Respir Med Case Rep. 2024 Dec 27;53:102160. doi: 10.1016/j.rmcr.2024.102160. eCollection 2025.

ABSTRACT

Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK TKIs) show robust efficacy and has revolutionized the treatment of NSCLC patients harboring an ALK-rearrangement. Side effects, sometimes even serious such as pneumonitis, can occur with ALK TKIs. We report a case of a patient with ALK positive advanced NSCLC who developed pneumonitis during treatment with first-line alectinib. With no alternative etiology of pneumonitis identified, the patient was treated with corticosteroids and discontinuation of alectinib. Following rapid clinical recovery and radiographic resolution of the opacities, the patient was started with brigatinib, with no recurrence of the clinical symptoms or radiographic findings of pneumonitis. While further descriptions are needed, our experience suggests that switching to a second ALK-TKI may be a safe therapeutic option in some patients who develop drug-induced pneumonitis on ALK TKIs.

PMID:39834688 | PMC:PMC11743586 | DOI:10.1016/j.rmcr.2024.102160

Heliyon. 2024 Dec 25;11(1):e41483. doi: 10.1016/j.heliyon.2024.e41483. eCollection 2025 Jan 15.

ABSTRACT

Cisplatin (CDDP) is one of the main chemotherapeutic drugs that is widely used in many cancers. However, CDDP resistance is a frequent therapeutic challenge that reduces prognosis in cancer patients. Since, CDDP has noticeable side effects in normal tissues and organs, it is necessary to assess the molecular mechanisms associated with CDDP resistance to improve the therapeutic methods in cancer patients. Drug efflux, detoxifying systems, DNA repair mechanisms, and drug-induced apoptosis are involved in multidrug resistance in CDDP-resistant tumor cells. Mammalian target of rapamycin (mTOR), as a serine/threonine kinase has a pivotal role in various cellular mechanisms such as autophagy, metabolism, drug efflux, and cell proliferation. Although, mTOR is mainly activated by PI3K/AKT pathway, it can also be regulated by many other signaling pathways. PI3K/Akt/mTOR axis functions as a key modulator of drug resistance and unfavorable prognosis in different cancers. Regarding, the pivotal role of mTOR in CDDP response, in the present review we discussed the molecular mechanisms that regulate mTOR mediated CDDP response in tumor cells.

PMID:39834411 | PMC:PMC11743095 | DOI:10.1016/j.heliyon.2024.e41483

Psychiatry Clin Neurosci. 2025 Jan 21. doi: 10.1111/pcn.13785. Online ahead of print.

ABSTRACT

AIM: This study aimed to explore the comparative risks for dystonia among different second-generation antipsychotics (SGAs), the influence of sex, and the relationship between the time-to-onset of dystonia and its outcomes.

METHODS: We analyzed data from the Japanese Adverse Drug Event Report database from April 2004 to November 2023. Cases involving oral SGAs, excluding clozapine, were extracted. We used the odds ratios to assess the reporting proportions among SGAs and sex, analyzed the median time-to-onset and interquartile ranges (IQRs), and conducted a receiver operating characteristic (ROC) curve analysis to investigate the time-to-onset of dystonia and its relationship to outcomes.

RESULTS: We extracted 9837 cases involving oral SGAs. Lurasidone was associated with a significantly higher proportion of dystonia reports than risperidone, aripiprazole, quetiapine, and olanzapine. The reporting proportion of dystonia associated with aripiprazole was lower than that of paliperidone and risperidone, but higher than that of quetiapine and olanzapine. Female sex was significantly associated with a higher reporting proportion of dystonia compared with males. Among the 148 cases of oral SGA-induced dystonia, the median time-to-onset was 125 days (IQR, 19.75-453.25 days). Divided into the three outcome groups (recovered, improved, and unrecovered/residual), those with better outcomes had a shorter time-to-onset than those with poorer outcomes. ROC curve analysis suggested a threshold of 91.5 days for discriminating outcomes, with a sensitivity of 71.7% and specificity of 69.9%.

CONCLUSIONS: The risks of dystonia may vary among SGAs and between sexes. SGA-induced dystonia often manifests in the tardive form.

PMID:39834274 | DOI:10.1111/pcn.13785

bioRxiv [Preprint]. 2025 Jan 7:2025.01.07.631715. doi: 10.1101/2025.01.07.631715.

ABSTRACT

WNT2B is Wnt ligand which is able to support intestinal stem cells (ISC) in culture and support the intestinal epithelium in vivo. We have previously shown that WNT2B is critical for resistance to colitis, but not small intestinal injury, in the adult mouse. WNT2B is thought to coordinate with WNT3 in supporting ISC, and we have also shown that WNT3 expression is low in the early postnatal ileum in mice. Here, we hypothesized that WNT2B may be more critical in the small intestine during early development, and we challenged Wnt2b KO mice and controls with experimental necrotizing enterocolitis (NEC) on postnatal days 5-8. Wnt2b KO mice had similar ileum histology and injury scores to control mice. Molecular analyses showed that Wnt2b KO mice have differences in Lgr5 and Tlr4 expression compared to wild type controls in untreated conditions, but under experimental NEC expression of epithelial markers and inflammatory genes associated with NEC were similar to wild type. Periodic acid Schiff positive cells were lower in the villi of Wnt2b KO mice during NEC, however expression of goblet cell markers was not different compared to wild type mice. We also used an organoid-based NEC model to highlight the epithelium in isolation and also found no impact of WNT2B KO in the setting of NEC. These data further affirm that WNT2B is critical for inflammation responses in the mouse colon, but does not appear to play a major role in the small intestine, no matter the developmental period.

PMID:39829885 | PMC:PMC11741354 | DOI:10.1101/2025.01.07.631715

Nat Neurosci. 2025 Jan 20. doi: 10.1038/s41593-024-01834-w. Online ahead of print.

ABSTRACT

Psychiatric disorders are multifactorial and effective treatments are lacking. Probable contributing factors to the challenges in therapeutic development include the complexity of the human brain and the high polygenicity of psychiatric disorders. Combining well-powered genome-wide and brain-wide genetics and transcriptomics analyses can deepen our understanding of the etiology of psychiatric disorders. Here, we leverage two landmark resources to infer the cell types involved in the etiology of schizophrenia, other psychiatric disorders and informative comparison of brain phenotypes. We found both cortical and subcortical neuronal associations for schizophrenia, bipolar disorder and depression. These cell types included somatostatin interneurons, excitatory neurons from the retrosplenial cortex and eccentric medium spiny-like neurons from the amygdala. In contrast we found T cell and B cell associations with multiple sclerosis and microglial associations with Alzheimer's disease. We provide a framework for a cell-type-based classification system that can lead to drug repurposing or development opportunities and personalized treatments. This work formalizes a data-driven, cellular and molecular model of complex brain disorders.

PMID:39833308 | DOI:10.1038/s41593-024-01834-w

Sci Rep. 2025 Jan 20;15(1):2581. doi: 10.1038/s41598-024-79377-0.

ABSTRACT

Human organic cation transporter 2 (hOCT2/SLC22A2) is a key drug transporter that facilitates the transport of endogenous and exogenous organic cations. Because hOCT2 is responsible for the development of adverse effects caused by platinum-based anti-cancer agents, drugs with OCT2 inhibitory effects may serve as prophylactic agents against the toxicity of platinum-based anti-cancer agents. In the present study, we established a machine learning-based quantitative structure-activity relationship (QSAR) model for hOCT2 inhibitors based on the public ChEMBL database and explored novel hOCT2 inhibitors among the FDA-approved drugs. Using our QSAR model, we identified 162 candidate hOCT2 inhibitors among the FDA-approved drugs registered in the DrugBank database. After manual selection and in vitro assays, we found that dequalinium, a quaternary ammonium cation antimicrobial agent, is a potent hOCT2 inhibitor (IC50 = 88.16 ± 7.14 nM). Moreover, dequalinium inhibited hOCT2-mediated transport of platinum anti-cancer agents (cisplatin and oxaliplatin) in a concentration-dependent manner. Our study is the first to demonstrate the construction of a novel machine learning-based QSAR model for hOCT2 inhibitors and identify a novel hOCT2 inhibitor among FDA-approved drugs using this model.

PMID:39833227 | DOI:10.1038/s41598-024-79377-0

J Transl Med. 2025 Jan 20;23(1):86. doi: 10.1186/s12967-025-06069-2.

ABSTRACT

BACKGROUND: Despite the use of Next-Generation Sequencing (NGS) as the gold standard for the diagnosis of rare diseases, its clinical implementation has been challenging, limiting the cost-effectiveness of NGS and the understanding, control and safety essential for decision-making in clinical applications. Here, we describe a personalized NGS-based strategy integrating precision medicine into a public healthcare system and its implementation in the routine diagnosis process during a five-year pilot program.

METHODS: Our approach involved customized probe designs, the generation of virtual panels and the development of a personalized medicine module (PMM) for variant prioritization. This strategy was applied to 6500 individuals including 6267 index patients and 233 NGS-based carrier screenings.

RESULTS: Causative variants were identified in 2061 index patients (average 32.9%, ranging from 12 to 62% by condition). Also, 131 autosomal-recessive cases could be partially genetically diagnosed. These results led to over 5000 additional studies including carrier, prenatal and preimplantational tests or pharmacological and gene therapy treatments.

CONCLUSION: This strategy has shown promising improvements in the diagnostic rate, facilitating timely diagnosis and gradually expanding our services portfolio for rare diseases. The steps taken towards the integration of clinical and genomic data are opening new possibilities for conducting both retrospective and prospective healthcare studies. Overall, this study represents a major milestone in the ongoing efforts to improve our understanding and clinical management of rare diseases, a crucial area of medical research and care.

PMID:39833864 | DOI:10.1186/s12967-025-06069-2

Genome Med. 2025 Jan 20;17(1):7. doi: 10.1186/s13073-025-01431-x.

ABSTRACT

BACKGROUND: Large-scale pharmacogenomic resources, such as the Connectivity Map (CMap), have greatly assisted computational drug discovery. However, despite their widespread use, CMap-based methods have thus far been agnostic to the biological activity of drugs as well as to the genomic effects of drugs in multiple disease contexts. Here, we present a network-based statistical approach, Pathopticon, that uses CMap to build cell type-specific gene-drug perturbation networks and integrates these networks with cheminformatic data and diverse disease phenotypes to prioritize drugs in a cell type-dependent manner.

METHODS: We build cell type-specific gene-drug perturbation networks from CMap data using a statistical procedure we call Quantile-based Instance Z-score Consensus (QUIZ-C). Using these networks and a large-scale disease-gene network consisting of 569 disease signatures from the Enrichr database, we calculate Pathophenotypic Congruity Scores (PACOS) between input gene signatures and drug perturbation signatures and combine these scores with cheminformatic data from ChEMBL to prioritize drugs. We benchmark our approach by calculating area under the receiver operating characteristic curves (AUROC) for 73 gene sets from the Molecular Signatures Database (MSigDB) using target gene expression profiles from the Comparative Toxicogenomics Database (CTD). We validate the drugs predicted in our proofs-of-concept using real-time polymerase chain reaction (qPCR) experiments.

RESULTS: Cell type-specific gene-drug perturbation networks built using QUIZ-C are topologically distinct, reflecting the biological uniqueness of the cell lines in CMap, and are enriched in known drug targets. Pathopticon demonstrates a better prediction performance than solely cheminformatic measures as well as state-of-the-art network and deep learning-based methods. Top predictions made by Pathopticon have high chemical structural diversity, suggesting their potential for building compound libraries. In proof-of-concept applications on vascular diseases, we demonstrate that Pathopticon helps guide in vitro experiments by identifying pathways that are potentially regulated by the predicted therapeutic candidates.

CONCLUSIONS: Our network-based analytical framework integrating pharmacogenomics and cheminformatics (available at https://github.com/r-duh/Pathopticon ) provides a feasible blueprint for a cell type-specific drug discovery and repositioning platform with broad implications for the efficiency and success of drug development.

PMID:39833831 | DOI:10.1186/s13073-025-01431-x

Cell Death Differ. 2025 Jan 20. doi: 10.1038/s41418-024-01430-2. Online ahead of print.

ABSTRACT

Accumulating evidence suggests that genetic and epigenetic biomarkers hold potential for enhancing the early detection and monitoring of breast cancer (BC). Epigenetic alterations of the Homeobox A2 (HOXA2) gene have recently garnered significant attention in the clinical management of various malignancies. However, the precise role of HOXA2 in breast tumorigenesis has remained elusive. To address this point, we conducted high-throughput RNA sequencing and DNA methylation array studies on laser-microdissected human BC samples, paired with normal tissue samples. Additionally, we performed comprehensive in silico analyses using large public datasets: TCGA and METABRIC. The diagnostic performance of HOXA2 was calculated by means of receiver operator characteristic curves. Its prognostic significance was assessed through immunohistochemical studies and Kaplan-Meier Plotter database interrogation. Moreover, we explored the function of HOXA2 and its role in breast carcinogenesis through in silico, in vitro, and in vivo investigations. Our work revealed significant hypermethylation and downregulation of HOXA2 in human BC tissues. Low HOXA2 expression correlated with increased BC aggressiveness and unfavorable patient survival outcomes. Suppression of HOXA2 expression significantly heightened cell proliferation, migration, and invasion in BC cells, and promoted tumor growth in mice. Conversely, transgenic HOXA2 overexpression suppressed these cellular processes and promoted apoptosis of cancer cells. Interestingly, a strategy of pharmacological demethylation successfully restored HOXA2 expression in malignant cells, reducing their neoplastic characteristics. Bioinformatics analyses, corroborated by in vitro experimentations, unveiled a novel implication of HOXA2 in the lipid metabolism of BC. Specifically, depletion of HOXA2 leaded to a concomitantly decreased expression of PPARγ and its target CIDEC, a master regulator of lipid droplet (LD) accumulation, thereby resulting in reduced LD abundance in BC cells. In summary, our study identifies HOXA2 as a novel prognosis-relevant tumor suppressor in the mammary gland.

PMID:39833374 | DOI:10.1038/s41418-024-01430-2

BMJ Open Respir Res. 2025 Jan 19;12(1):e002960. doi: 10.1136/bmjresp-2024-002960.

ABSTRACT

BACKGROUND: The most common cause of death in those with cystic fibrosis (CF) is respiratory failure due to bronchiectasis resulting from repeated cycles of respiratory infection and inflammation. Protease-activated receptor 1 (PAR1) is a cell surface receptor activated by serine proteases including neutrophil elastase, which is recognised as a potent modulator of inflammation. While PAR1 is known to play an important role in regulating inflammation, nothing is known about any potential role of this receptor in CF pathogenesis.

METHODS: PAR1 (PAR1-/- ) and intestinal-corrected CFTR (Cftr-/- ) deficient mice were crossed to generate double knock-out (DKO) mutants lacking both PAR1 and CFTR, as well as matching sibling single mutant and wildtype (WT) littermate controls. Mice were weighed weekly to 15 weeks of age; then, the lungs and intestines were examined.

RESULTS: Cftr-deficient mice gained body weight at a significantly slower rate than WT controls and presented with no lung inflammation, but had increased weights of their ilea and proximal colons. DKO mice (lacking both CFTR and PAR1) gained body weight at a similar rate to Cftr-/- mice but only gained weight in their proximal colons. Weight gain in the ilea of Cftr-/- but not DKO mice was associated with increased ileal levels in the pro-inflammatory cytokine interleukin (IL)-6.

CONCLUSIONS: This study provides the first evidence of PAR1 contributing to the pathological effects of Cftr deficiency in the intestine and suggests a possible effect of PAR1 on the regulation of IL-6 in CF pathogenesis.

PMID:39832889 | DOI:10.1136/bmjresp-2024-002960

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