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Background: The objective of this systematic review was to identify genetic variants of the IL-23, IL-17, IL-23R and IL-17R genes and isoforms and its possible association with increased development of periodontitis and peri-implantitis., Methods: A systematic review was prepared according to the guidelines, registered in the OSF database with the registration number: 10.17605/OSF. IO/X95ZC. The electronic search was performed in four databases: PubMed, Scopus, Web of Science, and Google Scholar from 1984 until March 15th, 2024. The JBI Critical Appraisal Checklist for Case-Control Studies was used to assess the quality of included studies., Results: Eighteen papers with a case-control design were those that ultimately met the eligibility criteria. A total of 3904 individuals (2315 with periodontitis and 90 with peri-implantitis), and 1589 healthy subjects) were studied. The age range of the study population was 14-70 years, with a mean age ± (SD) of 40.43 ± 6.33 years. A total of 28 genetic variants corresponding to the IL-17A (rs 2275913, rs 3819024, rs 10484879) IL-17F (rs 763780), IL-17R (rs 879576) and IL-23R (rs 11209026) genes were analyzed in this study. Six (33.3%) studies found an association between the IL-17A 197 G/A (rs 2275913) genetic variant and peri-implantitis and periodontitis. One study (5.5%) found an association between the IL-17A rs10484879 variant and peri-implantitis and periodontitis., Conclusion: Six polymorphisms were evaluated, highlighting rs 2275913 of the cytokine IL-17A in patients with periodontitis or peri-implantitis. Only 50% of studies found an association despite having a small sample. This suggests that other factors such as the degree of disease, systemic diseases and ethnic groups studied may play a role., (© 2025 The Author(s). Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Problem: Oxidative stress (OS) plays a key role in the pathogenesis of gestational diabetes mellitus (GDM), but it was not well understood. We aimed to investigate the biomarkers and underlying mechanisms of OS-related genes in GDM., Method of Study: The GSE103552 and GSE70493 datasets of GDM were acquired from the Gene Expression Omnibus (GEO) database. Then, oxidative stress-related differentially expressed genes (OSDEGs) were screened between GDM and normal samples from these two datasets. Further analyses were conducted by gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene set enrichment analysis (GSEA) for these OSDEGs. Subsequently, protein-protein interaction (PPI) network analyses of these OSDEGs were carried out to screen the hub genes. Eventually, we used single-sample Gene-set enrichment analysis (ssGSEA) to compare the immune cell infiltration between GDM and normal samples., Results: We identified 26 OSDEGs. Enrichment analysis suggested that the OSDEGs enriched in OS and diabetes-related pathways. GSEA revealed that these OSDEGs enriched in sensory perception of taste and negative regulation of notch4 signaling pathways. Moreover, PPI analysis showed that 15 OSDEGs were the hub gene in GDM. A total of 14 hub genes were highly expressed in GDM and might be used as diagnosis biomarkers. Moreover, many potential agents might target 10 hub genes for GDM treatment. In addition, immune infiltrate analyses revealed that expression of 14 hub genes was positively correlated to immune infiltrates in GDM., Conclusion: OSDEGs are significant in GDM and may provide potential diagnostic biomarkers and treatment targets for GDM., (© 2025 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Asthma is a heterogeneous, multifactorial disease with multiple genetic and environmental risk factors playing a role in pathogenesis and therapeutic response. Understanding of pharmacogenetics can help with matching individualized treatments to specific genotypes of asthma to improve therapeutic outcomes especially in uncontrolled or severe asthma., Areas Covered: In this review, we outline novel information about biology, pathways, and mechanisms related to interindividual variability in drug response (corticosteroids, bronchodilators, leukotriene modifiers, and biologics) for childhood asthma. We discuss candidate gene, genome-wide association studies and newer omics studies including epigenomics, transcriptomics, proteomics, and metabolomics as well as integrative genomics and systems biology methods related to childhood asthma. The articles were obtained after a series of searches, last updated November 2022, using database PubMed/CINAHL DB., Expert Opinion: Implementation of pharmacogenetic algorithms can improve therapeutic targeting in children with asthma, particularly with severe or uncontrolled asthma who typically have challenges in clinical management and carry considerable financial burden. Future studies focusing on potential biomarkers both clinical and pharmacogenetic can help formulate a prognostic test for asthma treatment response that would represent true bench to bedside clinical implementation.

Glaucoma comprises a heterogeneous set of eye conditions that cause progressive vision loss. Glaucoma has a complex etiology, with different genetic and non-genetic risk factors that differ across populations. Although difficult to diagnose in early stages, compromised cellular signaling, dysregulation of genes, and homeostatic imbalance are common precursors to injury and subsequent death of retinal ganglion cells (RGCs). Lowering intraocular pressure (IOP) remains the primary approach for managing glaucoma but IOP alone does not explain all glaucoma risks. Orthogonal approaches such as large-scale genetic screening, combined with studies of animal models have been instrumental in identifying genes and molecular pathways involved in glaucoma pathogenesis. Cell type dependent vulnerability among RGCs can reveal genetic basis for specific visual deficits. A growing body of knowledge and availability of modern tools to perform targeted assessments of cellular health in different animal models facilitate development of effective and timely interventions for vision rescue. This review highlights recent findings on genes, molecules, and cell types in the context of glaucoma pathophysiology and treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Myopia is a complex disorder with etiology involving an interplay between several genetic and environmental factors. Interphotoreceptor retinoid-binding protein (IRBP) is found in the subretinal space and is crucial in the visual cycle. The interphotoreceptor retinoid-binding protein knockout mouse (IRBP KO) was established as a model system to understand myopia and retinal degeneration. The current study investigated genes associated with myopia, retinal homeostasis, and inflammation in IRBP KO., Methods: RNA from retinas of congenic IRBP KO and wild-type C57BL/6J (WT) mice at postnatal day 5 (P5), P40, and P213 were subjected to digital droplet PCR (ddPCR) using a Bio-Rad automated droplet generator and QX200 reader. Target genes were selected based on genome-wide association studies, animal models, myopia studies, and other genes associated with retinal homeostasis and inflammation. HPRT, a housekeeping gene, was used for normalization. An average expression ratio (target/HPRT) and standard deviation (SD) were calculated. ANOVA assessed statistical significance, and a p  < 0.05 was considered significant., Results: The ddPCR data analysis indicated that numerous myopia and inflammation-associated genes were differentially regulated in IRBP KO retinas with distinct temporal variation (upregulated at P5, decreased at P40, and no change at P213 relative to WT). C1qa , Gjd2 , Sntb1 , and Vsx2 emerged as top genetic candidate pathways. Compared with WT, immunoblotting analysis of C1qa showed no significant differences at P5 but significantly increased protein levels at P7 in IRBP KOs. Vsx2 remained unaltered at P5 and P7 in KO when compared with WT., Conclusions: Data analysis indicated significant contributions from C1q , Gjd2 , Sntb1 , and Vsx2 genes in IRBP deficiency.

Pelvic floor disorder (PFD) is a common gynecological disorder, and with the ageing of the population, PFD has a serious impact on the physical and mental health of patients and their quality of life. The most prominent of these are pelvic organ prolapse (POP) and urinary incontinence (UI), about which the etiology is still unclear, and it is urgent to explore their pathogenesis. Advances in genetics and epigenetics have provided new insights into the pathophysiology of PFD. Candidate genes and genome-wide association studies have identified susceptibility genes for POP and UI. These susceptibility genes typically promote POP by affecting pelvic floor connective tissue. The role of susceptibility genes in UI is multifactorial and includes promoting inflammation, damaging pelvic floor connective tissue, and modulating neurogenic effects. The association of epigenetic changes with POP and UI has also been investigated. DNA methylation studies have identified several important pathways associated with POP. miRNAs play an important role in the development of POP and UI, and this may be an important therapeutic direction for the future. The studies conducted so far have shown that genetic and epigenetic techniques are of great importance in exploring the etiology of PFD and that more in-depth studies are needed in the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Fluoride (F), as a natural element found in a wide range of sources such as water and certain foods, has been proven to be beneficial in preventing dental caries, but concerns have been raised regarding its potential deleterious effects on overall health. Sodium fluoride (NaF), another form of F, has the ability to accumulate in reproductive organs and interfere with hormonal regulation and oxidative stress pathways, contributing to reproductive toxicity. While the exact mechanisms of F-induced reproductive toxicity are not fully understood, this review aims to elucidate the mechanisms involved in testicular and ovarian injury. In males, F exposure at different doses has been associated with reduced testis weight, reduced sperm quality in terms of count, motility, and viability, as well as abnormal sperm morphology and disruption of seminiferous tubules by altering hormone levels (especially testosterone), impairing spermatogenesis, and inducing oxidative stress and zinc deficiency. Similarly, administration of F can impact female reproductive health by affecting ovarian function, hormone levels, oocyte quality, and the regularity of the estrous cycle. However, the impact of F exposure on LH, FSH, and GnRH levels is controversial between males and females. In both males and females, F exerts its adverse effects by triggering apoptosis, autophagy, inflammation, mitochondrial dysfunction, reduction in ATP synthesis, and modulation of important genes involved in steroidogenesis. Furthermore, genetic susceptibility and individual variations in F metabolism may contribute to different responses to fluoride exposure., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: The authors approved this version of the manuscript to publish. Competing interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2025. The Author(s).)

Objective: Police, firefighters, dispatchers, and emergency medical technicians-collectively known as first responders-are a unique population frequently exposed to chronic, traumatic incidents. This exposure results in a high prevalence of PTSD, depression, and anxiety, posing a substantial public health concern. Genetic predispositions and epigenetic modifications that regulate gene expression are significant contributors to trauma-related pathologies. This systematic review aims to summarize current data on epigenetic and gene expression changes in first responders related to three post-trauma pathologies: PTSD, depression, and anxiety. We also explore genetic pathways across these disorders to identify potential commonalities and therapeutic targets., Methods: Following PRISMA guidelines, databases were searched from July to October 2023, yielding 1103 studies, 12 of which met the inclusion criteria (total N = 6943)., Results: Of the included studies, 11 examined PTSD, consistently implicating stress-response genes, such as those in the hypothalamic-pituitary-adrenal axis (e.g., FKBP5, NR3C1), and genes related to inflammation and immune responses. Three studies focused on depression-related genetic biomarkers but reported no significant genome-wide methylation differences between responders with current versus no major depressive disorder (MDD). No studies addressed epigenetic or gene expression changes linked to anxiety., Conclusion: This review identified novel genes and pathways related to trauma as potential targets for future research and pharmacological therapy. It also highlights a significant gap in the literature, emphasizing the need for broader research to investigate the genetic underpinnings of trauma exposure in first responders, aiming to identify relevant pathways and therapeutic targets., Competing Interests: Declaration of competing interest Financial Disclosures/Conflicts: The authors have no financial disclosures nor conflicts of interest to report., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

The dopamine (DA) system is central to mood regulation, motivation, and reward processing, making it a critical focus for understanding Major Depressive Disorder (MDD). While the dopaminergic system's role in MDD pathophysiology has been acknowledged, gaps remain in linking specific receptor subtypes and genetic factors to depression-like phenotypes. This study explores the interplay between dopamine receptor subtypes (D1-D5) and associated genetic variations, particularly focusing on receptor heterodimers and polymorphisms influencing dopamine biosynthesis, signalling, and metabolism. A comprehensive review of molecular mechanisms highlights key findings: alterations in D1-D2 heterodimers contribute to mood dysregulation; D3 receptor downregulation correlates with depressive behaviour; and genetic polymorphisms, including those in tyrosine hydroxylase and dopamine transporter (DAT) genes, influence dopamine levels and receptor functions. Emerging data from neuroimaging and animal models confirm the pivotal role of dopamine receptor subtypes in MDD, offering insights into their therapeutic targeting. Here, we show that dopaminergic dysfunction underpins MDD's pathophysiology, with receptor-specific mechanisms presenting novel drug targets. Understanding these pathways facilitates precision medicine approaches, bridging the gap between genetic predisposition and receptor pharmacology, and paving the way for tailored antidepressant strategies with improved efficacy and reduced side effects., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

This proposed review aims to shed light on the major genetic and epigenetic contributions to the ageing process and longevity of individuals. In this context, we summarize the state of knowledge on the most important longevity and ageing genetic variants, and their interactions with the environment, in achieving a healthy lifespan. We also explore the contribution of lifestyle and the influence of non-heritable environmental factors on ageing (i.e., epigenetics). Accordingly, we discuss the role of inflammageing as one of the major targets to overcome morbidity and mortality in older people for the maintenance of healthy ageing. This more integrated view of longevity will display not only the underlying mechanisms at play but also invites the reader to rethink both our ageing process and our attitudes toward age.

Post-traumatic stress disorder (PTSD) is a psychiatric disorder that frequently co-occurs with pain disorders including migraine. There are proposed biological, genetic and environmental factors associated with both PTSD and migraine suggesting shared etiology. Genome-Wide Association Studies (GWAS) have been used to identify genomic risk loci associated with various disorders and to investigate genetic overlap between traits. There is a significant genetic correlation between PTSD and migraine with no evidence of a causal relationship that could be attributed to pleiotropy. Cross-disorder genetic analyses were applied to investigate the genetic overlap and causal associations using GWAS summary statistics of PTSD ( n  = 214408), migraine ( n  = 873341) and 23 medication use traits ( n  = 78808-305913) including anti-depressants, anti-migraine preparations and beta-blocking agents. Across the entire genome, anti-thrombotic agents had a significant and negative genetic correlation with PTSD (rG = -0.2, P FDR  = 0.032) and a positive genetic correlation with migraine (rG = 0.26, P FDR  = 2.23 x 10 -8 ). PTSD showed significant genetic correlation with 11 other medication use traits including beta blocking agents (rG = -0.11, P FDR  = 0.034). Of the 2495 genomic regions tested, PTSD showed significant local genetic correlation with 12 medication use traits at 43 loci; while migraine showed significant genetic correlation with only anti-inflammatory agents and anti-rheumatic products at locus 12:57522282-57607142 ( DAB1 ) ( P  < 2 x 10 -5 ). The genetic liability to PTSD had a causal effect on increased risk of using pain medication such as opioids ( β ivw  = 0.59, P ). The genes in the genomic regions shared between PTSD and medication use traits were enriched in neural-related pathways such as neuron development, neurogenesis and protein kinase activity. These results provide further insight into the genetically controlled biological and environmental factors underlying the shared etiology between PTSD and migraine. The identified biomarkers can be used as a basis for investigation as potential drug targets for both disorders. These findings are significant for drug re-purposing and treatment of PTSD and migraine using monotherapy.-5 ) while the genetic liability to migraine had a causal effect on the increased risk of using anti-thrombotic agents ( β ivw  = 0.59, P  = 1.69 x 10 -7 ). The genes in the genomic regions shared between PTSD and medication use traits were enriched in neural-related pathways such as neuron development, neurogenesis and protein kinase activity. These results provide further insight into the genetically controlled biological and environmental factors underlying the shared etiology between PTSD and migraine. The identified biomarkers can be used as a basis for investigation as potential drug targets for both disorders. These findings are significant for drug re-purposing and treatment of PTSD and migraine using monotherapy., Competing Interests: The authors declare no competing interests., (© 2024 Published by Elsevier Inc.)

Background/Objectives: This study aimed to construct a risk score (RS) based on necroptosis-associated genes to predict the prognosis of patients with advanced epithelial ovarian cancer (EOC). Methods: EOC data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) series 140082 (GSE140082) were used. Based on known necroptosis-associated genes, clustering was performed to identify molecular subtypes of EOC. A least absolute shrinkage and selection operator (LASSO)-Cox regression analysis identified key genes related to prognosis. The expression of one of them, RIPK3 , was analyzed via immunohistochemistry in an EOC cohort. Results: An RS made from ten genes ( IDH2 , RIPK3 , FASLG , BRAF , ITPK1 , TNFSF10 , ID1 , PLK1 , MLKL and HSPA4 ) was developed. Tumor samples were divided into a high-risk group (HRG) and low-risk group (LRG) using the RS. The model is able to predict the overall survival (OS) of EOC and distinguish the prognosis of different clinical subgroups. Immunohistochemical verification of the receptor-interacting serine/threonine-protein kinase (RIPK) 3 confirmed that high nuclear expression is correlated with a longer OS. In addition, the score can predict the response to a programmed death ligand 1 (PD-L1) blockade treatment in selected solid malignancies. Patients from the LRG seem to benefit more from it than patients from the HRG. Conclusions: Our RS based on necroptosis-associated genes might help to predict the prognosis of patients with advanced EOC and gives an idea on how the use of immunotherapy can potentially be guided.

Haemonchus contortus is a gastrointestinal parasite that affects ruminants (cattle, sheep, etc.), having a significant welfare impact worldwide. The rise of anthelmintic resistance poses a growing challenge to adequate control, compromising the success of treatments. This study presents a systematic review of the molecular mechanisms involved in the resistance of H. contortus to anthelmintic drugs. Following an extensive literature search (9075 total articles/excluding duplications), 61 articles were examined. From these, benzimidazoles (BZD) and macrocyclic lactone (ML) were the most reported drug classes (17 and 29, respectively). The mutations in the β-tubulin gene were the primary mechanism of BZD resistance. Important comparisons from early reports of resistance mechanisms to ML (published before 2020) mainly based on parasite-population gene expression (e.g., ligand-gated chloride channels, LGCC, and P-glycoproteins, PGP) with more recent genomic and transcriptomic data (e.g., transcription factor, cky-1 gene) are highlighted. Additionally, resistance mechanisms to levamisole (LEV) and monepantel are discussed, showing evidence of polymorphisms in genes related to the nicotinic acetylcholine receptors (nAChR). Considering the available data, it is possible to divide the reports into two technological periods, evidencing that the availability of a chromosome-level genome for H. contortus in association with experiments based on controlled genetic crosses and transcriptome-wide data allowed for the visualization of genes and polymorphisms that were previously indistinguishable from unrelated genetic variation (i.e., genetic noise). Therefore, the study of anthelmintic resistance mechanisms is facing new possibilities, reflecting the large data banks and the speed at which this information is being processed. We suggest that new publications on drug resistance should adopt the approaches and refer to this new era of scientific discoveries. Consistent data interpretation, including artificial intelligence (AI) support, will help us to suggest novel biological mechanisms involved in drug resistance and predict its evolution, allowing a more comprehensible approach toward sustainable parasite control strategies., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Background: Streptomyces roseochromogenes NRRL 3504 produces clorobiocin, an aminocoumarin antibiotic that inhibits DNA replication. No other natural products have been isolated from this bacterium so far, despite the presence of a rich repertoire of specialized metabolite biosynthesis gene clusters (smBGCs) within its genome. Heterologous expression of smBGCs in suitable chassis speeds up the discovery of the natural products hidden behind these sets of genes., Results: In this work we focus on one intriguing smBGC of NRRL 3504 bearing some similarity to gene clusters involved in production of manumycin family polyketides. Through heterologous expression in Streptomyces chassis strains S. albus Del14 and S. lividans ΔYA9, this smBGC (hereafter referred to as lim BGC) was shown to direct the production of unusual polyketide limocrocin (LIM) known for its ability to interfere with viral reverse transcriptases. The organization of lim BGC, data on the structures of revealed metabolites as well as manipulations of lim genes allowed us to put forward an initial hypothesis about a biosynthetic pathway leading to LIM. We provide initial data on two LIM derivatives as well as updated NMR spectra for the main product., Conclusion: This study reveals the genetic control of biosynthesis of LIM that remained hidden for the last 70 years. This, in turn, opens the door to biological routes towards overproduction of LIM as well as generation of its derivatives., Competing Interests: Declarations. Ethical approval: This article does not contain studies with human participants or animals performed by any of the authors. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Telomere length (TL) is a marker of cellular health and aging. Physical exercise has been associated with longer telomeres and, therefore, healthier aging. However, results supporting such effects vary across studies. Our aim was to synthesize existing evidence on the effect of different modalities and durations of physical exercise on TL., Objective: The aim of this study was to explore the needs and expectations of individuals with physical disabilities and their interventionists for the use of a virtual reality physical activity platform in a community organization., Methods: We performed an umbrella review and meta-analysis. Data sources included PubMed, Embase, Web of Science, Cochrane Library, and Scopus. We selected systematic reviews and meta-analyses of randomized and nonrandomized controlled clinical trials evaluating the effect of physical exercise on TL., Results: Our literature search retrieved 12 eligible systematic reviews, 5 of which included meta-analyses. We identified 22 distinct primary studies to estimate the overall effect size of physical exercise on TL. The overall effect size was 0.28 (95% CI 0.118-0.439), with a heterogeneity test value Q of 43.08 (P=.003) and I² coefficient of 51%. The number of weeks of intervention explained part of this heterogeneity (Q&#95;B=8.25; P=.004), with higher effect sizes found in studies with an intervention of less than 30 weeks. Exercise modality explained additional heterogeneity within this subgroup (Q&#95;B=10.28, P=.02). The effect sizes were small for aerobic exercise and endurance training, and moderate for high-intensity interval training., Conclusions: Our umbrella review and meta-analysis detected a small-moderate positive effect of physical exercise on TL, which seems to be influenced by the duration and type of physical exercise. High quality studies looking into the impact of standardized, evidence-based physical exercise programs on TL are still warranted., (© Juan Luis Sánchez-González, Juan Luis Sánchez-Rodríguez, Rogelio González-Sarmiento, Víctor Navarro-López, Raúl Juárez-Vela, Jesús Pérez, Javier Martín-Vallejo. Originally published in JMIR Aging (https://aging.jmir.org).)

Objectives: This cross-sectional study aimed to evaluate the occurrence of Streptococcus spp., Streptococcus mutans, its serotypes (c, e, f, and k), collagen-binding genes (cnm/cbm), and Candida albicans in medium deep (D2) and deep (D3) dentin carious lesions of permanent teeth., Materials and Methods: Carious dentin was collected from D2 (n = 23) and D3 (n = 24) lesions in posterior teeth from 31 individuals. DNA was extracted and analyzed using polymerase chain reaction (PCR)., Results: Streptococcus spp. exhibited a high prevalence in both D2 and D3 lesions, with a 100% occurrence rate in D3. Although S. mutans was prevalent in both lesion types, serotype distribution highlighted differences in complexity. Serotype e was the most frequently detected in D2 samples. Serotype c was absent in D2 but present in 19.0% of D3; serotype k was exclusively found in multi-serotype D3 alongside f, c, and e. The cbm gene and undetermined serotypes were detected only in D3. Candida albicans was not found in any samples, regardless of lesion depth., Conclusion: Dentinal lesions exhibited a complex array of S. mutans serotypes, with a notable prevalence of the genus Streptococcus and an overall S. mutans prevalence of approximately 35%. Candida albicans was absent. In addition, a high diversity of serotypes was observed, including multiple and indeterminate serotypes, along with the presence of the collagen-binding cbm gene., Clinical Relevance: The identification of diverse Streptococcus mutans serotypes and the cbm gene in carious dentin from permanent teeth offers insights into microbial factors potentially linked to dentinal caries lesions. Additionally, the absence of Candida albicans suggests a limited role in this context., Competing Interests: Declarations. Ethical approval: The study was approved by the Research Ethics Committee of the Federal University of Ceará - CEP/UFC/PROPESQ (CAAE 54451316.7.0000.5054) and (CAAE 46268821.6.0000.5054). Informed consent: Written informed consent was obtained from all participants included in the study. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Mitochondria is the cell's powerhouse. Mitochondrial disease refers to a group of clinically heterogeneous disorders caused by dysfunction in the mitochondrial respiratory chain, often due to mutations in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) that encodes mitochondrial proteins. This dysfunction can lead to a variety of clinical phenotypes, particularly affecting organs with high energy demands, such as the brain and muscles. Epilepsy is a prevalent neurological disorder in children and is also a frequent manifestation of mitochondrial disease. The exact mechanisms underlying epilepsy in mitochondrial disease remain unclear and are thought to involve multiple contributing factors. This review explores common mitochondrial diseases associated with epilepsy, focusing on their prevalence, seizure types, EEG features, therapeutic strategies, and outcomes. It also summarizes the relationship between the molecular genetics of mitochondrial respiratory chain components and the development of epilepsy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 Zhang, Zhang, Tao and Liang.)

By processing and abstracting diverse omics datasets into associations between genes and their attributes, the Harmonizome database enables researchers to explore and integrate knowledge about human genes from many central omics resources. Here, we introduce Harmonizome 3.0, a significant upgrade to the original Harmonizome database. The upgrade adds 26 datasets that contribute nearly 12 million associations between genes and various attribute types such as cells and tissues, diseases, and pathways. The upgrade has a dataset crossing feature to identify gene modules that are shared across datasets. To further explain significantly high gene set overlap between dataset pairs, a large language model (LLM) composes a paragraph that speculates about the reasons behind the high overlap. The upgrade also adds more data formats and visualization options. Datasets are downloadable as knowledge graph (KG) assertions and visualized with Uniform Manifold Approximation and Projection (UMAP) plots. The KG assertions can be explored via a user interface that visualizes gene-attribute associations as ball-and-stick diagrams. Overall, Harmonizome 3.0 is a rich resource of processed omics datasets that are provided in several AI-ready formats. Harmonizome 3.0 is available at https://maayanlab.cloud/Harmonizome/., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

This review examines genetic markers associated with litter size in goats, a key reproductive trait impacting productivity in small ruminant farming. Goats play a vital socioeconomic role in both low- and high-income regions; however, their productivity remains limited due to low reproductive efficiency. Litter size, influenced by multiple genes and environmental factors, directly affects farm profitability and sustainability by increasing the output per breeding cycle. Recent advancements in genetic research have identified key genes and pathways associated with reproductive traits, including gonadotropin-releasing hormone ( GnRH ), inhibin ( INHAA ), Kit ligand ( KITLG ), protein phosphatase 3 catalytic subunit alpha ( PPP3CA ), prolactin receptor ( PRLR ), POU domain class 1 transcription factor 1 ( POU1F1 ), anti-Müllerian hormone ( AMH ), bone morphogenetic proteins ( BMP ), growth differentiation factor 9 ( GDF9 ), and KISS1 and suppressor of mothers against decapentaplegic ( SMAD ) family genes, among others. These genes regulate crucial physiological processes such as folliculogenesis, hormone synthesis, and ovulation. Genome-wide association studies (GWASs) and transcriptomic analyses have pinpointed specific genes linked to increased litter size, highlighting their potential in selective breeding programs. By incorporating genomic data, breeding strategies can achieve higher selection accuracy, accelerate genetic gains, and improve reproductive efficiency. This review emphasizes the importance of genetic markers in optimizing litter size and promoting sustainable productivity in goat farming.

Background and Aim: Ulcerative colitis (UC) is a chronic inflammatory disease driven by immune dysregulation. PANoptosis, a novel form of programmed cell death, has been implicated in inflammatory diseases, but its specific role in UC remains unclear. This study aimed to identify PANoptosis-related genes (PRGs) that may contribute to immune dysregulation in UC., Methods: Using bioinformatics analysis of the GEO databases, we identified seven hub PRGs. Based on these genes, we developed a predictive model to differentiate UC patients from healthy controls, and evaluated its diagnostic performance using ROC curve analysis. We further conducted functional enrichment, GSVA, and immune infiltration analyses. Immunohistochemistry (IHC) was used to validate the expression of hub genes in UC patients., Results: The prediction model, based on the seven hub genes, exhibited diagnostic ability in discriminating UC patients from controls. Furthermore, these hub PRGs were found to be associated with immune cells, including dendritic cells, NK cells, macrophages, regulatory T cells (Tregs), and CD8+ T cells. They were also linked to key signaling pathways implicated in UC pathogenesis, such as IFNγ, TNFα, IL6-and JAK-STAT3, as well as hypoxia and apoptosis. Immunohistochemistry analysis validated the expression levels of hub PRGs in UC patients using paraffin sections of intestinal biopsy specimens., Conclusions: This study identified PANoptosis-related genes with potential diagnostic value for UC and suggest that PANoptosis may contribute to the pathogenesis of UC by regulating specific immune cells and interacting with key signaling pathways. This highlights the potential importance of PANoptosis-related genes as therapeutic targets in UC management., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

The relationship between structure and function in microbial communities is intriguing and complex. In this study, we used single-carbon source domestication to derive consortium YL from the straw-degrading consortium Y. Y and YL exhibited similar straw degradation capabilities, yet YL harbored only half the species diversity of Y, with distinct dominant species. The most enriched microorganisms in Y were Ureibacillus, Acetanaerobacterium, and Hungateiclostridiaceae, whereas Bacillaceae, Bacillus, and Peptostreptococcales-Tissierellales were most enriched in YL. In-depth analysis revealed that Y and YL had comparable abundances of core lignocellulose-degrading genes, as validated by lignocellulolytic enzyme activity assays. However, the number of species harboring these key lignocellulose-degrading genes (K01179, K01181, K00432) in YL was reduced by over 50%, suggesting that functional redundancy enabled YL to maintain similar degradation capabilities to Y despite reduced diversity. Further analyses of key degradative species and co-occurrence networks highlighted the critical functional roles of dominant degradative species within these communities. An analysis of the overall functional pathways in the two microbial consortia revealed distinct metabolic characteristics between them. Pathways such as polycyclic aromatic hydrocarbon degradation and fluorobenzoate degradation were down-regulated in YL compared to Y, a finding corroborated by the metabolomic data. These results suggest a coupling between community structure and functional capacities within these microbial consortia. Overall, our findings deepen our understanding of the structure-function relationship in microbial communities and provide valuable insights for the design of lignocellulose-degrading consortia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The advancements in the sectors of forensic science along with biological sciences has proved to be a cornerstone in serving justice to people across the world. Genes are the coding languages that the body uses to define the definite characteristics of a human being that differentiates that being amongst million others. Now, to distinguish and get hands on the criminals, unique techniques are developed and introduced in the market to be implemented in the real world in order to handout proper verdict by the judicial system. This paper deals with few of those molecular biology techniques that are implemented in forensics to unfold the reality of the cases. The paper discusses the basics, principles, pros, and cons along with the future aspects of the techniques with the reader and aims at clarifying the concept of analysis of the DNA. Techniques such as PCR, STR, mtDNA, NGS along with forensic DNA database CODIS are analysed in the paper which showcase the importance of the presence of a technique with a database for an optimal inference of the results., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Both germline and somatic variants contribute to the genetic background and pathogenesis of melanoma. Germline variants include the presence of rare pathogenic or likely pathogenic variants of high, medium, and low penetrance melanoma-predisposing genes. Rare variants of high penetrance melanoma-predisposing genes are associated with melanoma development, whereas the medium and low penetrance predisposing genes can significantly increase melanoma risk. In this study, we clarified the germline genetic background of a Hungarian melanoma cohort (n = 17). Using a gene panel of 30 melanoma-predisposing genes, germline genetic variants were identified in 10 of the 17 patients (58.82%). A novel, likely pathogenic, missense variant (p.Y143C) in a medium penetrance melanoma-predisposing gene, melanocortin 1 receptor gene (MC1R), and two novel, likely pathogenic nonsense variants in low penetrance genes, p.Q218Ter in caspase 8 (CASP8) and p.Q40Ter in the fat mass- and obesity-associated (FTO) gene were detected. This study highlights the importance of elucidating the germline genetic background of melanoma, which may improve prediction of individual risk and the risk of family members and to optimize preventive, screening, and therapeutic measures for each patient and melanoma-prone families., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: In clinical practice, cardiologists frequently note substantial differences in coronary artery health among patients of the same age bracket. This observation led to our investigation into identifying genes that are shared between atherosclerosis and aging, as well as those that are specifically amplified in atherosclerosis alone., Methods: Our study leveraged existing gene expression datasets from the Gene Expression Omnibus (GEO), avoiding the need for new experimental research involving human or animal subjects. We focused on analyzing two specific datasets: one comprising artery samples from individuals with and without atherosclerosis, and the other featuring samples from people in middle age versus those in older age groups. To identify significant genes, we applied a technique known as the weighted average difference (WAD)., Results: Our analysis identified 14 genes that were upregulated in both aging and atherosclerosis, hinting at the involvement of the type I interferon response in both conditions. Conversely, 408 genes that exhibited heightened activity within atherosclerotic lesions indicated an augmentation in lysosome-related processes. While aging might create a groundwork that predisposes individuals to atherosclerosis, the progression of atherosclerosis also involves distinct factors such as type I interferon response and an increase in lysosomal activity., Conclusions: Aging encompasses more than just the senescence of vascular cells; it is significantly affected by extracellular factors such as type I interferon. The onset of atherosclerosis, therefore, cannot be attributed solely to aging. Instead, it likely involves enhanced mechanisms such as phagocytosis and heighted lysosomal activity. Geriatr Gerontol Int 2025; 25: 108-115., (© 2024 Japan Geriatrics Society.)

The increasing demand for sustainable alternatives to conventional plastics has propelled the interest in bioplastics. A few papers reported on the effects of plastics on crustaceans, but no indication about biodegradable polymers is available. Hippolyte inermis Leach, 1816 is a protandric shrimp commonly living on leaves of the seagrass Posidonia oceanica, in the Mediterranean Sea. This crustacean is typically chosen as a model to study sex differentiation processes. Here, we demonstrated its convenience as a model organism to study the effects of biodegradable polymers (BPs). Five BPs were studied: polybutylene succinate (PBS), polybutylene succinate-co-butylene adipate (PBSA), polycaprolactone (PCL), poly-3-hydroxybutyrates (PHB) and polylactic acid (PLA). Larvae of H. inermis were exposed to three concentrations of each BP (1, 5 and 10 mg/L, respectively) for ten days. After exposure, the expression levels of eighteen genes involved in stress response and detoxification processes, retrieved from a H. inermis transcriptomic library, were validated by Real Time qPCR. This study is the first using a molecular approach to detect H. inermis responses to contaminants and in particular to biodegradable polymers, through the evaluation of functional gene's pathways., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier B.V.)

Aims: The hepatic perivascular epithelioid cell tumour (PEComa), including angiomyolipoma, exhibits diverse morphology and clinical behaviour; however, its prognostic features remain undefined. This study aimed to investigate its histological features and prognostic factors., Methods and Results: In total, 132 patients were included. Clinical data and histopathological slides were assessed along with the p53 and Ki-67 immunohistochemistry. Targeted next-generation sequencing was performed in three cases. Based on the histologic subtypes, 7 (10%), 36 (51%), 13 (18%), and 15 (21%) patients were classified as inflammatory angiomyolipoma, conventional angiomyolipoma, epithelioid angiomyolipoma, and PEComa not otherwise specified (NOS), respectively, among 71 patients who underwent surgical resection. We proposed the risk prediction criteria after defining primary tumour size ≥7 cm, infiltrative border, mitotic rate >1/10 mm 2 , necrosis, vascular invasion, and PEComa NOS as worrisome features, as follows: high-risk: ≥3 worrisome features; intermediate-risk: 1-2 features; low-risk: none of the features. Applying these criteria, 4 (6%), 31 (44%), and 36 (51%) patients were classified into high-, intermediate-, and low-risk groups, respectively. One patient each in the high-risk (25%) and intermediate-risk (3%) groups developed peritoneal metastases and intrahepatic recurrence, respectively, whereas none in the low-risk group showed disease progression. A literature review of clinically malignant hepatic PEComa family tumours was conducted, and upon application of our criteria, 62% (16/26) of the patients were classified as high-risk and 35% (9/26) as intermediate- or high-risk., Conclusion: Our risk prediction criteria can effectively predict the clinical outcomes in primary hepatic PEComa., (© 2024 John Wiley & Sons Ltd.)

Understanding what people believe the causes of autism to be has implications for experiences of familial guilt and stigma. Using a qualitative approach, we investigated how Brazilian healthcare professionals, parents of young and adult autistic people and young and adult autistic people consider the origins of autism and the interaction between the biological and social environment concerning the challenges autistic people encounter. Eight health professionals who assist autistic people, five young autistic people, six family members of young autistic people, five autistic adults, and four parents of autistic adults participated in the research. After analysis, two major coding themes emerged from the interviews: (T1) Perceived origins of autism: genetic, environmental, or both, (T2) The impact of the structured family environment. Our respondents consider autism in Brazil strongly related to genetic origins and little to environmental and social origins. At the same time, the context of the structured social and family environment can influence challenges and opportunities for autistic people., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

This study investigated the effects of γ-polyglutamic acid (PGA) and alginic acid (ALA) on grapes and wines. Marselan grapes were utilized to assess the accumulation and synthesis of phenolic compounds and antioxidant activity. The 0.35 % ( v /v) PGA (PGA2) significantly enhanced the antioxidant activity of both grapes and wines in both years. Overall, treatments with 0.45 % (v/v) PGA (PGA3), 0.45 % (v/v) ALA (ALA3), and 0.25 % (v/v) ALA (ALA1) notably increased the total phenolic and anthocyanin content in both grapes and wines. Among these, PGA3 treatment significantly upregulated the levels of Delphinidin-3- O -(6-acetyl)-glucoside, Cyanidin-3- O -(6-acetyl)-glucoside, Peonidin-3- O -glucoside, and Malvidin-3- O -(trans-6- O -coumaryl)-glucoside in both years. Additionally, PGA3 treatment elevated the expression of the VvPAL , VvCHS , VvDFR and VvLDOX genes across both years. In contrast, ALA3 and ALA1 treatments increased anthocyanin content by upregulating the expression of VvCHS , VvF3'H and VvUFGT genes. In summary, PGA3 treatment significantly enhanced the phenolic compounds and antioxidant activity in both grapes and wines. These findings demonstrate the potential of PGA and ALA as biostimulants to significantly enhance grape and wine quality in viticulture., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2025 The Authors. Published by Elsevier Ltd.)

Background: Antibiotics have recently been suggested to increase the risk of colorectal cancer. Here, we aimed to investigate the association of frequent antibiotic use and genetic susceptibility with the increased risk of the development of colorectal cancer. Therefore, a genome-wide association study was conducted in colorectal cancer patients with frequent antibiotic use and controls to identify potential chromosomal regions that could indicate an increased risk of colorectal cancer associated with antibiotic use. The results were replicated with a case-case analysis., Methods: A genome-wide case-control study involving 143 colorectal cancer cases with frequent exposure to antibiotics and 1642 healthy individuals with unknown antibiotic use was undertaken. A logistic regression model was used to identify associations between certain chromosomal regions (loci) and the risk of colorectal cancer in cases with frequent antibiotic use. The results were replicated in a follow-up association case-case study comparing the frequent users to those with a more modest use of antibiotics., Results: Six chromosomal regions were associated with colorectal cancer in patients exposed to frequent antibiotic use. Two of the six regions contained genes already suggested to be associated with colorectal cancer tumorigenesis, epithelial-mesenchymal transition and colorectal cancer recurrence. The results for the six chromosomal regions were further replicated in a case-case analysis where all the chromosomal regions were confirmed with high odds ratios (ORs) supporting the hypothesis that frequent antibiotic use is associated with an increased risk of colorectal cancer development., Conclusions: The study suggested that genetic modifiers could influence the risk of colorectal cancer associated with the frequent use of antibiotics.

Increasing evidence indicates that human endogenous retroviruses (HERVs) are important to human health and are an underexplored component of many diseases. Certain HERV families show unique expression patterns and immune responses in autism spectrum disorder (ASD) patients compared to healthy controls, suggesting their potential as biomarkers. Despite these interesting findings, the role of HERVs in ASD needs to be further investigated. In this review, we discuss recent advances in genetic research on ASD, with a particular emphasis on the implications of HERVs on neurodevelopment and future genomic initiatives aimed at discovering ASD-related genes through Artificial Intelligence. Given their pro-inflammatory and autoimmune characteristics, the existing literature suggests that HERVs may contribute to the onset or worsening of ASD in individuals with a genetic predisposition. Therefore, we propose that investigating their fundamental properties could not only improve existing therapies but also pave the way for new therapeutic strategies.

Cold stress is an environmental factor that seriously restricts the growth, production and survival of plants, and has received extensive attention in recent years. Hydrogen sulfide (H 2 S) is an ubiquitous gas signaling molecule, and its role in alleviating plant cold stress has become a research focus in recent years. This paper reviews for the first time the significant effect of H 2 S on improving plant cold resistance, which makes up for the gaps in the existing literature. In general, H 2 S improves plant tolerance to cold stress by activating antioxidant reaction and promoting the accumulation of metabolic substances such as chlorophyll, flavonoids, proline, sucrose and total soluble sugar in plants. Interestingly, H 2 S also interacts with nitric oxide (NO), auxin, jasmonic acid (JA), salicylic acid (SA), and ethylene (ETH) to alleviate cold stress. More importantly, in the process of alleviating cold stress with H 2 S, gene expression related to H 2 S synthesis, cold response and antioxidant is up-regulated or down-regulated, leading to the improvement of plant cold resistance. This paper also points out the problems existing in the current research and the potential of H 2 S in agricultural practice, and provides relevant theoretical references for future research in this field., Competing Interests: Declaration. Conflict of interest: The authors declare no conflicts of interest., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Childhood-onset antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) represents a heterogeneous group of multi-system autoimmune conditions associated with chronic inflammation, characteristically affecting small blood vessels, leading to various organ and system manifestations. Although rare in paediatric populations, AAV poses challenges in early recognition, diagnosis and management of refractory cases. This review highlights the characteristics of clinical presentation and outcomes of AAV in children, as well as its current classification and progress achieved in understanding the disease pathogenesis, with a focus on adult and paediatric genetic studies. Furthermore, we discuss the management of AAV in children, as well as new emerging therapies and future research needs, while proposing a potential algorithm for a childhood-onset-AAV therapeutic approach based on the disease phenotype.

Background/Objectives : A combination of increased human presence in the Arctic zone alongside climate change has led to a decrease in the number of wild reindeer ( Rangifer tarandus ). Studying the genetic potential of this species will aid in conservation efforts, while simultaneously promoting improved meat productivity in domestic reindeer. Alongside reducing feed costs, increasing disease resistance, etc., acquiring genetic variation information is a crucial task for domestic reindeer husbandry. This study thus identified highly informative molecular genetic markers usable for assessing genetic diversity and breeding purposes in reindeer. Methods : We analyzed gene polymorphism that may potentially affect animal growth and development in populations of wild (Taimyr Peninsula) and domestic reindeer, including Nenets and Evenk breeds. We screened these populations for polymorphisms by sequencing the GH , GHR , LCORL and BMP2 genes. Results : Following generation of gene sequences, we compared the alleles frequency in the surveyed populations and their genetic divergence. Some loci lacked polymorphism in wild reindeer, unlike domestic breeds. This could suggest a selection-driven microevolutionary divergence in domestic reindeer populations. An isolated domestic population from Kolguyev Island appeared to be genetically remote from continental reindeer. Conclusions : Molecular genetic markers associated with economically important traits in reindeer can be further developed using the data obtained. Monitoring wild reindeer populations and better utilizing the genetic potential of domestic animals will depend on a panel of these marker genes. By using this marker panel, the amount of time spent on selection efforts will be greatly reduced to enhance meat performance during reindeer breeding.

Introduction: Sepsis-induced acute lung injury (ALI), a critical sequela of systemic inflammation, often progresses to acute respiratory distress syndrome, conferring high mortality. Although UMI-77 has demonstrated efficacy in mitigating lung injury in sepsis, the molecular mechanisms underlying its action have not yet been fully elucidated., Methods: This study aimed to delineate the mechanism by which UMI-77 counteracts sepsis-induced ALI using comprehensive transcriptomic and metabolomic analyses., Results: UMI-77 significantly ameliorated histopathological changes in the lungs of mice with sepsis-induced ALI Transcriptomic analysis revealed that 124 differentially expressed genes were modulated by UMI-77 and were predominantly implicated in chemokine-mediated signaling pathways, apoptosis regulation, and inflammatory responses. Integrated metabolomic analysis identified Atp4a, Ido1, Ctla4, and Cxcl10 as key genes, and inosine 5'-monophosphate (IMP), thiamine monophosphate, thymidine 3',5'-cyclic monophosphate (dTMP) as key differential metabolites. UMI-77 may regulate key genes (Atp4a, Ido1, Ctla4, and Cxcl10) to affect key metabolites (IMP, thiamine monophosphate, and dTMP) and their target genes (Entpd2, Entpd1, Nt5e, and Hprt) involved in cytokine-cytokine receptor interaction, gastric acid secretion, pyrimidine, and purine metabolism in the treatment of sepsis-induced ALI., Conclusion: UMI-77 exerts its therapeutic effect in sepsis-induced ALI through intricate modulation of pivotal genes and metabolites, thereby influencing critical biological pathways. This study lays the groundwork for further development and clinical translation of UMI-77 as a potential therapeutic agent for sepsis-associated lung injuries., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Zhang et al.)

Blueberry plants are among the most important fruit-bearing shrubs, but they have shallow, hairless roots that are not conducive to water and nutrient uptake, especially under drought conditions. Therefore, the mechanism underlying blueberry root drought tolerance should be clarified. Hence, we established a yeast expression library comprising blueberry genes associated with root responses to drought stress. High-throughput sequencing technology enabled the identification of 1475 genes potentially related to drought tolerance. A subsequent KEGG enrichment analysis revealed 77 key genes associated with six pathways: carbon and energy metabolism, biosynthesis of secondary metabolites, nucleotide and amino acid metabolism, genetic information processing, signal transduction, and material transport and catabolism. Metabolomic profiling of drought-tolerant yeast strains under drought conditions detected 1749 differentially abundant metabolites (DAMs), including several up-regulated metabolites (organic acids, amino acids and derivatives, alkaloids, and phenylpropanoids). An integrative analysis indicated that genes encoding several enzymes, including GALM , PK , PGLS , and PIP5K , modulate key carbon metabolism-related metabolites, including D-glucose 6-phosphate and β-D-fructose 6-phosphate. Additionally, genes encoding FDPS and CCR were implicated in terpenoid and phenylalanine biosynthesis, which affected metabolite contents (e.g., farnesylcysteine and tyrosine). Furthermore, genes for GST and GLT1 , along with eight DAMs, including L-γ-glutamylcysteine and L-ornithine, contributed to amino acid metabolism, while genes encoding NDPK and APRT were linked to purine metabolism, thereby affecting certain metabolites (e.g., inosine and 3',5'-cyclic GMP). Overall, the yeast functional screening system used in this study effectively identified genes and metabolites influencing blueberry root drought tolerance, offering new insights into the associated molecular mechanisms.

Introduction: Congenital Hyperinsulinism (CHI) has not been previously studied in Ukraine. We therefore aimed to elucidate the genetics, clinical phenotype, histological subtype, treatment and long-term outcomes of Ukrainian patients with CHI., Methods: Forty-one patients with CHI were recruited to the Ukrainian national registry between the years 2014-2023. Genetic testing (n=40), 18F-fluorodihydroxyphenylalanin and 68Ga-DOTANOC PET/CT imaging followed by surgical treatment and subsequent histological analysis (n=19) was performed through international collaboration., Results: Pathogenic variants were identified in 19/22 (86.3%) individuals with persistent CHI (p-CHI) and 8/18 (44.4%) with early remission CHI (er-CHI). Pathogenic variants in the K-ATP channel genes were the only identified genetic cause of p-CHI ( ABCC8 (n=17) and KCNJ11 (n=2)) with greater genetic heterogeneity observed in those with er-CHI ( ABCC8 (n=3), KMT2D (Kabuki Syndrome, n=1), Beckwith-Wiedemann syndrome (n=2) and INSR (Donohue syndrome (n=2)). Histological analysis performed on 19 children with persistent CHI confirmed focal disease in 14 (73.7%), diffuse disease in two (10.5%) and atypical histology in three (15.8%). After surgery, complete recovery was observed in all 14 with focal disease, while relapse occurred in three patients with diffuse or atypical histology., Conclusion: A genetic diagnosis was achieved for 67.5% (27/40) of the cohort with a higher pick-up rate observed in those with p-CHI. The genetics and imaging studies enabled subtype-targeted treatment with surgical cure achieved in all individuals with focal disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Globa, Christesen, Mortensen, Houghton, Nielsen, Detlefsen and Flanagan.)

Background: Changes in the Alzheimer's disease-related apolipoprotein genes expression, occurring parallel with brain ischemia-induced neurodegeneration in the hippocampal CA3 area, may be crucial for the development of memory loss and dementia., Objective: The aim of the study was to investigate changes in genes expression of apolipoprotein A1 ( APOA1 ) , apolipoprotein E ( APOE ) , and clusterin ( CLU ) in CA3 area post-ischemia with survival of 2 years., Methods: The gene expression was evaluated with the use of an RT-PCR protocol after 2, 7, and 30 days and 6, 12, 18, and 24 months post-ischemia., Results: The expression of the APOA1 gene (encoding apolipoprotein A1) was below the control values at 2 days, 6 and 12 months while at 7 and 30 days and 18 and 24 months post-ischemia this gene expression exceeded the control values. In the case of the CLU gene (encoding clusterin) expression, it was above the control values at all times post-ischemia. Similar expression was observed for the APOE gene (encoding apolipoprotein E) except on day 7 after ischemia where its expression was below the control value., Conclusions: The results seem to indicate that the observed changes in the gene expression may reflect the activation and inhibition of a variety of processes involved in ischemia-induced neurodegeneration. The enhanced expression of APOA1 and CLU genes may be associated with induction of neuroprotective mechanisms while increased expression of the APOE gene may produce detrimental effects., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Data availabilityThe data of this study are available on request from the corresponding author.

Antibiotic resistance is one of the major health threat for humans, animals, and the environment, according to the World Health Organization (WHO) and the Global Antibiotic-Resistance Surveillance System (GLASS). In the last several years, wastewater/sewage has been identified as potential hotspots for the dissemination of antibiotic resistance and transfer of resistance genes. However, systematic approaches for mapping the antibiotic resistance situation in sewage are limited and underdeveloped. The present review has highlighted all possible perspectives by which the dynamics of ARBs/ARGs in the environment may be tracked, quantified and assessed spatio-temporally through surveillance of wastewater. Moreover, application of advanced methods like wastewater metagenomics for determining the community distribution of resistance at large has appeared to be promising. In addition, monitoring wastewater for antibiotic pollution at various levels, may serve as an early warning system and enable policymakers to take timely measures and build infrastructure to mitigate health crises. Thus, by understanding the alarming presence of antibiotic resistance in wastewater, effective action plans may be developed to address this global health challenge and its associated environmental risks., (© 2024 Wiley‐VCH GmbH.)

Marine ecosystems are ideal for studying evolutionary adaptations involved in lineage diversification due to few physical barriers and reduced opportunities for strict allopatry compared to terrestrial ecosystems. Cetaceans (whales, dolphins, and porpoises) are a diverse group of mammals that successfully adapted to various habitats within the aquatic environment around 50 million years ago. While the overall adaptive transition from terrestrial to fully aquatic species is relatively well understood, the radiation of modern whales is still unclear. Here high-quality genomes derived from previously published data were used to identify genomic regions that potentially underpinned the diversification of baleen whales (Balaenopteridae). A robust molecular phylogeny was reconstructed based on 10,159 single copy and complete genes for eight mysticetes, seven odontocetes and two cetacean outgroups. Analysis of positive selection across 3,150 genes revealed that balaenopterids have undergone numerous idiosyncratic and convergent genomic variations that may explain their diversification. Genes associated with aging, survival and homeostasis were enriched in all species. Additionally, positive selection on genes involved in the immune system were disclosed for the two largest species, blue and fin whales. Such genes can potentially be ascribed to their morphological evolution, allowing them to attain greater length and increased cell number. Further evidence is presented about gene regions that might have contributed to the extensive anatomical changes shown by cetaceans, including adaptation to distinct environments and diets. This study contributes to our understanding of the genomic basis of diversification in baleen whales and the molecular changes linked to their adaptive radiation, thereby enhancing our understanding of cetacean evolution., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Sex chromosomes play a significant role in establishing sex-specific differences in gene expression, thereby contributing to phenotypic diversity and susceptibility to various diseases. MicroRNAs (miRNAs), which are small non-coding RNAs encoded by both the X and Y chromosomes, exhibit sex-specific regulatory characteristics. Computational analysis has identified several X-linked miRNAs differentially expressed in sex-specific cancers. This review aims to elucidate the genetic and epigenetic mechanisms that govern the sex-specific expression of X- and Y-linked miRNAs, with particular attention to their functional role in regulating diverse cellular processes in different cancer pathways. In addition, this review provides a comprehensive understanding of the targeted therapeutic interventions and critical insights into the potential clinical implications of targeting sex-specific miRNAs. In conclusion, this review opens new horizons for further research to effectively translate these findings into viable treatment options., Competing Interests: Declaration of competing interest the authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Bacteria play a crucial role in biodegradation of recalcitrant endocrine-disrupting compounds (EDCs), such as bisphenol A (BPA). However, in-situ identification of BPA-degrading bacteria remains technically challenging. Herein, we employed a conventional plating isolation (PI) and a new single cell Raman spectroscopy coupled with stable isotope probing (Raman-SIP) approach to enrich and identify BPA-degrading bacteria from activated sludge (AS). AS-inhabitant bacteria were exposed to either 12 C-BPA or 13 C-BPA as sole carbon source over three consecutive generations. While PI relies on colony proliferation on agar media, Raman-SIP enables identification of in situ BPA-degrading bacteria in a culture-independent way. The results showed that BPA dissipation correlated with increased bacterial growth. The uptake of 13 C-BPA by single cells was verified by Raman spectra, suggesting occurrence of both metabolic and biosynthesis processes. This direct tracking of the fate of 13 C-BPA within cells highlights the advantages of Raman-SIP over PI technique. PI isolated four BPA-degrading bacterial strains belonging to Comamonas, Pseudomonas, and Herbaspirillum genera. Meanwhile, Raman-SIP identified labeled cells belonging to Comamonas and Pseudomonas genera. Metagenomics of labeled cells revealed the presence of fifteen genes associated with benzene ring cleavage. This study provides a novel Raman-SIP approach for detecting and characterizing BPA-assimilating bacteria at a single cell level., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background & Aims: Lipoprotein(a) (Lp(a)) is an emerging biomarker for cardiometabolic factors. We studied the role of Lp(a) in the full spectrum of metabolic dysfunction-associated steatotic liver disease (MASLD)., Methods: Three independent analyses were implemented using a multi-center, cross-sectional, liver biopsy-based study (n = 332) (Study 1) and the UK Biobank prospective study (n = 270,004) (Study 2; median follow-up, 12.47 years). In Study 1, we studied the cross-sectional association between Lp(a) mass and MASLD stages (Analysis A). In Study 2, we studied the prospective association between Lp(a) concentration and MASLD, liver cirrhosis, and hepatocellular carcinoma (Analysis B). Finally, these analyses were accompanied by a prospective analysis using LPA Genetic Risk Score (Analysis C)., Results: In Study 1, an inverse association between Lp(a) and at-risk metabolic dysfunction-associated steatohepatitis (odds ratio per 1-SD increase , 0.64; 95% confidence interval [CI], 0.42-0.97) was observed. In contrast, when similar associations were examined prospectively (Study 2), subjects with Lp(a) <10.75 nmol/L had a higher risk for cirrhosis (hazard ratio, 1.49; 95% CI, 1.22-1.81) and HCC (hazard ratio, 1.69; 95% CI, 1.12-2.56) compared with subjects with Lp(a) within the 10.75 to 21.5 nmol/L range. Above these levels, the risk increased significantly and positively. Similarly, genetic analysis showed an L-shaped association with LPA Genetic Risk Score., Conclusions: The inverse association observed in cross-sectional studies should be attributed to reverse causality (ie, the presence of liver disease may decrease Lp(a) levels). Genetically predicted very low Lp(a) levels are also associated with impaired liver health prospectively. Clinical trials evaluating Lp(a)-lowering agents should thus be monitored carefully for adverse liver effects in subjects attaining extremely low concentrations., (Copyright © 2024. Published by Elsevier Inc.)

Adipose-derived stromal cells (ADSCs) are commonly used in regenerative medicine, but the genetic features of their development into neuronal cells are unknown. This study used single-cell RNA sequencing (scRNA-seq) to reveal gene expression changes during ADSCs to neuronal differentiation. Sequencing of the ADSCs group, the prei-1d group, and the induction 1 h, 3 h, 5 h, 6 h, and 8 h groups was performed using the BD Rhapsody platform. Sequence data were analyzed using t-SNE, Monocle2, GO, and KEGG algorithms. Results showed that a total of 38,453 cells were collected, which were divided into 0-13 clusters. Monocle2 structured analysis revealed that ADSCs were located at the beginning of the trajectory, and the cells after 5 h of induction were mainly distributed at the end of the trajectory in branches 1 and 2. Up-regulated differentially expressed genes (DEGs) at 5 h after induction enriched GO items including cellular protein metabolism, cell adhesion, endocytosis, and cell migration. KEGG analysis showed that induced 6 h and 8 h groups mainly enriched pathways were oxidative phosphorylation, glutathione metabolism, and expression of Parkinson's disease-related genes. In conclusion, two distinct cell state mechanisms stimulate ADSCs to develop into mature neurons. ADSCs induced for 5 h had developed into mature neurons. Later, the differentiated cells undergo degenerative changes associated with senescence., Competing Interests: Declarations. Conflict of interest: The authors declare no conflict of interest. Ethical Approval: All experimental procedures and protocols were approved by the Ethics Committee of Tangshan Kailuan General Hospital, Hebei Province, and it was confirmed that all experiments were performed by relevant naming guidelines and regulations (approval number: 2018010). Written informed consent for the use of their adipose tissue waste for scientific research was obtained from all volunteers before the experimental study., (© 2024. The Author(s).)

Background: Efforts toward tuberculosis management and control are challenged by the emergence of Mycobacterium tuberculosis (MTB) resistance to existing anti-TB drugs. This study aimed to explore the potential of machine learning algorithms in predicting drug resistance of four anti-TB drugs (rifampicin, isoniazid, streptomycin, and ethambutol) in MTB using whole-genome sequence and clinical data from Uganda. We also assessed the model's generalizability on another dataset from South Africa., Results: We trained ten machine learning algorithms on a dataset comprising of 182 MTB isolates with clinical data variables (age, sex, HIV status) and SNP mutations across the entire genome as predictor variables and phenotypic drug-susceptibility data for the four drugs as the outcome variable. Model performance varied across the four anti-TB drugs after a five-fold cross validation. The best model was selected considering the highest Mathews Correlation Coefficient (MCC) and Area Under the Receiver Operating Characteristic Curve (AUC) score as key metrics. The Logistic regression excelled in predicting rifampicin resistance (MCC: 0.83 (95% confidence intervals (CI) 0.73-0.86) and AUC: 0.96 (95% CI 0.95-0.98) and streptomycin (MCC: 0.44 (95% CI 0.27-0.58) and AUC: 0.80 (95% CI 0.74-0.82), Extreme Gradient Boosting (XGBoost) for ethambutol (MCC: 0.65 (95% CI 0.54-0.74) and AUC: 0.90 (95% CI 0.83-0.96) and Gradient Boosting (GBC) for isoniazid (MCC: 0.69 (95% CI 0.61-0.78) and AUC: 0.91 (95% CI 0.88-0.96). The best performing model per drug was only trained on the SNP dataset after excluding the clinical data variables because intergrating them with SNP mutations showed a marginal improvement in the model's performance. Despite the high MCC (0.18 to 0.72) and AUC (0.66 to 0.95) scores for all the best models with the Uganda test dataset, LR model for rifampicin and streptomycin didn't generalize with the South Africa dataset compared to the GBC and XGBoost models. Compared to TB profiler, LR for RIF was very sensitive and the GBC for INH and XGBoost for EMB were very specific on the Uganda dataset. TB profiler outperformed all the best models on the South Africa dataset. We identified key mutations associated with drug resistance for these antibiotics. HIV status was also identified among the top significant features in predicting drug resistance., Conclusion: Leveraging machine learning applications in predicting antimicrobial resistance represents a promising avenue in addressing the global health challenge posed by antimicrobial resistance. This work demonstrates that integration of diverse data types such as genomic and clinical data could improve resistance predictions while using machine learning algorithms, support robust surveillance systems and also inform targeted interventions to curb the rising threat of antimicrobial resistance., Competing Interests: Declarations. Ethical approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Cluster headache is a severe, poorly understood disorder for which there are as yet virtually no rationally derived treatments. Here, Lee Kudrow's 1983 theory, that cluster headache is an overly zealous response to hypoxia, is updated according to current understandings of hypoxia detection, signaling, and sensitization. It is shown that the distinctive clinical characteristics of cluster headache (circadian timing of attacks and circannual patterning of bouts, autonomic symptoms, and agitation), risk factors (cigarette smoking; male gender), triggers (alcohol; nitroglycerin), genetic findings (GWAS studies), anatomical substrate (paraventricular nucleus of the hypothalamus, solitary tract nucleus/NTS, and trigeminal nucleus caudalis), neurochemical features (elevated levels of galectin-3, nitric oxide, tyramine, and tryptamine), and responsiveness to treatments (verapamil, lithium, melatonin, prednisone, oxygen, and histamine desensitization) can all be understood in terms of hypoxic signaling. Novel treatment directions are hypothesized, including repurposing pharmacological antagonists of hypoxic signaling molecules (HIF-2; P2X3) for cluster headache, breath training, physical exercise, high-dose thiamine, carnosine, and the flavonoid kaempferol. The limits of current knowledge are described, and a program of basic and translational research is proposed.

Cleidocranial Dysplasia (CCD) is a rare genetic disorder characterized by skeletal abnormalities and dental anomalies, primarily caused by variants in the RUNX2 gene. Understanding the spectrum of RUNX2 variants and their effects on CCD phenotypes is crucial for accurate diagnosis and management strategies. This systematic review aimed to comprehensively analyze the genotypic and phenotypic spectra of RUNX2 variants in CCD patients, assess their distribution across functional regions, and investigate genotype-phenotype correlations. This review included 569 reported variants and 453 CCD patients from 103 articles. Of 569 variants, in-frame variants constituted 48.68%, while null variants accounted for 51.32%. Regarding locations, RUNX2 variants were predominantly located in the RHD (55.54%), followed by PST (16.34%), NMTS (6.33%), QA (4.75%), VWRPY (1.23%), and NLS (1.41%) regions while 10.19% were in non-coding regions. In-frame variants occurred primarily in the RHD (90.97%), while null variants were found across various regions of RUNX2. Data analysis revealed a correlation between variant location and specific skeletal features in CCD patients. Missense variants, predominantly found within the functionally critical RHD, were significantly associated with supernumerary teeth, macrocephaly, metopic groove, short ribs, and hypoplastic iliac wings compared to nonsense variants. They were also significantly associated with delayed fontanelle closure, metopic synostosis, hypertelorism, limited shoulder abduction, pubic symphysis abnormalities, and hypoplastic iliac wings compared to in-frame variants found in other regions. These findings underscore the critical role of the RHD, with missense RHD variants having a more severe impact than nonsense and other in-frame variants. Additionally, in-frame insertions and deletions in RUNX2 were associated with fewer CCD features, compared to missense, frameshift, and nonsense variants. Null variants in the NLS region exhibited weaker associations with delayed fontanelle closure, supernumerary teeth, Wormian bones, and femoral head hypoplasia than variants in other regions. Moreover, the NLS variants did not consistently alter nuclear localization, questioning the role of NLS region in nuclear import. In summary, this comprehensive review significantly advances our understanding of CCD, facilitating improved phenotype-genotype correlations, enhanced clinical management, and a deeper insight into RUNX2 functional domains. This knowledge has the potential to guide the development of novel therapeutic targets for skeletal disorders., (© 2024. The Author(s).)

Periprosthetic joint infection (PJI) is a multifactorial disease, and the risk of contracting infection is determined by the complex interplays between environmental and host-related factors. While research has shown that certain individuals may have a genetic predisposition for PJI, the existing literature is scarce, and the heterogeneity in the assessed genes limits its clinical applicability. Our review on genetic susceptibility for PJI has the following two objectives: (1) Explore the potential risk of developing PJI based on specific genetic polymorphisms or allelic variations; and (2) Characterize the regulatory cascades involved in the risk of developing PJI. This review focused on clinical studies investigating the association between genetic mutations or variations with the development of PJI. The genes investigated in these studies included toll-like receptors and humoral pattern recognition molecules, cytokines, chemokines, mannose-binding lectin (MBL), bone metabolism molecules, and human leukocyte antigen. Among these genes, polymorphisms in IL-1, MBL, vitamin D receptors, HLA-C, and HLA-DQ might have a relevant impact on the development of PJI. The literature surrounding this topic is limited, but emerging transcriptomic and genome-wide association studies hold promise for identifying at-risk genes. This advancement could pave the way for incorporating genetic testing into preoperative risk stratification, enhancing personalized patient care.

Introduction: Genetic studies of smoking cessation have been limited by short-term follow-up or cross-sectional design. Within seven genes (CHRNA3, CHRNA5, CHRNB2, CHRNB4, DRD2, DBH and CYP2A6) influencing biological mechanisms relevant to smoking, this study aimed to identify single nucleotide polymorphisms (SNPs) associated with smoking cessation throughout up to 38-years of follow-up., Methods: Participants were from two all-female cohort studies, Nurses' Health Study (NHS) (n = 10,017) and NHS-2 (n = 2,793). For 132 SNPs providing coverage of these genes, genotype associations with the probability of quitting smoking over time were evaluated using generalized estimating equations models. For SNPs reaching nominal statistical significance (p < 0.05) within NHS, NHS-2 was used as the replication cohort to control for multiple testing (false discovery rate (FDR) < 0.05). SNP genotype by smoking intensity (lifetime light versus non-light smoking) interactions were also evaluated., Results: Five SNPs identified in NHS were replicated in NHS-2 with FDR < 0.05. Women with the minor alleles of CHRNA5 SNPs rs637137 [OR = 1.21] and rs503464 [OR = 1.24] had increased odds of cessation. Women with the minor alleles of CYP2A6 SNPs rs56113850 [OR = 0.81] and rs56267346 [OR = 0.82] and DBH SNP rs6479643 [OR = 0.78] had lower odds of cessation throughout adulthood. An interaction with smoking intensity was indicated for three SNPs, CHRNB4 rs4887074, CHRNA3 SNP rs77438700, and CHRNA5 SNP rs76474922., Conclusion: Genetic associations with smoking cessation over decades of follow-up were observed and may guide targeted approaches for smokers most at risk for long-term relapse., Implications: This study identified single nucleotide polymorphisms (SNPs) within CHRNA5-A3-B4, CYP2A6, and DBH that were associated with smoking cessation in women over decades of follow-up. This study is the first to examine these genetic associations over years of follow-up. Some associations were novel while others replicated previous findings from short-term studies for the first time. Potential differences in some associations between light and non-light smokers were also observed. Genetic factors associated with long-term smoking behavior may help inform interventions modeled on long-term chronic disease management approaches; specifically, targeted maintenance interventions to sustain abstinence could be implemented among high-risk smokers., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Exoskeletons are a defining character of all arthropods that provide physical support for their segmented bodies and appendages as well as protection from the environment and predation. This ubiquitous yet evolutionarily variable feature has been instrumental in facilitating the adoption of a variety of lifestyles and the exploitation of ecological niches across all environments. Throughout the radiation that produced the more than one million described modern species, adaptability afforded by segmentation and exoskeletons has led to a diversity that is unrivalled amongst animals. However, because of the limited extensibility of exoskeleton chitin and cuticle components, they must be periodically shed and replaced with new larger ones, notably to accommodate the growing individuals encased within. Therefore, arthropods grow discontinuously by undergoing periodic moulting events, which follow a series of steps from the preparatory pre-moult phase to ecdysis itself and post-moult maturation of new exoskeletons. Each event represents a particularly vulnerable period in an arthropod's life cycle, so processes must be tightly regulated and meticulously executed to ensure successful transitions for normal growth and development. Decades of research in representative arthropods provide a foundation of understanding of the mechanisms involved. Building on this, studies continue to develop and test hypotheses on the presence and function of molecular components, including neuropeptides, hormones, and receptors, as well as the so-called early, late, and fate genes, across arthropod diversity. Here, we review the literature to develop a comprehensive overview of the status of accumulated knowledge of the genetic toolkit governing arthropod moulting. From biosynthesis and regulation of ecdysteroid and sesquiterpenoid hormones, to factors involved in hormonal stimulation responses and exoskeleton remodelling, we identify commonalities and differences, as well as highlighting major knowledge gaps, across arthropod groups. We examine the available evidence supporting current models of how components operate together to prepare for, execute, and recover from ecdysis, comparing reports from Chelicerata, Myriapoda, Crustacea, and Hexapoda. Evidence is generally highly taxonomically imbalanced, with most reports based on insect study systems. Biases are also evident in research on different moulting phases and processes, with the early triggers and late effectors generally being the least well explored. Our synthesis contrasts knowledge based on reported observations with reasonably plausible assumptions given current taxonomic sampling, and exposes weak assumptions or major gaps that need addressing. Encouragingly, advances in genomics are driving a diversification of tractable study systems by facilitating the cataloguing of putative genetic toolkits in previously under-explored taxa. Analysis of genome and transcriptome data supported by experimental investigations have validated the presence of an "ultra-conserved" core of arthropod genes involved in moulting processes. The molecular machinery has likely evolved with elaborations on this conserved pathway backbone, but more taxonomic exploration is needed to characterise lineage-specific changes and novelties. Furthermore, linking these to transformative innovations in moulting processes across Arthropoda remains hampered by knowledge gaps and hypotheses based on untested assumptions. Promisingly however, emerging from the synthesis is a framework that highlights research avenues from the underlying genetics to the dynamic molecular biology through to the complex physiology of moulting., (© 2024 The Author(s). Biological Reviews published by John Wiley & Sons Ltd on behalf of Cambridge Philosophical Society.)