Search Results (1,660)

Background: Intervertebral disc degeneration (IVDD) is closely linked to low back pain (LBP), a leading cause of disability worldwide. IVDD is characterized by the loss of proteoglycans (PGs), extracellular matrix (ECM) degradation, and reduced hydration of the nucleus pulposus (NP). Extracellular vesicles (EVs) derived from human umbilical cord mesenchymal stem cells (hUC-MSCs) exhibit tissue repair and immunomodulatory effects and are emerging as promising cell-free therapeutics. Methods: We established a rat IVDD model via fluoroscopy-guided needle puncture of three consecutive coccygeal discs and confirmed degeneration through Alcian Blue and hematoxylin & eosin (H&E) staining. The gene expression of inflammatory and pain markers (ADRβ2, COMP, CXCL1, COX2, PPTA, MMP13, YKL40) was measured by qPCR. Subsequently, we implanted hUC-MSCs or EVs to evaluate their reparative potential. Results: Upregulation of inflammatory and pain genes in IVDD was associated with an immunomodulatory response. Tracking DiI-labelled hUC-MSCs and EVs revealed enhanced survival of hUC-MSCs, retention of EVs, and dispersion within rat tail discs; EVs showed greater retention than hUC-MSCs. Implanted EVs were internalized by NP cells and remained within degenerative IVDs. EVs passively diffused, accumulated at the injury site, interacted with host cells, and enhanced function, as shown by increased expression of human chondrocyte-related markers (SOX9, TGFβ1, TGFβ2, COL2) compared to hUC-MSC treatment. Histological analysis of two weeks post-transplantation showed NP cellular patterns resembling chondromas in treated discs. EVs integrated into and distributed within degenerated NP regions, with greater glycosaminoglycan (GAG) content. Conclusions: Overall, hUC-MSC EVs demonstrated superior regenerative capacity, supporting a safe, cell-free strategy for disc repair. Full article

Dynamic compression (DC) bioreactors are widely used to mimic joint loading and study how human mesenchymal stem cells (hMSCs) respond to mechanical cues. However, it remains unclear whether DC alone is sufficient to induce chondrogenesis or how such cues interact during construct maturation. In this study, hMSCs were encapsulated in fibrin hydrogels at different cell densities and subjected to DC without, during, or after TGF-β3-mediated chondrogenic induction. DC alone modestly increased SOX9 expression but failed to upregulate key cartilage matrix genes such as ACAN and COL2A1, indicating that mechanical stimulation alone is insufficient to initiate chondrogenesis. When mechanical stimulation was coupled with TGF-β3, a more mature chondrogenic phenotype was observed for high cell seeding densities (HD). To simulate a post-implantation scenario, we applied DC following growth factor withdrawal and observed marked downregulation of SOX9, ACAN, and COL2A1 in low-density (LD) constructs. This reduction was not observed in HD constructs, which maintained a more stable chondrogenic phenotype under loading. These findings show that construct maturation critically influences mechanoresponsiveness and suggest that immature grafts may not tolerate mechanical stimulation. DC bioreactors may therefore serve not only to support cartilage engineering but also to predict in vivo graft performance. Full article

Osteoarthritis (OA) is a degenerative joint disease characterized by progressive cartilage breakdown, synovial inflammation, and subchondral bone remodeling. Previous studies have shown that cellular communication network factor 3 (CCN3) expression increases with age in cartilage, and its overexpression promotes OA-like changes by inducing senescence-associated secretory phenotypes. This study aimed to investigate the effect of Ccn3 knockout (KO) on OA development using a murine OA model. Destabilization of the medial meniscus (DMM) surgery was performed in wild-type (WT) and Ccn3-KO mice. Histological scoring and staining were used to assess cartilage degeneration and proteoglycan loss. Gene and protein expressions of catabolic enzyme (Mmp9), hypertrophic chondrocyte marker (Col10a1), senescence marker, and cyclin-dependent kinase inhibitor 1A (Cdkn1a) were evaluated. Single-cell RNA sequencing (scRNA-seq) data from WT and Sox9-deficient cartilage were reanalyzed to identify Ccn3⁺ progenitor populations. Immunofluorescence staining assessed CD44 and Ki67 expression in articular cartilage. The effects of Ccn3 knockdown on IL-1β-induced Mmp13 and Adamts5 expression in chondrocytes were examined in vitro. Ccn3 KO mice exhibited reduced cartilage degradation and catabolic gene expression compared with WT mice post-DMM. scRNA-seq revealed enriched Ccn3-Cd44 double-positive cells in osteoblast progenitor, synovial mesenchymal stem cell, and mesenchymal stem cell clusters. Immunofluorescence showed increased CCN3⁺/CD44⁺ cells in femoral and tibial cartilage and meniscus. Ki67⁺ cells were significantly increased in DMM-treated Ccn3 KO cartilage, mostly CD44⁺. In vitro Ccn3 knockdown attenuated IL-1β-induced Mmp13 and Adamts5 expressions in chondrocytes. Ccn3 contributes to OA pathogenesis by promoting matrix degradation, inducing hypertrophic changes, and restricting progenitor cell proliferation, highlighting Ccn3 as a potential therapeutic target for OA. Full article

Allogeneic chondrocyte therapies present an attractive alternative to existing autologous therapies for the repair of cartilage defects, enabling the selection of optimal donor cells and streamlined manufacturing processes. This study investigates the potential of juvenile chondrocytes derived from human infantile (aged 0–4 y) polydactyly digits and the iliac apophysis for cartilage repair using Good Manufacturing Practice bioreactor expansion. Iliac apophysis (n = 4) and polydactyly tissues (n = 4) were assessed histologically. Chondrocytes were isolated enzymatically and cultured using standard tissue culture plastic (TCP) methodology. Upon sufficient cell expansion, chondrocytes were seeded into the Quantum^® bioreactor system or onto TCP (±vitronectin coating). The manufactured chondrocytes growth rates, total cell yields, chondrogenic pellet forming capacity (GAG/DNA, histology), immunoprofiles (flow cytometry) and gene expression (RT-qPCR) were assessed. Equivalent chondrocyte numbers were isolated from polydactyly and iliac apophysis donors per wet weight of tissue. Quantum^®-expanded chondrocytes from both sources yielded comparable cell numbers; however, growth was slowed in the Quantum^® compared to TCP. Polydactyly and iliac apophysis-derived chondrocytes expressed chondrocyte cell surface markers (CD166, CD44, CD151, SOX9) and formed chondrogenic pellets. Quantum^® bioreactor expansion did not alter, gene expression or capacity to form glycosaminoglycans (GAGs (normalised to DNA content)) compared to matched TCP expansion. Juvenile cartilage donors are a promising chondrocyte source for the development of an allogeneic therapy. This novel study expanding juvenile chondrocytes in the Quantum^® GMP-compliant bioreactor suggests that culture conditions may need modification to improve growth, whilst retaining cartilage forming capacity. Full article

This study proposes a hybrid EGARCH-Informer framework for forecasting volatility and calibrating tail risk in financial time series. The econometric layer (EGARCH) captures asymmetric and persistent volatility dynamics, while the attention layer (Informer) models long-range temporal dependence with sparse attention. The framework produces horizon-specific forecasts (H = 1 and H = 5) that are mapped to VaR and CVaR at α = 0.95 and 0.99. Evaluation covers pointwise accuracy (MAE, RMSE) and risk coverage calibration (CVaR bias and Kupiec’s unconditional coverage), complemented by Conditional Coverage (CC) and Dynamic Quantile (DQ) diagnostics, and distributional robustness via a Student-t mapping of VaR/CVaR. Across four U.S. equity indices (SPX, IXIC, DJI, SOX), the hybrid matches GARCH at the short horizon and yields systematic error gains at the longer horizon while maintaining higher calibration quality than deep learning baselines. MAE and RMSE values remain near 0.0002 at H = 1, with relative improvements of 2–6% at H = 5. CVaR bias stays tightly bounded; DQ rarely rejects, and CC is stricter but consistent with clustered exceedances, and the Student-t results keep the median hit rates near nominal with small, mildly conservative CVaR biases. These findings confirm the hybrid model’s robustness and transferability across market conditions. Full article

(1) Background: IgA nephropathy (IgAN) is a leading cause of chronic kidney disease worldwide. Despite its prevalence, the molecular mechanisms of IgAN remain poorly understood, partly due to limited research scale. Identifying key genes involved in IgAN’s pathogenesis is critical for novel diagnostic and therapeutic strategies. (2) Methods: We identified differentially expressed genes (DEGs) by analyzing public datasets from the Gene Expression Omnibus. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed to elucidate the biological roles of DEGs. Hub genes were screened using weighted gene co-expression network analysis combined with machine learning algorithms. Immune infiltration analysis was conducted to explore associations between hub genes and immune cell profiles. The hub genes were validated using receiver operating characteristic curves and area under the curve. (3) Results: We identified 165 DEGs associated with IgAN and revealed pathways such as IL-17 signaling and complement and coagulation cascades, and biological processes including response to xenobiotic stimuli. Four hub genes were screened: three downregulated (FOSB, SLC19A2, PER1) and one upregulated (SOX17). The AUC values for identifying IgAN in the training and testing set ranged from 0.956 to 0.995. Immune infiltration analysis indicated that hub gene expression correlated with immune cell abundance, suggesting their involvement in IgAN’s immune pathogenesis. (4) Conclusion: This study identifies FOSB, SLC19A2, PER1, and SOX17 as novel hub genes with high diagnostic accuracy for IgAN. These genes, linked to immune-related pathways such as IL-17 signaling and complement activation, offer promising targets for diagnostic development and therapeutic intervention, enhancing our understanding of IgAN’s molecular and immune mechanisms. Full article

A subset of chondrocytes in various human cartilage tissues, including neoplastic, regenerative, and normal cartilage, expresses α-smooth muscle actin (α-SMA), a protein typically found in smooth muscle cells. These α-SMA-containing chondrocytes, termed myochondrocytes and myochondroblasts, may play important roles in cartilage physiology, regeneration, and structural integrity, particularly in auricular and articular cartilage. This review synthesizes current knowledge regarding the terminology, distribution, and biological significance of these cells across normal, osteoarthritic, transplanted, and neoplastic cartilage. We summarize key findings from immunohistochemical studies using markers such as S-100, α-SMA, and SOX9, along with ultrastructural confirmation of myofilament bundles via electron microscopy. Current evidence suggests that myochondrocytes exhibit enhanced regenerative potential and contribute to matrix remodeling. Furthermore, their presence reflects the inherent cellular heterogeneity of cartilage, potentially arising from transdifferentiation processes involving fibroblasts, mesenchymal stem cells, or chondroblasts. Finally, TGF-β1 and PDGF-BB are identified as a critical modulator of α-SMA expression and chondrocyte phenotype. A deeper understanding of nature and function of myochondrocytes and myochondroblasts may improve interpretations of cartilage pathology and inform strategies for tissue engineering and cartilage repair. This review highlights the need for further investigation into the molecular regulation and functional roles of these cells in both physiological and pathological contexts. Full article

Background/Objectives: Autoimmune encephalitis (AIE) comprises a heterogeneous group of inflammatory central nervous system (CNS) disorders characterized by variable clinical presentations and antibody profiles. This study aimed to identify poor prognostic factors in AIE by retrospectively evaluating patients diagnosed based on clinical, radiological, and serological findings. Methods: Forty-four patients diagnosed with AIE between 2014 and 2024 were included. Demographic, clinical, radiological, and serological data were collected retrospectively. Patients were grouped based on antibody localization (intracellular, surface, and seronegative) and classified by treatment response. Poor prognosis was defined as a lack of objective clinical improvement to treatment or death. Results: The mean age was 57.8 ± 13.6 years, with a female-to-male ratio of approximately 1:1. Limbic encephalitis (LE) was the most common clinical presentation (43.2%). Malignancy was detected in 33.3% of patients, most frequently in those with SOX1 (83.3%), anti-Hu (60.0%), and anti-Yo (50.0%) antibodies. Anti-SOX1 positivity was significantly associated with both malignancy (OR = 27.5, p = 0.007) and mortality (OR = 13.2, p = 0.009), while anti-LGI1 positivity correlated with the absence of malignancy (p = 0.036). Patients with LE showed significantly better treatment responses (OR = 14.0, p = 0.019). Mortality was 20.1% overall and highest among anti-SOX1-positive patients (66.7%). The presence of multiple antibodies was associated with higher mortality and poorer prognosis, although not statistically significantly. Conclusions: Anti-SOX1 positivity is a key indicator of poor prognosis in AIE and is strongly associated with both malignancy and mortality. In contrast, LE presentation was linked to a better treatment response. Antibody profile, clinical features, and malignancy screening are critical for risk stratification and guiding management in AIE. Full article

Skin health is significantly impacted by factors such as melanin production, UV-induced photodamage, and wound healing. Excessive melanin leads to hyperpigmentation, while UVA radiation accelerates skin aging and oxidative stress. This study investigated the multi-functional dermatological potential of S strain LS-derived cell-free supernatant (CFS-LS) to address these concerns. Our findings demonstrate that CFS-LS effectively inhibits melanogenesis in B16F10 cells. It significantly reduced α-MSH-induced melanin synthesis, comparable to arbutin, by downregulating key melanogenic enzymes (tyrosinase, TRP-1, and TRP-2) and regulatory proteins (p-CREB, MITF, SOX9, and SOX10). Mechanistically, CFS-LS suppressed the phosphorylation of MEK, ERK, p38, and JNK, indicating a dual inhibitory effect on both PKA/CREB and MAPK pathways. Furthermore, CFS-LS mitigated UVA-induced photodamage in HaCaT cells by significantly reducing intracellular reactive oxygen species and suppressing the downstream phosphorylation of p53 and α-MSH levels. It also restored UVA-suppressed Nrf-2 and HO-1 expression, enhancing cellular antioxidant defenses. Lastly, CFS-LS promoted skin wound healing by significantly enhancing HaCaT cell migration in a scratch assay, associated with increased p-MEK1/2 and p-ERK1/2 levels, and notably elevated collagen type I synthesis. Collectively, these results highlight CFS-LS as a potent multi-functional agent for skin protection and repair, with significant potential for cosmetic and therapeutic applications. The active components of CFS-LS warrant further investigation. Full article

The article addresses the issue of liquefied natural gas (LNG) distribution as a marine fuel, analyzing both ecological and economic aspects in the context of the Baltic Sea basin. The authors emphasize that LNG plays an increasingly significant role in the global energy balance, and its application in maritime transport is crucial for implementing sustainable development policies and advancing the energy transition. From an ecological perspective, LNG offers a substantial reduction in harmful emissions compared with conventional marine fuels such as marine diesel oil (MDO) and heavy fuel oil (HFO). In particular, the use of LNG results in lower emissions of carbon dioxide (CO₂), sulfur oxides (SO_x), nitrogen oxides (NO_x), and particulate matter (PM). The reduction in these pollutants is essential not only for improving air quality in port and coastal areas but also for mitigating global environmental impacts, including climate change. On the economic side, the article focuses on the cost structure of LNG distribution, highlighting that its price dynamics are subject to significant fluctuations. These variations are driven by geopolitical developments, crude oil price volatility, environmental regulations, and the expansion of bunkering infrastructure. From an economic perspective, LNG prices show significant volatility depending on the year and market conditions. Between 2018 and 2023, LNG prices ranged from approximately 450 to 530 USD/ton, at times exceeding the cost of HFO (400–550 USD/ton) but in some years remaining cheaper. In comparison, MDO prices were consistently the highest, increasing over the analyzed period from 600 USD/ton to over 720 USD/ton. This variability results from geopolitical factors, supply and demand dynamics, and environmental regulations, which highlight the strategic importance of LNG as a transitional fuel in shipping. The purpose of this study is to examine the role of LNG as an alternative fuel for shipping in the Baltic Sea, with particular emphasis on the scale of vessel emissions and the key factors influencing its distribution costs. Full article

Background/Objectives: Developmental biologist Conrad Waddington proposed that evolution is shaped not only by genetic mutations and natural selection but also by environmentally responsive developmental mechanisms. Building on this premise, the epigenetic regulation of three master genes central to mammalian embryogenesis—OCT4, SOX2, and hTERT—focusing on their intragenic CpG islands (iCpGIs), which are crucial for transcriptional control and chromatin state modulation, were investigated. Methods: By performing a phylo-epigenetic comparison across 12 primate species, strong conservation of CpG-rich regions, punctuated by lineage-specific CpG transitions, particularly CpG→TpG and CpG→CpA was identified. Results: These mutational patterns align with methylation-dependent deamination mechanisms and highlight iCpGIs as evolutionarily constrained, epigenetically plastic elements. Notably, CpG variation alone recapitulated known primate phylogenies, suggesting that methylation-sensitive sites within iCpGIs encode both developmental and evolutionary information. Conclusions: It is proposed that such sites are prone to Environmentally Determined Epimutations (EDEMs)—methylation-driven, nutrition-sensitive changes that persist across generations and modulate gene regulatory capacity. This integrative framework advances Waddington’s concept of canalization by providing a molecular mechanism through which environmental factors can reshape developmental trajectories and contribute to evolutionary innovation. Full article

The search for markers applicable for efficient differential diagnosis and personalized therapy is a priority task of experimental neuro-oncology. Modern molecular methods allow us to analyze human biopsy material; however, further actions with this extracted tumor tissue are limited. Relevant and sophisticated CNS tumor models are required for precise therapy development. Although it is possible to use human biomaterial to create 2D and 3D cultures and implant them into xenograft animals, the data generated from such models is limited. Due to changes in the classification of the CNS tumors in 2021, a representative model should have not only morphological similarity to human tumors but also key genetic aberrations for studying the mechanisms of carcinogenesis and personalized therapy (such as PDGFRa, Olig1/2, Sox2, and Mki67) for different glioma models such as astrocytoma, oligodendroglioma, and glioblastoma. On the basis of a unique scientific facility “The Collection of experimental tumors of the nervous system and neural tumor cell lines” (Avtsyn Research Institute of Human Morphology of “Petrovsky National Research Center of Surgery”), there is a biobank of chemically induced transplantable tumors of laboratory animals. Their properties, mechanisms, and progression closely correlate with malignant CNS neoplasms in humans. These are potentially useful for identifying novel signaling pathways associated with oncogenesis in the nervous system and personalizing therapeutic approaches. In our work, we characterized a tissue-transplantable brain tumor strain of rat glioma101.8 using MRI, IHC, scRNA-seq, and qPCR-RT methods. According to this study, the cellular composition of the tissue-transplantable rat glioma 101.8 strain was determined, as well as the major genetic signature characteristics of each cell population of this tissue-transplantable strain and its microenvironment. Full article

Human induced pluripotent stem cells (hiPSCs) hold great potential for patient-specific therapies. Transplantation of hiPSC-derived neural progenitor cells (NPCs) is a promising reparative strategy for spinal cord injury (SCI), but clinical translation requires efficient differentiation into desired neural lineages and purification before transplantation. Here, differentiated hiPSCs—reprogrammed from human skin fibroblasts using Sendai virus-mediated expression of OCT4, SOX2, KLF4, and C-MYC—into neural rosettes expressing SOX1 and PAX6, followed by neuronal precursors (β-tubulin III⁺/NESTIN⁺) and glial precursors (GFAP+/NESTIN+). Both neuronal and glial precursors expressed the A2B5 surface antigen. A2B5+ NPCs, purified by fluorescence-activated cell sorting (FACS), proliferated in vitro with mitogens, and differentiated into mature neurons and astrocytes under lineage-specific conditions. Then, NOD-SCID mice received a T9 contusion injury followed by transplantation of A2B5+ NPCs, human fibroblasts, or control medium at 8 days post-injury. At two months, grafted NPCs showed robust survival, progressive neuronal maturation (β-tubulin III⁺→doublecortin⁺→NeuN⁺), and astrocytic differentiation (GFAP+), particularly in spared white matter. Transplantation significantly increased spared white matter volume and improved hindlimb locomotor recovery, with no teratoma formation observed. These results demonstrate that hiPSC-derived, FACS-purified A2B5+ NPCs can survive, differentiate into neurons and astrocytes, and enhance functional recovery after SCI. This approach offers a safe and effective candidate cell source for treating SCI and potentially other neurological disorders. Full article

Background: Endothelial cell (EC) dysfunction is an early sign of compromised vascular integrity and is associated with various cardiovascular diseases (CVDs). Activation of Toll-like receptor 4 (TLR4) plays a central role in this process. Extracellular vesicles (EVs) derived from milk have known anti-inflammatory properties, particularly in suppressing TLR4 activation. This study investigates the therapeutic potential of human breast milk-derived EVs (HBM-EVs) in mitigating EC dysfunction related to CVDs. Methods: HBM-EVs were isolated from the breast milk of healthy nursing mothers using ultracentrifugation. HBM-EVs were applied to lipopolysaccharide (LPS)-treated human umbilical vein endothelial cells (HUVECs), and inflammatory marker expression was assessed through qPCR and Western blotting. Mitochondrial oxidative stress was measured using MitoSOX. The effects of HBM-EVs were further evaluated in ex vivo studies using mesenteric arteries from diet-induced obese mice. Additionally, the effect of HBM-EVs on angiogenesis was tested via a wound closure assay. Results: In HUVECs, pre-treatment with HBM-EVs inhibited LPS-induced expression of inflammatory markers, including IL-6 and VCAM-1, as well as the phosphorylation of NFκB. Additionally, HBM-EVs reduced LPS-induced mitochondrial oxidative stress. In animal studies, HBM-EV treatment restored EC-dependent vasorelaxation in mesenteric arteries from diet-induced obese mice. Furthermore, HBM-EVs enhanced EC migration, leading to improved wound closure in HUVECs. Conclusion: This study demonstrates the therapeutic potential of HBM-EVs in alleviating EC dysfunction, offering a promising new approach to the treatment of CVDs. Future research will focus on identifying the specific cargo of HBM-EVs and further exploring their therapeutic mechanisms in endothelial dysfunction. Full article

Little is known about cartilaginous endplate (CEP) mechanobiology or how it changes in a catabolic microenvironment, partly due to difficulties in conducting mechanotransduction in vitro. Recent studies have found blended collagen–agarose hydrogels to offer improved mechanotransduction in chondrocytes compared to agarose alone. It was hypothesized that blended collagen–agarose hydrogels would be sufficient to improve the mechanobiological response in CEP cells relative to that in agarose alone, while maintaining the chondrocyte phenotype and ability to respond to pro-inflammatory stimulation. Thus, human CEP cells were seeded into blended 2% agarose and 2 mg/mL type I collagen hydrogels, followed by culture with dynamic compression up to 7% and stimulation with TNF. Results confirmed CEP cells retained a rounded phenotype and high cell viability during culture in blended collagen–agarose hydrogels. Additionally, TNF induced a catabolic response through downregulation of pericellular marker COL6A1 and anabolic markers ACAN and COL2A1. No significant changes were seen due to dynamic compression, suggesting addition of collagen to agarose was not sufficient to induce mechanotransduction in human CEP cells in this study. However, blended collagen–agarose hydrogels increased stiffness by 4× and gene expression of key cartilage marker SOX9 and physioosmotic mechanosensor TRPV4, offering an improvement on agarose alone. Full article