Search Results (8,651)

Aim: To report on the clinical and genetic spectrum of retinopathy associated with CDHR1 variants in a Hungarian cohort. Methods: A retrospective cohort study was conducted at a single tertiary care referral center. The study enrolled nine patients harboring biallelic variants in the CDHR1 gene. Detailed clinical history, multimodal imaging, electroretinography, and molecular genetics are presented. Results: We identified four CDHR1 variants predicted to cause loss-of-function and five phenotypes (cone dystrophy, central areolar choroidal dystrophy, cone-rod dystrophy, rod-cone dystrophy, and late-onset macular dystrophy). The most frequent variant was the synonymous CDHR1 c.783G>A (p.Pro261=) variant (10/18 alleles, 55.6%). A novel splice acceptor site variant, CDHR1 c.349-1G>A, and a novel intronic variant, CDHR1 c.1168-10A>G, were also detected. Fundus examination revealed macular atrophy with or without peripheral retinal changes. Full-field electroretinography, available in seven patients, demonstrated decreased light-adapted and extinguished dark-adapted responses in both the rod-cone dystrophy group and patients with macular involvement. OCT imaging indicated ellipsoid zone disruption with foveal sparing in two out of nine patients and severe retinal damage in rod-cone dystrophy cases. Conclusions: The predominant clinical manifestations of cone dystrophy, cone-rod dystrophy, and macular dystrophy in the Hungarian patient cohort showed heterogeneity, with a rod-cone dystrophy phenotype observed in five of nine cases (55.6%). The natural history of CDHR1-associated retinopathy typically follows a slow progression, providing a therapeutic window, which makes the disease a candidate for gene therapy. Full article

Gastrointestinal nematode (GIN) infections are the most prevalent parasitic diseases in grazing sheep worldwide, causing significant productivity losses, high mortality and, as a result, economic losses and emerging animal welfare concerns. Conventional control strategies, primarily relying on anthelmintic treatments, face limitations due to rising drug resistance and environmental concerns, underscoring the need for sustainable alternatives. Selective breeding for host genetic resistance has emerged as a promising strategy, while recent advances in transcriptomics and integrative omics research are providing deeper insights into the immune pathways and molecular and genetic mechanisms that underpin host–parasite interactions. This review summarizes current evidence on transcriptomic signatures associated with resistance and susceptibility to H. contortus and T. circumcincta GIN infections, highlighting candidate genes, functional genetic markers, key immune pathways, and regulatory networks. Furthermore, we discuss how other omics approaches, including genomics, proteomics, metabolomics, microbiome, and multi-omics integrations, provide perspectives that enhance the understanding of the complexity of the GIN resistance trait. Transcriptomic studies, particularly using RNA-Sequencing technology, have revealed differential gene expression, functional genetic variants, such as SNPs and INDELs, in expressed regions and splice junctions, and regulatory long non-coding RNAs that distinguish resistance from susceptible sheep, highlighting pathways related to Th2 immunity, antigen presentation, tissue repair, and stress signaling. Genomic analyses have identified SNPs, QTL, and candidate genes linked to immune regulation and parasite resistance. Proteomic and metabolomic profiling further elucidates breed- and tissue-specific alterations in protein abundance and metabolic pathways, while microbiome studies demonstrate distinct microbial signatures in resistant sheep, suggesting a role in modulating host immunity. In conclusion, emerging multi-omics approaches and their integration strategies provide a comprehensive framework for understanding the complex host–parasite interactions that govern GIN resistance, offering potential candidate biomarkers for genomic selection and breeding programs aimed at developing sustainable, parasite-resistant sheep populations. Full article

Protein-losing enteropathy (PLE) is a spectrum of gastrointestinal disorders in which protein loss occurs through the gastrointestinal tract. One of the underlying causes is chronic inflammatory enteropathy (CIE). Conventional therapies for CIE often include diet, immunosuppressives, anti-microbials, probiotics, and, recently, fecal microbial transplantation (FMT). This case report highlights the use of lyophilized material-based FMT through oral capsules and enema in a dog with PLE and concurrent protein-losing nephropathy (PLN). The patient initially had a significantly increased dysbiosis index (DI) and required repeated FMT treatments, resulting in a positive clinical response through improvement in body weight, serum albumin concentrations, fecal scores, and normalization of the DI over time. To maintain clinical responses, FMT had to be performed monthly. Approximately 1 year after starting FMT therapy, the patient then developed an episode of acute hemorrhagic diarrhea syndrome (AHDS) associated with netF-gene-encoding Clostridium perfringens strains, after which the DI became abnormal again. The patient responded clinically well to monthly FMT treatments again, but it took several months for normalization of the DI after the AHDS episode. In summary, this case report highlights the continued use of adjunct lyophilized FMT in a dog with PLE resulting in improved clinical control over time. Full article

Enhancer of zeste homologs inhibitory protein (EZHIP) is a eutherian-specific protein, with poorly defined developmental functions and physiological expression restricted to germ cells. Its aberrant re-expression characterizes posterior fossa ependymoma subtype A and a subset of diffuse midline gliomas with wild-type histone H3—aggressive pediatric brain tumors marked by global loss of the repressive H3 lysine 27 trimethylation (H3K27me3). Functionally analogous to the H3 lysine 27 to methionine (H3K27M) oncohistone, EZHIP inhibits Polycomb repressive complex 2 (PRC2), altering genome-wide H3K27me3 distribution and fate commitment. Unlike H3K27M, EZHIP is epigenetically silenced under physiological conditions yet inducible, suggesting context-dependent oncogenic roles. Its intrinsically disordered structure enables multifunctional interactions and biological versatility. Beyond brain tumors, EZHIP has emerged as an oncogenic driver in osteosarcoma, underscoring broader relevance across cancers. This review integrates current insights into EZHIP—from gene discovery and the mechanism of PRC2 inhibition to its emerging roles in metabolism, DNA repair, 3D chromatin regulation, and development. We outline EZHIP’s clinico-pathological significance in pediatric and adult malignancies, with an emphasis on EZHIP-driven hindbrain tumors. Finally, we discuss therapeutic opportunities, from the direct targeting of intrinsically disordered proteins to the indirect modulation of EZHIP-associated epigenetic and metabolic landscapes, highlighting implications for tumor evolution and precision oncology. Full article

Neurodevelopmental disorders (NDDs) are a heterogeneous group of conditions characterised by impairments in cognition, motor function, behaviour, and social interaction. Their genetic basis is highly diverse, and next-generation sequencing has become central to improving diagnostic yield. We retrospectively analysed 94 paediatric patients (0–18 years) with NDDs referred to the Paediatric and Rare Diseases Clinic, Microcitemico Hospital “A. Cao,” between January 2019 and July 2024. Each patient underwent detailed clinical evaluation and whole-exome sequencing (WES). Variants were prioritised according to ACMG guidelines. Gene burden analysis of rare predicted loss-of-function variants was performed using the Cohort Allelic Sums Test to detect enrichment in NDD cases relative to controls. WES identified 12 pathogenic variants, 16 likely pathogenic variants, and 10 variants of uncertain significance. Autosomal dominant disorders were the most frequent (n = 35 patients), while autosomal recessive and X-linked dominant conditions were identified in a single case each. The findings of this study further highlight the importance of WES in identifying novel genetic variants and in providing explanations for previously unexplained NDD cases. Moreover, the Cohort Allelic Sums Test (CAST) demonstrated that rare variants are enriched in genes implicated in neuronal development in affected individuals. Full article

Background/Objectives: Staphylococcus aureus is a multifaceted pathogen responsible for diseases in humans and in several animal species, including dairy cows. This study aimed to characterize and compare the genetic diversity, lineage distribution, and antimicrobial resistance profiles of S. aureus isolates from bovine milk with human-derived reference genomes to investigate host adaptation and inter-species transmission. Methods: Genomic analyses were performed on S. aureus isolates from quarter milk samples of dairy cows together with human-derived sequences from public databases. Whole-genome sequencing and multi-locus sequence typing (MLST) were used to determine sequence type (ST) distribution, and the presence of key antibiotic resistance genes and mobile genetic elements (MGEs) was assessed. Comparative genomics was applied to evaluate gene content, phylogenetic relationships, and lineage–host associations. Results: The dataset encompassed bovine-adapted lineages (CC97, CC133, CC151) and human-associated lineages (CC1, CC5, CC8, CC30, CC45), as well as livestock-associated ST398 in bovine samples and human-adapted ST5 and ST6 in animals. ST8 was the only ST shared between animal and human isolates and showed differing resistance profiles, with animal ST8 carrying resistance determinants absent from human ST8. Bovine-adapted strains were characterized by recurrent loss of human-associated virulence genes and acquisition of bovine-associated mobile genetic elements, and blaZ and mecA were rarely detected in bovine-adapted CC97 but were frequently present in human CC5 and CC8. Overall, animal isolates carried fewer resistance genes than human isolates. Conclusions: S. aureus from dairy cows and humans displayed substantial genetic diversity, with evidence of host-associated lineages and dynamic changes in gene and mobile element content. These findings support the need for integrated One Health surveillance to track shared and host-adapted lineages and their antibiotic resistance determinants. Full article

Colorectal cancer (CRC) develops through evolutionary processes involving genomic alterations, epigenetic regulation, and microenvironmental interactions. While traditionally explained by the stepwise accumulation of driver mutations, contemporary evidence supports a ‘Big Bang’ model in which many early-arising clones expand simultaneously to establish extensive heterogeneity. We reviewed recent studies employing spatially resolved multi-omic sequencing of tumour glands combined with computational modelling. These approaches enable high-resolution reconstruction of clonal architecture, transcriptional states, and chromatin accessibility. Findings show that although early clonal mutations shape tumour expansion, gene expression variability can be independent of genetic ancestry and instead reflects phenotypic plasticity driven by microenvironmental cues. Epigenomic analyses identified recurrent somatic chromatin accessibility alterations in promotors and enhancers of oncogenic pathways, frequently in the absence of DNA mutations, suggesting alternative mechanisms of gene regulation. Immune-focused studies demonstrated that early silencing of antigen-presenting genes and loss of neoantigens facilitate immune escape despite active surveillance. CRC is shaped by an interplay of genome, epigenome, and immune evolution, with non-genetic mechanisms and tumour plasticity emerging as important drivers of progression and therapeutic resistance. Full article

Background/Objectives: Vedolizumab (VDZ), a monoclonal antibody targeting α4β7 integrin, is used in Crohn’s disease (CD) management, yet patients’ responses vary, underscoring the need for pharmacogenomic (PGx) markers. This study aimed to identify PGx pathways associated with suboptimal VDZ response using a rare-variant analytical framework. Methods: DNA from 63 CD patients treated with VDZ as first-line advanced therapy underwent whole-exome sequencing. Clinical response at week 14 classified patients as optimal responders (ORs) or suboptimal responders (SRs). Sequencing data were processed using GATK Best Practices, annotated with variant effect predictors, and filtered for rare damaging variants (damaging missense and high-confidence loss-of-function; minor allele frequency < 0.05). Variants were mapped to genes specific for SRs and ORs, and analyzed for pathway enrichment using the Reactome database. Rare-variant burden and composition differences were assessed with Fisher’s exact test and SKAT-O gene-set association analysis. Results: Suboptimal VDZ response was associated with pathways related to membrane transport (ABC-family proteins, ion channels), L1–ankyrin interactions, and bile acid recycling, while optimal response was associated with pathways involving MET signaling. SKAT-O identified lipid metabolism-related pathways as significantly different—SRs harbored variants in pro-inflammatory lipid signaling and immune cell trafficking genes (e.g., PIK3CG, CYP4F2, PLA2R1), whereas ORs carried variants in fatty acid oxidation and detoxification genes (e.g., ACADM, CYP1A1, ALDH3A2, DECR1, MMUT). Conclusions: This study underscores the potential of exome-based rare-variant analysis to stratify CD patients and guide precision medicine approaches. The identified genes and pathways are potential PGx markers for CD patients treated with VDZ. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuronal loss and abnormal α-synuclein aggregation. Circulating microRNAs (miRNAs) have emerged as promising biomarkers and potential modulators of PD-related molecular pathways. In this study, we investigated the expression levels of four candidate miRNAs—miR-15a-5p, miR-16-5p, miR-139-5p, and miR-34a-3p—in patients with PD compared with healthy controls. A total of 47 PD patients and 45 age- and sex-matched controls were enrolled. Plasma miRNA levels were quantified using standardized RNA extraction, cDNA synthesis, and qPCR protocols. We observed marked upregulation of miR-15a-5p and robust downregulation of both miR-139-5p and miR-34a-3p in PD patients, whereas miR-16-5p showed no significant difference between groups. Target gene prediction and functional enrichment analysis identified 432 unique genes, with enrichment in biological processes related to protein ubiquitination and catabolic pathways, and signaling cascades such as mTOR, PI3K-Akt, MAPK, and Hippo pathways, all of which are implicated in neurodegeneration. Elevated miR-15a-5p may contribute to pro-apoptotic mechanisms, while reduced miR-139-5p and miR-34a-3p expression may reflect impaired mitochondrial function, diminished neuroprotection, or compensatory regulatory responses. Together, these dysregulated circulating miRNAs provide novel insight into PD pathophysiology and highlight their potential as accessible, non-invasive biomarkers. Further longitudinal studies in larger and more diverse cohorts are warranted to validate their diagnostic and prognostic value and to explore their utility as therapeutic targets. Full article

Thrombophilia is considered one of the key mechanisms underlying reproductive disorders. Clinical heterogeneity of reproductive disorders and a lack of stratification by phenotype often limit interpretation. Therefore, evaluating thrombophilia-associated genetic markers separately in fetal loss syndrome, postpartum hemorrhage (PPH), and hypertensive disorders of pregnancy is essential. Background/Objectives: To assess the frequency of thrombophilia-related genetic polymorphisms in women with various reproductive disorders and evaluate their association with clinical–anamnestic characteristics and obstetric antiphospholipid syndrome. Methods: A total of 132 women with reproductive disorders (fetal loss syndrome, postpartum hemorrhage, preeclampsia). Results: Statistically significant differences were found when comparing between the groups. Thus, heterozygous F13 genetic polymorphisms were statistically more common in the group with a history of preeclampsia compared to the group with PPH (the G/A genotype was detected in 22.2% versus 10.7%, p = 0.045), and heterozygous ITGA2 gene genetic polymorphisms were also more common (the C/T genotype was detected in 66.7% versus 42.9%, p = 0.023). In women with a history of PPH, homozygous ITGA2 genetic polymorphisms were statistically more common (the T/T genotype was detected 2.6 times more often—21.4% versus 8.8% compared to the group with fetal loss syndrome, p = 0.022; and 3.8 times more often—21.4% versus 5.6% compared to the group with PE, p = 0.022). Conclusions: A study of thrombophilia gene polymorphisms in women with reproductive disorders showed that the G/A genotype of F13, the C/T genotype of ITGA2, and the A/G genotype of MTR:2756 were significantly more common in women with preeclampsia than in the group with postpartum hemorrhage; the T/T genotype of the ITGA2 gene was detected in postpartum hemorrhage. The MTHFR 1286A > C (A/C) polymorphism was associated with a reduced risk of postpartum hemorrhage. In contrast, the MTR 2756A > G (A/G) genotype was associated with an increased risk of preeclampsia. Full article

Background: Hair loss (alopecia) is primarily driven by the premature transition of hair follicles from the anagen (growth) to the catagen (regression) phase. Intracellular calcium signaling is implicated in hair follicle biology, including the regulation of Wnt/β-catenin activity and the modulation of catagen-associated factors such as TGF-β2. Cyclic ADP-ribose (cADPR), a calcium-mobilizing second messenger synthesized by CD38, has recently emerged as a potential modulator of intracellular calcium dynamics. This study investigated whether cADPR is associated with changes in intracellular calcium retention and anagen-associated signaling pathways in human hair follicle dermal papilla cells (HHDPCs). Methods: HHDPCs were treated with cADPR (0.001–0.5 ppm) and analyzed for cell viability, intracellular calcium retention, β-catenin-dependent transcription, and the gene expression of LEF-1 and TGF-β2. Cell viability was evaluated using the MTT assay, intracellular calcium content was quantified by ICP–OES, β-catenin activation was assessed using a TOPFlash luciferase assay, and gene expression was measured by qRT-PCR. Results: cADPR did not induce marked cytotoxicity, maintaining more than 98% cell viability across all concentrations. The highest response was observed at 0.05 ppm, at which intracellular calcium content remained elevated for up to six hours as assessed by ICP–OES. At this concentration, β-catenin-dependent transcription increased by approximately 2.3-fold relative to control, LEF-1 expression was significantly upregulated (~2.5-fold), and TGF-β2 expression was significantly downregulated (~0.3-fold). These responses showed an overall concentration-dependent trend across assays. Conclusions: These findings indicate an association between cADPR treatment and modulation of intracellular calcium retention and anagen-related signaling readouts in HHDPCs, supporting the need for further studies to establish mechanistic causality and physiological relevance. Full article

Background: Population aging increases susceptibility to cognitive decline, anxiety, and metabolic dysregulation, yet safe and effective interventions remain limited. Saffron (Crocus sativus L.) has been traditionally used to enhance mood and cognition, and its main metabolites, crocins and safranal, exert neuroprotective, anxiolytic, and metabolic effects. However, variability in extract composition and frequent adulteration hinder reproducibility. Objectives: To clarify the efficacy of genuine saffron preparations in aging, we investigated a saffron extract standardized for safranal and crocin content (SSE). Methods: Safranal bioavailability was first characterized in rats, followed by an evaluation of behavioral, neuroendocrine, and metabolic outcomes after 35 days of oral SSE administration (25 or 200 mg/kg/day) in 25-month-old male C57BL/6 mice. Behavioral performance was assessed using open field and novel object recognition tests, while molecular analyses targeted neuropeptides in the hypothalamus and amygdala, hippocampal plasticity markers, cortical inflammatory proteins, and hepatic lipid metabolism genes. Results: SSE administration induced a rapid but transient increase in the plasma’s safranal, confirming its bioavailability. In aged mice, the low dose prevented age-related weight loss and modulated hepatic lipid metabolism, whereas the high dose reduced anxiety-like behavior and improved recognition memory. The anxiolytic effects are consistent with elevated hypothalamic Npy, an anxiolytic peptide, reduced amygdalar Crh, a key mediator of stress and anxiety, and decreased hypothalamic Hcrt, an arousal modulator. The improvement in memory is associated with modulation of the cortical and hippocampal inflammatory and endocannabinoid proteins involved in neural plasticity. Conclusions: These findings highlight content-standardized saffron extracts as a promising multi-target nutraceuticals for healthy aging. Full article

Panax notoginseng, a high-value medicinal crop, suffers substantial yield losses due to Fusarium oxysporum-mediated root rot, for which no molecularly defined control targets are currently available. Histone acetyltransferases (HATs) serve as crucial epigenetic regulators of fungal development and stress responses; however, their functional roles in F. oxysporum remain largely unexplored. In this study, we systematically identified six FoHAT genes via genome-wide analysis and classified them into evolutionarily conserved subfamilies through phylogenetic comparison with orthologs from Saccharomyces cerevisiae, Homo sapiens, and Arabidopsis thaliana. Structural analyses revealed distinct motif compositions and domain architectures among FoHAT members, while promoter cis-element profiling suggested potential subfunctionalization via stress-responsive regulatory mechanisms. Functional investigations demonstrated that major notoginsenosides present in P. notoginseng root exudates—R₁, Rg₁, Rg₂, Re, and Rd—dynamically influenced both spore germination and FoHAT expression profiles. Intriguingly, each notoginsenoside exerted concentration-dependent non-linear effects on spore germination, either inhibiting or promoting the process. Concurrently, notoginsenoside exposure triggered compensatory transcriptional responses, most notably a rebound in Fo-Hat1_N expression from 9% to 112% under Rd treatment. This work establishes an initial epigenetic framework for combating Fusarium root rot in medicinal plants and offers a foundation for developing HAT-targeted small-molecule inhibitors. Full article

Obesity, an escalating global health crisis, is characterized by adipose tissue hypertrophy and chronic low-grade inflammation. Although anti-obesity drugs can induce weight loss, their use is limited by adverse effects, underscoring the need for safer therapeutic strategies. In this study, we generated a recombinant form of Trichinella spiralis-derived macrophage migration inhibitory factor (rTs-MIF) and investigated its anti-inflammatory and anti-obesity effects via immunometabolic regulation. Male C57BL/6 mice fed a 45% high-fat diet were orally administered rTs-MIF, and its effects were evaluated by measuring fat mass, glucose metabolism, serum cytokines, liver histology, and adipose tissue parameters. In 3T3-L1 cells, we examined the effects of rTs-MIF on adipocyte differentiation, obesity-related gene expression, and intracellular signaling pathways. Oral rTs-MIF suppressed body weight gain, reduced fat mass, improved glucose levels, and decreased the food efficiency ratio. It also lowered pro-inflammatory cytokines and increased markers associated with M2 macrophages. In 3T3-L1 cells, rTs-MIF inhibited adipocyte differentiation and reduced the expression of lipogenic transcription factors and mouse Mif while modulating AKT and p44/42 MAPK signaling. These findings identify rTs-MIF as a potential bioactive candidate that ameliorates obesity by regulating the immune–metabolic axis. Full article

Background/Objectives: Advances in the genetic understanding of pheochromocytoma–paraganglioma (PPGL) have considerably refined personalized approaches to diagnosis and management. This study aims to present our institutional experience on the diagnostic characteristics, clinical course, and genetic background of patients with PPGL, in the context of the current literature. Methods: This retrospective analysis included 35 patients diagnosed with PPGL between years 2020 and 2024, all of whom underwent surgical resection and next-generation sequencing for germline mutations in major PPGL susceptibility genes. Clinical presentation, biochemical profile, pathological findings, and follow-up outcomes were compared between mutation-positive and mutation-negative cases. Results: Of the 35 patients with PPGL, germline mutations were identified in 6 patients (17%): 2 in Cluster 1A genes (SDHA, SDHB), 2 in Cluster 1B (VHL), and 2 in Cluster 2 (NF1). Consistent with existing literature, pathogenic germline variants—particularly SDHB and VHL—were identified in our cohort exclusively in patients younger than 30 years (ages 17, 20, and 25). Mutation-positive patients more frequently exhibited noradrenergic or non-secretory profiles (p = 0.01). Among the three non-secretory tumors in the cohort, two harbored genetic mutations (SDHA, NF1). Interestingly, both NF1-positive patients were normotensive—one (c.3496G > A) with a non-secretory tumor and the other (c.2329T > A) presenting at an unusually late age (63 years)—a strikingly atypical spectrum that underscores the phenotypic variability of NF1-associated PPGL. Bilateral disease was observed exclusively in VHL carriers (p = 0.03). Importantly, we identified a rare VHL c.369delG frameshift variant, not previously reported in association with PPGLs, in a patient with PPGL. No significant difference was observed between SDHB loss (p = 0.1) and proliferative indices (mitotic count, Ki-67) (p = 0.07, p = 0.6) between the two groups. During a median follow-up of 24 months (IQR: 18–36), one SDHB-positive patient had a recurrence, while no distant metastases were detected in the remaining mutation carriers. Conclusions: These findings support characteristic clinical patterns among mutation-positive PPGL and underscore the importance of systematic germline testing in all cases—irrespective of age, family history, or biochemical profile—to guide individualized management and enable cascade screening. The identification of a rare VHL c.369delG variant, previously unreported in association with PPGL, within a characteristic VHL-related clinical phenotype highlights the importance of this association. Similarly, atypical NF1 cases emphasize phenotypic variability and reinforce the importance of germline testing even in clinically silent presentations. Full article