Search Results (6,855)

Autism spectrum disorder (ASD) and Fragile X syndrome (FXS) are neurodevelopmental disorders marked by deficits in communication and social interaction, often accompanied by anxiety, seizures, and intellectual disability. FXS, the most common monogenic cause of ASD, results from silencing of the FMR1 gene and consequent loss of FMRP, a regulator of synaptic protein synthesis. Disruptions in cyclic nucleotide (cAMP and cGMP) signaling underlie both ASD and FXS contributing to impaired neurodevelopment, synaptic plasticity, learning, and memory. Notably, reduced cAMP levels have been observed in platelets, lymphoblastoid cell lines and neural cells from FXS patients as well as Fmr1 KO and dfmr1 Drosophila models, linking FMRP deficiency to impaired cAMP regulation. Phosphodiesterase (PDE) inhibitors, which prevent the breakdown of cAMP and cGMP, have emerged as promising therapeutic candidates due to their ability to modulate neuronal signaling. Several PDE isoforms—including PDE2A, PDE4D, and PDE10A—have been implicated in ASD, and FXS, as they regulate pathways involved in synaptic plasticity, cognition, and social behavior. Preclinical and clinical studies show that PDE inhibition modulates neuroplasticity, neurogenesis, and neuroinflammation, thereby ameliorating autism-related behaviors. BPN14770 (a PDE4 inhibitor) has shown promising efficacy in FXS patients while cilostazol, pentoxifylline, resveratrol, and luteolin have showed improvements in children with ASD. However, challenges such as isoform-specific targeting, optimal therapeutic window, and timing of intervention remain. Collectively, these findings highlight PDE inhibition as a novel therapeutic avenue with the potential to restore cognitive and socio-behavioral functions in ASD and FXS, for which effective targeted treatments remain unavailable. Full article

Cell towers play a key role in providing telecommunications infrastructure, especially in remote mountainous regions. This paper presents an approach to the efficient design of 42-metre-high cell towers intended to install high-power equipment in remote mountainous regions of the Carpathians (750 m above sea level). The region requires rapid deployment of many standardized towers adapted to geographical features. The main design challenges were the limited space available for the base, the impact of extreme weather conditions, and the need for a fast project implementation due to the critical importance of ensuring stable communication. Special methodological attention is given to how the transition between pyramidal and prismatic segments in cell tower shafts influences overall structural performance. The effect of this geometric boundary on structural efficiency and material usage has not been addressed in previous studies. A dedicated investigation shows that positioning the transition at a height of 33 m yields the best compromise between stiffness and weight, minimizing a generalized penalty function that accounts for both the horizontal displacement of the tower top and its total mass. Modal analysis confirms that the chosen configuration maintains a natural frequency of 1.68 Hz, ensuring a safe margin from resonance. For the final analysis of the behavior of towers with elements of different cross-sectional shapes, finite element modeling was used for a detailed numerical study of their structural and performance characteristics. This allowed us to assess the impact of geometric constraints of structures and take into account the most unfavorable combinations of static and dynamic loads. The study yields a concise rule of thumb for towers with compact foundations, namely that the pyramidal-to-prismatic transition should be placed at roughly 78–80% of the total tower height. Full article

Autoimmune diseases result from dysregulated immune responses that mistakenly attack the body’s own tissues, causing chronic inflammation and progressive damage. Macrophages, with their remarkable plasticity, play key roles in both promoting and resolving inflammation, with pro-inflammatory M1 and anti-inflammatory M2 states shaping disease outcomes. Macrophage-derived exosomes have emerged as important mediators of intercellular communication, reflecting the functional state of their parent cells while influencing recipient cell behavior. Exosomes from M1 macrophages amplify inflammation through cytokines and microRNAs, whereas M2-derived exosomes support tissue repair and immune regulation. Studies in rheumatoid arthritis, lupus, multiple sclerosis, inflammatory bowel disease, type 1 diabetes, and psoriasis highlight their dual roles in pathology and resolution. In addition, macrophage exosomes can be engineered to deliver targeted therapeutic molecules, offering cell-free interventions with advantages in specificity, biocompatibility, and immunomodulation. This review summarizes current insights into macrophage-derived exosomes, their role in autoimmune pathogenesis, and emerging strategies to harness their therapeutic potential, highlighting their promise as precision-guided treatments for autoimmune diseases. Full article

Type 1 Diabetes Mellitus (T1D) is an autoimmune disease characterized by the destruction of pancreatic β-cells, predominantly manifesting in childhood or adolescence. The lack of clearly interpretable biological markers in the early stages, combined with the insidious onset of the disease, poses significant challenges to early diagnosis and the implementation of preventive strategies. The applicability of classic T1D biomarkers for understanding the mechanisms of the autoimmune process, preclinical diagnostics and treatment efficiency is limited. Despite advances in next-generation sequencing (NGS) technologies, which have enabled large-scale genome-wide association studies (GWASs) and the identification of polygenic risk scores (PRSs) associated with T1D predisposition, as well as progress in bioinformatics approaches for assessing dysregulated gene expression, no universally accepted risk assessment model or definitive predictive biomarker has been established. Until now, the use of new promising biomarkers for T1D diagnostics is limited by insufficient evidence base. However, they have great potential for the development of diagnostic methods on their basis, which has been shown in single or serial large-scale studies. This critical review covers both well-known biomarkers widely used in clinical practice, such as HLA-haplotype, non-HLA SNPs, islet antigen autoantibodies, C-peptide, and the promising ones, such as cytokines, cfDNA, microRNA, T1D-specific immune cells, islet-TCR, and T1D-specific vibrational bands. Additionally, we highlight new approaches that have been gaining popularity and have already demonstrated their potential: GWAS, single-cell transcriptomics, identification of antigen-specific T cells using scRNA-seq, and FTIR spectroscopy. Although some of the biomarkers, in our opinion, are still limited to a research context or are far from being implemented in clinical diagnostics of T1D, they have the greatest potential of being applied in clinical practice. When integrated with the monitoring of the classical autoimmune diabetes markers, they would increase the sensitivity and specificity during diagnostics of early and preclinical stages of the disease. This critical review aims to evaluate the current landscape of classical and emerging biomarkers in autoimmune diabetes, with a focus on those enabling early detection—prior to extensive destruction of pancreatic islets. Another goal of the review is to focus the attention of the scientific community on the gaps in early T1D diagnostics, and to help in the selection of markers, targets, and methods for scientific studies on creating novel diagnostic panels. Full article

Autism spectrum disorder (ASD) is a complex group of severe neurodevelopmental disorders characterized by varying degrees of dysfunctional communication and social abilities as well as repetitive and compulsive stereotypic behaviors. We aim to evaluate the genetic predisposition to oxidative response and its relationship with altered oxidative stress markers in ASD patients. Genomic DNA was isolated from peripheral blood lymphocytes of 106 (83 M, 23 F; 7.9 ± 3.2 years) ASD patients and 90 healthy subjects (63 M, 27 F; 21.2 ± 1.8 years). Genotyping was performed by real-time PCR-based allelic discrimination, PCR and electrophoresis of GST deletion variants. Reactive oxygen metabolites (dROMs), the Biological Antioxidant Potential (BAP), and the advanced oxidation protein products (AOPP) were also measured. Furthermore, we assessed oxidative DNA damage by Single Cell Gel Electrophoresis. The evaluation of oxidative stress markers indicated a mild oxidative stress status and a higher level of DNA damage in nuclei of ASD patients’ lymphocytes. We found significant associations between ASD and several polymorphisms of genes involved in the detoxification and the response to oxidative stress. Genetic and environmental factors contribute to the onset of autism spectrum disorder, and ASD patients’ treatment requires a multimodal approach, including behavioral, educational, and pharmacological approaches. Full article

Macrophages play a central role in joint inflammation and bone destruction in rheumatoid arthritis (RA). While activator protein-1 (AP-1) transcription factors have been implicated in RA pathogenesis, the specific roles of individual AP-1 members in regulating synovial macrophages remain unclear. To address this, two public single-cell transcriptomic datasets were first analyzed to profile synovial macrophages, and then to identify AP-1 family members and associated pathways via differential expression and gene set enrichment analyses. JUND, FOSL2, and FOSB were found to be highly enriched in the RA synovium, and a distinct CXCL3⁺FOSL2⁺ macrophage subset was identified, characterized by pro-inflammatory, metabolic, and differentiation-related pathways. Intercellular communication analysis further revealed that this CXCL3⁺FOSL2⁺ macrophage subset interacted with ACKR1⁺ endothelial cells within the synovial microenvironment. Validation in a large-cohort bulk transcriptomic dataset, together with functional assays using in vitro FOSL2 knockdown in U937 cell lines, further confirmed FOSL2’s role in promoting macrophage-driven inflammation. Collectively, these findings indicate that CXCL3⁺FOSL2⁺ macrophages drive RA synovitis via the FOSL2/AP-1 axis, highlighting a potential therapeutic target. Full article

The advent of sixth-generation (6G) wireless networks and cell-free massive multiple-input multiple-output (MIMO) architectures underscores the need for efficient resource allocation to support federated learning (FL) at the network edge. Existing approaches often treat communication, computation, and learning in isolation, overlooking dynamic heterogeneity and fairness, which leads to degraded performance in large-scale deployments. To address this gap, we propose a joint optimization framework that integrates communication–computation co-design, fairness-aware aggregation, and a hybrid strategy combining convex relaxation with deep reinforcement learning. Extensive experiments on benchmark vision datasets and real-world wireless traces demonstrate that the framework achieves up to 23% higher accuracy, 18% lower latency, and 21% energy savings compared with state-of-the-art baselines. These findings advance joint optimization in federated learning (FL) and demonstrate scalability for 6G applications. Full article

Adipose tissue plays a crucial role in the tumor microenvironment (TME), where its secreted extracellular vesicles (EVs) are involved in the complex signaling between tumor cells and surrounding stromal components. This study aims to unravel the mechanisms through which adipocyte-derived EVs influence breast cancer (BC) progression. Human mesenchymal stem cells (hMSCs) were differentiated into adipocytes following a 21-day induction protocol that led to significant accumulation of lipid droplets within the cells. EVs were isolated from the conditioned medium of both hMSC-derived adipocytes and BC cells. Particle size distribution, morphology, and uptake into the recipient cell were investigated via nanoparticle tracking analysis, transmission electron microscopy, and fluorescence microscopy, respectively. Our results show that BC-derived EVs notably impaired cell viability and modulated the expression of key genes involved in apoptosis resistance within stromal cells. On the other hand, stromal-derived EVs significantly altered tumor cell behavior, indicating a dynamic, bidirectional exchange of bioactive signals. These findings underscore the pivotal role of EV-mediated communication in the tumor-stroma interplay, suggesting that adipocyte-cancer cell EV crosstalk contributes to the remodeling of the TME, potentially facilitating tumor progression. Full article

β-thalassemia is a chronic genetic blood disorder characterized by defective β-globin synthesis, requiring frequent transfusions and resulting in iron overload, immune dysfunction, and increased susceptibility to infections. In these immunocompromised patients, altered immune responses lead to significant changes in the human virome, promoting viral persistence, reactivation, and expansion of pathogenic viral communities. This review explores the intricate relationship between β-thalassemia and the human virome, focusing on how clinical interventions and immune abnormalities reshape viral dynamics, persistence, and pathogenicity. Patients with β-thalassemia exhibit profound innate and adaptive immune dysregulation, including neutrophil dysfunction, T cell senescence, impaired B cell and NK cell activity, and expansion of myeloid-derived suppressor cells. These alterations create an immunological niche that favors viral reactivation and virome expansion. Iron overload enhances viral replication, while chronic transfusions introduce transfusion-transmitted viruses. Splenectomy and allo-HSCT further compromise viral surveillance. Additionally, disruptions in the gut virome, particularly bacteriophage-driven dysbiosis, may exacerbate inflammation and impair host–virus homeostasis. The human virome is not a passive bystander but a dynamic player in the pathophysiology of β-thalassemia. Understanding virome–immune interactions may offer novel insights for infection monitoring, risk stratification, and precision therapies in thalassemic patients. 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

The ovary is among the earliest organs to undergo age-related degeneration, limiting the reproductive potential of elite horses and constraining the growth of the equine industry. Follicular development during estrus is a key determinant of fertility, yet the molecular mechanisms underlying its decline, particularly at the level of specific ovarian cell types, remain poorly understood in equids. Here, we constructed a single-cell transcriptomic atlas to investigate ovarian changes in Kazakh horses. Using single-cell RNA sequencing (scRNA-seq), we profiled 112,861 cells from follicle-containing and follicle-absent ovaries, identifying nine distinct ovarian cell types and their subtypes, each with distinct gene expression signatures. Functional enrichment analyses revealed cell type-specific engagement in biological pathways, including ECM–receptor interaction, PI3K-Akt signaling, and oxytocin signaling. Gene expression patterns indicated tightly regulated processes of ovarian activation and cell differentiation. Notably, stromal cells exhibited high expression of ROBO2, LOC111770199, and TMTC2, while smooth muscle cells (SMCs) were marked by elevated levels of CCL5, KLRD1, and NKG7. Moreover, cell–cell interaction analyses revealed robust signaling interactions among SMCs, endothelial cells, neurons, and proliferating (cycling) cells. Together, these findings provide a comprehensive single-cell transcriptomic map of normal and abnormal ovarian states during estrus in Kazakh horses, offering novel insights into the cellular mechanisms of follicular development and identifying potential diagnostic biomarkers and therapeutic targets for ovarian quiescence in equids. Full article

Autologous Chimeric antigen receptor (CAR) T-cell therapies have demonstrated substantial efficacy in patients with relapsed or refractory hematologic malignancies; however, their implementation has been constrained by regulatory barriers. Risk Evaluation and Mitigation Strategies (REMS), mandated by the U.S. Food and Drug Administration (FDA), were initially implemented to mitigate risks associated with cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and other treatment-related toxicities. On 27 June 2025, the FDA removed REMS requirements for all approved B-cell maturation antigen (BCMA) and CD19-directed autologous CAR T-cell therapies, citing that current product labeling sufficiently communicates safety information. Key regulatory changes include the elimination of site certification and tocilizumab stocking requirements, a reduction in the recommended post-infusion proximity period from four weeks to two weeks, increased flexibility regarding monitoring locations, and a shortened driving restriction from eight weeks to two weeks. This review examines the rationale for the REMS requirements for CAR T-cell therapies, synthesizes contemporary safety data from clinical trials and real-world practice, and explores the implications of this regulatory shift for access to care, particularly in rural and underserved populations. The removal of REMS requirements may facilitate broader implementation of CAR T-cell therapies and alleviate logistical and institutional barriers, offering the potential to expand access while preserving patient safety. Full article

Because of the active influx of chemical compounds into the marine environment, a significant portion is transformed and accumulates in bottom sediments (BS), posing a threat to benthic organisms. The eastern coast of the Kamchatka Peninsula, with its characteristic volcanic, seismic, and gas–chemical features, is of particular interest to our research. This study is the first to assess the cyto- and genotoxicity of BS in coastal waters off the eastern coast of the Kamchatka Peninsula using biotesting on representatives of the benthic community (the mussel Mytilus trossulus and the sand dollar Scaphehinus mirabilis). Of the aqueous extracts exposure of BS from all stations, M. trossulus showed destabilization of lysosomal membranes in gills and digestive gland cells. It was shown that aqueous extracts from BS of Kamchatka Bay (station 1) and Avachinskaya Bay (station 3) had no negative effect on DNA molecules in the gills and digestive gland cells of mussels, and the values obtained corresponded to the control. Extracts from BS of Kronotsky Bay (station 2) and Avacha Bay (station 4) damaged the integrity of the genome in the cells of the gills M. trossulus and sperm of S. mirabilis. The level of DNA damage in sperm increased by 3 and 3.5 times, respectively, compared with that in control gametes. The results of the biotests on two biological models show that sediments from Kronotsky Bay and Avacha Bay exhibit cytotoxicity and induce DNA damage in both somatic cells and gametes. Full article

Human T-cell leukemia virus type 1 (HTLV-1), the first oncogenic human retrovirus, causes adult T-cell leukemia/lymphoma (ATLL), an aggressive neoplasm of mature CD4+ T-cells that is incurable in most patients and is associated with a median survival of less than 1 year. HTLV-1 also causes inflammatory disorders, including HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and uveitis. The estimated lifetime risks of ATLL and HAM/TSP in HTLV-1 carriers are 3–5% and 0.25–1.8%, respectively. Although there is uncertainty about other health effects of HTLV-1, a recent meta-analysis showed an association between HTLV-1 and cardiovascular, cerebrovascular, and metabolic diseases and a 57% increased risk of early mortality in HTLV-1 carriers, independent of ATLL or HAM/TSP. Furthermore, emerging studies in endemic areas show that outcomes for common cancers, such as cervical cancer and lymphoma (non-ATLL), are inferior in HTLV-1 carriers compared to publicly reported data. Thus, the impact of HTLV-1 may be greater and more diverse than currently understood. This review provides an outline of the prevalence and impact of HTLV-1 and associated disorders in the US, focused on—but not limited to—ATLL, with an emphasis on the social determinants of health that can affect the success of screening and prevention strategies. We also discuss the mechanisms by which HTLV-1 drives the pathogenesis of ATLL and potential strategies for early diagnosis and intervention. Finally, we conclude by suggesting approaches to designing and implementing community-informed research initiatives in HTLV-1 and ATLL. Full article

This study explores the use of a pre-acclimated Geobacter-enriched inoculum as a novel strategy to accelerate the start-up of biocathodes. Unlike conventional inoculation with broad-spectrum communities, the proposed inoculum combines a long-term electroactive consortium, previously adapted to anaerobic bioelectrochemical conditions, with digestate produced under controlled laboratory conditions. This prior acclimation ensures the presence of Geobacter strains already conditioned to electrode-associated growth, promoting rapid colonization and early electrochemical activity. Experiments were conducted in a dual-chamber electrochemical cell equipped with a three-electrode setup polarized at −1 V vs. Ag/AgCl. The enriched biocathode reached current densities exceeding 1.4 A/m² within 24 h, whereas the control exhibited significantly lower, less stable, and inconsistent performance. Unlike previously reported approaches based on broad-spectrum co-inoculation, this work presents a tailor-made inoculum in which the electroactive community is not only dominated by Geobacter, but also selectively preconditioned under functional bioelectrochemical conditions. This prior adaptation is a key differentiator that markedly enhances start-up efficiency. The results demonstrate that strategic enrichment with pre-acclimated Geobacter significantly accelerates start-up and improves electrochemical performance, offering a promising pathway toward more efficient and scalable bioelectrochemical systems for wastewater treatment and renewable energy generation. Full article