Search Results (2,104)

The orbital fat of bighead carp (Hypophthalmichthys nobilis) represents a structural fat deposit located posterior to the eyes and constitutes an important edible component of the head region. Nevertheless, molecular mechanisms governing lipid accumulation during ontogenetic development remain insufficiently characterized. Here, we performed RNA-Seq on orbital fat tissues from 6-month-old (juvenile) and 18-month-old (market-size) bighead carp. A total of 1042 DEGs were identified, with 807 up-regulated and 235 down-regulated in the 6-month-old stage. Functional enrichment revealed key pathways including fatty acid metabolism, PPAR signaling, and glycolysis/gluconeogenesis. qRT-PCR validation confirmed RNA-Seq reliability. Notably, the differential expression patterns of genes such as cpt1a, cpt1b, slc27a1, fads2, and scd suggest their association with an elevated capacity for lipid synthesis in the orbital fat of 18-month-old bighead carp. This study presents the first transcriptome analysis of orbital fat development in a freshwater fish, offering insights into the genetic improvement of head meat quality traits and growth in bighead carp head. Full article

Percocypris pingi was listed in the China Vertebrate Red List in 2015, and albino P. pingi exhibits remarkable ocular phenotypes due to melanin synthesis defects, including the deficiency of melanin granules in the iris and retinal pigment epithelium (RPE). However, the regulatory mechanism of pigment loss in the eyes of albino P. pingi has not yet been clarified. This study systematically revealed the potential mechanisms underlying the obstruction of ocular melanin synthesis in albino P. pingi through histopathological analysis, transcriptomics, and proteomics techniques. The results showed that the synergistic effects of abnormal H⁺ transport mediated by SLC45A2, excessive activation of retinol metabolism, and cytoskeletal transport disorders led to the inhibition of tyrosinase activity and retention of pigment granules, ultimately causing melanin deficiency in the eyes. This study first elucidates the molecular network of ocular albinism in fish from a multi-omics perspective, providing a new perspective for the mechanistic research of pigmentation disorders in vertebrates. Full article

The search for an effective treatment for adult high-grade glioblastoma (GBM) remains urgent. Background/Objectives: The study aimed to determine the expression of carcinogenesis-related genes, such as SLC12A2, SLC12A5, CDH1, CDH2, EZH2, and GFAP, in primary glioblastoma (WHO Grade IV; IDH-wild-type) cells from three adult women: GBM5-1, GBM5-2F, and GBM5-3F. Methods: The impact of the combination of sodium valproate and sodium dichloroacetate (2 mM NaVPA–3 mM NaDCA) on the expression of these genes was determined and compared with the effects of 50 µM temozolomide after 24 h of treatment. Results: 2 mM NaVPA–3 mM NaDCA, as well as temozolomide, had individual impacts on the SLC12A2, SLC12A5, CDH1, CDH2, EZH2, and GFAP expressions of tested GBM5-1, GBM5-2F, and GBM5-3F primary cells of female GBM patients. Conclusions: The combination of 2 mM NaVPA–3 mM NaDCA may have an advantage in antitumor activity and may be more effective than TMZ; however, the effect is individual. Full article

Background/Objectives: Patients with epilepsy commonly experience patterns of seizures that change with sleep/wake behavior or diurnal rhythms. The cellular and molecular mechanisms that underlie these patterns in seizure activity are not well understood but may involve non-neuronal cells, such as astrocytes. Our previous studies show the critical importance of one specific astrocyte factor, the brain-type fatty acid binding protein Fabp7, in the regulation of time-of-day-dependent electroshock seizure threshold and neural activity-dependent gene expression in mice. Here, we examined whether Fabp7 influences differential seizure activity-dependent protein expression, by comparing Fabp7 knockout (KO) to wild-type (WT) mice under control conditions and after reaching the maximal electroshock seizure threshold (MEST). Methods: We analyzed the proteome in cortical–hippocampal extracts from MEST and SHAM groups of WT and KO mice using mass spectrometry (MS), followed by Gene Ontology (GO) and pathway analyses. GO and pathway analyses of all groups revealed a diverse set of up- and downregulated differentially expressed proteins (DEPs). Results: We identified 65 significant DEPs in the comparison of KO SHAM versus WT SHAM; 33 proteins were upregulated and 32 were downregulated. We found downregulation in mitochondrial-associated proteins in WT MEST compared to WT SHAM controls, including Slc1a4, Slc25a27, Cox7a2, Cox8a, Micos10, and Atp5mk. Several upregulated DEPs in the KO SHAM versus WT SHAM comparison were associated with the 20S proteasomal subunit, suggesting proteasomal activity is elevated in the absence of Fabp7 expression. We also observed 92 DEPs significantly altered in the KO MEST versus WT MEST, with 49 proteins upregulated and 43 downregulated. Conclusions: Together, these data suggest that the astrocyte Fabp7 regulation of time-of-day-mediated neural excitability is modulated by multiple cellular mechanisms, which include proteasomal pathways, independent of its role in activity-dependent gene expression. Full article

Renal phosphate transporters NaPi-IIa (SLC34A1) and NaPi-IIc (SLC34A3) play a crucial role in phosphate reabsorption in the proximal tubule. Biallelic loss-of-function variants in SLC34A1 and SLC34A3 cause two rare phosphate-wasting tubulopathies: idiopathic infantile hypercalcemia (IIH) and hereditary hypophosphatemic rickets with hypercalciuria, respectively. The phenotypes associated with these diseases are highly variable and sometimes overlap. Here, we report a rare case of a six-month-old girl of consanguineous parents with symptoms related to these diseases, including failure to thrive, nephrocalcinosis, hypercalcemia, hypophosphatemia with low TRP, elevated levels of 1,25-(OH)₂D₃, and suppressed PTH. An exome sequencing analysis was carried out to determine the genetic variants associated with her disease. Bioinformatics tools were used to assess variant pathogenicity. We identify a novel homozygous mutation in the SLC34A1 gene, c.1361C>T; p.(T454M), and a previously described heterozygous SLC34A3 101 bp deletion. Mutation p.(T454M) affects transmembrane domain 5 of the NaPi-IIa protein, which is involved in substrate binding, probably impairing phosphate transport. Our results suggest the diagnosis of IIH type 2 in our patient and highlight the importance of exome analysis in diagnosing these tubulopathies. We suggest that the coexistent heterozygous SLC34A3 deletion could increase the risk of renal calcifications and the severity of other symptoms. Full article

Pharmacotherapy in the geriatric population is one of the greatest challenges in modern medicine. Elderly patients, characterized by multimorbidity and the resulting polypharmacy, are significantly more exposed to adverse drug reactions (ADRs), which often lead to hospitalization and a decline in quality of life. Understanding the reasons for this difference requires an analysis of the physiological changes that occur during the aging process at the molecular level. This article presents a perspective on the molecular aspects of geriatric pharmacotherapy, focusing on the fundamental mechanisms that are modified with age. The analysis covers changes in pharmacokinetics, including the role and regulation of cytochrome P450 (CYP) enzymes, whose activity, especially in phase I reactions, is significantly reduced. The age-dependent dysfunction of drug transporters from the ABC (ATP-binding cassette) and SLC (solute carrier) families in key organs such as the intestines, liver and kidneys is discussed, which affects the absorption, distribution and elimination of xenobiotic compounds, including drugs. The article also provides a comprehensive analysis of the blood–brain barrier (BBB), describing changes in neurovascular integrity, including the dysfunction of tight junctions and a decrease in the activity of P-glycoprotein, sometimes referred to as multidrug resistance protein (MDR). This increases the susceptibility of the central nervous system to the penetration and action of drugs. In the realm of pharmacodynamics, changes in the density and sensitivity of key receptors (serotonergic, dopaminergic, adrenergic) are described based on neuroimaging data, explaining the molecular basis for increased sensitivity to certain drug classes, such as anticholinergics. The paper also explores new research perspectives, such as the role of the gut microbiome in modulating pharmacokinetics by influencing gene expression and the importance of pharmacoepigenetics, which dynamically regulates drug response throughout life via changes in DNA methylation and histone modifications. The clinical implications of these molecular changes are also discussed, emphasizing the potential of personalized medicine, including pharmacogenomics, in optimizing therapy and minimizing the risk of adverse reactions. Such an integrated approach, incorporating data from multiple fields (genomics, epigenomics, microbiomics) combined with a comprehensive geriatric assessment, appears to be the future of safe and effective pharmacotherapy in the aging population. Full article

Background: Tumor-educated platelets (TEPs) represent a promising biosource for non-invasive multi-cancer early detection (MCED). While machine learning (ML) has been applied to TEP data, the integration of explainability to reveal gene-level contributions and regulatory associations remains underutilized. This study aims to develop an interpretable ML framework for cancer detection using platelet RNA-sequencing data, combining predictive performance with biological insight. Methods: This study analyzed 2018 TEP RNA samples from 18 tumor types using seven machine learning classifiers. SHAP (Shapley Additive Explanations) was applied for model interpretability, including global feature ranking, local explanation, and gene-level dependence patterns. A weighted SHAP consensus was built by combining model-specific contributions scaled by Area Under the Receiver Operating Characteristic Curve (AUC). Regulatory insights were supported through network analysis using GeneMANIA. Results: Neural models, including shallow Neural Network (NN) and Deep Neural Network (DNN) achieved the best performance (AUC ~0.93), with Extreme Gradient Boosting (XGB) and Support Vector Machine (SVM) also performing well. Early-stage cancers were predicted with high accuracy. SHAP analysis revealed consistent top features (e.g., SLC38A2, DHCR7, IFITM3), while dependence plots uncovered conditional gene interactions involving USF3 (KIAA2018), ARL2, and DSTN. Multi-hop pathway tracing identified NFYC as a shared transcriptional hub across multiple modulators. Conclusions: The integration of interpretable ML with platelet RNA data revealed robust biomarkers and context-dependent regulatory patterns relevant to early cancer detection. The proposed framework supports the potential of TEPs as a non-invasive, information-rich medium for early cancer screening. Full article

Background and Clinical Significance: Cystinuria is the most common genetic cause of pediatric nephrolithiasis, characterized by impaired renal cystine reabsorption and resulting in increased urinary cystine excretion. Due to the poor solubility of cystine at normal urine pH, increased urinary cystine excretion leads to urine supersaturation and precipitation of cystine, resulting in nephrolithiasis. Case Presentation: Here, we report two cases of female patients diagnosed with cystinuria caused by SLC7A9 mutations. Both patients were initially managed with conservative treatments to minimize stone recurrence including increased oral fluid intake, a low-salt/low-protein diet, and potassium citrate supplementation with the goal of reducing urinary cystine levels and minimizing stone recurrences. Due to persistent stone formation, the patients were started on two distinct cystine-binding thiol medications. One patient was initiated on tiopronin, and the other on D-penicillamine. Tiopronin and D-penicillamine are both used in the treatment of pediatric cystinuria, although tiopronin is often preferred due to its more favorable side effect profile. However, due to insurance constraints, D-penicillamine was initiated for one patient in place of tiopronin. Since the initiation of these two distinct cystine-binding thiol medications, both patients have demonstrated reduced urinary cystine excretion and minimal to no recurrence of kidney stones. Conclusions: Cystine-binding thiols, including tiopronin and D-penicillamine, can both be used in the management of cystinuria in pediatric patients. Full article

Background/Objectives: Sex determination and differentiation exhibit remarkable molecular diversity across taxa, driven by genetic, epigenetic, and environmental factors. Invertebrates with sequential hermaphroditism, such as the Pacific oyster (Magallana gigas), represent a poorly understood system despite their role as keystone species and contribution to a substantial aquaculture industry. Methods: To identify sex-related molecular markers during gametogenesis, we repeatedly sampled hemolymph from artificially conditioned oysters over two months, and sex phenotypes were assigned at the end of the experiment by biopsy. Results: RNA-sequencing analysis of five males and five females revealed subtle yet consistent sex-specific transcriptional signatures in hemolymph. We show that gametogenesis proceeds asynchronously among oysters, even within the same sex individuals. Complex physiological trade-offs were discovered between sexes during gonad maturation; in early stages of sexual maturation, females prioritized cell division, whereas males suppressed it. Females exhibited higher expression of solute carrier family (SLC) genes, suggesting enhanced nutrient exchange during oogenesis. Temporal dynamics highlighted differential expression of genes regulating cross-membrane ion gradients (e.g., transient receptor potential channels) and signal transduction (e.g., signal transducer and activator of transcription), previously linked to environmental sex determination (ESD) in some reptilian species. Conclusions: Together, these findings underscore that gametogenesis in Pacific oysters is complex and dynamic, and that molecular pathways of ESD may be partially conserved between invertebrate and vertebrate species. Full article

SLC35A2-CDG is a congenital disorder of glycosylation caused by mutations in the SLC35A2 gene encoding a Golgi-localized UDP-galactose transporter. This transporter plays an essential role in glycan synthesis by transporting UDP-galactose from the cytoplasm into the Golgi lumen. Its dysfunction leads to impaired galactose-containing glycans and various neurological symptoms, although the underlying mechanisms remain largely unknown. We identified a novel SLC35A2-CDG patient carrying a pathogenic variant (c.617_620del, p.(Gln206ArgfsTer45)) who exhibited neurological abnormalities including bilateral ventriculomegaly. To investigate the disease mechanism, we established the first Drosophila model of SLC35A2-CDG. Knockout of Ugalt, the fly ortholog of SLC35A2, resulted in embryonic lethality, indicating its essential role. Knockdown of Ugalt reduced mucin-type O-glycans on muscles and neuromuscular junctions (NMJs), without affecting N-glycans. Ugalt knockdown larvae exhibited mislocalized NMJ boutons accompanied by a deficiency in basement membrane components on muscles. This phenotype resembles that of mutants of dC1GalT1 and dGlcAT-P, both involved in mucin-type O-glycosylation. Genetic interaction between Ugalt and dC1GalT1 was confirmed through double knockdown and double heterozygous analyses. Given that Drosophila NMJs are widely used as a model for mammalian central synapses, our findings suggest that Ugalt regulates NMJ architecture via mucin-type O-glycosylation and provide insights into the molecular basis of neurological abnormalities in SLC35A2-CDG. Full article

Liver fibrosis (LF) poses significant challenges in diagnosis and treatment. This study aimed to identify effective biomarkers for diagnosis and therapy, as well as to gain deeper insights into the immunological features associated with LF. LF-related datasets were retrieved from the Gene Expression Omnibus (GEO) database. Two datasets were merged to generate a metadata cohort for bioinformatics analysis and machine learning, while another dataset was reserved for external validation. Seventy-eight machine learning algorithms were employed to screen signature genes. The diagnostic performance of these genes was evaluated using receiver operating characteristic (ROC) curves, and their expression levels were validated via qRT-PCR experiments. The R language was utilized to delineate the immune landscape. Finally, correlation analysis was conducted to investigate the relationship between the signature genes and immune infiltration. Through the intersection of GEO datasets and Weighted Gene Co-expression Network Analysis (WGCNA), 42 genes were identified. Machine learning methods further narrowed down 13 signature genes (alpha-2-macroglobulin (A2M), ankyrin-3 (ANK3), complement component 7 (C7), cadherin 6 (CDH6), cysteine-rich motor neuron protein 1 (CRIM1), dihydropyrimidinase-like 3 (DPYSL3), F3, gamma-aminobutyric acid (GABA) receptor subunit epsilon (GABRE), membrane metalloendopeptidase (MME), solute carrier family 38 member 1 (SLC38A1), tropomyosin alpha-1 chain (TPM1), von Willebrand factor (VWF), and zinc finger protein 83 (ZNF83)), and qRT-PCR confirmed these genes’ expression patterns. Furthermore, these signature genes demonstrated strong correlations with multiple immune cell populations. In conclusion, the 13 genes (A2M, ANK3, C7, CDH6, CRIM1, DPYSL3, F3, GABRE, MME, SLC38A1, TPM1, VWF, and ZNF83) represent robust potential biomarkers for the diagnosis and treatment of LF. Among these genes, we first identified Gabre as related to LF and expressed in hepatocytes and cholangiocytes. The immune response mediated by these signature biomarkers plays a pivotal role in the pathogenesis and progression of LF through dynamic interactions between the biomarkers and immune-infiltrating cells. Full article

Background: Breast cancer (BC) is the most common cancer and the leading cause of cancer death in women. Hereditary BC risk accounts for 25% of all cases. Pathological variants in known BC precursor genes explain only about 30% of hereditary BC cases, while the underlying genetic factors in most families remain unknown. Identifying hereditary cancer risk factors will help improve genetic counseling, cancer prevention, and cancer care. Methods: Here, we used whole-exome sequencing (WES) to identify genetic variants in 105 Vietnamese patients with BC and 50 healthy women. BC-associated variants were screened by the Franklin software and the criteria of the American College of Medical Genetics and Genomics (ACMG) and evaluated based on in silico analysis. Results: In total, 56 variants were identified in 37 genes associated with BC, including ACVR1B, APC, AR, ARFGEF1, ATM, ATR, BARD1, BLM, BRCA1, BRCA2, CASP8, CASR, CHD8, CTNNB1, ESR1, FAN1, FGFR2, HMMR, KLLN, LZTR1, MCPH1, MLH1, MSH2, MSH3, MSH6, NF1, PMS2, PRKN, RAD54L, RB1CC1, RECQL, SLC22A18, SLX4, SPTBN1, TP53, WRN, and XRCC3 in 41 patients. Among them, 12 variants were novel, and 10 variants were assessed as pathogenic/likely pathogenic by ACMG and ClinVar. Variants of uncertain significance (VUS) were evaluated using in silico prediction software to predict whether they are likely to cause the disease in patients. Conclusions: This is the first WES study to identify BC-associated genetic variants in Vietnamese patients, providing a comprehensive database of BC susceptibility gene variants. We suggest using WES as a tool to identify genetic variants in BC patients for risk prediction and treatment guidance. Full article

Wenchang Chickens (WCCs) and Recessive White Feather Chickens (RWFCs) are two important broiler breeds in China, although their susceptibility to E. tenella has not been compared. This study explores these differences in susceptibility. The results showed that WCCs exhibited lower susceptibility, as evidenced by no mortality and significantly reduced oocyst production compared to RWFCs. Additionally, WCCs had higher levels of CD3⁺CD4⁺ T lymphocytes and lower levels of CD3⁺CD8α⁺ T lymphocytes, both before and after infection, compared to RWFCs. Notably, serum IgA and IgG antibody levels in WCCs were significantly higher than those in RWFCs. RNA−seq analysis at 2, 4, and 7 days post-infection (dpi) revealed a consistent upward trend in gene expression in WCCs, while RWFCs exhibited a fluctuating pattern. Functional analysis indicated that the stable immune response, as annotated by the differentially expressed genes (DEGs) in WCCs, along with distinct metabolic alterations, may contribute to their enhanced resistance. Several hub genes, including SLC7A11, CCL19, CD4, HSPA5, and HSP90AA1, were identified within gene interaction networks specific to each breed. These findings provide valuable insights into the molecular mechanisms underlying the differential susceptibility of WCCs and RWFCs, offering potential targets for new coccidiosis control strategies. Full article

Background/Objectives: The location and distribution of excess fat, rather than overall adiposity, are stronger predictors of cardiometabolic risk and are commonly assessed using the waist-to-hip ratio (WHR). Fat distribution in women has a heritable component, yet the genetic factors that influence it remain poorly understood. We aim to assess the association between obesity-related polymorphisms with WHR and cardiometabolic risk in overweight and obese women. Methods: A cohort study was conducted in 512 women (56.1 ± 6.4 years; body mass index (BMI) ≥ 25 kg/m²). WHR was calculated, and participants were classified into android (WHR > 0.85) or gynoid (WHR ≤ 0.85) obesity groups. We genotyped 15 SNPs previously associated with obesity using TaqMan real-time PCR. Different genetic models (dominant, recessive, and allelic) were analysed, and bivariate and multivariate analyses were performed to compare the fat distribution groups. Results: Of the 15 SNPs studied, only 3 presented a significant association with WHR > 0.85. PSRC1 rs599839 in a dominant model (AA + GA vs. GG) with OR = 3.18 (p = 0.041), SLC30A8 rs1326634 in a recessive model (CC vs. TC + TT) (OR = 2.38; p = 0.004), both showing increased susceptibility to central obesity. KIF6 rs20455 offers protection in a recessive model (CC vs. TC + TT) with an OR of 0.47 (p = 0.043). After adjusted multivariate analysis, only SLC30A8 and diabetes remained independently associated with an increased risk of android obesity (OR = 2.50; p = 0.003 and OR = 3.63; p = 0.004, respectively). Conclusions: The SLC30A8 variant was significantly associated with android fat distribution and high cardiometabolic risk in overweight/obese women. Identifying genetic factors that influence fat distribution may help specify targeted lifestyle changes or pharmacological interventions to reduce risk. Full article

Solute carrier family 12 (SLC12) encodes electroneutral cation-coupled chloride cotransporters responsible for transmembrane ion transport (Na⁺, K⁺, and Cl⁻), which play a critical role in aquatic osmoregulation. However, the SLC12 gene of Exopalaemon carinicauda (EcSLC12) has not been systematically identified or functionally characterized. In this study, six EcSLC12 genes were identified across the genome and classified into N(K)CC, KCC, CCC9, and CIP subfamilies. Three NKCC1 homologous genes (EcSLC12A2.1, EcSLC12A2.2, and EcSLC12A2.3) were reported for the first time in crustaceans. The EcSLC12 family exhibited distinct expression patterns in response to low-salinity, high-alkalinity, and saline–alkaline stress. EcSLC12A2.2 was highly expressed in the gill, and its expression was closely correlated with saline–alkaline acclimation. Additionally, EcSLC12A2.2 knockdown decreased E. carinicauda survival under saline–alkaline stress. Thus, EcSLC12A2.2 plays critical roles in osmotic regulation and saline–alkaline acclimation. This study provides crucial insights into E. carinicauda’s saline–alkaline tolerance mechanisms, and the discovery of multiple NKCC1 homologs fills a gap in the crustacean SLC12 gene family research. Full article