Search Results (164,558)

Biochemical recurrence (BCR) after radical prostatectomy (RP) remains a major clinical challenge. Although metabolic reprogramming drives prostate cancer (PCa) progression, its predictive value for BCR and its interplay with the tumor immune microenvironment (TIME) remain incompletely understood. By integrating weighted gene co-expression network analysis (WGCNA) with machine learning, we identified four metabolic-related hub genes (GDPD1, PLA2G7, PTGDS, and SRD5A2) and developed an XGBoost-Cox model that accurately stratified BCR risk (training 5-year AUC: 0.858; validation 5-year AUC: 0.745). SHAP analysis enhanced the model’s interpretability, while immunohistochemistry (IHC) validated differential protein expression of these targets across 32 clinical specimens. Furthermore, immune profiling demonstrated that these genes are closely linked to M2 macrophage-mediated immunosuppression and altered T-cell infiltration. To translate these biomarkers into therapeutic targets, we employed in silico screening, molecular docking, and molecular dynamics simulations, identifying (-)-epigallocatechin gallate (EGCG) as a promising multi-target candidate. Subsequent in vitro assays confirmed that EGCG binds stably to GDPD1, PTGDS, and SRD5A2, effectively suppressing malignant PCa phenotypes and prostate-specific antigen (PSA) secretion. In summary, we established a robust and interpretable model for predicting BCR after RP, and our in vitro validation suggests that EGCG holds promise as a therapeutic agent to delay PCa progression. Full article

Matrix metalloproteinases (MMPs) are zinc-dependent proteolytic enzymes involved in extracellular matrix remodelling in oral and dental tissues, including the periodontal ligament, alveolar bone, dentin, dental pulp, and periapical tissues. This narrative review summarises selected evidence on the role of MMPs and tissue inhibitors of metalloproteinases (TIMPs) in orthodontic tooth movement, dental trauma and root resorption, restorative adhesive dentistry, and pulp/periapical disease. Particular attention is given to signalling pathways that regulate MMP/TIMP activity, including nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK), Wnt/β-catenin, and transforming growth factor beta (TGF-β)/Smad-related mechanisms. The review also discusses the biomarker potential and translational status of MMP-targeted strategies. Across clinical contexts, MMP activity contributes to both matrix degradation and tissue repair, and its biological effect depends on local stimuli, TIMP-mediated regulation, pathway crosstalk, and the stage of disease or treatment. Full article

Rising ambient temperatures and the increasing frequency of training and competition in hot climates have made heat stress a major challenge in football. Under such conditions, players experience greater cardiovascular and thermoregulatory strain, faster glycogen use, higher perceived exertion, and progressive impairment in repeated high-intensity actions and decision-making. These responses have intensified interest in nutritional strategies that might complement heat acclimation, hydration/electrolyte planning, cooling practices, and recovery management. This narrative review critically synthesizes current evidence on nutritional interventions that may be relevant to football performed in the heat, with emphasis on hydration and electrolyte replacement, carbohydrate–protein strategies, taurine, branched-chain amino acids (BCAAs), creatine, menthol, antioxidant- and nitrate-related approaches, and selected multi-ingredient products. Across the available literature, hydration/electrolyte planning and carbohydrate–protein feeding remain the practical foundation, menthol appears most consistently useful for perceptual cooling, creatine seems safe and potentially helpful for repeated-sprint support, and taurine is promising but still supported by relatively few trials. By contrast, evidence for BCAAs, antioxidants, nitrates, and caffeine as stand-alone heat strategies, as well as for many compound supplements, remains inconsistent, context-specific, or too indirect for strong football-specific endorsement. Overall, the evidence base remains heterogeneous in study quality, protocol design, exercise mode, and sport specificity. A substantial proportion of the available data is derived from cycling, endurance, or laboratory heat-exercise models rather than football-specific trials. Accordingly, any practical recommendation should be interpreted cautiously and embedded within broader heat-management strategies. Future work should prioritize ecologically valid randomized controlled trials in football or football-like intermittent protocols, with transparent reporting of dose, timing, perceptual outcomes, and match-relevant performance measures. Full article

Highly virulent African swine fever virus (ASFV) genotype II strains have been responsible for the global epidemic in domestic pigs and are typically characterized by a hemadsorption (HAD)-positive phenotype mediated by the CD2v protein encoded by the EP402R gene. Here, we report the detection and genetic characterization of three non-HAD genotype II ASFV isolates (VNUA/ASFV/VP2023-isolate1, VNUA/ASFV/TB2024-isolate2, and VNUA/ASFV/HY2024-isolate3) recovered from whole-blood samples collected from pigs exhibiting prolonged clinical signs in northern Vietnam. Whole-genome analysis revealed nonsense mutations in the EP402R gene (G57A in isolates VNUA/ASFV/TB2024-isolate2 and VNUA/ASFV/HY2024-isolate3, and G132A in VNUA/ASFV/VP2023-isolate1), resulting in premature stop codons and a HAD-negative phenotype. Furthermore, additional genetic alterations, including deletions and frameshift mutations, were identified within multigene families (MGF110, MGF360, and MGF505), which are known to play critical roles in virulence, host range, and immune evasion. Notably, VNUA/ASFV/VP2023-isolate1 harbored a partial deletion of the I177L gene along with the insertion of an mCherry marker gene, suggesting possible evolution of the modified live ASFV-G-ΔI177L vaccine strain under field conditions. Collectively, these findings underscore the ongoing evolution and genomic plasticity of ASFV strains circulating in Vietnam. Full article

Background/Objectives: Spinal muscular atrophy (SMA) is a rare genetic disorder caused by mutations or deletions in SMN1, resulting in the loss of SMN protein and severe neuromuscular consequences. Nusinersen, an antisense oligonucleotide that promotes full-length SMN2 transcript formation, has significantly improved SMA outcomes. However, standardized in vitro procedures for evaluating nusinersen efficacy remain limited. This study aimed to optimize in vitro efficacy assessment of nusinersen across two human cellular models. Methods: Experiments were performed using HEK293 cells and the SMA patient-derived fibroblast line GM03813. Transfection conditions were optimized for each model. In HEK293 cells, several seeding densities were evaluated for nucleofection, while in GM03813 fibroblasts, multiple transfection reagents and protocols were tested. Nusinersen activity was quantified at the transcript and protein levels, and dose–response curves were generated to determine EC₅₀ values. Results: In HEK293 cells, a higher seeding density (1 × 10⁶ cells) yielded the most efficient nucleofection. In GM03813 fibroblasts, Lipofectamine 3000 outperformed the other transfection reagents tested. Nusinersen exhibited dose-dependent effects in both models. The EC₅₀ for transcript induction in HEK293 cells was 293 nM, whereas in GM03813 fibroblasts the EC₅₀ was 10 nM, demonstrating substantial model-dependent differences in response. Conclusions: This study establishes optimized conditions for in vitro efficacy assessment of nusinersen in HEK293 and GM03813 cellular models. These protocols provide a robust and reproducible framework for evaluating nusinersen and can be readily applied to other antisense oligonucleotides designed to correct SMN2 splicing. Full article

Neuroinflammation is increasingly implicated in depression pathogenesis, yet the underlying mechanisms are still unclear. This study explores whether PSMB4/MHC-I signaling in the cerebrospinal fluid (CSF)-contacting nucleus mediates neuroinflammatory depression. A persistent neuroinflammation-associated depression model was established in mice by repeated intracerebroventricular lipopolysaccharide (LPS) administration. Depressive-like behaviors were evaluated using established assays. Neuroinflammatory responses and target protein expression were assessed by immunofluorescence, Western blotting, RT-qPCR, and laser capture microdissection. Neuronal activity was mapped by c-Fos staining and manipulated using chemogenetics, alongside pharmacological and genetic interventions. Repeated LPS administration induced significant depressive-like behaviors and obvious neuroinflammation in the CSF-contacting nucleus. Under these conditions, neuronal activity in this nucleus was selectively enhanced. Crucially, chemogenetic activation of these neurons alleviated depressive phenotypes, whereas their inhibition induced depression. Molecularly, LPS significantly upregulated PSMB4 and MHC-I expression. Pharmacological suppression of upstream neuroinflammation reversed this PSMB4 upregulation, and targeted PSMB4 knockdown reduced MHC-I expression, ultimately ameliorating depressive-like behaviors. These findings identify the CSF-contacting nucleus as a critical node in neuroinflammation-induced depression and reveal a novel PSMB4/MHC-I signaling axis linking central inflammatory responses to behavioral deficits. Full article

Store-operated calcium entry (SOCE), mediated by the endoplasmic reticulum (ER) Ca²⁺ sensors stromal interaction molecule (STIM) proteins and the plasma membrane (PM) Orai channels, is essential for calcium signaling and a wide range of physiological processes. Precise regulation of SOCE is critical for maintaining tissue homeostasis, whereas its dysregulation contributes to diverse pathological conditions, particularly organ fibrosis. In this review, we outline the molecular basis of SOCE and discuss how its dysregulation is implicated in human disease. We further emphasize the pivotal role of SOCE in driving fibrotic progression across major organ systems. Finally, we summarize current therapeutic strategies targeting SOCE and highlight their potential for the treatment of fibrosis. Full article

Background: PPP1CB-related Noonan syndrome-like disorder with loose anagen hair type 2 (NSLH2; OMIM #617506) is a rare RASopathy caused by pathogenic variants in PPP1CB, encoding the catalytic beta subunit of protein phosphatase 1 (PP1C). Since its first description in 2016, only a limited number of patients have been reported, leaving the full phenotypic spectrum and genotype–phenotype correlations largely undefined. Objectives: To systematically review the clinical, molecular, and functional characteristics of NSLH2, we define its phenotypic spectrum, explore genotype–phenotype correlations, and summarize current evidence on therapeutic management. Methods: A systematic literature search was conducted across PubMed/MEDLINE, Embase, Web of Science, and Google Scholar, supplemented by searches of Orphanet, OMIM, and ClinVar, from 2016 to 2026. Studies reporting patients with pathogenic or likely pathogenic variants in PPP1CB were included. Individual patient-level data were extracted and analyzed descriptively. Additionally, we report a novel patient identified at our institution. Results: Thirty patients from 14 publications were included, harboring nine distinct PPP1CB variants. The most frequently identified variant was p.Pro49Arg (n = 17, 56.7%), followed by p.Met182Lys (n = 4, 13.3%) and p.Glu183Ala (n = 3, 10.0%). The majority of variants arose de novo (n = 26, 86.7%). Ectodermal anomalies, predominantly slow-growing and structurally abnormal hair consistent with loose anagen hair, were present in 79.3% of patients. Congenital heart defects were identified in 75.9%, with pulmonary stenosis and atrial septal defect representing the most common lesions. Short stature was documented in 69.2% of cases, and neurodevelopmental delay—encompassing motor and language delay—affected the majority of patients (72.4–84.6%). Brain structural anomalies were detected in 35.7%. Facial dysmorphic features were universal. Macrocephaly was present in 58.6% of cases, intellectual disability was reported in 26.9%, and epilepsy in 6.7%. Three familial cases with inherited p.Met182Lys transmission from an affected mother to three children are described, representing the largest reported familial cluster. Conclusions: NSLH2 is a clinically recognizable RASopathy with a consistent core phenotype comprising loose anagen hair, congenital heart defects, short stature, macrocephaly, and neurodevelopmental delay. The p.Pro49Arg variant accounts for the majority of reported cases and appears associated with a broad phenotypic expression. Larger cohorts and functional studies are needed to fully delineate genotype–phenotype correlations and guide therapeutic strategies. Full article

Pregnancy modulates the function of the thyroid gland to facilitate maternal immune tolerance, and nuclear factor kappa B (NF-κB) subunits, the IκB family, and toll-like receptors (TLRs) and complement signaling pathways may be implicated in maternal thyroid immunoregulation. However, it is unclear whether early pregnancy modulates the expression of NF-κB subunits, the IκB family, TLRs, and complement components in the maternal thyroid. The objective of this study was to analyze the effects of early pregnancy on the expression of genes and proteins of these signaling pathways in the maternal thyroid in ewes. In this study, ovine thyroids (n = 6 for each group) were sampled on day 16 of the estrous cycle (N16) and on days 13, 16, and 25 of pregnancy (P13, P16, and P25) with one conceptus. The ewes had an average weight of 41 kg and a body condition score of 3. The mRNA and protein expression of the NF-κB subunits and IκB family were analyzed by RT-qPCR, western blot, and immunohistochemistry. The results showed that the expression of all NF-κB subunits, the IκB family, and TLRs, as well as C1q, C1r, C2, C4a, C5b, and C9, peaked at P16 among these four stages (p < 0.05). In addition, C1s expression was greater at N16 and P16 than at P13 and P25 (p < 0.05), and C3 expression was stronger at P16 and P25 compared to N16 and P13 (p < 0.05). In conclusion, early pregnancy modulates the expression of NF-κB subunits, the IκB family, TLRs, and complement components in the ovine thyroid at both the mRNA and protein levels, which may be essential for maternal thyroid adaptation to pregnancy and beneficial for the prevention of pregnancy-related thyroid diseases in ewes. Full article

Alveolar echinococcosis is a life-threatening zoonotic parasitic disease caused by infection of Echinococcus multilocularis larvae. To survive within the host’s immune milieu, E. multilocularis has evolved sophisticated immune evasion strategies, including the expression of immunomodulatory proteins that regulate the host immune response. Our previous studies have demonstrated that E. multilocularis calreticulin (EmCRT) possessed strong binding ability to human complement component C1q to inhibit C1q-initiated complement activation and biological functions. To further elucidate the mechanism by which EmCRT mediates C1q inactivation and immune evasion, the precise C1q-binding site on EmCRT was identified and analyzed in this study through expression of overlapping fragments and synthesis of overlapping peptides covering the identified functional fragment. The fragment expression and functional assay narrowed down the C1q-binding site to the EmCRT-S1 fragment located between amino acids 140 and 204 of EmCRT. The precise binding site was further pinpointed to the P5 peptide (EmCRT160–174 aa) by testing the synthetic peptides covering this region. The binding of peptide P5 to C1q markedly suppressed the activation of the C1q-mediated classical complement pathway and C1q-induced neutrophil chemotaxis, production of reactive oxygen species, cathepsin G, and myeloperoxidase. These findings suggest that the C1q-binding P5 peptide of EmCRT may serve as a potential target for the development of vaccines against echinococcosis or therapeutic drugs for complement-associated inflammatory or autoimmune diseases. Full article

This study evaluates volatile extracts (HE1 and HE2) from the lichen Pseudevernia furfuracea as eco-friendly agents to control algal proliferation, specifically targeting the cyanobacterium Microcystis aeruginosa and the green microalga Chlorella sorokiniana. Both extracts exhibited potent anti-microalgal activity against the two species with a minimum inhibitory concentration (MIC) ranging from 375 to 750 µg/mL. Furthermore, both extracts reduced cell density by more than 98% after eight days of treatment. Chlorophyll a and protein levels decreased significantly (>80%) in both species, indicating suppression of pigment synthesis. However, their physiological responses were distinct: M. aeruginosa underwent early acute oxidative stress and severe membrane damage, while C. sorokiniana exhibited delayed oxidative activation and a negative growth rate, suggesting non-lytic metabolic inhibition. An in silico study by molecular docking of the most abundant compounds identified in these volatile extracts, such as terpenoids (abietatriene, δ-cadinene) and a phenolic compound (atraric acid), showed that these compounds interact with vital cellular targets in M. aeruginosa and C. sorokiniana and likely contribute to the effects observed in these two species. Predictive toxicity by applying the ADMET framework confirmed the favorable bioavailability and low acute toxicity of these volatile compounds. Therefore, P. furfuracea volatiles are promising, species-specific, and environmentally safe candidates for mitigating aquatic algal proliferation through targeted oxidative and metabolic interference. Full article

A significant concern with IVF is that many embryos fail to develop despite proper fertilization. This gap indicates that factors outside sperm-oocyte fusion influence developmental competency. The maternal-zygotic transition (MZT) is a crucial developmental phase during which control shifts from maternally inherited transcripts to activation of the embryonic genome. During the early stages following fertilization, the embryo depends only on maternal mRNA and proteins amassed throughout oogenesis. For successful development, these transcripts must be expeditiously removed with the concurrent genome activation. Any disruption, whether due to inadequate maternal mRNA degradation, aberrant translational control, or delayed genome activation, has been associated with premature developmental stoppage and diminished blastocyst formation. Principal regulators, such as BTG4, CPEB1, DAZL, and components of the translational machinery, govern this modification and seem to be affected by the quality of the oocyte and the age of the mother. Increasing evidence suggests that disruption of MZT may account for instances of suboptimal embryo development that conventional assessment techniques cannot elucidate. MZT offers a biological framework for assessing embryo competency beyond simple appearance. If scientists had a deeper understanding of this process, they might identify molecular markers and enhance the selection of embryos in IVF. Full article

Gaucher disease is a prototypical lysosomal sphingolipid storage disorder caused by pathogenic variants in GBA1, resulting in glucocerebrosidase deficiency and accumulation of bioactive lipids, including glucosylceramide and glucosylsphingosine (lyso-Gb1). While non-neuronopathic Gaucher disease is effectively managed with enzyme replacement and substrate reduction therapies, neuronopathic forms remain largely refractory to treatment due to progressive central nervous system (CNS) involvement and limited penetration of current therapies across the blood–brain barrier. Disease pathobiology extends beyond lysosomal substrate accumulation to encompass dysregulated sphingolipid signaling, particularly sphingosine-1-phosphate (S1P)-mediated “inside-out” signaling, alongside neuroinflammation, oxidative stress, and glial activation, which collectively drive neurodegeneration. In this review, we synthesize current knowledge on sphingolipid metabolism and signaling in neuronopathic Gaucher disease and integrate these mechanisms into a three-tier, CNS-focused biomarker framework. The first tier comprises substrate-proximal markers of lysosomal burden (lyso-Gb1), which reflect GCase deficiency and correlate with systemic disease severity but incompletely capture CNS pathology. The second tier comprises markers of glial activation and neuroinflammation (glial fibrillary acidic protein [GFAP], glycoprotein non-metastatic melanoma protein B [GPNMB]), which reflect the downstream neuroimmune response to sphingolipid accumulation. The third tier comprises markers of neuroaxonal injury (neurofilament light chain [NfL]), which index irreversible neuronal damage as the terminal consequence of uncontrolled CNS disease. Together, these tiers map distinct but mechanistically interconnected stages of disease progression, from lysosomal dysfunction through glial activation to neuroaxonal loss, enabling stage-specific interpretation of biomarker signals that single-analyte approaches cannot provide. We further examine how S1P-mediated inside-out signaling links intracellular lipid dysregulation to extracellular neuroimmune and neurovascular responses and how the blood–brain barrier shapes compartment-dependent biomarker behavior across cerebrospinal fluid and blood. By grounding biomarker selection in this mechanistic cascade, the framework provides explicit criteria for pairing analytes across tiers, interpreting discordance between peripheral and CNS compartments, and designing multi-modal endpoints for clinical trials of CNS-penetrant therapies. Despite these advances, significant challenges remain, including limited longitudinal datasets, variability in assay methodologies, and incomplete validation of biomarkers as surrogates of CNS disease progression. Addressing these gaps will require harmonized, multi-modal approaches integrating biochemical, functional, and imaging measures. By positioning neuronopathic Gaucher disease as a model of sphingolipid-driven neurodegeneration, this review highlights opportunities for biomarker-guided therapeutic development relevant to Gaucher disease and the broader spectrum of sphingolipid-associated neurological disorders. Full article

The ubiquitin-26S proteasome system provides a key mechanism for regulating protein turnover in plants and contributes to the control of diverse developmental and stress-related processes. Within this system, Skp1-Cullin1-F-box (SCF) E3 ligases rely on F-box proteins to confer substrate specificity, enabling selective and dynamic regulation of target protein stability. The large size and structural diversity of the F-box protein family in plants suggest extensive functional specialization, although many members remain poorly characterized. Here, we review recent advances in the understanding of F-box protein function, with a focus on their roles in plant development, stress adaptation, and immunity. Specifically, this review integrates findings across development, abiotic stresses, and immunity to highlight shared and diverging regulatory nodes and critically assesses the strength of substrate evidence to distinguish bona fide from putative F-box targets. We highlight how F-box proteins modulate key regulatory pathways, including phytohormone signaling, reproductive development, root architecture, and secondary metabolism, as well as responses to abiotic and biotic stresses. Emerging evidence indicates that F-box-mediated proteolysis acts as an important layer of control linking environmental signals to downstream transcriptional and physiological outputs. A better understanding of F-box protein substrates and regulatory networks is important for dissecting plant adaptive mechanisms and may provide molecular targets for future crop improvement strategies. Full article

Background: Germline variants of the immune checkpoint receptor CTLA4 may modulate T-cell activation, potentially influencing post-transplant immune reconstitution and clinical outcomes. Methods: In this retrospective single-center study, 140 AML patients who underwent ASCT were stratified into three groups according to the CTLA4 rs231775 geno-types A17hom, T17Ahet, and T17hom. Clinical outcomes, including overall survival (OS) and progression-free survival (PFS), were evaluated. Multivariate analysis was performed to adjust for known prognostic covariates. Results: Baseline clinical characteristics varied according to CTLA4 genotype with a higher proportion of favorable cytogenetic risk in A17hom carriers. Comparative analysis revealed differences in survival rates, with superior outcomes in A17hom carriers. In multivariate analysis directional trends persisted across all endpoints. Conclusion: The prognostic impact of CTLA4 rs231775 on post-ASCT outcomes suggests that T-cell inhibitory signaling may contribute to anti-leukemic immune surveillance in the autologous setting. These findings provide a rationale for investigating CTLA4 inhibition as consolidation therapy following ASCT in future prospective studies, particularly in T17hom carriers, who may harbor a less favorable immune profile. CTLA4 genotyping at diagnosis may represent a practical tool to support risk stratification in AML. Full article