Search Results (6,480)

Pain remains one of the most burdensome symptoms in rheumatoid arthritis (RA), often persisting despite inflammatory remission and profoundly impairing quality of life. This review aimed to evaluate the clinical efficacy and mechanistic pathways by which Janus kinase (JAK) inhibitors alleviate RA-related pain. Evidence from randomized clinical trials demonstrates that JAK inhibitors have demonstrated rapid and significant pain relief, often exceeding that of methotrexate or biologic DMARDs. Improvements in patient-reported pain scores seem to typically emerge within 1–2 weeks and are sustained over time. Beyond anti-inflammatory effects, JAK inhibitors modulate central sensitization and nociceptive signaling by attenuating IL-6 and GM-CSF activity, reducing astrocyte and microglial activation, and downregulating nociceptor excitability in dorsal root ganglia and spinal pathways. Preclinical models further suggest that JAK inhibition interrupts neuroimmune feedback loops critical to chronic pain maintenance. Comparative and network meta-analyses consistently position JAK inhibitors among the most effective agents for pain control in RA. However, individual variability in response, partly due to differential JAK-STAT activation and cytokine receptor uncoupling, underscores the need for biomarker-guided treatment approaches. JAK inhibitors represent a mechanistically distinct and clinically impactful class of therapies that target both inflammatory and non-inflammatory pain in RA. Their integration into personalized pain management strategies offers a promising path to address one of RA’s most persistent unmet needs. Full article

Acute promyelocytic leukemia (APL) is a rare subtype of acute myeloid leukemia (AML) characterized by chromosomal translocation forming the fusion protein that blocks the differentiation of myeloid progenitors and increases the self-renewal of leukemia cells. The introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has dramatically improved outcomes in APL, making it a leading example of successful treatment through differentiation of cancer cells. However, life-threatening side effects and treatment resistance may develop; therefore, modulation of the safety and efficacy of these drugs may contribute to further improving treatment results. Recently, zinc, involved in the structure and function of transcription factors, has received special attention for its potential role in the development and treatment response of cancer. Zinc homeostasis is disrupted in APL, with intracellular accumulation stabilizing oncogenic proteins. Zinc depletion promotes degradation of PML–RARA and induces apoptosis, while supplementation enhances genotoxic stress in leukemic cells but protects normal hematopoiesis. Zinc also regulates key transcription factors involved in differentiation and proliferation, including RUNX2, KLF4, GFI1, and CREB. In this review, we examine how zinc may impact zinc-finger (ZnF) and non-ZnF transcription factors and differentiation therapy in APL, thereby identifying potential strategies to enhance treatment efficacy and minimize side effects. Full article

Structural variation (SV) serves as a fundamental driver of phenotypic diversity and environmental adaptation in plants and animals, significantly influencing key agronomic traits in crops. Common wheat (Triticum aestivum L.), an allohexaploid species, harbors extensive chromosomal SVs and distant hybridization-induced recombination events that provide critical resources for genetic improvement. This study utilizes non-denaturing fluorescence in situ hybridization (ND-FISH) and oligonucleotide multiplex probe-based FISH (ONPM-FISH) to analyze the karyotypes of 153 BC₁F₄–BC₁F₆ lines derived from the hybrid line Xiaoyan 7430 and common wheat Yannong 1212. The results revealed that Xiaoyan 7430 carries 8 alien chromosome pairs and 20 wheat chromosome pairs (lacking 6B), and Yannong 1212 contains 21 pairs of wheat chromosomes. The parental lines exhibited presence/absence variations (PAVs) on chromosomes 2A, 6A, 5B, 1D, and 2D. Chromosomal variations, including numerical chromosomal variation (NCV), structural chromosomal variation (SCV), and complex chromosomal variation (CCV), were detected in the progeny lines through ONPM-FISH analysis. The tracking of alien chromosomes over three consecutive generations revealed a significant decrease in transmission frequency, declining from 61.82% in BC₁F₄ to 26.83% in BC₁F₆. Telosomes were also lost during transmission, declining from 21.82% in BC₁F₄ to 9.76% in BC₁F₆. Alien chromosome 1J^S, 4J, and 6J exhibited the highest transmission stability and were detected across all three generations. Association analysis showed that YN-PAV.2A significantly affected the length/width ratio (LWR) and grain diameter (GD); YN-PAV.6A, XY-PAV.6A, and PAV.5B increased six grain traits (+2.25%~15.36%); YN-PAV.1D negatively affected grain length (GL) and grain circumference (GC); and XY-PAV.2D exerted positive effects on thousand-grain weight (TGW). Alien chromosomes differentially modulated grain characteristics: 1J^S and 6J both reduced grain length and grain circumference; 1J^S increased LWR; and 4J negatively impacted TGW, grain width (GW), GD, and grain area (GA). Meanwhile, increasing alien chromosome numbers correlated with progressively stronger negative effects on grain traits. These findings elucidate the genetic mechanisms underlying wheat chromosomal variations induced by distant hybridization and their impact on wheat grain traits, and provide critical intermediate materials for genome design breeding and marker-assisted selection in wheat improvement. Full article

Background/Objectives: Galectin-3 (Gal-3), encoded by LGALS3, is a β-galactoside-binding lectin involved in diverse tumor-associated processes, including immune modulation, cell cycle regulation, and stress adaptation. Despite its known roles in cancer biology, the full extent of its molecular functions and prognostic relevance across tumor types remains incompletely understood. This study aimed to systematically investigate the transcriptomic impact of LGALS3 deletion and assess its clinical significance in cancer. Methods: We analyzed CRISPR-Cas9 knockout transcriptomic data from the SigCom LINCS database to characterize the consensus gene signature associated with LGALS3 loss using functional enrichment analyses. Pan-cancer survival analyses were conducted using TIMER2.0. Differential Gal-3 protein levels in ductal adenocarcinoma and normal pancreatic tissues were evaluated using the Human Protein Atlas. Finally, functional analyses were performed in pancreatic ductal adenocarcinoma (PDAC). Results: LGALS3 deletion across multiple cancer cell lines led to transcriptomic changes involving mitotic progression, stress responses, and axonal guidance pathways. High LGALS3 expression was significantly associated with worse overall survival in lower-grade glioma, PDAC, uveal melanoma, and kidney renal papillary cell carcinoma. LGALS3 knockout in YAPC cells recapitulated the pan-cancer findings, linking LGALS3 to cell morphogenesis and proliferation. Conclusions: These findings identify Galectin-3 as a key regulator of oncogenic programs and a potential prognostic biomarker in PDAC and other malignancies, with implications for therapeutic targeting. Full article

Generating non-standard fonts, such as running script (e.g., XingShu), poses significant challenges due to their high stroke continuity, structural flexibility, and stylistic diversity, which traditional component-based prior knowledge methods struggle to model effectively. While diffusion models excel at capturing continuous feature spaces and stroke variations through iterative denoising, they face critical limitations: (1) style leakage, where large stylistic differences lead to inconsistent outputs due to noise interference; (2) structural distortion, caused by the absence of explicit structural guidance, resulting in broken strokes or deformed glyphs; and (3) style confusion, where similar font styles are inadequately distinguished, producing ambiguous results. To address these issues, we propose a novel skeleton-guided diffusion model with three key innovations: (1) a skeleton-constrained style rendering module that enforces semantic alignment and balanced energy constraints to amplify critical skeletal features, mitigating style leakage and ensuring stylistic consistency; (2) a cross-scale skeleton preservation module that integrates multi-scale glyph skeleton information through cross-dimensional interactions, effectively modeling macro-level layouts and micro-level stroke details to prevent structural distortions; (3) a contrastive style refinement module that leverages skeleton decomposition and recombination strategies, coupled with contrastive learning on positive and negative samples, to establish robust style representations and disambiguate similar styles. Extensive experiments on diverse font datasets demonstrate that our approach significantly improves the generation quality, achieving superior style fidelity, structural integrity, and style differentiation compared to state-of-the-art diffusion-based font generation methods. 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

White tea quality is primarily determined by its chemical composition, which varies significantly among cultivars. This study aimed to elucidate the chemical basis underlying quality differentiation in Baimudan white tea produced from three major Fujian tea cultivars: “Zhenghe Dabaicha” (ZHDB), “Fuan Dabaicha” (FADB), and “Fuding Dahaocha” (FDDH). Headspace solid-phase microextraction coupled with gas chromatography–mass spectrometry (HS-SPME-GC-MS), liquid chromatography–mass spectrometry (LC-MS), and quantitative descriptive analysis (QDA) were employed to characterize volatile compounds, amino acids, and saccharides. Odor Activity Values (OAVs) and Taste Activity Values (TAVs) were calculated to identify key contributors to sensory perception. Results showed that theanine, glutamic acid, asparagine, and serine were the primary contributors to umami taste, especially in ZHDB and FADB. Sweetness differences were largely due to sucrose, serine, and asparagine. OAV analysis further identified 22 critical aroma compounds: methyl salicylate, linalool, and β-ionone predominantly imparted floral notes, while β-ocimene, benzaldehyde, and geraniol enhanced sweet and fruity aromas. In contrast, (Z)-3-hexenol, (Z)-3-hexenal, and (E)-2-hexenal contributed grassy and refreshing characteristics, together defining the unique aroma profiles of each cultivar. This study provides an integrated chemical and sensory framework for understanding white tea quality variation, offering a theoretical basis for targeted flavor modulation. Full article

Adipose tissue renewal requires precise coordination of stem/progenitor cell proliferation, preadipocyte commitment, and terminal adipocyte differentiation. T-cadherin (CDH13), an atypical GPI-anchored cadherin, is expressed in adipose tissue and functions as a receptor for high-molecular-weight (HMW) adiponectin—a key adipokine produced by adipose tissue and involved in metabolic regulation. While T-cadherin is implicated in cardiovascular and metabolic homeostasis, its role in adipogenesis still remains poorly understood. In this study, we used the 3T3-L1 preadipocyte model to investigate the function of T-cadherin in adipocyte differentiation. We analyzed T-cadherin expression dynamics during differentiation and assessed how T-cadherin overexpression or knockdown affects lipid accumulation, expression of adipogenic markers, and key signaling pathways including ERK, PI3K–AKT, AMPK, and mTOR. Our findings demonstrate that T-cadherin acts as a negative regulator of adipogenesis. T-cadherin overexpression ensured a proliferative, undifferentiated cell state, delaying early adipogenic differentiation and suppressing both lipid droplet accumulation and the expression of adipogenic markers. In contrast, T-cadherin downregulation accelerated differentiation, enhanced lipid accumulation, and increased insulin responsiveness, as indicated by PI3K–AKT pathway activation at specific stages of adipogenesis. These results position T-cadherin as a key modulator of adipose tissue plasticity, regulating the balance between progenitor expansion and terminal differentiation, with potential relevance to obesity and metabolic disease. Full article

Pulmonary fibrosis (PF) is a progressive and fatal lung disease characterized by irreversible alveolar destruction and pathological extracellular matrix (ECM) deposition. Currently approved agents (pirfenidone and nintedanib) slow functional decline but do not reverse established fibrosis or restore functional alveoli. Multifunctional bioscaffolds present a promising therapeutic strategy through targeted modulation of critical cellular processes, including proliferation, migration, and differentiation. This review synthesizes recent advances in scaffold-based interventions for PF, with a focus on their dual mechano-epigenetic regulatory functions. We delineate how scaffold properties (elastic modulus, stiffness gradients, dynamic mechanical cues) direct cell fate decisions via mechanotransduction pathways, exemplified by focal adhesion–cytoskeleton coupling. Critically, we highlight how pathological mechanical inputs establish and perpetuate self-reinforcing epigenetic barriers to regeneration through aberrant chromatin states. Furthermore, we examine scaffolds as platforms for precision epigenetic drug delivery, particularly controlled release of inhibitors targeting DNA methyltransferases (DNMTi) and histone deacetylases (HDACi) to disrupt this mechano-reinforced barrier. Evidence from PF murine models and ex vivo lung slice cultures demonstrate scaffold-mediated remodeling of the fibrotic niche, with key studies reporting substantial reductions in collagen deposition and significant increases in alveolar epithelial cell markers following intervention. These quantitative outcomes highlight enhanced alveolar epithelial plasticity and upregulating antifibrotic gene networks. Emerging integration of stimuli-responsive biomaterials, CRISPR/dCas9-based epigenetic editors, and AI-driven design to enhance scaffold functionality is discussed. Collectively, multifunctional bioscaffolds hold significant potential for clinical translation by uniquely co-targeting mechanotransduction and epigenetic reprogramming. Future work will need to resolve persistent challenges, including the erasure of pathological mechanical memory and precise spatiotemporal control of epigenetic modifiers in vivo, to unlock their full therapeutic potential. Full article

The methylation of CpG sites with 5mC mark is a dynamic epigenetic modification. However, the relationship between the methylation and the surrounding genomic sequence context remains poorly explored. Investigation of the allele methylation provides an opportunity to decipher the interplay between differences in the primary DNA sequence and epigenetic variation. Here, we performed high-coverage long-read whole-genome direct DNA sequencing of one individual using Oxford Nanopore technology. We also used Illumina whole-genome sequencing of the parental genomes in order to identify allele-specific methylation sites with a trio-binning approach. We have compared the results of the haplotype-specific methylation detection and revealed that trio binning outperformed other approaches that do not take into account parental information. Also, we analysed the cis-regulatory effects of the genomic variations for influence on CpG methylation. To this end, we have used available Deep Learning models trained on the primary DNA sequence to score the cis-regulatory potential of the genomic loci. We evaluated the functional role of the allele-specific epigenetic changes with respect to gene expression using long-read Nanopore RNA sequencing. Our analysis revealed that the frequency of SNVs near allele-specific methylation positions is approximately four times higher compared to the biallelic methylation positions. In addition, we identified that allele-specific methylation sites are more conserved and enriched at the chromatin states corresponding to bivalent promoters and enhancers. Together, these findings suggest that significant impact on methylation can be encoded in the DNA sequence context. In order to elucidate the effect of the SNVs around sites of allele-specific methylation, we applied the Deep Learning model for detection of the cis-regulatory modules and estimated the impact that a genomic variant brings with respect to changes to the regulatory activity of a DNA loci. We revealed higher cis-regulatory impact variants near differentially methylated sites that we further coupled with transcriptomic long-read sequencing results. Our investigation also highlights technical aspects of allele methylation analysis and the impact of sequencing coverage on the accuracy of genomic phasing. In particular, increasing coverage above 30X does not lead to a significant improvement in allele-specific methylation discovery, and only the addition of trio binning information significantly improves phasing. We investigated genomic variation in a single human individual and coupled computational discovery of cis-regulatory modules with allele-specific methylation (ASM) profiling. In this proof-of-concept analysis, we observed that SNPs located near methylated CpG sites on the same haplotype were enriched for sequence features suggestive of high-impact regulatory potential. This finding—derived from one deeply sequenced genome—illustrates how phased genetic and epigenetic data analyses can jointly put forward a hypotheses about the involvement of regulatory protein machinery in shaping allele-specific epigenetic states. Our investigation provides a methodological framework and candidate loci for future studies of genomic imprinting and cis-mediated epigenetic regulation in humans. Full article

The present study analyses various mathematical models from the technical literature for calculating photovoltaic cell temperature, emphasizing wind velocity as a key parameter. Since cell temperature significantly affects photovoltaic module efficiency, researchers are actively pursuing simple and cost-effective cooling methods for these systems. First, the study surveys existing mathematical models for computing cell temperature and evaluates how model parameters affect calculations. Second, it demonstrates computational outcomes using selected formulae—chosen based on criteria outlined in the paper—to predict PV cell temperatures under varying wind conditions using meteorological data from Bucharest, Romania. The analysis employs a transient mathematical model based on a single ordinary differential equation, validated against experimental data from previous studies. The results reveal circumstances where alternative mathematical approaches produce similar outcomes, alongside situations where substantial discrepancies emerge. The investigation concludes by contrasting computational forecasts against empirical observations, providing valuable guidance for future research in this domain. Full article

Atopic dermatitis (AD) is the most common chronic inflammatory skin disease, characterized by pruritic and eczematous lesions. Skin barrier dysfunction and aberrant inflammatory responses are hallmark features of AD. Recent genome-wide association studies have implicated NLRP10, a unique member of the NOD-like receptors (NLRs) lacking a leucine-rich repeat (LRR) domain, in AD susceptibility. Unlike other NLRs, the physiological role of NLRP10 in skin remains incompletely understood. Emerging evidence shows that NLRP10 regulates keratinocyte survival and differentiation, acts as a molecular sensor for mitochondrial damage, enhances anti-microbial response and contributes to skin barrier function. This review summarizes current insights into NLRP10′s functions in skin homeostasis, its interplay with cell death pathways, and its role in maintaining skin barrier function. Furthermore, therapeutic opportunities to target NLRP10 as a novel strategy for modulating epidermal cell death and restoring barrier function in AD are highlighted. Full article

We present a tunable diode-laser absorption spectroscopy (TDLAS) system operating at 1.5711 µm for CO₂ gas concentration measurements. The system can operate in either a traditional direct-mode (dTDLAS) sawtooth wavelength scan or a recently demonstrated wavelength-toggled single laser differential-absorption lidar (WTSL-DIAL) mode using precompensated current pulses. The use of such precompensated pulses offsets the slow thermal constants of the diode laser, leading to fast toggling between ON and OFF-resonance wavelengths. A short measurement time is indeed pivotal for atmospheric sensing, where ambient factors, such as turbulence or mechanical vibrations, would otherwise deteriorate sensitivity, precision and accuracy. Having a system able to operate in both modes allows us to benchmark the novel experimental procedure against the well-established dTDLAS method. The theory behind the new WTSL-DIAL method is also expanded to include the periodicity of the current modulation, fundamental for the calculation of the OFF-resonance wavelength. A two-detector scheme is chosen to suppress the influence of laser intensity fluctuations in time (1/f noise), and its performance is eventually benchmarked against a one-detector approach. The main difference between dTDLAS and WTSL-DIAL, in terms of signal processing, lies in the fact that while the former requires time-consuming data processing, which limits the maximum update rate of the instrument, the latter allows for computationally simpler and faster concentration readings. To compare other performance metrics, the update rate was kept at 2 kHz for both methods. To analyze the dTDLAS data, a four-parameter Lorentzian fit was performed, where the fitting function comprised the six main neighboring absorption lines centered around 1.5711 µm. Similarly, the spectral overlap between the same lines was considered when analyzing the WTSL-DIAL data in real time. Our investigation shows that, for the studied time intervals, the WTSL-DIAL approach is 3.65 ± 0.04 times more precise; however, the dTDLAS-derived CO₂ concentration measurements are less subject to systematic errors, in particular pressure-induced ones. The experimental results are accompanied by a thorough explanation and discussion of the models used, as well as their advantages and limitations. Full article

The Nile tilapia (Oreochromis niloticus), a key aquaculture species, displays marked sexual growth dimorphism, with males growing faster than females. This process is governed by intricate interactions between antagonistic regulators, including transcription factors, growth factors, and steroid hormones, operating through sex-specific developmental pathways. While circular RNAs (circRNAs) are known to modulate gene expression by sponging microRNAs (miRNAs), their role in teleost sex differentiation remains poorly understood. To address this gap, we profiled circRNA expression in tilapia gonads by constructing six circRNA libraries from testes and ovaries of 180 days after hatching (dah) fish, followed by high-throughput sequencing. We identified 6564 gonadal circRNAs distributed across all 22 linkage groups, including 226 differentially expressed circRNAs (DECs; 108 testis-biased, 118 ovary-biased). Functional enrichment analysis linked their host genes to critical pathways such as cAMP signaling, cell adhesion molecules, and—notably—sexual differentiation processes (e.g., estrogen signaling, oocyte meiosis, and steroid hormone biosynthesis). Furthermore, we deciphered competing endogenous RNA (ceRNA) networks, uncovering circRNA–miRNA–mRNA interactions targeting germ cell determinants, sex-specific transcription factors, and steroidogenic enzymes. This study provides the first systematic exploration of circRNA involvement in tilapia sex differentiation and gonadal differentiation, offering novel insights into the post-transcriptional regulation of sexual dimorphism. Our findings advance the understanding of circRNA biology in fish and establish a framework for future studies on aquaculture species with similar reproductive strategies. Full article

Goose astrovirus (GAstV) infection has emerged as a prevalent cause of urate deposition and viral gout in major goose farming across China, leading to high mortality and substantial economic losses. However, the molecular mechanisms linking GAstV to gout pathogenesis remain elusive. Here, a total of 10 five-day-old Jiangnan white goslings were selected, and tissue damage and kidney gene expression profiles were investigated. The results showed multi-organ damage in GAstV-infected gosling, including kidney, liver, spleen, and lung. Also, 342 differentially expressed genes were identified in infected kidney tissues after 10 days post-infection using transcriptomic sequencing, including 185 upregulated and 157 downregulated genes. In addition, gene set enrichment analysis revealed significant positive correlations between GAstV infection and bile acid metabolism and fatty acid metabolism pathways. Notably, bile acid metabolism was implicated in uric acid regulation and gout progression. Protein–protein interaction network analysis identified AGXT as a central hub gene within the bile acid metabolic pathway, with key upregulated interactors including PIPOX, ALDH1A1, and CAT. AGXT, a critical enzyme in glyoxylate detoxification, directly modulates uric acid biosynthesis. Our findings propose that GAstV-induced activation of bile acid metabolism, particularly AGXT upregulation, drives hyperuricemia and subsequent gout pathology. This study elucidates a novel mechanism of GAstV-associated metabolic dysregulation and provides actionable genetic targets for antiviral breeding strategies in waterfowl. Full article