporting odds ratios (ROR), proportional reporting ratios (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item Poisson shrinkage (MGPS), significant associations between ADEs and paliperidone palmitate were evaluated.

RESULTS: A total of 27,672 ADE reports related to paliperidone palmitate were identified in FAERS, with 285 significantly disproportionate preferred terms (PTs) identified by all four algorithms. Paliperidone palmitate-associated ADEs encompassed 27 System Organ Classes (SOCs). The top three PTs with the highest reported cases were off-label use, drug ineffective, and hospitalization. Common ADEs included increased blood prolactin, galactorrhea, and schizophrenia, which was consistent with drug label. Noteworthy, unexpected signals not listed in the drug label were also identified, such as psychosexual disorders, prolactin-producing pituitary tumors, suicide attempt, and sudden death. The median onset time for all ADEs was 40 days. Furthermore, gender-based difference in risk signals was detected. Females are more likely to experience elevated blood prolactin and weight increase, whereas males are more prone to sexual dysfunction. Among the 1,065 ADE reports from the JADER database, we identified 51 positive signals, 35 of which overlapped with those found in FAERS, including schizophrenia, hyperprolactinemia, and erectile dysfunction.

CONCLUSION: The study findings from two independent databases serve as crucial references for ensuring the safe of paliperidone palmitate. Additionally, the gender-specific monitoring references provided can enhance clinical surveillance efforts and facilitate more effective risk identification.

PMID:39833706 | DOI:10.1186/s12888-025-06493-0

bioRxiv [Preprint]. 2025 Jan 9:2025.01.09.632114. doi: 10.1101/2025.01.09.632114.

ABSTRACT

In vertebrates, germ layer specification represents a critical transition where pluripotent cells acquire lineage-specific identities. We identify the maternal transcription factors Foxi2 and Sox3 to be pivotal master regulators of ectodermal germ layer specification in Xenopus . Ectopic co-expression of Foxi2 and Sox3 in prospective endodermal tissue induces the expression of ectodermal markers while suppressing mesendodermal markers. Transcriptomics analyses reveal that Foxi2 and Sox3 jointly and independently regulate hundreds of ectodermal target genes. During early cleavage stages, Foxi2 and Sox3 pre-bind to key cis-regulatory modules (CRMs), marking sites that later recruit Ep300 and facilitate H3K27ac deposition, thereby shaping the epigenetic landscape of the ectodermal genome. These CRMs are highly enriched within ectoderm-specific super-enhancers (SEs). Our findings highlight the pivotal role of ectodermal SE-associated CRMs in precise and robust ectodermal gene activation, establishing Foxi2 and Sox3 as central architects of ectodermal lineage specification.

HIGHLIGHTS: Foxi2 and Sox3 are master regulators for the ectodermal germ layer and sub-lineagesFive ectodermal cell states of early gastrulae are regulated by Foxi2 and Sox3Foxi2 and Sox3 binding sites in the genome are enriched in ectoderm super-enhancersSE-associated genes show high expression levels, low noise, stabilizing ectodermal regulation.

PMID:39829826 | PMC:PMC11741269 | DOI:10.1101/2025.01.09.632114

J Pharm Pharmacol. 2025 Jan 20:rgaf002. doi: 10.1093/jpp/rgaf002. Online ahead of print.

ABSTRACT

OBJECTIVES: Chronic kidney disease (CKD) is a serious health issue with rising morbidity and mortality rates. Despite advances in understanding its pathophysiology, effective therapeutic options are limited, necessitating innovative treatment approaches. Also, current frontline treatments that are available against CKD are not uniformly effective and often come with significant side effects. Therefore, identifying new therapeutic targets or improving existing treatments for CKD is crucial. Drug repurposing is a promising strategy in the drug discovery process that involves screening existing approved drugs for new therapeutic applications.

KEY FINDINGS: This review discusses the pharmacological mechanisms and clinical evidence that support the efficacy of these repurposed drugs. Various drugs classes such as inodilators, endothelin-1 type A (ET-1A) receptor antagonists, bisphosphonates, mineralocorticoid receptor (MR) antagonists, DNA demethylating agents, nuclear factor erythroid 2-related factor 2 (NRF2) activators, P2X7 inhibitors, autophagy modulators, hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHI) are discussed that could remarkably contribute against CKD.

SUMMARY: The review critically examines the potential for repurposing well-established drugs to slow the progression of CKD and enhance patient outcomes. This review emphasizes the importance of a multidisciplinary approach in advancing the field of drug repurposing, ultimately paving the way for innovative and effective therapies for patients suffering from CKD.

PMID:39832316 | DOI:10.1093/jpp/rgaf002

medRxiv [Preprint]. 2025 Jan 9:2025.01.08.25320199. doi: 10.1101/2025.01.08.25320199.

ABSTRACT

BACKGROUND: Analyzing disease-linked genetic variants via expression quantitative trait loci (eQTLs) is important for identifying potential disease-causing genes. Previous research prioritized genes by integrating Genome-Wide Association Study (GWAS) results with tissue- level eQTLs. Recent studies have explored brain cell type-specific eQTLs, but they lack a systematic analysis across various Alzheimer's disease (AD) GWAS datasets, nor did they compare effects between tissue and cell type levels or across different cell type-specific eQTL datasets. In this study, we integrated brain cell type-specific eQTL datasets with AD GWAS datasets to identify potential causal genes at the cell type level.

METHODS: To prioritize disease-causing genes, we used Summary Data-Based Mendelian Randomization (SMR) and Bayesian Colocalization (COLOC) to integrate AD GWAS summary statistics with cell-type-specific eQTLs. Combining data from five AD GWAS, three single-cell eQTL datasets, and one bulk tissue eQTL meta-analysis, we identified and confirmed both novel and known candidate causal genes. We investigated gene regulation through enhancer activity using H3K27ac and ATAC-seq data, performed protein-protein interaction and pathway enrichment analyses, and conducted a drug/compound enrichment analysis with the Drug Signatures Database (DSigDB) to support drug repurposing for AD.

RESULTS: We identified 27 candidate causal genes for AD using cell type-specific eQTL datasets, with the highest numbers in microglia, followed by excitatory neurons, astrocytes, inhibitory neurons, oligodendrocytes, and oligodendrocyte precursor cells (OPCs). PABPC1 emerged as a novel astrocyte-specific gene. Our analysis revealed protein-protein interaction (PPI) networks for these causal genes in microglia and astrocytes. We found the "regulation of aspartic-type peptidase activity" pathway being the most enriched among all the causal genes. AD-risk variants associated with candidate causal gene PABPC1 is located near or within enhancers only active in astrocytes. We classified the genes into three drug tiers and identified druggable interactions, with imatinib mesylate emerging as a key candidate. A drug-target gene network was created to explore potential drug targets for AD.

CONCLUSIONS: We systematically prioritized AD candidate causal genes based on cell type- specific molecular evidence. The integrative approach enhances our understanding of molecular mechanisms of AD-related genetic variants and facilitates the interpretation of AD GWAS results.

PMID:39830273 | PMC:PMC11741481 | DOI:10.1101/2025.01.08.25320199

J Clin Nurs. 2025 Jan 20. doi: 10.1111/jocn.17664. Online ahead of print.

ABSTRACT

AIM: To cross-culturally adapt a framework for person-centred leadership in residential care for older people in Sweden.

DESIGN: This study has an exploratory and descriptive design.

METHODS: The translation procedure followed a cyclic process of translation into Swedish and back-translation into English by two independent bilingual linguists. An evaluation of conceptual and semantic equivalence and comprehensiveness between the original English version and the translated Swedish version was performed by an expert committee. The translated version of the framework was validated by leaders (n = 34) in residential care, who assessed its relevance through a web form. The adaptation of the framework followed recommended guidelines for cross-cultural adaptation.

RESULTS: The translation procedure resulted in two minor changes related to the wording in two descriptors. The results of the validation procedure showed that the framework is relevant for leaders in Swedish residential care for older people.

CONCLUSION: The cross-culturally adapted framework is useful and suitable for leaders in Swedish residential care for older people. The framework clarifies the leader's role and identifies leadership attributes and requirements for person-centred leadership in residential care, thereby providing support to leaders by framing person-centred leadership.

IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: The framework can be used as a guide for leadership training and/or development initiatives in residential care. It can be further extended to nursing curriculums, leadership development programs, and organisational performance and development processes. It may also provide a foundation for policy and guidelines by establishing the activities required for leaders to promote person-centredness in the care of older people.

REPORTING METHOD: This study followed the STROBE checklist for cross-sectional studies.

PATIENT AND PUBLIC CONTRIBUTION: There was no patient or public contribution.

PMID:39831575 | DOI:10.1111/jocn.17664