Fetal alcohol spectrum disorders (FASD) encompass a broad range of effects caused by prenatal alcohol exposure. In the United States, conservative estimates place the incidence of FASD at a rate of 5 in 100 births. Children with FASD can have morphological afflictions including congenital defects of the brain, spinal cord, heart, eyes, and skeleton, as well as poor formation of facial structures such as the nose and mouth. Cognitive and behavioral abnormalities such as learning disabilities, socio-developmental delays and emotional disorders are also highly prevalent. There is no known cure for FASD and in utero detection methods are not available. In terms of urinary tract defects, kidney and renal related maladies may represent underreported aspects of FASD. To better understand the renal phenotypes associated with prenatal alcohol exposure, we employed the zebrafish, Danio rerio, a vertebrate species well suited for developmental nephrology and teratological work that has been used extensively to model FASD. We treated zebrafish embryos with ethanol then examined pattern formation and physiological activity of nephrons, which are the basic structural and functional unit of the kidney. Using whole mount in situ hybridization, we found that the formation of several cell types in the nephron blood filter and tubule, as well as renal progenitor populations, were perturbed by alcohol exposure. Interestingly, supplementation with all-trans retinoic acid, a vitamin A derivative associated with mitigating the effects of ethanol exposure in zebrafish and other animals, was sufficient to completely or partially rescue multiple ethanol induced kidney cell defects and restore nephron physiological activity. These studies have revealed several consequences of ethanol exposure that lead to the deregulation of renal ontogeny, and implicate a key role for reduced RA levels, thereby contributing useful insights relevant to the broader field of FASD research.

This study evaluated the effects of vitamin B1/B6/B12 complex supplementation on methotrexate (MTX)-induced hepatorenal injury in a short-term, single-dose acute rat model. Male Wistar rats were assigned to control, MTX, low-dose (MTX + VB-L), and high-dose (MTX + VB-H) vitamin B complex groups. A single MTX (20 mg/kg) was administered intraperitoneally on day 7. Vitamin B1/B6/B12 was administered intraperitoneally daily at 16/16/0.16 or 32/32/0.32 mg/kg on days 1-14. Samples were collected on day 14. Serum AST, ALT, urea, and creatinine, hepatic, and renal thiobarbituric acid reactive substances (TBARS) and total thiol (TT), and histopathological changes were evaluated. MTX significantly increased AST, urea, creatinine, hepatic and renal TBARS, and multiple histopathological scores compared with controls. Compared with MTX alone, AST and hepatic TBARS were significantly lower only in the MTX + VB-H group, whereas creatinine and renal TBARS were significantly lower in both treatment groups. Renal TBARS was significantly lower in MTX + VB-L than in MTX + VB-H. Neither the treatment group differed significantly from the MTX group in ALT, urea, TT, or any hepatic or renal histopathological parameter. Vitamin B complex co-administration was associated with improvements in selected biochemical markers and lower TBARS levels, without statistically significant histopathological improvement. The absence of a vitamin-only group limits distinction between MTX-specific attenuation and independent formulation effects. Further preclinical studies are required before clinical implications can be established.

Mammalian kidneys, although exposed to a diverse array of environmental pollutants and commonly used drugs that are dose-limited by nephrotoxicity, have a significant but limited capacity for repair and regeneration. Primary cultures of human proximal tubular (hPT) cells were used to investigate the cellular response to exposures to one of two environmental toxicants (mercuric chloride [HgCl2] or S-(1,2-dichlorovinyl)-L-cysteine [DCVC; key metabolite of trichloroethylene] or one of three nephrotoxic drugs (cisplatin [CDDP], polymyxin B [PmxB], tenofovir disoproxil fumarate [TDF]) at concentrations that cause no to modest cellular injury. Cellular phenotype was first characterized by measuring protein expression of key drug metabolism enzymes and plasma membrane transporters. To enable identification of biomarkers when the hPT cells are still capable of repair and regeneration, release of Kidney Injury Molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) from exposed hPT cells was determined. Results validated that for each of the 3 concentrations of the 5 toxicants or drugs tested at the 3 time points, there was either no significant pattern of or modest cellular injury. Untargeted metabolomics was conducted to identify high resolution mass spectrometry features representing metabolites that differ after exposures. Pathway analysis was then conducted to map these metabolites into altered pathways. Prostaglandin metabolism from arachidonate, multiple fatty acid metabolism pathways, several amino acid metabolism pathways, and pentose phosphate and related vitamin metabolism pathways were the most common pathways altered by all 5 chemicals. Detection of these altered pathways can be used as indicators to identify renal injury and promote repair.

Water-soluble flavor precursors (WSFPs) in sheep meat are key foundational substances that confer its unique and intense flavor. This study established an efficient analytical method for the simultaneous quantification of 34 WSFPs in sheep meat by combining streamlined sample preparation with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Sheep meat samples were homogenized in water, followed by cleanup using dispersive solid-phase extraction (d-SPE), and subsequently analyzed by LC-MS/MS. Separation was achieved on a BEH Amide column (2.1 mm × 100 mm, 1.7 μm) with a gradient elution of ammonium formate aqueous solution and acetonitrile solution as the mobile phase. Detection was performed in electrospray ionization (ESI) mode with positive/negative ion switching and multiple reaction monitoring (MRM). Isotope-labeled internal standards were employed for quantification. The 34 analytes, spanning five chemical classes - 24 amino acids, 2 nucleotides, 3 reducing sugars, 4 small peptides, and 1 vitamin B1 (thiamine) - were successfully quantified. The method exhibited excellent linearity (R[2] ≥ 0.9909), with quantification limits ranging from 0.01 to 5 mg/kg, average spike recovery rates of 80.1%-109%, and relative standard deviations (RSD) below 9.9%. The developed method was validated using real sheep meat samples and demonstrated to be simple, accurate, reliable, and suitable for the simultaneous quantification of these 34 WSFPs. Furthermore, it proved applicable for monitoring changes in WSFP content during sheep meat storage.

VITALITY was established as a single-centre, doubleblind, randomised controlled trial (RCT) to determine whether daily supplementation of 400 International Units (IU) of vitamin D in the first year of life reduces the prevalence of food allergy at 12 months of age, compared to placebo. It recruited 2739 healthy, term, breastfed infants from 2014 to 2022 in Greater Melbourne, Australia. With an overall high retention rate despite the COVID-19 pandemic of over 83%, VITALITY is a rich cohort with extensive samples and data at baseline (six-12 weeks) and at six-, nine- and 12-months of age. Questionnaires collected information on demographics and environmental exposure, allergic diseases, infant feeding and factors thought to influence vitamin D levels at all timepoints. The majority of participants had a family history of allergic disease (89.2%) and 61.2% had both parents born in Australia. The standardized clinic visit at 12 months of age, attended by 79% of participants, included skin prick tests (SPT) +/- oral food challenges (OFC) and eczema assessment. Biospecimen collection included blood, skin and nasal swabs, stool and breastmilk which can be used for multi-omics profiling. Overall we performed SPTs on 2151 infants and undertook 612 OFCs. A six year follow up of VITALITY participants is underway and will determine the effect of early-life vitamin D supplementation on outcomes of asthma and other allergic diseases, lung function, infection and oral health. VITALITY is a large longitudinal cohort with data collected at multiple timepoints in childhood on a range of health outcomes. It provides a unique opportunity to explore early-life risk factors including genetic and environmental markers for food allergy, asthma, other atopic and non-communicable diseases as the cohort matures, in addition to establishing the role of vitamin D as an early-life strategy for prevention of disease and sustaining immune health.

Interactions between microbes shape the structure and function of microbial communities. While studying interactions is key to understanding microbial communities as a whole, gaining a detailed mechanistic view is challenging due to the number of co-occurring interactions. Here, we focus on a single class of shared nutrients, the cobalamin (vitamin B12) family of enzyme cofactors known as cobamides, to study nutrient interactions in laboratory consortia of increasing complexity. Measuring cobamide-dependent growth of two soil Caulobacter isolates in monoculture revealed that each grows faster within a distinct range of cobamide concentrations. Co-culturing the two isolates demonstrated that the cobamide concentration predictably determines which isolate predominates. These results suggest that, although the two organisms appear functionally redundant, with identical metabolic capabilities predicted in their genomes, they may occupy distinct niches in their environment based on cobamide concentration. We further examined the ability of cobamide-producing Mesorhizobium and Priestia isolates to share cobamides and found that both support the cobamide-dependent growth of the two Caulobacter isolates. The Caulobacter isolates could coexist in tri-cultures with each producer following serial passaging, indicating the producers can support the growth of multiple cobamide-dependent organisms. We analyzed the metabolic capacity encoded in the genomes of the four isolates and found that cobamides are likely the main shared nutrient in our co- and tri-cultures. These results highlight the utility of cobamides as a model nutrient to characterize and predict interactions in bacterial consortia of increasing complexity.IMPORTANCEInteractions between microbes shape their communities and the world around them. Because microbial communities are physically and chemically complex, predicting microbial interactions is often difficult. Using a set of four bacteria isolated from the same soil environment, we generated and tested predictions about the interactions involving a family of model nutrients related to cobalamin (vitamin B12). Understanding and predicting interactions can lead to greater insights into microbiome function.

Gait speed is a key indicator for diagnosing sarcopenia, validated by both the European Working Group on Sarcopenia in Older People in 2018 and the Asian Working Group on Sarcopenia in 2019 for assessing physical performance. While global data link vitamin D to physical performance, regional sex-stratified evidence in East Asian populations remains limited. This study aims to validate and confirm the association between gait speed and vitamin D levels in a middle-aged and older population in Taiwan. This cross-sectional investigation focused on community-dwelling residents. Participants were assigned to vitamin D sufficiency (≥30 ng/mL), insufficiency (<30 ng/mL and ≥ 20 ng/mL), and deficiency (<20 ng/mL) defined by the American Endocrine Society and International Osteoporosis Foundation criteria. Analyses included Student's t-tests, analysis of variance (ANOVA), Chi-square test and sex-stratified multiple linear regression. A total of 396 participants (164 men and 232 women) were recruited, with a mean age of 65.18 ± 8.75 years; mean serum vitamin D concentration of 28.25 ± 9.45 ng/mL; and mean gait speed of 0.91 ± 0.23 m/s. A positive association between gait speed and 25(OH)D (p = 0.047), and a negative association between gait speed and age (p < 0.001) and body mass index (BMI) (p = 0.005) were observed in men. Conversely, in women, gait speed was negatively associated with age (p < 0.001), BMI (p = 0.010), hypertension (p = 0.027), and diabetes mellitus (p = 0.009). This study demonstrated a positive association between gait speed and serum 25(OH)D levels in middle-aged and older men.

Multiple sclerosis (MS) is a complex neuroinflammatory disorder shaped by environmental and genetic factors. Vitamin D, a well-known environmental factor associated with the disease, exerts its immunoregulatory effects mainly through vitamin D receptor (VDR). Single nucleotide variants (SNVs) within the VDR gene may modify receptor function. Although previous studies have examined VDR SNVs in patients with MS, results have been inconsistent. In addition, their involvement in disease phenotypic variability remains poorly understood. The study aimed to examine potential correlation between FokI (rs2228570), TaqI (rs731236), and BsmI (rs1544410) SNVs in VDR, and MS susceptibility, as well as clinical characteristics in a Southeastern European Caucasian case-control population. Genotypic analysis for the SNVs was performed using genomic DNA extracted from samples of 200 MS patients and 265 neurologically healthy controls. Statistical analysis indicated no significant associations between individual SNVs and MS susceptibility in univariate analyses. However, logistic regression showed a significant interaction between rs2228570 (CT) variant and rs731236 (AG), which remained after FDR correction (padj = 0.041). In genotype-phenotype analyses, the rs1544410 (AA) and rs731236 (GG) genotypes were associated with motor symptoms, after adjusting for sex and age. Furthermore, the rs731236 (AA) and rs1544410 (GG) genotypes were more frequent among patients without cervical spinal cord lesions. While the investigated VDR variants do not appear to independently influence MS susceptibility, specific genotype combinations and alleles may contribute to the clinical expression of the disease. These findings highlight the value of integrating interaction modelling and phenotype stratification in genetic studies. The results also support a potential role for vitamin D signalling in shaping MS heterogeneity.

Multiple sclerosis (MS) is a chronic immune and neurodegenerative condition that affects the central nervous system (CNS). Multiple factors, both genetic (including the HLA gene locus) and environmental (Epstein-Barr virus, low vitamin D levels), may contribute to MS development. Growing evidence supports the importance of the gut-brain axis and hormones in disease pathogenesis and progression. This review focuses on identifying the role of specific gut microbial products (short-chain fatty acids, tryptophan derivatives, bile acids, and polyamines) in this process and how they affect the immune system, blood-brain barrier (BBB), and glial cells. The review will also describe key differences between female and male patients with MS, including the higher prevalence in females and the tendency toward a progressive course in males. Estrogens, progesterone, and androgens have immunomodulatory, neuroprotective, and remyelinating activities, and this review will describe their impact on multiple sclerosis based on preclinical and clinical findings from pregnancy, menopause, and hormone replacement therapy. This paper discusses the intersection of these ideas through the "microgenderome" concept, which describes how hormones influence gut microbiota composition and how the microbiota, in turn, modulates hormone metabolism and levels.

Snakebite envenomation remains a significant neglected tropical disease, particularly in South Asia, where Daboia russelii (Russell's viper) causes substantial morbidity and mortality. Current antivenom therapy is limited by poor efficacy against local tissue damage, high production costs, restricted toxin specificity, and adverse immune reactions, highlighting the need for alternative or adjunct therapeutic strategies. Using an integrated computational and experimental approach, phytocompounds identified from Glycosmis pentaphylla leaf extracts were evaluated as potential inhibitors of major venom proteins. A total of 32 compounds identified by GC-MS were screened against phospholipase A2 (PLA2), snake venom metalloproteinases (SVMPs), snake venom serine proteases (SVSPs), L-amino acid oxidase (LAAO), and snake C-type lectin-like proteins (SNACLECs) using molecular docking. Representative high-affinity protein-ligand complexes were further evaluated by 100 ns molecular dynamics simulations. Pharmacokinetic, toxicity, protein-protein interaction, and pathway enrichment analyses were also performed to assess the therapeutic potential of the identified compounds. Preliminary experimental validation was conducted using trypsin-casein protease inhibition, skim milk agar protease inhibition, and erythrocyte membrane stabilization assays. Compared with N-acetyl cysteine (NAC), β-sitosterol, 3-chloro-5-cholestene, and vitamin E exhibited stronger binding affinities and more stable interactions with multiple venom proteins. Molecular dynamics analyses (RMSD, RMSF, radius of gyration, solvent-accessible surface area, and hydrogen bonding) further supported the stability of the selected protein-ligand complexes. Pharmacokinetic and toxicity predictions indicated acceptable drug-likeness and comparatively safe toxicity profiles for most selected compounds. STRING-based protein-protein interaction and pathway enrichment analyses revealed associations with inflammatory, coagulation, oxidative stress, and extracellular matrix-related pathways involved in venom pathology. The G. pentaphylla extract demonstrated concentration-dependent protease inhibition (56.86% at 5 mg/mL), reduced caseinolytic activity (28.19% inhibition), and significant erythrocyte membrane stabilization (39.23%), providing preliminary experimental support for the computational predictions. Overall, these findings identify G. pentaphylla-derived phytocompounds as potential lead compounds for future antivenom development and provide a computational foundation for subsequent venom-specific biochemical and in vivo validation toward safer and more affordable adjunct therapies for snakebite management.

A case of a patient with Turner syndrome (TS) with a karyotype of 45, X/46, XX/47, XXX who was admitted to the Department of Endocrinology at Peking Union Medical College Hospital in March 2025 were reported. The patient presented with primary amenorrhea and recurrent fractures. Dual-energy X-ray absorptiometry revealed osteoporosis, and spinal X-rays showed multiple vertebral wedge-shaped deformities. Screening for other secondary causes of osteoporosis revealed no significant abnormalities. Based on these results, together with the patient's sex hormone levels indicating hypergonadotropic hypogonadism and a peripheral blood karyotype of 45, X/46, XX/47, XXX, the patient was diagnosed with mosaic TS complicated by osteoporosis. The patient was treated with denosumab 60 mg subcutaneously once every 6 months, in combination with calcium carbonate/vitamin D3 600 mg orally once daily and vitamin D3 2 000 U orally once daily. No new fractures occurred through 9 months of follow-up. A literature review revealed that 26 cases of 45, X/46, XX/47, XXX mosaic TS with complete clinical data have been reported worldwide to date. The median age at diagnosis was 20.50 (range, 7.38-32.75) years. Patients diagnosed under 18 years of age predominantly presented with short stature; patients of reproductive age may present with infertility, with some achieved a successful pregnancy through assisted reproductive technology; and patients over 40 years of age often presented with other systemic diseases, such as hearing impairment, psychiatric disorders, epilepsy, ovarian stromal cell tumors, multiple myeloma, and sideroblastic anemia.