Search Results (37,327)

Sox9, a pivotal transcription factor belonging to the Sox family, orchestrates critical processes throughout embryonic development, maintenance and differentiation, and exerts a profound influence on organogenesis. Its regulatory versatility stems from precise binding to defined DNA regions, often in collaboration with tissue-specific partners. The dysregulation of Sox9 during chondrogenesis leads to a skeletal malformation termed campomelic dysplasia and has emerged as a significant factor in various other human diseases, including cancer. A point mutation at position 76 (alanine to glutamic acid, A76E) of Sox9 is recognized as one of the causes of campomelic dysplasia. We have used a combination of biophysical, structural and computational techniques to characterize the Sox9 A76E mutant and compare it with the wild-type (WT) Sox9. WT and A76E Sox9 assemble as homodimers, but form predominantly monomeric complexes in the presence of Sox-specific DNA. A CD analysis shows that the A76E mutant preserves the folding as well as the overall secondary structure of Sox9. Both A76E and WT Sox9 behave similarly in the presence of Sox-specific DNA. Perturbation, with increased temperature, displays a lower melting point for A76E, relative to WT Sox9, indicating decreased stability that may arise due to the long and charged side chain of glutamic acid compared to the small hydrophobic alanine, making unfavorable intra-molecular interactions. The destabilizing effect of the A76E mutant may disturb the formation of a stable higher-order complex that is a prerequisite for normal gene expression. Full article

Per- and polyfluoroalkyl substances (PFAS) are a class of synthetic chemicals notable for their high persistence and extensive applications. With the advancement of detection technologies in recent years, PFAS have been frequently identified in environmental media and human biological samples, raising significant global concerns about their potential health risks. PFAS exhibit distinctive toxicokinetic behaviors, including efficient absorption, strong protein binding, limited metabolism, and slow excretion, which lead to prolonged biological half-lives and considerable bioaccumulation in humans. These properties contribute to a range of adverse health outcomes, such as endocrine disruption, immune suppression, liver damage, reproductive toxicity, carcinogenic potential, and cardiovascular disease. This review synthesizes evidence on PFAS-associated health risks from a multisystem, multitarget perspective, elucidating the key molecular pathways involved, thereby providing a scientific basis for understanding their complex toxicological effects and for developing targeted prevention and control strategies. Future research should prioritize characterizing the toxicological profiles of individual PFAS compounds, evaluating the health impacts of combined (mixture) exposures, and assessing risks associated with chronic, low-dose exposure to support the development of public health strategies and regulatory decisions. Full article

Antimicrobial resistance (AMR) is increasingly becoming a major global public health concern, as antibiotics are losing their effectiveness at an alarming rate due to drug resistance. The ß-lactam group of antibiotics are widely used in dairy farms to treat animal infections, and their presence in the food chain is a significant concern. Addressing this issue requires the development of effective analytical tools for the rapid detection of antibiotics. In this work, a miniaturized Biosensor-on-Pillar platform was developed for detecting ß-lactam antibiotics in milk, which operates in a rapid, cost-effective, and user-friendly format, making it particularly suitable for resource-limited settings. The platform employs an enzyme induction-based approach, wherein Bacillus cereus spores germinate in the presence of β-lactam antibiotics, leading to the production of β-lactamase enzyme, which is then recognized using a chromogenic substrate functionalized on paper associated with the pillar platform. The developed biosensor can detect 12 β-lactam antibiotics with limits of detection (LODs) ranging from 1 to 1000 ppb, achieving sensitivity at or below the maximum residue limits (MRLs) set by regulatory bodies (FSSAI/CODEX) for the majority of the tested antibiotics. The performance of the platform, including the design, fabrication, and working principle, was further evaluated by analyzing six blind milk samples, yielding significant results compared to the commercially available AOAC-approved gold-standard method. Hence, the developed biosensor demonstrates promising potential for the rapid, cost-effective and high-throughput screening of milk samples for β-lactam antibiotics, benefiting the dairy industry and ensuring food safety. Full article

Cognitive models of depression posit a core role for attentional biases, though empirical evidence remains inconsistent, likely due to variations in task demands. This study utilized eye-tracking to assess attentional patterns in individuals with depressive symptoms during a goal-directed visual search task, specifically dissociating early orienting and late disengagement. Seventy-seven participants, classified into high (HD) and low (LD) depressive-symptom groups based on PHQ-9 scores, completed a “face-in-the-crowd” (FITC) task. The set size (4, 8, or 12 faces) was varied to examine the role of perceptual load. The task involved searching for a single emotional target among neutral distractors (assessing early orienting) and searching for a single neutral target among emotional distractors (assessing late disengagement). Contrary to the negativity-bias hypothesis, the HD group demonstrated what might be interpreted as adaptive attentional regulation. During early orienting (8-face condition), the HD group showed reduced total dwell time on happy targets, suggesting accelerated identification. An attentional bias index (sad minus happy dwell time) correlated positively with depression severity. During late disengagement (8-face condition), the HD group exhibited shorter target fixation latency specifically with sad distractors, indicating facilitated disengagement from negative information. The corresponding bias index correlated negatively with depression levels. Under explicit goal-directed demands, individuals with high depressive symptoms displayed facilitated processing of happy faces and accelerated disengagement from sad faces, rather than an enhanced negativity bias. This pattern tentatively suggests a possible adaptive attentional regulatory mechanism in early depression, although the findings were limited to the 8-face condition and no significant group differences emerged at set sizes 4 or 12. Replication is required before firm conclusions can be drawn. The result underscores the critical influence of task demands and highlights the value of early identification and targeted intervention. Full article

Teat number is an important economic trait in pigs because it affects sow reproductive performance and piglet nursing ability, yet its genetic basis and molecular regulatory mechanisms remain incompletely understood. In this study, a combined-population genome-wide association study was performed in Canadian and French Large White pigs to identify loci associated with teat number traits. A total of 4217 pigs were genotyped, and 2,244,684 autosomal single-nucleotide polymorphisms were retained after quality control and genotype imputation. Multiple association signals for total teat number were detected, with major peaks located on chromosomes 7 and 10. Among the positional candidate genes, PROX2 was prioritized for further validation, and genotype–phenotype association analysis showed that pigs with the CC genotype at the PROX2 polymorphic locus had significantly lower total teat number than those with the CT and TT genotypes. To investigate its biological role, PROX2 was silenced in porcine mammary epithelial cells. Transcriptome analysis identified 887 differentially expressed genes after PROX2 knockdown, and functional assays showed that PROX2 silencing inhibited cell proliferation, altered cell cycle progression, and affected the expression of proliferation- and development-related genes. These findings indicate that PROX2 is an important candidate gene associated with teat number variation in pigs. Full article

Nitrate (NO₃⁻) serves as a pivotal molecule with dual functions in nutrient supply and signaling during plant growth and development. Precise monitoring of its spatiotemporal dynamics in planta is therefore essential for dissecting the regulatory mechanisms underlying plant nitrogen metabolism. However, conventional nitrate detection methods suffer from inherent limitations, including destructive sampling, insufficient spatiotemporal resolution, and an inability to achieve real-time whole-plant monitoring. Here, we report a genetically encoded nitrate biosensor, designated NitNRCL1, constructed using a split firefly luciferase complementation system. Functional validation in both prokaryotic and eukaryotic systems demonstrates that NitNRCL1 responds to changes in nitrate availability and generates stable chemiluminescent signals in bacteria and diverse plant species. Importantly, NitNRCL1 enables non-invasive, real-time, and whole-plant monitoring of nitrate levels in living plants. Using NitNRCL1, we successfully imaged the spatiotemporal dynamics of nitrate signaling in Arabidopsis thaliana. Collectively, our findings establish NitNRCL1 as a robust and novel tool for investigating nitrate transport, signaling, and metabolic pathways in plants. This biosensor advances our mechanistic understanding of plant nitrate biology and provides a technical foundation for breeding nitrogen-use-efficient crops and developing precision fertilization strategies. Full article

The decarbonization of international shipping has accelerated interest in ammonia as a zero-carbon marine fuel. However, its acute toxicity poses safety challenges fundamentally different from those associated with LNG. This study presents a structured comparative regulatory analysis of the IGF Code and the IMO Interim Guidelines for Ships Using Ammonia as Fuel through a chapter-by-chapter review of key safety domains. The results show that, despite structural similarities, the two frameworks diverge significantly in their underlying safety logic: LNG regulation is primarily oriented toward flammability and explosion prevention, whereas ammonia regulation adopts a toxicity-driven safety architecture. This shift is reflected in ppm-level gas detection thresholds, ammonia release mitigation systems (ARMS), toxic area and Safe Haven concepts, broader secondary containment measures, and enhanced personnel protection requirements. These findings suggest that ammonia safety cannot be adequately addressed through incremental extensions of LNG-based rules alone. Instead, it requires a dedicated regulatory approach that explicitly incorporates toxic exposure management into ship design and operation. Full article

Cropland protection enforcement is central to food security and sustainable land management, yet small-scale encroachments within Permanent Basic Farmland (PBF) boundaries frequently evade conventional field surveys and reactive inspection regimes. Existing remote sensing approaches rely mainly on comprehensive land-cover classification or bi-temporal change detection, which often generate alerts beyond the regulatory scope and require annotation efforts that limit county-scale deployment. To address this gap, this study reframes PBF monitoring as a boundary-constrained anomaly screening task, defined as the detection of surface conditions that deviate from expected cultivation norms within legally defined parcels. To operationalise this task, we adapt a DeepLabv3+-based segmentation pipeline by incorporating an auxiliary edge branch and a composite loss to improve sensitivity to minority-class anomalies and preserve fragmented parcel boundaries. The model is trained on the LoveDA dataset and evaluated in Mancheng District, Hebei Province, China, without site-specific fine-tuning. Multi-temporal imagery from 2021 to 2023 is further used as a post hoc consistency check to distinguish persistent anomalies from transient surface conditions, rather than to model temporal dynamics explicitly. Cross-regional zero-shot evaluation further examines model robustness under heterogeneous environmental conditions. Benchmarked against five comparison architectures, the adapted pipeline achieves a Recall of 61.25%, representing a 10.24 percentage-point improvement over DeepLabv3+ and expanding the set of candidate encroachments for field verification. This result should be interpreted in terms of screening sensitivity rather than overall segmentation optimisation. The outputs are intended as preliminary screening leads that support, rather than replace, expert review. The principal contribution of this study therefore lies in reframing PBF monitoring as an operational anomaly-screening task aligned with enforcement needs, rather than in proposing a fundamentally new segmentation architecture. Full article

Immune dysregulation is being increasingly recognized as a prominent feature of a wide range inborn errors of immunity (IEIs) with different molecular backgrounds. Among the manifestations of immune dysregulation, inflammatory arthritis has emerged as an important yet underrecognized complication that may occur across multiple IEI categories, including humoral immunodeficiencies (such as X-linked agammaglobulinemia, hyper-IgM syndrome, common variable immunodeficiency, and others), complement deficiencies, disorders of immune dysregulation (STAT3 gain of function mutation, CTLA4 and LRBA haploinsufficiency), and combined immunodeficiencies. In some patients, arthritis may represent the first or predominant clinical manifestation, resulting in a diagnostic challenge in the rheumatologic setting. The pathogenesis of arthritis in IEIs reflects different immunological mechanisms, including the defective clearance of immune complexes, dysregulated B- and T-cell responses, impaired regulatory T-cell function, and aberrant cytokine signaling. Clinically, IEI-associated arthritis may mimic classical rheumatologic conditions such as juvenile idiopathic arthritis, rheumatoid arthritis, or other connective tissue diseases, although distinctive immunological and histopathological features are often present. Recognizing arthritis as a potential manifestation of IEIs has important clinical implications. The presence of specific “red flags”, including treatment refractoriness, recurrent infections, or additional signs of immune dysregulation (other autoimmune diseases, atopy, lymphoproliferation, enteropathy), should prompt targeted immunological evaluation. While management often relies on conventional immunosuppressive therapies, advances in the molecular characterization of IEIs are increasingly enabling the use of targeted treatments directed at the underlying pathogenic mechanisms. This paper provides an overview of the current knowledge of arthritis associated with IEIs, highlighting diagnostic challenges, underlying immunopathogenic mechanisms, and emerging therapeutic perspectives. Full article

The article provides a comprehensive overview of the role of hydrogen as a key vector in the decarbonization of the global transport sector. The study situates hydrogen within the broader context of energy transition and climate neutrality targets, emphasizing its potential to replace fossil fuels in road, rail, maritime, and aviation applications. The analysis integrates a review of current technological, infrastructural, and policy developments, covering both combustion-based and fuel-cell hydrogen propulsion systems. Quantitative and qualitative data were assessed from international reports, scientific publications, and ongoing industrial projects to evaluate performance, efficiency, safety, and cost parameters such as Levelized Cost of Hydrogen (LCOH) and Total Cost of Ownership (TCO). The results indicate that while hydrogen remains economically challenging, technological progress in electrolysis, fuel cells, and refueling infrastructure significantly improves its competitiveness, particularly in heavy-duty and long-range transport. The paper highlights the critical role of international strategies, including the European Hydrogen Strategy and Fit for 55 package, in driving market adoption and regulatory alignment. The conclusions suggest that by 2050, hydrogen could contribute up to one-quarter of total transport energy demand, positioning it as a cornerstone of sustainable mobility and a bridge toward a fully decarbonized transport ecosystem. Full article

Breast cancer stem-like cells (bCSCs) fundamentally represent a highly dynamic “immune-adaptive functional state” rather than a fixed cellular lineage, serving as the core engine driving tumor recurrence, metastasis, and therapeutic resistance. Despite rapid advances, the heterogeneity of bCSC states and their intricate interactions with the immune microenvironment lack systematic integration. This review centers on the dynamic evolution and niche adaptation of bCSCs. First, we systematically dissect the multilayered regulatory network maintaining stemness, encompassing core transcription factors, epigenetic–metabolic coupling, and the synergistic mechanisms of critical signaling pathways such as Wnt and Notch. Second, we propose a trinary “stemness–immune–spatial” feedback model, elucidating how bCSCs achieve active immune evasion by downregulating antigen presentation, secreting immunosuppressive factors, and embedding within perivascular “immune-cold niches.” Finally, leveraging a multi-omics integration perspective, we reconstruct precision intervention strategies, exploring the synergistic potential of targeting stemness pathways in conjunction with immunotherapies like PD-1/PD-L1 blockade and STING agonists. Furthermore, we highlight the pivotal role of integrating organoids, PDX models, and AI-assisted decision systems in overcoming heterogeneity and enabling personalized treatment. By establishing a closed-loop framework spanning mechanistic insight to spatially precise intervention, this review aims to provide novel theoretical foundations and translational pathways to surmount the bottleneck of therapeutic resistance in breast cancer. Full article

Osmotic stress limits rice productivity, yet the crosstalk between hydrogen sulfide signaling and redox regulation remains incompletely understood. We previously showed that redox-dependent oligomerization of the basic (region) leucine zippers transcription factor bZIP68 at Cys245 confers osmotic tolerance. However, the role of an adjacent cysteine, Cys171, was undefined. Here, we demonstrate that osmotic stress induces persulfidation of bZIP68 specifically at Cys171. This modification facilitates Cys245-mediated oxidation-dependent oligomerization, thereby enhancing bZIP68 transcriptional activity toward COLD-REGULATED413-THYLAKOID MEMBRANE1 (COR413-TM1). Transgenic complementation and physiological assays confirmed that Cys171 persulfidation is essential for full bZIP68 function in osmotic adaptation. Transcriptomic analysis further revealed that Cys171 is required for bZIP68-driven transcriptional reprogramming under stress. Our findings establish a hierarchical redox cascade wherein persulfidation primes bZIP68 for oxidative activation, highlighting a regulatory crosstalk between distinct post-translational modifications. These mechanistic insights expand our understanding of H₂S signaling and identify the bZIP68 cysteine network as a potential target for improving crop stress resilience. Full article

Ethylene is a key phytohormone regulating fruit ripening, the senescence of ornamental plants, and the post-harvest quality of horticultural products. Although numerous studies have described compounds that inhibit ethylene biosynthesis or perception, the available evidence remains fragmented across chemical groups, plant species, and pre- and post-harvest applications. This review addresses that gap by critically integrating current knowledge on the principal inhibitors of ethylene biosynthesis and perception used in horticulture, with emphasis on their sites of action, practical effectiveness, and limitations. Biosynthesis inhibitors, including aminoethoxyvinylglycine (AVG), aminooxyacetic acid (AOA), daminozide, benzyl isothiocyanate (BITC), and oxalic acid (OA), reduce ethylene production at different stages of the ethylene pathway, whereas perception inhibitors such as 1-methylcyclopropene, 1-DCP, silver compounds, alkenes, and diazocyclopentadiene interfere with receptor binding and downstream ripening responses. The available literature indicates that 1-methylcyclopropene remains the most widely used commercial inhibitor, while oxalic acid is emerging as a promising natural modulator of ethylene-related processes. However, the efficacy of these compounds is strongly dependent on species, maturity stage, dose, temperature, and storage conditions, and some are additionally constrained by regulatory concerns, incomplete mechanistic understanding, or inconsistent performance. Overall, ethylene inhibitors are important tools for extending shelf life, maintaining firmness, delaying senescence, and reducing post-harvest losses. Further comparative and crop-specific studies are needed to optimize application strategies, improve environmental safety, and support the development of effective natural alternatives. Full article

Decentralised manufacturing is expanding as digitally controlled fabrication tools become accessible to SMEs, independent operators, and community workshops outside traditional factory settings, but the resulting heterogeneous, autonomously operated network introduces systemic uncertainty that no central authority governs. This paper proposes a systems-theoretic framework in which Free and Open-Source Software (FOSS) governance acts as the structural interoperability layer of a distributed cyber–physical manufacturing system (CPS), and node-local digital twins—each hosting a machine learning (ML) disturbance estimator—provide local adaptive compensation without centralised data aggregation. A defining property of the architecture is automatic improvement propagation: learned corrections distribute via federated learning to structurally similar nodes without operator intervention, and the open, observable FOSS ecosystem enables advances in one fabrication modality to transfer to others through shared interface standards. The framework is applied analytically to three disturbance classes: regulatory restriction, technical process variability, and supply chain disruption. Across cases, the analysis shows how open modular interfaces and local adaptation preserve functional continuity under perturbations that would more strongly affect centralised architectures. The contribution is a unified mathematical basis for robustness analysis in decentralised manufacturing CPS and a foundation for future simulation and empirical validation. Full article

Oxidative stress is a key contributor to the pathogenesis of immune-mediated diseases through its effects on cellular metabolism, mitochondrial function, immune signaling pathways, and inflammatory tissue injury. Disruption of redox homeostasis promotes metabolic reprogramming and persistent activation of innate and adaptive immune responses, contributing to disease progression across multiple inflammatory and autoimmune disorders. Recent advances in high throughput molecular technologies have generated large scale multi-omics datasets that enable comprehensive investigation of redox-associated mechanisms at a systems level. Integration of these datasets with computational analytical approaches has facilitated the identification of multidimensional molecular signatures associated with disease development and progression. This systematic review evaluates studies applying computational frameworks to analyze redox-related molecular data in immune-mediated diseases including multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis, Sjögren’s syndrome, and inflammatory bowel disease. Across the reviewed studies, oxidative stress associated with molecular signatures were consistently linked to immune activation, mitochondrial metabolism, and inflammatory signaling pathways. Computational analyses also identified regulatory genes involved in antioxidant defense and metabolic regulation, as well as pathways associated with regulated cell death. These findings highlight the translational potential of computational redox analysis for biomarker discovery, disease stratification, and development of targeted therapeutic strategies aimed at restoring redox balance and improving clinical management of immune-mediated diseases. Full article