Search Results (3,468)

Health, social, and ethical considerations highlight the need for new male contraceptives. Pimozide is an FDA approved drug known to block T-type calcium channels and which shares structural similarities with mibefradil, a proven antagonist of the CatSper channel. In this study, we examined the effect of pimozide on CatSper, a key target for non-hormonal male contraception. Molecular docking and molecular dynamics simulations were carried out to assess how pimozide binds within the channel pore, and binding energies were estimated using MM-GBSA. To determine its impact on sperm function, we evaluated hyperactivation, the acrosome reaction, and CatSper activity. Our computational analyses indicate that pimozide functions as a pore blocker of the CatSper channel. Experimental findings further support this, showing that pimozide inhibits CatSper activity, and impairs hyperactivation and the acrosome reaction in human spermatozoa. Overall, these results identify pimozide as a novel CatSper antagonist and propose a binding mode, offering a basis for the rational design of reversible, non-hormonal male contraceptives that target the CatSper channel. Full article

Type 1 Diabetes (T1D) is a complex autoimmune disorder characterized by immune-mediated destruction of pancreatic β cells, driven by genetic susceptibility and modulated by environmental factors, notably the gut microbiome. Dysbiosis, manifested as reduced microbial diversity, perturbations in the Firmicutes/Bacteroidetes ratio, and compromised short-chain fatty acid production, contributes to T1D pathogenesis through mechanisms involving immune system dysregulation and heightened intestinal permeability. Emerging evidence indicates a relationship between the gut and oral microbiomes, as well as the potential influence of the virome and mycobiome. This narrative review synthesizes the current literature on the intricate interplay between the gut microbial ecosystem, the host immune response, and the development of T1D, highlighting the potential for targeted microbiome-based interventions to ameliorate disease progression. A more nuanced understanding of these multi-kingdom interactions is essential for developing precise therapeutic strategies to prevent or delay T1D onset and to improve patient outcomes through restoration of immune tolerance and gut homeostasis. Full article

Type 2 diabetes mellitus (T2DM) is a major global health burden characterized by insulin resistance, progressive pancreatic β-cell dysfunction, and chronic metabolic dysregulation. Marine seaweeds have emerged as a valuable source of bioactive natural products, particularly polyphenols and polysaccharides, with promising potential for diabetes management. This review focuses on three major contributions: first, the structural diversity of seaweed-derived polyphenols and polysaccharides; second, their multi-target mechanisms of glucose regulation; and third, the structure–activity relationships governing their bioactivities. Current evidence shows that these compounds may help manage type 2 diabetes in several ways, including inhibition of α-amylase and α-glucosidase, attenuation of oxidative stress and chronic inflammation, enhancement of insulin secretion and insulin sensitivity, regulation of lipid metabolism, and modulation of gut microbiota. Key structural determinants such as degree of polymerization, hydroxyl group density, sulfation level, molecular weight, and chemical modifications are discussed in relation to their functional properties. By linking chemical structure with biological function, these findings highlight marine seaweeds as a rich reservoir of multi-target therapeutic candidates for T2DM management and provide a scientific basis for their development as functional food ingredients or lead compounds for novel diabetes management drugs. Full article

Carbonyl stress, chronic inflammation, and progressive tissue injury accompany type 2 diabetes mellitus (T2DM) and obesity. Yet, the molecular systems that connect these processes with cardiac, vascular and neuronal complications are incompletely defined. This review examines the AGE–RAGE–DIAPH1 axis as a mechanistic link between metabolic dysfunction and diabetic myocardial and neuronal injury, with emphasis on vascular and myocardial remodeling and emerging implications for autonomic neuronal vulnerability. We summarize current evidence on the formation and accumulation of advanced glycation end-products and other RAGE ligands in metabolic disease, DIAPH1’s structural and signaling role as an intracellular effector of RAGE, and the cellular consequences of pathway activation in vascular, neural, and cardiac tissues. Across experimental models, this signaling axis promotes oxidative stress and inflammatory activation, leading to endothelial dysfunction and barrier failure. Subsequent fibrotic remodeling provides a biologically plausible route through which metabolic stress may be translated into persistent organ injury. In the heart, these mechanisms are linked to coronary microvascular dysfunction, altered cardiomyocyte phenotype, calcium handling abnormalities, and myocardial fibrosis. In the autonomic nervous system, limited but emerging data connect RAGE activation to oxidative injury and mitochondrial dysfunction, abnormal neuronal excitability, and structural vulnerability. Direct evidence linking DIAPH1 to autonomic neurons is lacking. We also review biomarker candidates related to this pathway, including circulating AGEs and soluble RAGE isoforms, skin AGE measurements, imaging markers of myocardial remodeling, and autonomic functional measures. Finally, we discuss pharmacological and natural compounds that target AGE formation, ligand accumulation, RAGE signaling, or intracellular protein interactions linked to this axis. Overall, the available evidence supports the AGE–RAGE–DIAPH1 axis as a credible mechanistic concept and a potentially informative translational hypothesis in T2DM. However, the AGE–RAGE component is supported more strongly than DIAPH1-specific involvement in human diabetic myocardial disorder or cardiovascular autonomic neuropathy. The value of DIAPH1 as a biomarker or therapeutic target in these neurocardiac complications remains to be established. Full article

Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM) are major global health burdens that share interconnected pathological mechanisms involving impaired insulin signaling, metabolic stress, and chronic neuroinflammation. This study applied an integrative systems biology and atomistic simulation framework to investigate bioactive compounds from Caesalpinia sappan L. targeting shared molecular regulators linking AD and T2DM. Network topology analysis identified four central hub genes, STAT3, SRC, HSP90AA1, and TP53, representing key regulatory nodes involved in inflammatory signaling, kinase regulation, proteostasis, and cellular stress responses. Compound-specific interaction analysis revealed distinct target preferences among phytochemical subclasses. Protosappanin B showed strong binding toward both STAT3 and HSP90α, whereas flavonols including quercetin and rhamnetin exhibited high affinity for SRC, and the chalcone derivative sappanchalcone preferentially interacted with TP53. Atomistic molecular dynamics simulations and MM-PBSA calculations supported stable protein ligand interactions and favorable binding energetics, while density functional theory analysis indicated electronic properties consistent with sustained intermolecular interactions. Collectively, these findings suggest that structurally distinct subclasses of C. sappan phytochemicals converge on complementary regulatory hubs within the shared AD and T2DM molecular network, supporting coordinated multi-target modulation of interconnected inflammatory, kinase signaling, proteostasis, and cellular stress pathways underlying AD–T2DM comorbidity. Full article

Background/Objectives: MicroRNAs are key post-transcriptional regulators involved in various diseases. Despite its status as the gold standard, real-time RT-PCR faces challenges arising from high sequence homology among closely related microRNAs and the substantial biomaterial required to enrich small RNA fractions. This study aimed to develop an optimized protocol for simultaneous analysis of microRNA and mRNA expression from a single total RNA sample using mouse (Mus musculus) brain tissue, avoiding dependence on pre-designed commercial assay panels. Methods: We optimized a real-time RT-PCR workflow enabling simultaneous analysis of mature microRNAs and mRNAs from a single total RNA sample. Modifications include a redesigned universal reverse primer, LNA-modified TaqMan probes, and omission of the 65 °C denaturation step during reverse transcription. The method was validated for five microRNAs in mouse brain tissue. Results: The assay showed high specificity, discriminating closely related miR-125a-5p and miR-125b-5p with a ΔCt difference of 6.7 ± 1.2 cycles. Co-analysis with Oligo(dT)₁₈ and Random hexamer primers did not interfere with microRNA detection. Conclusions: The developed approach enables reliable detection of closely related microRNAs and parallel analysis of different RNA types, which is particularly important for studying regulatory networks when working with limited amounts of biomaterial. This protocol provides a complementary, accessible option for targeted studies in resource-limited settings or for non-cataloged miRNA targets. Full article

Background: Dysregulated G protein-coupled receptor (GPCR) signaling is increasingly implicated as an important driver for oncogenesis. Uveal melanoma (UM) represents a highly metastatic intraocular malignancy primarily driven by activating mutations in G protein family members Gαq/11. Although Tebentafusp, the first FDA-approved bi-specific T-cell engager for UM, improves survival, its activity is restricted to specific human leukocyte antigen (HLA) alleles, highlighting the need to identify broadly expressed targetable proteins for immunotherapeutic strategies. Here we aimed to define surfaceome and phospho-signaling signatures associated with oncogenic Gαq-signaling. Methods: Heterologous and UM in vitro systems were used to interrogate Gαq-driven changes. HEK293T cells were transfected with wild-type Gαq or the oncogenic Gαq (R183Q) mutant, with surface marker profiles quantified by flow cytometry. Complementary immunophenotyping was performed in the Gαq-mutant UM cell line MP46 and Gα11-mutant line MP41. Kinase phosphorylation was assessed in control and Gαq mutant conditions followed by effect size estimation (Hedges’ g), Welch’s t-test, principal component analysis, and Spearman correlation-based network analysis of surface and phosphoprotein readouts. Results: Hyperactive Gαq in HEK293T cells induced graded remodeling of surface protein profiles, including reduced CD56 (NCAM) and CD49c (ITGA3) expression. Similarly, in UM models, MP46 versus MP41 had limited expression of CD56 and CD49c. Moreover, phospho kinase profiling and network analysis identified altered surface-phosphoprotein relationships, including a CD56-p70 S6 kinase association. Conclusions: These data provide new insights into Gαq-driven modulators of UM phenotype of relevance for studies of tumor–microenvironment interaction and metastasis. Full article

Background/Objectives: Nocturnal glycemic variability in pediatric type 1 diabetes (T1D) disrupts caregiver sleep and quality of life; advanced hybrid closed-loop (AHCL) systems may be associated with reduced caregiver burden by providing more stable overnight glucose control. We aimed to evaluate changes in caregiver-reported sleep quality and continuous glucose monitoring (CGM) targets three months after transition to an AHCL system. Methods: We conducted a prospective single-center real-world study in a tertiary pediatric diabetes unit that included children aged 6–17 years with T1D who switched from continuous subcutaneous insulin infusion (MiniMed) and intermittently scanned CGM (FreeStyle Libre 2) to an AHCL system (MiniMed 780G) with Guardian 4 sensor. Caregivers completed the Pittsburgh Sleep Quality Index (PSQI) at baseline and after 3 months; CGM metrics (TIR 70–180 mg/dL, TAR1 180–250 mg/dL, TAR2 > 250 mg/dL, TBR1 54–70 mg/dL, TBR2 < 54 mg/dL) were extracted at the same time points. Analyses used Shapiro–Wilk, Wilcoxon signed-rank, Spearman correlations, and McNemar tests (α = 0.05). Results: Twenty-two caregivers completed baseline PSQI; 16 provided PSQI data at three months. The proportion with PSQI > 5 decreased from 56.3% to 18.8% (p = 0.034), and 81.3% showed lower global PSQI at 3 months (p = 0.018). The largest mean improvements were observed in daytime dysfunction (−0.94), subjective sleep quality (−0.81), and sleep duration (−0.63), with slight increases in sleep disturbance (+0.13) and sleep-medication use (+0.13). The proportion of participants meeting international CGM consensus targets improved: the percentage achieving TIR > 70% increased from 26.7% to 80.0% (p = 0.008); those meeting TAR > 180 mg/dL < 30% increased from 26.7% to 80.0% (p = 0.008); and those meeting TAR2 > 250 mg/dL < 5% increased from 20.0% to 53.3% (p = 0.008). Hypoglycemia-related targets showed no significant change, and no episodes of symptomatic or level 3 hypoglycemia were reported. Exploratory analyses suggested that poorer PSQI at 3 months was associated with greater Δ TBR1, and increases in TAR2 with higher sleep disturbance and sleep-medication use. Conclusions: Transition to an AHCL system was associated with improvements in caregiver-reported sleep and attainment of CGM consensus targets within three months. Residual nocturnal hyperglycemia was associated with features of ongoing sleep disturbance, highlighting the potential relevance of individualized alert settings, sleep-focused education, and inclusion of objective sleep measures in future studies. Full article

Sensitive skin is characterized by hypersensitivity to normal stimuli, and objective diagnostic tools and treatments are still limited. Currently, cosmetics for sensitive skin are developed through the exclusion of known irritants rather than investigation into the underlying mechanisms of sensitivity. In this study, we developed an integrated pipeline combining transcriptome analysis via microneedle-based skin sampling (MISSM), bioinformatics, in vitro validation, and clinical assessment to identify sensitive skin-associated inflammatory biomarkers and cosmetic ingredients that regulate them. Candidate biomarkers and matched cosmetic ingredients were identified from transcriptomic data and validated in lactic acid-stimulated HaCaT and human dermal fibroblasts via qRT-PCR. A prototype emulsion was developed and evaluated in a 4-week open-label pilot clinical trial with longitudinal molecular monitoring via MISSM. After lactic acid stimulation, sensitive skin-associated biomarkers (MCOLN1, CYR61, PMAIP1, PTGS2, and HMGB2) were significantly upregulated in both cell types, and cosmetic ingredients that regulate these biomarkers were confirmed in vitro. The emulsion prototype demonstrated hypoallergenicity in a primary irritation test. In the pilot clinical trial, target biomarker expression was significantly reduced in MISSM-derived samples, with improvements in skin hydration, barrier function, redness, and sensory reactivity also observed. This integrated pipeline will enable the discovery of inflammatory biomarker-regulating cosmetic ingredients, with potential applicability to various inflammatory skin conditions. Full article

Background and Objectives: Among CNS malignancies arising in infancy, ATRT stands out as the most frequently diagnosed in children younger than six months. Disruption of the SMARCB1 gene underlies the overwhelming majority of cases. Progress toward effective treatment has been hampered by two persistent challenges. Current mouse models, while informative, fall short of reproducing the full clinical and biological picture of human ATRT, and their ability to predict therapeutic outcomes in patients remains uncertain. Compounding this, the rarity of the disease makes it difficult to assemble patient cohorts of sufficient size for meaningful clinical trials. At the molecular level, germline loss of SMARCB1 exons 4 and 5 has emerged as a particularly penetrant predisposing event, with affected individuals presenting at an earlier age than those harboring other mutation types. The porcine SMARCB1 gene offers a compelling basis for translational modeling as its protein product is identical to the human ortholog at every amino acid position across isoforms, a degree of conservation that exceeds what is seen in the mouse. Methods: Thus, we hypothesized that germline deletion of exons 4 and 5 would predispose heterozygote swine to ATRT development. In this manuscript, we describe the creation of an ATRT porcine model through a CRISPR/Cas9 mediated gene-editing approach. Results: 15 piglets were produced, two of which had confirmed SMARCB1 targeted excisions. However, none developed tumors. To induce further tumorigenicity, one pig with confirmed exons 4 and 5 excision was crossed with a pig with TP53 exon 2 truncation. In total, 11 piglets were born, of which one contained the original excision without a TP53 mutation. This piglet developed a spinal mass at the T1 level. Conclusion: To our knowledge, this is the first ATRT porcine model ever developed and provides proof-of-concept feasibility for large animal modeling of SMARCB1-deficient rhabdoid tumors. These findings support the continued development of porcine RTPS-1 models toward preclinical application. Full article

Parents of children and adolescents with type 1 diabetes (T1D) are responsible for intensive daily disease management and often experience high levels of emotional distress. This study examined whether fear of hypoglycemia mediates the association between parents’ emotion regulation strategies and diabetes-related distress. Participants were recruited through Facebook and WhatsApp groups for parents of children and adolescents with T1D, and data was collected via self-report online questionnaires. A total of 102 parents, 92.2% mothers (aged 32–58 years) of children with T1D aged 8–17 years, completed measures of fear of hypoglycemia (Hypoglycemia Fear Survey—Parent Version), diabetes distress (Problem Areas in Diabetes-Parent Revised) and emotion regulation strategies (Emotion Regulation Questionnaire), along with a sociodemographic questionnaire. Four mediation models were tested using PROCESS, including cognitive reappraisal and expressive suppression as predictors and the worry and behavior subscales of fear of hypoglycemia as mediators. Results revealed a significant indirect effect of worry on the relationship between cognitive reappraisal and diabetes distress (indirect effect = −0.15, 95% CI [−0.35, −0.02]), highlighting worry as a potential mediator between these variables, while the direct effect was negative but non-significant. No significant indirect effects were found for expressive suppression on the behavior subscale (indirect effect = 0.12; 95% IC [−0.07; 0.36]) or on the worry subscale (indirect effect = 0.07; 95% IC [−0.08; 0.24]). These findings suggest that cognitive reappraisal may be associated with lower diabetes-related distress through lower levels of excessive worry about hypoglycemia. Clinically, the results highlight fear-related cognition can be a relevant intervention target, alongside emotion regulation skills, in psychosocial support programs for parents of youth with T1D. Full article

Obesity and type 2 diabetes mellitus (T2DM) represent intertwined global epidemics driven by gut dysbiosis, chronic inflammation, and impaired SCFA production, identifying the microbiome as a therapeutic target. This review synthesizes mechanistic insights and clinical evidence on the role of probiotics as microbiome modulators in the management of metabolic disease. A comprehensive literature search across PubMed, Scopus, Web of Science, and Google Scholar up to May 2026 identified ~230 records using keywords such as probiotics, SCFAs, obesity, and T2DM; a narrative synthesis integrated preclinical, RCT, and meta-analytic data without formal pooling due to heterogeneity. Probiotics restore eubiosis via strain-specific mechanisms, Lacticaseibacillus rhamnosus GG enhances tight junctions (ZO-1), Bifidobacterium breve BBr60 boosts butyrate cross-feeding, and pasteurized Akkermansia muciniphila remodels bile acids (FXR/FGF19), activating G-Protein Coupled Receptor 41 (GPR41)/43-GLP-1 signaling, Treg expansion, and NF-κB suppression. Beyond immunometabolic effects, probiotics mitigate obesity- and T2DM-related oxidative stress by upregulating endogenous antioxidant enzymes (e.g., SOD, catalase, GPx), modulating Nrf2/Keap1 signaling, and reducing lipid peroxidation and other oxidative stress markers in experimental and clinical settings. Meta-analyses of RCTs reveal modest benefits: BMI reductions (~0.3 kg m⁻²), waist circumference (WC) reductions (1–2 cm), HbA1c reductions (0.3–0.4%), and improvements in homeostatic model assessment of insulin resistance (HOMA-IR), especially with multi-strain (>10⁹ CFU day⁻¹, ≥12 weeks) synbiotics. Innovative strategies—synbiotics, postbiotics, AI-tailored consortia, and fermented dairy—address engraftment and response variability. Current guidelines recommend 10⁹–10¹¹ CFU day⁻¹ using multi-strain formulations for 12–24 weeks alongside lifestyle measures, with regimen selection tailored to the dysbiosis phenotype (e.g., NAFLD). Future longitudinal RCTs integrating multi-omics endpoints with AI-driven strain selection should refine—and ultimately individualize—precision probiotic strategies for metabolic therapy. Full article

Translation and post-editing both integrate reading into bilingual text production, yet it remains unclear which computational predictors from multilingual pre-trained models best account for translators’ reading patterns across task types and translation directions. We recruited twenty-six Chinese L1 translators who completed en→zh and zh→en translation and post-editing tasks, yielding 104 eye-tracking sessions. Dependent measures were source reading time (TrtS), target reading time (TrtT), and target production duration (Dur). Predictors were derived from two model architectures, a decoder-only language model (LM) and an encoder–decoder neural machine translation (NMT) model, and they included monolingual surprisal, translation surprisal with source context, and attention features computed from models’ internal weights. Analyses showed that LM surprisal provided the strongest account of target reading, while source reading was most strongly predicted by encoder self-attention with LM surprisal, a robust secondary predictor, and target production duration drew on both LM and NMT translation surprisal. Direction effects were broader than task effects, especially on target measures. These findings suggest that although translation reading is bilingual in task structure, cumulative reading time is best explained by monolingual LM surprisal, whereas production duration additionally reflects NMT translation surprisal and revision behavior. Full article

To tackle the issues of high energy consumption, substantial carbon emission intensity in the cement industry, as well as under-utilization of agricultural waste, this study took an 8000 t/d cement production line at a plant in Indonesia as the research object. Using a Computational Fluid Dynamics (CFD)-based numerical method, the co-firing of pulverized coal with rice husk was simulated in both In-Line Calciner (ILC) and Separate-Line Calciner (SLC) precalciners. Four rice husk replacement levels (10%, 20%, 30%, and 40%) were evaluated in terms of temperature distribution, species concentration, raw meal calcination, and pollutant formation. The results indicate that increasing the rice husk ratio reduces the high-temperature region, lowers the peak temperature, and decreases overall thermal levels. The decomposition rate of CaCO₃ at the outlet of the ILC-type precalciner decreased from 81.11% to 75.32%, while that of the SLC-type precalciner fell from 93.27% to 88.50%. CO₂ and NO_X emissions were remarkably reduced, with the emission reduction effect positively correlated with the rice husk substitution ratio. Taking into account both decomposition rate requirements and emission reduction targets, it is recommended that the blending ratio of rice husk in ILC precalciners should be controlled at 10%, while for SLC precalciners, it can be increased to 40%. This provides a technical reference for low-carbon transformation and biomass resource utilization in the cement industry. Full article

The prioritization of biomarkers that inform molecular-targeted cancer research remains challenging because tumor vulnerabilities are context-dependent. The ubiquitin–proteasome system is essential for cancer cell survival; however, the functional and biomarker-level relevance of individual proteasome subunits has not been systematically defined across cancer types. In this study, we performed an integrative pan-cancer analysis to prioritize proteasome subunits that function as context-dependent vulnerability biomarkers. We analyzed proteasome subunits and proteasome-associated genes across 54 cancer types by integrating large-scale CRISPR (n = 1178 cell lines) and RNAi (n = 707 cell lines) dependency datasets with transcriptomic, survival, immune infiltration, and co-essentiality network analyses. PSMB5 and PSMB6 were prioritized as robust cross-platform and cross-lineage dependency biomarkers, exhibiting reproducible and selective vulnerability patterns across diverse malignancies. Their dependency strength was quantitatively associated with immune-related signaling pathways, including MHC and interferon responses, and inversely correlated with key immune regulatory genes such as NLRC5 and IRF1. Co-essentiality network analysis revealed modular functional organization of proteasome-associated genes, supporting context-dependent roles rather than uniform essentiality. Importantly, the association between proteasome subunits and tumor immune context was externally validated through meta-analysis across 24 independent hepatocellular carcinoma cohorts, demonstrating reproducible correlations with CD4-positive T cell, CD8 T cell, and macrophage infiltration signatures. Functional validation further confirmed that siRNA-mediated knockdown of PSMB5 and PSMB6 significantly impaired proliferation across multiple hepatocellular carcinoma cell lines. Collectively, this study prioritizes PSMB5 and PSMB6 as consistently associated functional biomarkers that integrate genetic dependency and immune context, providing a data-driven framework for stratifying proteasome-targeted therapeutic strategies across cancers. Full article