Search Results (8,673)

Dientamoeba fragilis is a protozoan of the human digestive tract, yet its transmission and pathogenic role remain poorly understood. This study aimed to evaluate its impact on the efficacy and safety of fecal microbiota transplantation (FMT) in treating recurrent Clostridioides difficile infection (rCDI). This longitudinal cohort study analyzed stool samples from FMT donors and recipients pre-treatment and at 2 and 8 weeks post-FMT. All samples were retrospectively tested using real-time PCR. Shotgun metagenomics was also performed on selected donor–recipient pairs to explore transmission. CDI cure rates, gastrointestinal adverse events (AEs), and serious adverse events (SAEs) were assessed prospectively. A total of 53 FMT were analyzed (179 samples), with 23 (43%) derived from D. fragilis-positive donor stool (4 of 10 donors, 40%). Four of 52 recipients (18.2%), initially negative and who received treatment from positive donors, tested positive post-FMT. Shotgun metagenomics could not definitely confirm transmission due to the lack of a good reference genome. No significant differences in efficacy, AE, or SAE were observed between FMT from D. fragilis-positive versus -negative donors, even in immunocompromised patients. No SAEs were attributed to FMT. D. fragilis may be transmitted via FMT without evidence of short-term clinical impact. Consequently, RT-PCR detection should be interpreted cautiously in the context of donor exclusion decisions. Full article

Melamine, a nitrogen-rich industrial chemical, has raised increasing concern as an emerging environmental contaminant with potential reproductive toxicity. While its nephrotoxic effects are well established, the direct impact of melamine on human sperm remains poorly defined. In this study, we investigated the in vitro effects of melamine on human sperm, under both capacitating and non-capacitating conditions. Functional analyses revealed that the exposure to 0.8 mM melamine, the highest non-cytotoxic concentration in vitro, significantly compromised sperm motility and disrupted key capacitation processes, including tyrosine phosphorylation patterns, cholesterol efflux, and the acrosome reaction. Molecular assessments demonstrated melamine-induced mitochondrial dysfunction, characterized by COX4I1 downregulation, reduced mitochondrial membrane potential, and altered reactive oxygen species production. In parallel, gene expression analyses revealed the activation of apoptotic pathways, with the upregulation of BAX and downregulation of BCL2, changes that were more pronounced during capacitation. Furthermore, melamine exposure significantly increased sperm DNA fragmentation and denaturation, indicating genotoxic stress. Collectively, these findings demonstrate that even low, non-cytotoxic concentrations of melamine compromise sperm function by disrupting capacitation, mitochondrial activity, and genomic integrity. This study identifies capacitation as a critical window of vulnerability and underscores the need to consider melamine as a potential environmental risk factor for male reproductive health. Full article

Human non-polio enteroviruses (NPEVs) cause a plethora of infections in humans, ranging from mild to severe neurological diseases including aseptic meningitis. NPEVs are the leading cause of aseptic meningitis in both children and adults worldwide. In Russia, reports of NPEV infections have surged, especially in the post-COVID era starting in 2022, with elevated infection rates into 2023. A comprehensive examination of the whole genome is crucial for understanding the evolution of NPEV genes and for predicting potential outbreaks. This study focused on identifying the circulating NPEV strains in the Ural Federal District and Western Siberia, using Sanger sequencing and next-generation sequencing (NGS) methodologies. Biological samples were collected from (n = 225) patients diagnosed with aseptic meningitis. Bioinformatics analysis targeted the nucleotide sequences of the major capsid protein (partial VP1) gene fragment, and the assembly of whole NPEV genomes. A total of 159 NPEVs were characterized, representing 70.7% of the collected samples. The main capsid variants forming the predominant genotypic profile included E30 (n = 39, 24.3%), E6 (n = 31, 19.3%), and CVA9 (n = 25, 15.6%). Using NGS, we successfully assembled 13 whole genomes for E6, E30, EV-B80, CVA9, CVB5, E11, and EV-A71 and 3 partial genomes for E6 and EV-B87. This molecular-genetic analysis provides contemporary insights into the genotypic composition, circulation patterns, and evolutionary dynamics of the dominant NPEV associated with aseptic meningitis in the Ural Federal District and Western Siberia. The laboratory-based monitoring and epidemiological surveillance for genetic changes and evolutionary studies are important for improving prevention and healthcare. Full article

Piscine lactococcosis is an emerging bacterial disease that threatens freshwater and marine aquaculture in the Mediterranean region. This study characterized isolates of Lactococcus garvieae and Lactococcus petauri from farmed fish through molecular identification, genomic typing and antimicrobial susceptibility testing. A total of 39 bacterial strains were analyzed using species-specific real-time PCR assays, multilocus sequence typing and broth microdilution to determine minimum inhibitory concentrations. Results suggest a temporal shift in freshwater systems, where L. garvieae predominated in earlier isolates (mainly ST13, CC4), while L. petauri (ST14, CC14) appears as the dominant species in recent years. In marine fish, only L. garvieae was detected, mainly ST95 (CC95), a lineage previously reported in Europe. Molecular variability was found in both species with lineages capable of infecting livestock and humans. Amoxicillin displayed promising results; florfenicol showed moderate activity, while flumequine exhibited no inhibitory effect. Oxytetracycline and trimethoprim–sulfamethoxazole showed variable results requiring prudent use. These region-specific susceptibility profiles provide updated baseline data to guide empirical antimicrobial therapy while awaiting laboratory confirmation, highlighting the evolution of lactococcosis in aquaculture and emphasizing the need for molecular surveillance, antimicrobial stewardship, and vaccine updates within a One Health framework to mitigate impacts on Mediterranean aquaculture and public health. Full article

DNA double-strand breaks (DSBs) can be induced by cellular byproducts or genotoxic agents. Improper processing of these lesions leads to increased genome instability, which constitutes a hallmark of pathological conditions and fuels carcinogenesis. DSBs are primarily repaired by homologous recombination (HR) and non-homologous end joining (NHEJ) and the proper balance between these two pathways is finely modulated by specific molecular events. Here, we report that the histone chaperone DAXX plays a fundamental role in the response to DSBs. Indeed, in human cells, DSBs induce ATM/ATR-dependent phosphorylation of DAXX on serine 424 and 712 and promote its binding to chromatin and the deposition of the histone variant H3.3 in proximity to DNA breaks. Enrichment of H3.3 at DSBs promotes 53BP1 recruitment to these lesions and the repair of DNA breaks by HR pathways. Moreover, H3.3-specific post translational modifications, particularly K36 tri-methylation, play a key role in these processes. Altogether, these findings indicate that DAXX and H3.3 mutations may contribute to tumorigenesis-enhancing genome instability. Full article

Influenza A viruses exhibit broad host tropism, infecting multiple species including humans, avian species, and swine. Swine influenza virus (SIV), while primarily circulating in porcine populations, demonstrates zoonotic potential with sporadic human infections. In this investigation, we identified two H1N1 subtype swine influenza A virus strains designated A/swine/China/SD6591/2019(H1N1) (abbreviated SD6591) and A/swine/China/SD6592/2019(H1N1) (abbreviated SD6592) in Shandong Province, China. The GenBank accession numbers of the SD6591 viral gene segments are PV464931-PV464938, and the GenBank accession numbers corresponding to each of the eight SD6592 viral gene segments are PV464939-PV464946. Phylogenetic and recombination analyses suggest potential evolutionary differences between the isolates. SD6591 displayed a unique triple-reassortant genotype: comparative nucleotide homology assessments demonstrated that the PB2, PB1, NP, NA, HA, and NEP genes shared the highest similarity with classical swine-origin H1N1 viruses. In contrast, SD6592 maintained genomic conservation with previously characterized H1N1 swine strains, although neither of these two isolates exhibited significant intrasegmental recombination events. Through comprehensive sequence analysis of these H1N1 SIVs, this study provides preliminary insights into their evolutionary history and underscores the persistent risk of cross-species transmission at the human–swine interface. These findings establish an essential foundation for enhancing national SIV surveillance programs and informing evidence-based prevention strategies against emerging influenza threats. Full article

CRISPR/Cas systems have transformed molecular medicine, yet the field still lacks principled guidance on when transient editing suffices versus when sustained exposure through in vivo viral delivery is necessary and how to keep prolonged exposure safe. Notably, EDIT-101 was designed for a permanent edit in post-mitotic photoreceptors with lifelong Cas9 persistence. This review addresses this gap by defining the biological and therapeutic conditions that drive benefit from extended Cas activity while minimizing risk. We will (i) examine relationships between expression window and efficacy across Cas9/Cas12/Cas13 modalities, (ii) identify genome-wide off-target liabilities alongside orthogonal assays, and (iii) discuss controllable, self-limiting, and recallable editor platforms. By separating durable edits from persistent nuclease exposure, and by providing validated control levers, this work establishes a generalizable framework for safe, higher-efficacy CRISPR medicines. Furthermore, we highlight key studies in cell lines, murine models, non-human primates, and humans that examine the long-term effects of sustained expression of CRISPR/Cas systems and discuss the safety and efficacy of such approaches. Current evidence demonstrates promising therapeutic outcomes with manageable safety profiles, although there is a need for continued monitoring as CRISPR/Cas therapies are increasingly applied in clinical contexts and therapies are developed for broader clinical applications. Full article

Abdominal fat deposition in chickens significantly impacts production efficiency and is influenced by complex genetic and molecular mechanisms. This review summarizes current genomic and transcriptomic research on the regulation of adipogenesis and fat accumulation in chickens, highlighting key genes and loci identified through genome-wide association studies as well as other candidates involved in lipogenesis, lipolysis, and transcriptional regulation. Major metabolic pathways, including MAPK, AMPK, PI3K/AKT/mTOR, TGFβ1/Smad3, FoxO, JAK–STAT, Wnt/β-catenin, and Sonic Hedgehog signaling, are examined for their roles in fat deposition. The regulatory functions of non-coding RNAs, including microRNAs, long non-coding RNAs, and circular RNAs, are discussed, focusing on their interactions with target mRNAs and signaling networks that control lipid metabolism, adipocyte differentiation, and energy balance. Integrating insights from both avian and human studies, this review emphasizes the molecular mechanisms underlying adipogenesis and highlights potential strategies for genetic selection aimed at reducing excessive abdominal fat and improving poultry productivity. Full article

The Body Mass Index (BMI), integrating body weight and length, is a widely used metric for obesity assessment in humans. As pigs serve as crucial biomedical models, the application of BMI in swine and its genetic basis remain poorly explored. This study aimed to investigate the genetic architecture of pig BMI and compare two carcass-based BMI metrics (BMI-S and BMI-O) for breeding applicability. A total of 439 Landrace × Yorkshire crossbred pigs were genotyped with a 50 K SNP chip; heritability was estimated via a mixed linear model, and genome-wide association study (GWAS) was performed using the BLINK model. BMI-S and BMI-O exhibited moderate-to-high heritability of 0.55 and 0.47, respectively, with 17 genome-wide significant SNPs detected—including the top associated SNP rs81382440 on chromosome 4 and rs80898583 on chromosome 7. Key candidate genes (GPHN, ADAM33, KCNH8, PDCD4) and 5 SNP-trait associations validated in PigQTLdb were linked to lipid/energy metabolism and muscle development. Carcass-based BMI improved phenotypic accuracy, and our findings provide core genetic markers and a theoretical basis for molecular breeding of pig body conformation and lipid deposition traits. Full article

Background/Objectives: This review integrates evolutionary, metabolic, genetic, and nutritional perspectives to explain how sterol-derived vitamin D pathways shape human physiology and inter-individual variability in vitamin D status. Methods: The literature on sterol and vitamin D metabolism across animals, plants, fungi, and algae was synthesized with data from metabolomics databases, genome-wide association studies, RNA-seq resources (including GTEx), structural biology, and functional genomics. Results: Vitamin D₂ and vitamin D₃ likely emerged early in evolution as non-enzymatic photochemical sterol derivatives and were later co-opted into a tightly regulated endocrine system in vertebrates. In humans, cytochrome P450 enzymes coordinate vitamin D activation and degradation and intersect with oxysterol production, thereby linking vitamin D signaling to cholesterol and bile acid metabolism. Tissue-specific gene expression and regulatory genetic variants, particularly in the genes DHCR7, CYP2R1, CYP27B1, and CYP27A1, contribute to population-level differences in vitamin D status and metabolic outcomes. Structural analyses reveal selective, high-affinity binding of 1,25-dihydroxyvitamin D₃ to VDR, contrasted with broader, lower-affinity ligand recognition by LXRs. Dietary patterns modulate nuclear receptor signaling through distinct yet convergent ligand sources, including cholesterol-derived oxysterols, oxidized phytosterols, and vitamin D₂ versus vitamin D₃. Conclusions: Sterol and vitamin D metabolism constitute an evolutionarily conserved, adaptable network shaped by UV exposure, enzymatic control, genetic variation, and diet. This framework explains inter-individual variability in vitamin D biology and illustrates how evolutionary and dietary modulation of sterol-derived ligands confers functional flexibility to nuclear receptor signaling in human health. Full article

Thyroid nodule evaluation relies heavily on ultrasound imaging, yet it suffers from significant inter-operator variability. To address this, we present a preliminary validation of the Synergy-Net platform, an AI-driven Computer-Aided Diagnosis (CAD) system designed to standardize acquisition and improve diagnostic accuracy. The system integrates a U-Net architecture for anatomical segmentation and a ResNet-50 classifier for lesion characterization within a Human-in-the-Loop (HITL) workflow. The study enrolled 110 patients (71 benign, 39 malignant) undergoing surgery. Performance was evaluated against histopathological ground truth. The system achieved an Accuracy of 90.35% (95% CI: 88.2–92.5%), Sensitivity of 90.64% (95% CI: 87.9–93.4%), and an AUC of 0.90. Furthermore, the framework introduces a multimodal approach, performing late fusion of imaging features with genomic profiles (TruSight One panel). While current results validate the 2D diagnostic pipeline, the discussion outlines the transition to the ANTHEM framework, incorporating future 3D volumetric analysis and digital pathology integration. These findings suggest that AI-assisted standardization can significantly enhance diagnostic precision, though multi-center validation remains necessary. Full article

Tick-borne encephalitis virus (TBEV) causes tick-borne encephalitis (TBE), a severe disease of the human central nervous system. Currently, the data on the genetic variants of TBEV in Kyrgyzstan are practically absent. Therefore, the aim of this study was to analyze and describe the genetic diversity of TBEV in this region. The complete genome sequences of seven TBEV strains from the collection of the Scientific Centre for Family Health and Human Reproduction Problems (Irkutsk, Russia) were determined. These strains, isolated from Ixodes persulcatus ticks from Kyrgyzstan, were sequenced using the next generation sequencing approach on a MiSeq high-performance sequencer (Illumina, San Diego, CA, USA). A molecular genetic analysis of the obtained sequences, along with sequences of two previously isolated TBEV strains from Kyrgyzstan available in the GenBank database, demonstrated that the Siberian subtype of three genetic lineages (Zausaev, Vasilchenko and Bosnia) is predominantly distributed in Kyrgyzstan. The Far Eastern subtype of TBEV is also present. To date, this location probably represents the southernmost boundary of these TBEV subtypes’ ranges. Full article

Cervical cancer remains a major global public health concern, with persistent infection by high-risk human papillomavirus (hrHPV) types recognized as the primary etiological factor. This review explores the multifactorial nature of the disease, focusing on the complex interplay between host genetic susceptibility and epigenetic alterations that drive cervical carcinogenesis. Evidence from genome-wide association studies (GWAS) is discussed, highlighting the contribution of specific genetic loci, predominantly within the HLA region, to susceptibility to HPV infection and disease progression. In parallel, the review examines the molecular mechanisms by which the viral oncoproteins E6 and E7 promote genetic instability and epigenetic reprogramming, including histone modifications and dysregulation of non-coding RNAs. Particular emphasis is placed on DNA methylation, affecting both the viral genome and host genes such as FAM19A4, CADM1, PAX1, and MAL, as a promising biomarker for triage and detection of high-grade intraepithelial lesions (CIN2+). Finally, the review evaluates currently available methylation-based assays and self-sampling devices, highlighting their potential to enhance diagnostic accuracy and increase participation in cervical cancer screening programs. Full article

Background/Objectives: Metabolism is fundamental to all living organisms. It comprises a highly complex network of fine-tuned chemical reactions that sustain life but also generate by-products that damage cellular biomolecules, including DNA, thereby contributing to aging and disease. As metabolism can be largely modified by dietary alterations, it has the potential to positively or negatively affect health and disease. Interestingly, many aging-associated illnesses known to be influenced by diet also show a causal relation with DNA damage. As DNA keeps all instructions for life, and DNA lesions, if unrepaired, interfere with vital processes such as DNA replication and transcription, DNA damage may be an important mediator of the impact of nutrition on health and aging. Methods: Here, we discuss the genome-protective effects of various oral interventions in mice, aiming to elucidate which nutritional alterations lower DNA damage and promote overall health. Results: Our analysis covers a wide range of interventions with reported positive impacts on genomic stability, including modified diets (e.g., dietary restriction, probiotics, micronutrients, fatty acids, and hormones), NAD+ precursors (e.g., nicotinamide riboside), plant derivatives, and synthetic drugs. Among these, caloric and dietary restriction emerge as the most potent, generic modulators of DNA damage and repair processes, enhancing aspects of repair efficiency through metabolic recalibration and improved cellular resilience. Other interventions, like NAD+ precursors, activate partly similar pathways without necessitating reduced food intake. Conclusions: While many interventions show promise, their effects are often less pronounced or are process-specific compared to caloric or dietary restriction. Additionally, many substances lack comprehensive exploration of their genome-protective effects in mice, with often only a small number of studies examining their impact on genome stability. Moreover, the heterogeneity between studies limits direct comparison. However, the observed overlap in mechanistic effects between treatments lends credibility to their potential efficacy. Ultimately, a deeper understanding of these mechanisms could pave the way for translating these findings into, e.g., combination treatments to promote healthy aging in humans. Full article

Multidrug resistance (MDR) in Gram-negative bacteria is a global issue and needs to be addressed urgently. MDR can emerge through genetic mutations and horizontal gene transfer and deteriorate under antibiotic selective pressure. The emergence of resistance to last-resort antibiotics, which are used to treat MDR bacteria, is of particular concern. Colistin has been recognized as a last-line antibiotic for the treatment of MDR Gram-negative bacterial infections caused by Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Recently, the increasing reports of colistin resistance pose a significant threat to public health, caused by both acquired and intrinsic mechanisms. The review aimed to elucidate the trends in colistin resistance, the use of colistin in human and veterinary medicine, underlying resistance mechanisms and transmission pathways, and potential mitigation of this emerging threat through novel intervention strategies. Colistin resistance is mediated by plasmid-encoded phosphoethanolamine transferases (mcr-1 to mcr-10) and chromosomal lipid A remodeling pathways. In Escherichia coli, resistance involves mcr-1–10, acrB efflux mutations, pmrA/pmrB, arnBCADTEF, and mgrB inactivation. Klebsiella pneumoniae exhibits mcr-1, mcr-8, mcr-9, mgrB disruption and phoP/phoQ–pmrAB activation. Acinetobacter baumannii harbors mcr-1–4, while Salmonella enterica and Enterobacter spp. carry mcr variants with arnBCADTEF induction. Therapeutic options include adjunct strategies such as antimicrobial peptides, nanomaterials, therapeutic adjuvants, CRISPR-Cas9-based gene editing, probiotics, vaccines, and immune modulators to restore susceptibility. This review identified that specific and wide actions are required to handle the growing colistin resistance, including genomic surveillance, tracing novel resistance mechanisms, and the application of alternative management strategies. The One Health approach is considered a key strategy to address this growing issue. Full article