Search Results (218)

Background/Objectives: Identifying molecular liabilities and understanding disease heterogeneity are prerequisites for advancing therapies in T-cell prolymphocytic leukemia (T-PLL), a rare T-cell malignancy with a poor prognosis. Methods: RNA-seq profiling of T-PLL samples (n = 10) and the normal counterpart (n = 5) allowed us to report gene expression and pathway alterations in malignant cells, revealing that non-coding, antisense and circular RNA expression is profoundly altered in T-PLL. Results: T-PLL displayed activation of several oncogenic pathways, particularly PI3K/AKT/mTOR and Wnt, suppression of healthy T-cell activities and cell death escape. Tumor suppressor lncRNAs (NEAT1, MIAT and LUCAT1) with reduced expression and upregulated oncogenic pro-proliferative lncRNAs (FIRRE, TERC, XIST and PVT1) were identified. CircRNAs ectopically expressed in T-PLL included circSEMA4B and circSATB1, linked to the Wnt pathway, circFIRRE and oncogenic circPVT1 and circFKBP5. Focusing on five genes with validated recurrent oncogenic variants (STAT5B, JAK3, ATM, KMT2C, and ARID1A), we investigated genotype/phenotype relations. A multiple predictor linear model suggested potential links between driver variants and alterations in gene and circRNA expression, including association between STAT5B mutations and LTF upregulation, JAK3 lesions and increased PLXNA4 expression along with CCR4 suppression. Conclusions: Our transcriptomic profiling and genotype–phenotype association analysis identified specific genes, non-coding RNAs, pathways and candidate genotype-associated transcriptional signatures that warrant further investigation as potential targets for the development of new therapeutic approaches for this rare and heterogeneous malignancy. Full article

This study investigates how smallholder farmers and vendors in Piracicaba, Brazil, navigate the tensions between standardized spatial governance and heterogeneous livelihood strategies in the rural–urban transition. Based on 25 semi-structured interviews with participants in municipal open-air markets (varejões), we analyze how policies implemented by the Municipal Secretariat of Agriculture and Food Supply (SEMA), including rigid price controls, mandatory MEI registration, and inflexible infrastructure rules, clash with the realities of organic, family-based, and mixed production systems. The findings reveal that SEMA’s one-size-fits-all approach fails to account for real production costs, quality differentiation, and informal cooperation, thereby penalizing innovation and marginalizing vulnerable producers. Rather than passive recipients, vendors actively resist and reshape governance through income diversification, informal cooperatives, direct sales, and ethical redefinitions of agricultural work. We argue that effective spatial governance must move beyond technical standardization and instead recognize productive heterogeneity and local agency as central to sustainable rural–urban transitions. This Brazilian case offers a critical counterpoint to top-down models and underscores the need for flexible, participatory, and context-sensitive policy design. Full article

Accurate detection in the early stages of a fire is a crucial prerequisite for the efficient implementation of fire suppression and emergency rescue operations. Its accuracy and timeliness directly affect the control of disaster loss severity. Traditional fire detection methods mainly include three categories, which are manual inspection, sensor detection, and visual recognition. However, manual inspection is restricted by labor costs and time efficiency, making it difficult to achieve large-scale, high-frequency and real-time fire monitoring. Sensor detection is easily interfered by environmental factors such as temperature, humidity, and dust, leading to frequent false alarms and missed alarms. Visual recognition technology has shortcomings in aspects such as detailed feature perception, dynamic scene modeling, and reasoning robustness in complex environments, making it difficult to meet the requirements of high-precision detection. To address these issues, this study innovatively proposes a lightweight fire and smoke detection model based on semantic enhancement and frequency domain perception modeling, which is named the SemaFire you only look once (SemaFire-YOLO) model. The model constructs a large language and vision assistant (LLaVA) semantic guidance module, which uses a large language model to understand and guide the semantic features of images, thereby enhancing the saliency representation intensity of small and weak target regions. Then, a Haar wavelet-based downsampling module is adopted, which compresses spatial information while preserving high-frequency features such as flame edges and smoke textures, improving the accuracy of target recognition. Next, the convolution modulation mechanism is introduced to replace the traditional attention mechanism, enhancing the overall modeling efficiency and reducing computational overhead. Finally, a Dynamic Tanh normalization module is adopted to replace the batch normalization module in the traditional YOLO algorithm, strengthening the model’s representation stability and reasoning robustness under unstable input distributions. Experimental results show that the SemaFire-YOLO model achieves a mean average precision (mAP@0.5) of 64.30% on the fire image dataset, which is 0.8, 2.0, 0.6, and 3.8 percentage points higher than that of mainstream models such as YOLOv5n, YOLOv8n, YOLOv11n, and YOLOv12n, respectively. It exhibits better boundary detection capability and practical deployment potential. Through visual analysis, the results indicate that the improved SemaFire-YOLO model achieves more accurate detection and higher confidence in actual complex scenarios, further verifying the model’s robustness and accuracy in complex scenarios such as low contrast and dynamic fire conditions. Full article

Total RNA was isolated from sections of healthy testes and Leydig cell tumors of mixed-breed dogs using TMA Master II device. The RNA-seq libraries were sequenced on the Illumina platform. Following differential expression analysis, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) were applied with quality control obtained using FastQC and Trimmomatic. This analysis revealed 1500 transcripts, including 982 upregulated and 168 downregulated genes. The results demonstrated that a significant proportion of these differentially expressed genes are directly involved in the control of sex steroid production (CYP11A1, STAR, and 3β-HSD3B1) or tube formation, angiogenesis, and extracellular matrix remodeling in interstitial cells (ESM1, FGG, and VEGFA). Moreover, we identified the upregulation of transcripts responsible for neurotransmitter or neuroendocrine signaling (SLC6A4, GRIN2C, GABRB3) and cholesterol metabolism and its regulation (GPX3, MSMO1, DHCR24). These genes were strongly associated with the phosphatidylinositol-3-kinase (PI3K)-Protein Kinase B (Akt) cascade and extracellular matrix interactions, features shared with various malignancies. Alterations in estrogen and relaxin signaling appear to be distinctive, understudied mechanisms specific to canine Leydig cell tumors. Concurrently, downregulated genes (e.g., DMRTC2, SEMA3C, ALOX12) were linked with cell differentiation, signaling and immunoregulatory pathway suppression involved in tumorigenesis. A complex transcriptomic profile of canine Leydig cell tumors was developed, revealing a conserved oncogenic core shared in some aspects with human malignancies alongside unique species-specific alterations. Findings seem to be useful for identifying novel diagnostic biomarkers and targeted therapies in veterinary oncology, establishing canine reproductive tissues as a valuable comparative biomedical model for research in human. Full article

Semaphorin 3A (Sema3A), a known axon chemorepulsive protein during development, is localised in perineuronal nets (PNNs) in the adult brain. PNNs are condensed aggregates of extracellular matrix molecules surrounding specific types of neurons, which regulate neuroplasticity and memory. However, the role of PNN-associated Sema3A in these processes remains unclear. To address this topic, we investigated the contribution of Sema3A to cerebellum-dependent learning and memory in adult mice using the eyeblink conditioning (EBC) paradigm. We interfered with Sema3A signalling by employing: (i) a molecular approach, in which secreted Sema3A receptors (neuropilin-1 bodies) were expressed in the anterior interposed nuclei (AIN) via viral vector injection; and (ii) a genetic approach, using mutant mice with impaired Sema3A signalling (K108N mice). Mice expressing neuropilin-1 bodies showed reduced EBC performance at the beginning of the memory retention phase. However, increased inflammation was found in the AIN of these mice, challenging the interpretation of these findings. K108N mice showed enhanced EBC performance at the beginning of the memory retention phase. No synaptic structural changes were detected in the AIN of K108N mice at the end of the EBC paradigm. Based on our findings in K108N mice, constitutively altered Sema3A signalling is associated with subtle improvement in cerebellar memory. Full article

Astrocytes are increasingly implicated in the pathophysiology of schizophrenia (SCZ), yet how astrocytic dysfunction contributes to disease-relevant neuronal abnormalities remains unclear. Here, we used mass spectrometry–based proteomics to profile lysates (proteome) and secreted proteins (secretome) from iPSC-derived astrocytes originating from 9 SCZ patients and 8 healthy controls. Compartment-specific analyses showed that lysates were enriched for mitochondrial and nuclear pathways, whereas astrocyte-conditioned media (ACM) were enriched for extracellular matrix (ECM) and vesicle-associated proteins. Differential expression analysis revealed minimal overlap between dysregulated proteins in lysates and ACM, suggesting modality-specific effects of SCZ-associated donor background. Interestingly, ECM proteins and key secreted cues involved in synaptic development, including MFGE8 and SEMA3C, were selectively reduced in SCZ ACM, whereas RNA-processing proteins were aberrantly increased. This is in line with previously reported microRNA enrichment in extracellular vesicles (EV) derived from SCZ patients. Gene set analyses further identified the alteration in secretion and nuclear processes as well as the potential involvement of autophagy-dependent release mechanism in SCZ astrocytes. Together, these findings suggest disrupted astrocytic protein homeostasis and extracellular signalling in SCZ iPSC-derived astrocytes, providing mechanistic insight into astrocyte-mediated contributions to synaptic and circuit deficits in the disorder. Full article

Background/Objectives: The gene solute carrier family 52 member 3 (SLC52A3) encodes riboflavin transporter-3, a transmembrane protein essential for riboflavin absorption. Emerging evidence suggests that metabolic transporters may play a role in tumor biology. This study aimed to investigate the expression patterns, prognostic significance, genetic alterations, and functional associations of SLC52A3 in gynecological cancers. Methods: A comprehensive bioinformatic analysis was conducted using multi-omics datasets from The Cancer Genome Atlas (TCGA). Gene expression and survival analyses were performed via GEPIA3. Genetic alterations, including mutations and copy number variations, were assessed using cBioPortal. Immune infiltration correlations were analyzed through TIMER3. Protein–protein interactions and gene enrichment analyses were performed using STRING and GEPIA2, followed by Gene Ontology (GO) and KEGG pathway analyses. Results: SLC52A3 expression was significantly upregulated in ovarian, cervical, and endometrial cancers. Reduced expression of SLC52A3 was associated with poorer overall survival and shorter progression-free interval specifically in endometrial cancer. Genetic alterations in SLC52A3 were not significantly associated with survival outcomes (OS, DFS, and PFS). Functional enrichment analysis indicated that SLC52A3 is involved in biological processes such as cell junction organization and protein localization to the plasma membrane. Additionally, SLC52A3 expression showed positive correlations with genes implicated in tumor progression and metastasis, including NECTIN4, PROM2, TACSTD2, PKP3, SEMA4B, and CD46. Conclusions: These findings suggest that SLC52A3 may serve as a potential prognostic biomarker in endometrial cancer and could play a role in tumor progression pathways. Its functional associations highlight its potential relevance as a therapeutic target, warranting further experimental validation. Full article

Semaphorins are a large family of proteins originally identified for their roles in axon guidance during neural development. Recent findings have established the importance of semaphorins members in modulating diverse immune responses of T cells in vitro and in vivo. Class 3 semaphorins, typified by Sema3A, signal through Neuropilin-1 and Plexin-A receptors in an activation-dependent manner, suppressing effector proliferation while promoting regulatory T cell stability and shaping cytokine profiles in autoimmunity and cancer. Sema3E and Sema3F similarly fine-tune host defense and inflammation by directing Th1/Th17 responses or restraining aberrant chemotaxis. Class 4 members, such as Sema4A and Sema4D, engage Plexin-B1, Plexin-D1, and CD72 to deliver both “forward” co-stimulatory and “reverse” signals: they amplify CD4⁺ and CD8⁺ effector functions, support T helper-B cell crosstalk, and influence tumor immunity via receptor shedding and bidirectional signaling. Finally, although less well defined, class 7 Sema7A operates indirectly—through APCs and Tregs—to regulate inflammatory recall responses and Th1/Th17 driven pathology. Together, these semaphorin-mediated pathways underscore a complex, context-dependent network that balances protective immunity against immunopathology, offering novel therapeutic targets in autoimmunity, infection, and cancer. Full article

Bacground/Objectives: There is limited evidence on the role of glucagon-like peptide-1 receptor agonists in heart failure. We aimed to analyze the clinical efficacy of oral semaglutide in terms of health status and change in body weight in patients with heart failure with reduced ejection fraction, type 2 diabetes, and obesity. Methods: This observational, retrospective, real-world study included patients treated with oral semaglutide (Oral-Sema Group) and without glucagon-like peptide-1 receptor agonists (Control Group). The primary outcome was heart failure status, defined as a ≥5 point difference in the Kansas City Cardiomyopathy Questionnaire total symptom score, and change in body weight at 24 months. Results: After 1:1 propensity score matching, 162 patients were included in each group (mean age 71.0 years, mean body mass index 32.1, 52.9% females). Patients in the Oral-Sema Group were more likely to have improvement in heart failure health status from baseline to 24 months (OR: 2.45; 95%CI: 1.25–3.65; p = 0.012). The mean change in body weight was −8.0 ± 2.1 kg in patients with oral semaglutide and −1.9 ± 1.0 kg in control patients (p < 0.01). After treatment, there were negative correlations between the Kansas City Cardiomyopathy Questionnaire total symptom score and body weight (r = −0.558, p < 0.01) and glycated hemoglobin (r = −0.491, p = 0.017). It had good tolerability and safety. Conclusions: Oral semaglutide was associated with an improvement in heart failure health status and weight loss in patients with heart failure with reduced ejection fraction, type 2 diabetes, and obesity. Further research on glucagon-like peptide-1 receptor agonists in heart failure with reduced ejection fraction is needed. Full article

Skeletal muscle satellite cells (SMSCs) are essential for embryonic myogenesis and postnatal muscle regeneration; however, their cellular heterogeneity and transcriptional dynamics during avian development remain largely unexplored. Here, we performed single-cell RNA sequencing (scRNA-seq) on 42,886 cells isolated from goose leg muscles across four embryonic stages (E13, E15, E18, and E23), with each stage comprising pooled tissues from four female embryos. Unbiased clustering resolved 22 transcriptionally distinct clusters representing six major cell types—satellite cells, myocytes, fibro-adipogenic progenitors, endothelial cells, immune cells, and Schwann cells—with satellite cells being the most abundant. Satellite cells were further subdivided into three functional states (quiescent, activated, and proliferative/differentiating), which followed a continuous, linear pseudotime trajectory from early to late embryonic stages. This trajectory was marked by a progressive downregulation of stemness-associated regulators (e.g., PAX7) and upregulation of myogenic commitment and differentiation factors (e.g., MYF5, MYOD1, and MYOG), faithfully mirroring chronological development. Cell–cell communication analysis revealed that quiescent satellite cells exhibited the most extensive intercellular signaling networks (e.g., FGFR, Ephrin, collagen, CADM), whereas activated and proliferative/differentiating cells showed progressively diminished communication capacity. Across developmental stages, the contribution intensities of key signaling pathways—including SEMA6, CDH, FGF, LAMININ, MK, MPZ, CADM, FN1, and COLLAGEN—varied significantly among satellite cell states, indicating state-specific responsiveness to microenvironmental cues. Collectively, these findings demonstrate that satellite cells dynamically coordinate extrinsic signal integration with intrinsic differentiation programs to achieve orderly myogenic progression. This study provides a high-resolution single-cell atlas of goose SMSC development, uncovering subpopulation heterogeneity, state-specific molecular signatures, and key signaling pathways, with important implications for avian muscle biology and genetic improvement of poultry. Full article

Background: Several studies have demonstrated that adding semaglutide to the treatment of patients with type 2 diabetes mellitus (T2DM) reduces insulin requirements and glycated hemoglobin (HbA1c) levels. This study aimed to investigate real-world evidence for the effects of semaglutide dose escalation on HbA1c, body weight, dyslipidemia, and insulin dose reduction in patients with T2DM in the Cukurova region of Türkiye. Methods: This retrospective cohort study enrolled 500 patients (255 male, 245 female; mean age 56.1 ± 10.8 years) who initiated semaglutide therapy for T2DM between 2024 and 2025. Patients were grouped according to their maximum semaglutide dose: 0.25 mg (Group I), 0.50 mg (Group II), and 1.00 mg (Group III). The primary endpoint was the change in HbA1c from baseline to end of study (30 weeks) across semaglutide dose escalation groups. Secondary endpoints included changes in body weight, frequency of insulin dose reduction, and effects on lipid parameters. Results: A total of 117 patients (23.4%) discontinued semaglutide therapy, while 383 patients (76.6%) completed the study. The primary endpoint revealed a mean HbA1c reduction of −1.03 ± 0.35% from baseline to end of study (95% CI 0.99–1.07; t = 58.644; p < 0.001). Reductions in HbA1c increased progressively from Group I to Group III (HbA1c: −0.72 ± 0.28, −1.02 ± 0.26, −1.27 ± 0.34%). Insulin dose reduction frequency increased significantly from Group I to Group III (40%, 41%, and 51%, respectively; p = 0.010), with a statistically significant difference only between Group I and Group III. At the end of follow-up, rates of hypoglycemic episodes and gastrointestinal (GI) adverse events were similar across groups. Conclusions: In a real-world population from the Cukurova region of Türkiye, semaglutide dose escalation in T2DM patients achieved clinically meaningful glycemic control, body weight reduction, LDL-cholesterol lowering, and a significant increase in insulin dose reduction frequency, without a significant increase in GI adverse events. Full article

Thyroid hormones (THs) are essential regulators of human brain development, and disrupted TH availability during pregnancy or early life is linked to adverse neurodevelopmental outcomes. Concerns that environmental chemicals interfere with TH signalling have increased the need for human-relevant in vitro systems to identify thyroid hormone system-disrupting chemicals (THSDCs) for risk assessment. Here, we compared two human-induced pluripotent stem cell (hiPSC)-derived brain organoid models for THSDC assessment: (i) human cortical organoids (COs) generated by unguided differentiation, offering higher architectural complexity but lower throughput; and (ii) neural stem cell-derived organoids (NSCOs), designed for scalability with reduced cellular diversity. Both models expressed key TH handling components, including the transporter SLC16A2 (MCT8) and the inactivating enzyme DIO3. Using LC–MS/MS, we show that exogenous T3 is depleted from culture media and metabolized to 3,3′-T2 and 3′-T1 in both models, alongside upregulation of T3-responsive genes (HR, KLF9, DIO3, SEMA3C). Pulse and chronic co-exposures to reference disruptors iopanoic acid (IA, deiodinase inhibitor) and silychristin (SC, MCT8 inhibitor) altered T3 metabolism and modulated T3-responsive transcriptional endpoints. In NSCOs, high-content imaging revealed treatment-associated changes in cell composition, with chronic T3 reducing the SOX2-positive progenitor pool and THSDCs blocking this effect. Together, these findings provide a framework for organoid qualification—linking TH handling, transcriptomic responsiveness, and scalable phenotypic readouts—as a necessary step toward model validation and implementation of brain organoids in THSDC risk assessment pipelines. Full article

Archery is a fine-grained skill sport in which small posture deviations can markedly affect performance, motivating the need for reliable automated technique assessment. However, most existing methods still focus on large-amplitude sports and cannot match coach-level nuance. To overcome these limitations, we introduce SEMA (Semantic Evidence-Driven Multimodal Assessment), a large language model (LLM)-based end-to-end system for fine-grained archery action quality assessment. Beyond score prediction and evaluation-text generation, SEMA further supports knowledge-grounded question answering and feedback generation through a hierarchical multi-source knowledge framework that integrates assessment outputs, structured coaching guidance, and general archery knowledge. Experimental results show that SEMA achieves strong performance on the novel AAV dataset, outperforming general-purpose VLMs and adapted prior AQA methods. In addition, we introduce the AAV (Archery Action Video) dataset, the first multimodal, fine-grained action quality assessment (AQA) dataset dedicated to archery, and release it publicly to the community. This dataset addresses a critical gap in current benchmarks for assessing archery action quality and intelligent archery training. Full article

Epidermal hyperinnervation is a major cause of intractable itch in barrier dysfunction conditions such as atopic dermatitis. Keratinocyte-derived semaphorin 3A (Sema3A) suppresses epidermal hyperinnervation, but its expression is markedly reduced in barrier-disrupted skin. Although konjac ceramide (kCer) has been reported to act as a Sema3A-like ligand, the mechanisms by which it regulates Sema3A expression in keratinocytes remain unclear. Normal human epidermal keratinocytes (NHEKs) were treated with kCer, konjac glucosylceramide (kGlcCer), or C24 ceramide. Sema3A mRNA and protein levels were assessed by quantitative real-time PCR and enzyme-linked immunosorbent assay, respectively. The involvement of intracellular signaling was examined using mitogen-activated protein kinase (MAPK) inhibitors, activator protein-1 (AP-1) inhibitors, retinoic acid-related orphan receptor alpha (RORα) inverse agonists, and siRNAs targeting c-Jun, c-Fos, and RORα. kCer induced Sema3A expression in NHEKs more potently than kGlcCer or C24 ceramide and promoted Sema3A protein secretion. Pharmacological inhibition or genetic knockdown of MEK1/2, JNK, AP-1 components, or RORα significantly attenuated kCer-induced Sema3A expression, indicating involvement of the MAPK/AP-1 signaling axis and RORα. kCer upregulates Sema3A expression in human keratinocytes through MAPK/AP-1 signaling and RORα, suggesting it may represent a promising antipruritic agent for epidermal hyperinnervation associated with skin barrier dysfunction. Full article

Natural killer T (NKT) cells bridge innate and adaptive immune responses and play a critical role in anti-tumor immunity. The goal of the study was to assess NKT cell and T cell function in lymphoma patients and to investigate whether specific cytokines correlate with outcomes and/or immune cell function. Patient diagnoses were confirmed by histology. NKT and T cell number and function were assessed by flow cytometry and stimulation with artificial antigen-presenting cells (aAPCs) followed by ELISA and quantitative RT-PCR (qPCR). Cytokine expression levels were compared using online databases, and protein levels in the plasma were assessed by ELISA. NKT cell activation, indicated by at least 1.5-fold IFN-γ induction over baseline following stimulation, was detected in 82% of healthy donors, compared to 44% of lymphoma patients. Lymphoma patients have significantly higher levels of circulating pro- and anti-inflammatory cytokines IL-10, IL-6, and Sema4D as compared to healthy donors. In addition, NKT cell function in the blood correlated with NKT cell function in the bone marrow in lymphoma patients. We found that aAPC-qPCR can be used to quickly assess immune cell function in cancer patients. Circulating NKT cell function positively correlated with bone marrow NKT cell function, suggesting that circulating NKT responses reflect systemic immune competence. Outcome-associated transcriptomic analyses showed that lower expression of TGF-β, IL-6, IL-10, and IFN-γ mRNA correlated with poorer clinical outcomes, whereas higher Sema4D expression was associated with worse prognosis, identifying Sema4D as a potential immunologic biomarker linked to disease progression and immune dysfunction in B cell lymphoma. Full article