Search Results (1,394)

Interleukin-13 receptor α2 (IL-13Rα2) has traditionally been considered a decoy receptor; however, its cellular functions beyond the immune system remain unclear. We aimed to investigate the role of IL-13Rα2 in C2C12 myoblast proliferation and differentiation. IL-13Rα2 expression was knocked down in C2C12 cells using siRNA. Myogenic differentiation was evaluated by myosin heavy chain (MyHC) immunostaining and by quantifying the expression of myogenic regulatory and fusion-related genes. Myoblast proliferation was assessed using BrdU incorporation and cell number analyses, and signaling events induced by IL-13Rα2 knockdown were analyzed via immunoblotting and immunocytochemical analysis. IL-13Rα2 knockdown did not alter myogenic differentiation or the expression of fusion-associated genes. In contrast, IL-13Rα2 knockdown significantly increased BrdU incorporation and cell number, accompanied by increased Akt phosphorylation and decreased ERK phosphorylation. Cyclin D1 and cyclin-dependent kinase 4 (CDK4) levels were also increased. Akt inhibition abolished the enhanced proliferation and normalized Cyclin D1/CDK4 levels, whereas ERK activation did not further modify the knockdown-associated phenotype. These findings demonstrate that IL-13Rα2 negatively regulates myoblast proliferation by modulating the Akt–Cyclin D1–CDK4 signaling pathway, while being dispensable for myogenic differentiation. Full article

Skeleton-based human action recognition (HAR) requires models that preserve the local kinematic structure of the human body while capturing long-range spatiotemporal dependencies under noisy or incomplete joint observations. Traditional Graph Convolutional Networks (GCNs) provide topology-aligned inductive bias but are often limited by local information aggregation from neighboring joints. In contrast, attention-based mechanisms capture global interactions, yet they may attend to spurious correlations when skeletal constraints are weakly enforced. This paper proposes Differential Hyperedge Attention-enhanced GCN (DHA-eGCN), a hybrid architecture that couples structure-aware Differential Hyperedge Attention with multi-scale temporal convolution for spatiotemporal skeleton sequence processing. DHA injects skeletal structure into attention via hop-distance relative positional encoding and hyperedge context tokens generated via joint-to-part pooling. It further employs differential attention to suppress shared noisy correlations and enhance interaction selectivity. To strengthen spatial grounding, an explicit GCN branch is added under partial- or full-depth configurations, where the first four or all ten layers are applied with graph convolutions. The model further employs an ensemble strategy that combines predictions from multiple complementary model instances. Our experiments on NTU RGB+D 60 under the X-Sub and X-View protocols, NTU RGB+D 120 under the X-Sub and X-Set protocols, and Northwestern-UCLA demonstrate that DHA-eGCN consistently outperforms or remains competitive with strong graph-based, transformer-based, and hybrid state-of-the-art methods based on the same four-stream architecture. The best configuration achieves 93.7% and 97.0% on NTU RGB+D 60 X-Sub and X-View, respectively; 90.9% and 91.9% on NTU RGB+D 120 X-Sub and X-Set, respectively; and 97.6% on Northwestern-UCLA. Full article

LRRK1 is essential for osteoclast-mediated bone resorption, and loss of LRRK1 function causes osteopetrosis in mice and humans. However, the mechanisms by which LRRK1 regulates osteoclast activity remain incompletely defined. We previously identified that phosphorylation of OSTM1 at threonine 328 and serine 329 was compromised in LRRK1-deficient osteoclasts. To test the role for OSTM1 phosphorylation in LRRK1 regulation of osteoclast functions, we expressed a phosphomimetic OSTM1 variant in LRRK1-null osteoclasts. Overexpression of phosphomimetic, but not a dephosphomimetic variant, partially restored resorptive activity in LRRK1-deficient osteoclasts in vitro. To test OSTM1’s role in rescuing defective bone resorption in Lrrk1-null mice, we generated Ostm1-T328E/S329D knock-in (KI) mice and crossed them onto the Lrrk1-deficient background. Ostm1-T328E/S329D KI mice displayed normal skeletal development and bone remodeling. When crossed to the Lrrk1-deficient background, OSTM1-T328E/S329D expression increased osteoclast resorptive activity and bone formation and partially improved trabecular architecture, although bone volume remained unchanged. These findings demonstrate that OSTM1 phosphorylation contributes to LRRK1-dependent regulation of osteoclast function and identify the LRRK1–OSTM1 pathway as a mechanistic node controlling bone resorption. Our work provides new insight into the molecular basis of LRRK1-mediated osteoclast function and highlights OSTM1 phosphorylation as a potential therapeutic target for metabolic bone diseases. Full article

Vitamin D is a fat-soluble secosteroid essential for skeletal development and calcium homeostasis, but it also exerts pleiotropic effects on numerous biological processes via its active metabolites. Vitamin D metabolites act as steroid hormones that regulate cell-cycle progression, proliferation, differentiation, apoptosis, immune responses, and multiple intracellular signaling pathways. Moreover, they modulate the expression of genes involved in carcinogenesis. As circulating vitamin D levels are influenced by diet, fortified foods, and supplementation, they represent a potentially modifiable factor. Whether vitamin D status affects cancer risk or disease progression in carriers of pathogenic BRCA1 variants remains unclear and continues to be actively investigated. Clarifying this relationship could have significant clinical implications for risk stratification and prevention in this high-risk population. This narrative review summarizes current evidence from epidemiological, clinical, and molecular studies examining the role of vitamin D in BRCA1 pathogenic variant carriers. It also highlights key limitations in the existing literature and identifies critical directions for future research, emphasizing the need for well-designed prospective studies in representative cohorts. Full article

Background/Objectives: Vitamin D, universally recognized for its role in calcium–phosphate homeostasis and skeletal health, has emerged as a key immuno-endocrine modulator. Its active metabolite interacts with the vitamin D receptor (VDR) across immune and endocrine cell populations, influencing gene transcription, cytokine balance, and immune tolerance. This narrative review synthesizes mechanistic, epidemiological, and clinical evidence on the role of vitamin D in immune modulation across autoimmune and infectious diseases. Methods: This narrative review incorporated a structured and comprehensive literature search across PubMed/MEDLINE, Scopus, Web of Science, Embase, and Google Scholar. Results: Vitamin D modulates both innate and adaptive immunity through antimicrobial peptide induction, macrophage and NK cell activation, and promotion of tolerogenic dendritic cells. Clinical and interventional trial outcomes remain heterogeneous and are influenced by baseline vitamin D status, dosing regimens, genetic variability, and disease context. Conclusions: Vitamin D functions in endocrine and immune regulation, contributing to host defense and immune tolerance. Current evidence supports that for autoimmune and infectious conditions, well-designed randomized trials are required to clarify effective dosing, identify responsive subpopulations, and elucidate genetic determinants of therapeutic benefit. Full article

Type 2 diabetes mellitus (T2D) is associated with dyslipidemia, characterized by elevated plasmatic triglycerides and free fatty acids, particularly palmitate (PA), which may cause lipotoxicity in skeletal muscle cells. This leads to inflammation, activation of the unfolded protein response (UPR), insulin resistance, and cell death. Herbal medicines such as Uncaria tomentosa (UT) have shown potential as complementary treatments for T2D due to their protective effects. Purpose and study design: This study investigates the effect of UT aqueous extract on UPR and insulin resistance induced by PA in C2C12 myotubes. C2C12 myoblasts were grown in DMEM medium supplemented with 10% fetal bovine serum and differentiated into myotubes with 3.5% horse serum. The myotubes were incubated with 100 or 500 μM PA, 2–100 µM thapsigargin (Tg) or tunicamycin (Tn), in the presence or absence of 250 μg/mL UT extract or 100 µM TUDCA, for 2 or 6 h. The myotubes treated with UT extract for 6 h, after the incubation with 20 µM Tg, Tn or 500 µM PA, presented reduction in the expression of UPR-related genes ATF4 and CHOP by approximately 1.5-fold, and increased by 3-fold the expression of IRS-1, an insulin-signaling protein, when compared to myotubes incubated with only 20 µM Tg, Tn or 500 µM PA. These findings suggest that UT extract may serve as a modulator against skeletal muscle dyslipidemia by downregulating ATF4 and CHOP, reducing cell stress and death, while enhancing IRS-1 expression, which supports the use of the UT extract in managing insulin resistance and T2D. Full article

The extracellular matrix (ECM) regulates skeletal muscle development through biochemical signaling and mechanical interactions. While Matrigel supplementation is commonly used to enhance engineered muscle formation, the contribution of specific ECM proteins remain incompletely defined in 3D systems. Here, we evaluated the effects of laminin and fibronectin supplementation on myogenic differentiation in collagen type I hydrogels and assessed their influence on passive tissue compaction and alignment in 3D constructs. Two-dimensional collagen hydrogels supplemented with increasing concentrations (0–100 µg/mL) of laminin or fibronectin were screened to maximize the myoblast fusion index. These concentrations were incorporated into 3D myocyte-seeded hydrogels cultured between flexible posts to quantify passive compaction forces via cantilever mechanics. Fibronectin supplementation (10 µg/mL) resulted in significantly greater early post displacement and sustained passive compaction compared to laminin-supplemented and unsupplemented controls. Constructs cultured under tension between posts exhibited enhanced alignment, with fibronectin further increasing the proportion of fibers oriented within 0–20° of the tension axis. Together, these findings demonstrate that fibronectin enhances early passive compaction dynamics and tension-mediated alignment in collagen-based skeletal muscle constructs. These results provide insight into how specific ECM components influence 3D tissue organization and may inform the design of engineered muscle models for regenerative applications. Full article

Background/Objectives: Obesity and menopause are major determinants of skeletal deterioration; however, their combined effects on bone remodeling and associated cellular bioenergetics remain incompletely understood. This study aimed to determine whether obesity induces osteoporotic alterations under both estrogen-replete and estrogen-deficient conditions and to evaluate the therapeutic potential of dental tissue-derived mesenchymal stem cells (D-MSCs). Methods: Female mice were subjected to ovariectomy (OVX) and/or high-fat diet (HFD) feeding for 16 weeks to establish obesity-associated osteoporosis models. D-MSCs were administered intraperitoneally at defined intervals. Body weight and serum leptin levels were measured to assess metabolic status. Femoral tissues were analyzed by quantitative real-time PCR for estrogen receptors (ERα, ERβ), inflammatory markers (Il-1β, Tnf-α), mitochondrial regulators (Pgc1α, Pgc1β), and the OPG/RANKL ratio. Histological analysis was performed to evaluate bone marrow adiposity. Results: HFD significantly increased body weight and serum leptin levels in both intact and OVX mice. Obesity was associated with reduced expression of ERα and ERβ, decreased Pgc1α levels, and a lower OPG/RANKL ratio, accompanied by increased Il-1β, Tnf-α, and Pgc1β expression. D-MSC administration attenuated body weight gain and reduced leptin levels, particularly in OVX mice. In femoral tissue, D-MSC treatment restored estrogen receptor expression, increased Pgc1α, decreased Pgc1β, and normalized the OPG/RANKL ratio. In addition, inflammatory marker expression and bone marrow adiposity were reduced following MSC administration. Conclusions: Obesity induces bone remodeling dysregulation under both intact and estrogen-deficient conditions, characterized by altered estrogen signaling, inflammatory activation, and mitochondrial imbalance. D-MSC administration was associated with partial restoration of these alterations, suggesting a potential role in modulating metabolic and skeletal homeostasis in obesity-associated bone loss. Full article

Background/Objectives: Type 2 diabetes (T2D)-associated sarcopenia is characterized by impaired insulin signaling, lipotoxicity, oxidative stress, and progressive muscle loss. Although liraglutide improves glucose control and reduces lipid burden, its ability to preserve muscle integrity under diabetic lipotoxic conditions remains limited. This study investigated whether β-hydroxy-β-methylbutyrate (HMB) could enhance liraglutide-mediated protection against high-glucose plus free fatty acid (HG+FFA)-induced injury in skeletal muscle cells. Methods: Differentiated C2C12 myotubes were exposed to HG+FFA to establish a sublethal lipotoxic model and treated with liraglutide, HMB, or their combination. Cell viability, lipid accumulation, myotube morphology, insulin signaling, glucose uptake, mitochondrial function, reactive oxygen species (ROS), antioxidant gene expression, and atrophy-related signaling were assessed. Results: HG+FFA induced marked lipid droplet accumulation, impaired insulin signaling, reduced glucose uptake, disrupted mitochondrial membrane potential, increased ROS production, suppressed antioxidant gene expression, and promoted an atrophic phenotype characterized by increased atrogin-1 and MuRF1 and reduced myogenic markers. Liraglutide alone reduced large lipid droplets and partially improved insulin signaling but showed limited efficacy in preserving the myotube phenotype. HMB alone exerted modest effects on lipid accumulation but preserved myotube area. Notably, combined HMB and liraglutide treatment more effectively reduced lipid burden, restored insulin signaling and glucose uptake, attenuated mitochondrial dysfunction and oxidative stress, restored antioxidant gene expression, and preserved MyHC-positive area and myotube diameter while suppressing atrogin-1/MuRF1 activation. These protective effects were largely attenuated by rapamycin, indicating at least partial dependence on mTOR-associated signaling. Conclusions: Overall, HMB and liraglutide exert complementary protective effects against diabetic lipotoxic and atrophic stress, supporting the potential utility of this combination strategy for T2D-associated sarcopenia. Full article

Patient-specific implants (PSIs) in orthognathic surgery offer optimal intraoperative accuracy. However, evidence regarding their postoperative skeletal stability, specifically comparing distinct fixation designs and segmentation patterns, remains limited. We present a retrospective cohort study that evaluated 64 adult patients undergoing customized maxillary orthognathic surgery between January 2020 and June 2025. The primary predictor variables were fixation design (conventional customized plates vs. minimally invasive plates) and maxillary segmentation (monoblock vs. multisegmental). The outcome variable was 3D skeletal stability, measured as linear displacement between preoperative planning and 6-month postoperative imaging. Non-parametric tests compared displacements and clinical instability rates (defined as ≥2.0 mm). Mann–Whitney tests compared landmark displacements, Fisher’s exact tests compared proportions with ≥2.0 mm displacement, and ORs with 95% CIs were computed (α = 0.05). Analysis of 64 patients revealed that median displacement across landmarks ranged from 0.7 to 4.28 mm and 28.1% exhibited displacement ≥ 2.0 mm, primarily in molar and canine regions. While overall instability rates did not differ significantly between single-segment and multisegmental osteotomies (p = 0.28), multisegmental cases showed significantly higher displacement at the left canine (p = 0.027). Plate design was not associated with skeletal instability (p = 0.88), suggesting that minimally invasive plates provide comparable stability to conventional designs. Customized maxillary plates provide reliable postoperative stability with median displacements within clinically acceptable limits (<2 mm). Minimally invasive PSI designs offer stability comparable to conventional extended designs. However, localized instability in multisegmental cases suggests a need for careful biomechanical management regardless of the fixation method used. Full article

The following narrative review discusses the use of deep learning and 3D modeling in facial reconstruction from skeletal remains, focusing on accuracy, algorithmic bias, and evidential reliability. Forensic facial reconstruction (FFR) is a multidisciplinary field combining anthropology, medicine, and visual sciences to approximate the facial appearance of unidentified individuals from skeletal remains. Traditional manual methods, based on anatomical knowledge and facial soft tissue thickness (FSTT) measurements, are limited by subjectivity, labor intensity, and inter-expert variability. This narrative review summarizes contemporary AI-assisted approaches, with emphasis on convolutional neural networks (CNNs), generative adversarial networks (GANs), variational autoencoders (VAEs), and diffusion models, which enable probabilistic prediction of facial morphology while accounting for demographic variables such as sex, age, and population ancestry. Key challenges affecting reconstruction accuracy—including dataset limitations, population-specific variability, and algorithmic bias—are discussed, alongside quantitative validation methods and concerns regarding model transparency. Legal and ethical considerations, such as privacy, biometric data protection, and the need for explainable AI (XAI) frameworks, are highlighted. Future perspectives include hybrid expert–AI workflows, the development of globally representative datasets, and the integration of multimodal data sources, including DNA phenotyping, 3D morphometrics, and biomechanical modeling. These advances aim to create standardized, interpretable, and biologically informed frameworks that enable AI to support expert judgment and enhance the reliability of forensic facial reconstructions. Full article

Background/Objectives: Sarcopenia is characterized by progressive skeletal muscle loss and impaired myogenic differentiation and is closely associated with inflammation and metabolic dysfunction. Methods: This study investigated the protective effects of Momordica charantia extract against dexamethasone-induced sarcopenia and explored the underlying mechanisms using network pharmacology, C2C12 cell-based assays, Western blotting, and molecular docking. Network pharmacology analysis identified quercetin, ascorbic acid, and tocopherol as major active compounds associated with targets related to inflammation, extracellular remodeling, and metabolic dysfunction. Results: M. charantia extract (MCE) did not markedly reduce cell viability at concentrations up to 100 μg/mL and improved dexamethasone-induced morphological impairment of myotubes. The extract reduced MAFbx, MMP-2, and MMP-9 expression while restoring phosphorylated p38, MyoD, and myogenin expression, indicating suppression of atrophy- and remodeling-related responses, together with the recovery of myogenic signaling. Among the major identified compounds, all attenuated dexamethasone-induced myotube atrophy and quercetin showed the most pronounced morphological recovery. Molecular docking analysis targeting p38α showed the highest binding affinity for α-tocopherol, followed by quercetin and ascorbic acid, supporting potential interactions between the major compounds and p38 MAPK-related signaling. Conclusions: Collectively, these findings suggest that M. charantia attenuates sarcopenic changes by promoting myogenic differentiation and modulating the p38 MAPK-associated pathways. Full article

Secondary hyperparathyroidism (SHPT) is a major component of chronic kidney disease–mineral and bone disorder (CKD-MBD), reflecting progressive disturbances in mineral metabolism, endocrine signaling, skeletal remodeling, and parathyroid-gland biology. Traditionally, preoperative parathyroid hormone (PTH) has been used primarily as a biochemical threshold for surgical referral. However, persistent PTH elevation in advanced CKD-related SHPT may reflect more than isolated endocrine activity; available evidence suggests it integrates parathyroid-gland remodeling, receptor resistance, skeletal turnover, treatment refractoriness, and systemic CKD-MBD severity. This review summarizes key molecular and cellular mechanisms of progressive SHPT, including diffuse-to-nodular hyperplastic transition, downregulation of calcium-sensing receptor (CaSR) and vitamin D receptor (VDR) signaling, disruption of the fibroblast growth factor 23 (FGF23)–Klotho axis, and activation of transforming growth factor-α (TGF-α)/epidermal growth factor receptor (EGFR) proliferative pathways. Building on this mechanistic framework, we discuss how persistent PTH elevation has been linked to glandular remodeling, resistance to calcimimetic and vitamin D therapy, high-turnover renal osteodystrophy, hungry bone syndrome, altered intraoperative PTH kinetics, postoperative endocrine–skeletal remodeling, and long-term recurrence. Severe SHPT is also increasingly recognized as a systemic CKD-MBD phenotype associated with vascular calcification, cardiovascular risk, metabolic instability, and impaired quality of life. Within this framework, preoperative PTH is best interpreted as an integrated biomarker within a broader assessment of glandular remodeling, skeletal metabolic activity, endocrine resistance, and systemic CKD-MBD biology, rather than as an isolated biochemical threshold. Full article

Purpose: To develop a fully automated 2D nnU-Net pipeline for multi-class skeletal muscle segmentation (psoas, paraspinal, and abdominal wall) at the third lumbar (L3) vertebral level, and to quantitatively evaluate its diagnostic performance and reliability compared to manual segmentation. Materials and Methods: A 2D nnU-Net was trained on 164 axial L3 CT slices from the multi-institutional AMOS22 dataset, spanning diverse abdominal pathologies and multivendor imaging. To assess generalizability under severe anatomical distortion, independent external validation was performed in 50 consecutive patients with advanced liver disease from a single institution (January–December 2025; mean age, 63 ± 15 years; 32 women, 18 men), of whom 88% had moderate-to-severe ascites. Model stability was examined by comparing a five-fold ensemble with the best-performing single-fold model. Intra-observer reliability of the manual reference standard was evaluated in a random subset of 30 cases. Inter-observer agreement was additionally assessed using an independent second reader. Performance metrics included the Dice Similarity Coefficient (DSC), Pearson correlation coefficient (r), and Bland–Altman analysis for cross-sectional areas and mean attenuation. The inference workflow was deployed via a custom Streamlit-based graphical user interface (GUI). Results: In this anatomically complex external validation cohort, the 5-fold ensemble 2D nnU-Net achieved an overall mean DSC of 0.937 ± 0.043 (95% CI, 0.925–0.950), with 80% of cases achieving a mean DSC ≥ 0.90. While the mean DSC was statistically comparable to the best single-fold model (0.937, [95% CI, 0.921–0.952], p = 0.736), the ensemble strategy increased the minimum observed DSC (worst-case performance) from 0.720 to 0.822. Class-specific external validation performance for the 5-fold ensemble was highest for the paraspinal muscles (DSC: 0.960; 95% CI, 0.952–0.967), followed by the psoas muscles (DSC: 0.941; 95% CI, 0.927–0.956), and lowest for the anatomically complex abdominal wall muscles (DSC: 0.911; 95% CI, 0.893–0.929). Comparison between the ensemble model and manual segmentation yielded a Pearson correlation of r = 0.955 (p < 0.001) for total skeletal muscle area, with a mean bias of +7.17 cm². Intra- and inter-observer agreements for the manual reference standard demonstrated correlation coefficients of r = 0.995 and 0.090 for total areas, respectively. The automated pipeline required 3–5 s per case for inference and quantitative reporting, compared to 3–5 min for manual segmentation. Conclusions: In patients with advanced liver disease and substantial anatomical distortion from ascites, an ensemble-based 2D nnU-Net provides high quantitative agreement with manual L3 skeletal muscle segmentation, while mitigating lower-bound (worst-case) errors relative to single-fold models. Integration with a dedicated GUI enables substantial time savings and supports scalable quantitative body composition measurement. Full article

Indolent systemic mastocytosis (ISM) is an under-recognised cause of secondary osteoporosis, and skeletal fragility may be the only presenting feature, delaying diagnosis. We describe four adults referred to a tertiary endocrinology service for unexplained osteoporosis or low-trauma fractures, in whom systemic mastocytosis (SM) was identified during work-up. All had elevated basal serum tryptase (41.4–87.0 µg/L), bone-marrow biopsy showing atypical mast cells and the KIT D816V variant; cutaneous lesions were absent in every case. Three patients fulfilled WHO 2022 criteria for ISM. The fourth had coexistent JAK2 V617F-positive post-essential-thrombocythaemia myelofibrosis and was classified as SM with associated haematological neoplasm (SM-AHN); his mast cell clone (tryptase 43.7 µg/L; KIT D816V VAF 0.391%) behaved indolently and contributed clinically through osteoporosis alone, illustrating that an indolent mast cell component can be overlooked when a chronic myeloid neoplasm dominates the picture. Presentations ranged from an isolated low-energy L5 fracture in a 55-year-old man, to multiple vertebral compression fractures despite denosumab in a 71-year-old woman with primary hyperparathyroidism, to severe wasp-sting anaphylaxis in a 43-year-old man. After multidisciplinary review, all received intravenous zoledronic acid with vitamin D repletion; KIT-targeted therapy is under consideration in selected patients. Although causal inferences cannot be drawn from four retrospectively identified cases, the series illustrates how ISM may be missed in unexplained or treatment-refractory osteoporosis—particularly in younger men, those with prior severe anaphylaxis, and those fracturing on antiresorptive therapy—and supports combining basal serum tryptase with high-sensitivity peripheral-blood KIT D816V testing, in line with the WHO/ICC/AIM-ECNM 2022–2024 criteria. Prospective studies are needed. Full article