Search Results (6,316)

Saline–alkaline water resources are globally widespread, and their rational development offers significant potential to alleviate freshwater scarcity. Saline–alkaline water aquaculture farming not only affects fish growth and survival but also impairs reproductive and developmental functions. Largemouth bass (Micropterus salmoides), an economically important fish, has demonstrated excellent high tolerance to such environments, in order to investigate the effects of alkaline water aquaculture environments on its growth performance, sex hormone levels, gonadal development, and molecular adaptation mechanisms. In this study, largemouth bass were chronically exposed to freshwater (0.55 mmol/L), low alkalinity (10 mmol/L), or high alkalinity (25 mmol/L) and cultured for 80 days. Alkalinity exposure more severely impacted the growth rate of females. High alkalinity significantly increased the hepatosomatic index and decreased the gonadosomatic index in both sexes; moreover, it induced oxidative stress in both sexes, evidenced by reduced superoxide dismutase (SOD), catalase (CAT), and total antioxidant capacity (TAOC) levels and elevated malondialdehyde (MDA) content. Furthermore, the levels of sex hormones Serum estradiol (E2), 11-ketotestosterone (11-KT), and testosterone were significantly reduced, accompanied by either an elevated ratio of primary oocytes and follicular atresia, or by reduced spermatogenesis. Apoptotic signals appeared in gonadal interstitial cells, with upregulated expression of genes P53, Bax, Casp3, and Casp8. Ultrastructural damage included fewer mitochondria and cristae blurring, further indicating tissue damage causing dysfunction. Transcriptome results showed that oxidative stress damage and energy metabolism imbalance caused by carbonate alkalinity were key to the delayed gonadal development, which was mainly manifested in enrichment of the ECM–receptor interaction and PI3K-Akt signaling pathways in females exposed to low alkalinity, and the GnRH secretion and chemokine signaling pathways in males. Glycosphingolipid biosynthesis and Ferroptosis pathway were enriched in females exposed to high alkalinity, and the Cortisol synthesis and secretion pathway were enriched in males. Overall, high-alkalinity exposure significantly delayed gonadal development in both sexes of largemouth bass, leading to reproductive impairment. Full article

Since 2007, white-nose syndrome (WNS), caused by the fungus Pseudogymnoascus destructans, has killed millions of bats across North America by disrupting hibernation cycles, causing premature fat depletion and starvation. Little brown bats (Myotis lucifugus) from some populations persisting after WNS store larger pre-hibernation fat reserves than bats did before WNS, which may help bats survive winter starvation and mount an immune response to Pd in spring. MicroRNAs (miRNAs) are highly conserved, small, non-coding RNA molecules that regulate gene expression post-transcriptionally. Aberrant miRNA expression can affect metabolic pathways in mammals and has been linked to various diseases. If fat reserves and immune mechanisms influence survival from WNS, then miRNAs regulating metabolic and immune-related genes might affect WNS pathogenesis and bat survival. A previous study identified 43 miRNAs differentially expressed in bats with WNS. We analyzed these miRNAs for their roles in metabolism and immune-related pathways, using DIANA Tools and KEGG analysis, to determine a subset that could serve as biomarkers of pathophysiology or survival in WNS-affected bats. We identified miR-543, miR-27a, miR-92b, and miR-328 as particularly important because they regulate multiple pathways likely important for WNS (i.e., immune response, lipogenesis, insulin signaling, and FOXO signaling). As proof-of-concept, we used reverse transcription quantitative real-time PCR (RT-qPCR) to quantify the prevalence of these miRNAs in plasma samples of bats (n = 11) collected from a post-WNS population during fall fattening. All the selected miRNAs were detectable in at least some bats during fall fattening although prevalence varied among miRNAs. Future in vivo validation studies would help confirm functional roles and biomarker utility of these miRNAs for WNS-affected bats. Full article

Thyroid hormone (TH) regulates cell proliferation, differentiation, and metabolism. Increased TH levels in circulation are associated with a higher incidence of age-related macular degeneration. In mice, TH treatment causes photoreceptor degeneration, which is accompanied by an increase in receptor-interacting serine/threonine-protein kinase 3 (RIPK3) in the retina. Here, we investigated the contribution of RIPK3/necroptosis to TH-induced photoreceptor degeneration using mice deficient in RIPK3 and the necroptotic mixed lineage kinase domain-like protein (MLKL). Wild-type (C57BL/6) and mutant mice at postnatal day 30 received triiodothyronine (T3, 20 µg/mL in drinking water) for four weeks, followed by the evaluation of photoreceptor survival/death and retinal function. Deletion of Ripk3 preserved photoreceptor integrity against T3-induced degeneration, evidenced by improved retinal morphology, increased cone density, improved retinal light responses, and reduced cell death. This protection was observed in both global and photoreceptor-specific Ripk3 knockout mice. In contrast, the deletion of Mlkl did not protect photoreceptors. This work supports the view that RIPK3, but not MLKL, contributes to TH-induced photoreceptor degeneration. The lack of protection from Mlkl deletion suggests that RIPK3’s action is likely mediated via a necrosome-independent mechanism. These findings provide significant insight into how TH signaling induces photoreceptor degeneration and implicate RIPK3 as a potential therapeutic target. Full article

We previously demonstrated that the activation of FGFR signaling in GIST may be a mechanism of GIST resistance to imatinib mesylate (IM). We show here that IM-resistant GIST cells lacking secondary KIT mutations overexpress claudin-1 on both transcriptional and translational levels. In contrast, a knockdown of CLDN1 or inhibition of its activity by PDS-0330 effectively restored GIST’s sensitivity to IM both in vitro and in vivo. This was evidenced by the increased expression of apoptotic markers (e.g., cleaved PARP and caspase-3) and the decreased proliferation rate of IM-resistant GIST T-1R cells treated with a combination of IM and PDS-0330 (or siRNA CLDN1). In concordance with these findings, a significant synergy was observed between IM and PDS-0330 in GIST T-1R cells. Importantly, decreased tumor size and weight were observed in IM-resistant GIST xenografts treated with a combination of IM and PDS-0330. Furthermore, the combined treatment of IM-resistant tumors induced an increase in intratumoral apoptosis and other changes, as defined by the histopathologic response rate. Based on the co-immunoprecipitation and immunofluorescence microscopy data, we also demonstrated the strong interaction pattern between CLDN1 and FGFR2. Of note, the inhibition or knockdown of CLDN1 effectively decreased the phosphorylation of FGFR2 and FRS-2, a well-known FGFR adaptor protein, thereby illustrating CLDN1’s ability to regulate FGFR-signaling and thereby promote FGFR-mediated survival in KIT-inhibited GIST. Consequently, CLDN1 inhibition in GIST effectively disrupted the FGFR-mediated pathway and re-sensitized tumor cells to IM. In concordance with these data, molecular profiling of CLDN1-inhibited GIST T-1R cells illustrated a significant decrease in the majority of FGFR transcripts, including FGFR2, 3, and 4. Additionally, several FGFR ligands (e.g., FGF14, -19, and -23) were also down-regulated in PDS-0330-treated GIST. Notably, exogenous FGF-2 increased CLDN1 expression in a time-dependent manner. In contrast, pan-FGFR inhibitors effectively reduced CLDN1 levels in IM-resistant GIST T-1R cells, thereby illustrating a cross-talk between CLDN1- and FGFR-mediated pathways in IM-resistant GIST. Based on subcellular fractionation and immunofluorescence microscopy data, we also observed partial relocalization of CLDN1 into the cytoplasm in IM-resistant GIST. Notably, PDS-0330 effectively abrogated this relocalization, suggesting that changes in CLDN1 subcellular distribution might also impact GIST resistance to IM. Lastly, based on our small cohort clinical study (n = 24), we observed the increased expression of CLDN1 in most “high-risk” primary GIST known to be associated with poor prognosis and aggressive behavior, thereby illustrating the prognostic value of increased CLDN1 expression in GIST and providing a further rationale to evaluate the effectiveness of CLDN1 inhibition for GIST therapy. Full article

The germination and elongation of maize in the early growth stage are closely related to the elongation of the mesocotyl, which is one of the earlier parts that are able to sense external temperature, except for the coleoptile. And, low-temperature (LT) stress can significantly influence the survival and growth of maize seedlings. In addition, the brassinosteroids (BRs) have also been applied to alleviate the damage suffered by various plants in LT in recent years. However, the interaction relationship among LT, BRs, and sugar remains unclear. Therefore, we examined the changing relationships among the contents of glucose, sucrose, and starch, as well as the changes in differentially expressed genes (DEGs) in the starch and sucrose metabolism and glycolysis/gluconeogenesis pathways. Herein, compared to CK (0 μM 24-epibrassinolide (EBR) application at 25 °C), the contents of glucose and sucrose all increased by 0.26, 0.47, and 0.70 mg g⁻¹ FW and 0.80, 0.30, and 0.61 mg g⁻¹ FW, respectively, under the CKE (2.0 μM 24-epibrassinolide (EBR) application at 25 °C), LT (0 μM 24-epibrassinolide (EBR) application at 10 °C), and LTE (2.0 μM 24-epibrassinolide (EBR) application at 10 °C) treatments, but the contents of starch decreased under LT and LTE treatments by −0.54% and −0.20%, compared to CK. This suggested that not only did the sugar signaling and metabolism play key roles in regulating LT tolerance but the application of EBR can also alleviate the damage caused by LT by regulating the sugar accumulation level. Meanwhile, 108 DEGs in the starch and sucrose metabolism pathway and 65 DEGs in the glycolysis pathway were identified at the transcriptome level. The common Zm00001d042146 in both pathways is always down-regulated, and the down-regulation multiple when EBR is added is less than the LT. In addition, key genes such as Zm00001d021598, Zm00001d034017, and Zm00001d029091, were all differentially expressed under LT, and the expression multiples decreased when EBR was added. In conclusion, our results provide new insights into the molecular mechanism by which exogenous application of EBR enhances the low-temperature tolerance of maize seedlings. The germination and elongation of maize in the early growth stage are closely related to the elongation of the mesocotyl, which is one of the first parts to sense external temperature, aside from the coleoptile. Low-temperature (LT, 10~15 °C) stress can significantly affect the survival and growth of maize seedlings. Additionally, brassinosteroids (BRs) have been used in recent years to help alleviate damage caused by LT in various plants. However, the interaction among LT, BRs, and sugar remains unclear. Therefore, we examined the relationships among the contents of glucose, sucrose, and starch, along with the changes in differentially expressed genes (DEGs) involved in starch and sucrose metabolism and glycolysis/gluconeogenesis pathways. Compared to CK (0 μM 24-epibrassinolide (EBR) application at 25 °C), the contents of glucose and sucrose increased by 0.26, 0.47, and 0.70 mg g⁻¹ FW and 0.80, 0.30, and 0.61 mg g⁻¹ FW, respectively, under the CKE (2.0 μM 24-epibrassinolide (EBR) application at 25 °C), LT (0 μM 24-epibrassinolide (EBR) application at 10 °C), and LTE (2.0 μM 24-epibrassinolide (EBR) application at 10 °C) treatments. However, starch contents decreased under LT and LTE treatments, by −20.54% and −0.20%, respectively, compared to CK. This suggests that sugar signaling and metabolism play key roles in regulating LT tolerance, and the application of EBR may alleviate LT damage by regulating sugar accumulation levels. Furthermore, 108 DEGs were identified in the starch and sucrose metabolism pathways, along with 23 in glycolysis, with 65 DEGs at the transcriptome level. The common Zm00001d042146 (hexokinase-3) in both pathways is usually down-regulated, and the degree of down-regulation when EBR is added is less than under LT alone. Additionally, key genes such as Zm00001d021598 (glucan endo-1,3-beta-glucosidase 3), Zm00001d034017 (uncharacterized LOC541703), and Zm00001d029091 (sucrose synthase 2) were differentially expressed under LT, with their expression levels decreasing further when EBR was added. In conclusion, our results provide a new direction into the molecular mechanisms by which exogenous EBR application enhances low-temperature tolerance in maize seedlings. Full article

The Wntβ-catenin signaling pathway is a key regulator of gastrointestinal (GI) tumorigenesis, modulating cellular processes such as proliferation, differentiation, and epithelial-to-mesenchymal transition (EMT). In this review, we evaluate the expression and mutation profiles of core Wntpathway components in the most common GI malignancies. Our findings outline notable alterations in ligands, receptors, co-receptors, and intracellular effectors across different GI cancers. In gastric cancer tissue, elevated levels of Wnt proteins, FZD7 receptor, and LRP5/6, along with β-catenin accumulation and reduced APC expression, are associated with poor prognosis. In colorectal cancer samples, common APC mutations and Wnt ligand overexpression contribute to β-catenin nuclear localization and EMT. Esophageal cancer specimens exhibit co-overexpression of Wnt2 and Wnt5A, as well as receptors such as FZD2 and FZD6, which are linked to worse prognosis and reduced survival. Liver cancer tissue commonly harbors CTNNB1 mutations, which encode β-catenin and are associated with poor differentiation. In pancreatic cancer samples, overexpression of Wnt ligands, FZD receptors, and β-catenin is associated with the presence of distant metastasis and poor clinical outcomes. In conclusion, this pathway represents a promising avenue for identifying novel diagnostic, prognostic, and therapeutic biomarkers in GI cancers, warranting further clinical investigation. Full article

The progression of inflammation during sepsis represents a multifaceted biological cascade that requires effective therapeutic interventions to improve survival. In septic neonatal foals, oxidative stress (OS) arises due to a compromised antioxidant defense system. Oxidative stress may disrupt the functionality of redox-sensitive organelles, such as the endoplasmic reticulum (ER). Endoplasmic reticulum stress disorder affects multiple cellular signaling pathways, including redox balance, inflammation, and apoptosis, and contributes to the pathogenesis of sepsis. The study aimed to elucidate whether OS conditions in sepsis influenced gene expression associated with ER stress. Blood samples were collected from 7 healthy and 21 hospitalized neonatal foals and processed for RNA extraction. RNA sequencing was employed to identify ER stress-responsive genes. Novel findings reported here indicate activation of the ER stress pathway in foals with sepsis. Several genes associated with ER stress, such as clusterin (CLU), BCL2-like 1 (BCL2L1), ubiquitin specific peptidase 14 (USP14), bifunctional apoptosis regulator (BFAR), and optic atrophy 1 (OPA1), were upregulated and positively correlated with sepsis scores and negatively correlated with the combined activities of antioxidant enzymes. In contrast, X-box binding protein 1 (XBP1), homocysteine inducible ER protein with ubiquitin-like domain 1 (HERPUD1), leucine-rich repeat kinase 2 (LRRK2), and selenoprotein S (SELENOS) were negatively correlated with sepsis scores and were downregulated in sepsis and positively correlated with the combined activities of antioxidant enzymes. Furthermore, a positive correlation was observed between cAMP responsive element binding protein 3 like 2 (CREB3L2) and BCL2L1, as well as between the expressions of USP14 and YOD1 deubiquitinase (YOD1) in sepsis. Similarly, the expression levels of XBP1 and Herpud1 demonstrated a positive correlation with each other in sepsis. Additionally, the downregulation of genes with protective function against OS, such as XBP1, HERPUD1, and SELENOS, in septic foals also highlights their significance in mitigating OS in sepsis treatment. The study reported here highlights the potential of ER stress as a promising therapeutic target and prognostic marker in septic foals. Full article

Background: Melanoma, the deadliest human skin cancer, frequently harbors activating BRAF mutations, with V600E being the most prevalent. These alterations drive constitutive activation of the MAPK pathway, promoting uncontrolled cell proliferation, survival, and dissemination. The advent of BRAFi and MEKi has significantly improved outcomes in BRAF V600-mutant melanoma. However, therapeutic resistance remains a major clinical barrier. Methods: This review integrates recent findings from preclinical and clinical studies to delineate resistance mechanisms to BRAF-targeted therapy. It categorizes resistance into primary (intrinsic), adaptive, and acquired forms, and analyzes their molecular underpinnings, including genetic and epigenetic alterations, pathway reactivation, and microenvironmental interactions. Results: Primary resistance is linked to pre-existing genetic and epigenetic changes that activate alternative signaling pathways, such as PI3K-AKT. Adaptive and acquired resistance includes secondary BRAF mutations, pathway redundancy, phenotype switching, and immune and stromal interactions. High-throughput sequencing has revealed novel mutations, including NRAS, NF1, and PTEN alterations, that contribute to resistance. Discussion: Understanding the multifaceted nature of resistance is critical to improving outcomes in advanced melanoma. This review highlights emerging strategies to overcome resistance, including combinatorial therapies, metabolic targeting, and biomarker-driven approaches, aiming to inform future therapeutic development and precision oncology strategies. Full article

STK26 is highly expressed in colorectal cancer (CRC) and linked to tumorigenesis. Although implicated in unfolded protein response (UPR)-related oxidative stress, whether STK26 regulates CRC occurrence via the ATF6 pathway—a classic UPR branch governing proteostasis and cell survival—remains unestablished. In our research, we found that STK26 expression aberrantly upregulated in CRC is closely associated with poor prognosis. In vitro, tumor phenotype assays showed that STK26 drives CRC cell growth, proliferation, and migration. These effects were reversed by the ATF6 inhibitor Ceapin-A7, demonstrating that STK26’s oncogenic function depends on ATF6. Moreover, transcriptome sequencing revealed that STK26 is associated with the protein folding, sorting, and degradation pathway, and a luciferase reporter assay showed that STK26 activated the ATF6 signal pathway. Furthermore STK26 interacted with p50ATF6 and enhanced its protein stabilization. In vivo studies demonstrated that the administration of the STK26 inhibitor Hesperadin significantly suppressed CRC growth, suggesting a tumor-promoting role for STK26 in CRC pathogenesis. In summary, our research reveals that STK26 is a novel regulator that promotes the growth, proliferation, and migration of CRC cells by activating the ATF6 signaling pathway and stabilizing p50ATF6. Hence, the STK26-ATF6 axis has the potential to become a new target for treating colorectal cancer. Full article

Precise control of protein translocation is essential for synthetic biology and protein engineering. Here, we present a temperature-responsive system using elastin-like polypeptides (ELPs) to regulate the translocation of a conditionally lethal enzyme in Escherichia coli. The enzyme, levansucrase, whose activity becomes lethal in the presence of sucrose, was engineered with an N-terminal signal peptide and a C-terminal ELP tag. At 37 °C, the ELP tag induced intracellular aggregation of the fusion protein, preventing its secretion and allowing cell survival, as indicated by translucent colony formation. In contrast, at 16 °C, the ELP remained soluble, permitting levansucrase secretion into the medium. The resulting conversion of sucrose into levan by the secreted enzyme led to host cell death. These findings highlight ELP-mediated aggregation as a reversible and tunable strategy for regulating protein localization and secretion in E. coli, with potential applications in synthetic biology, metabolic engineering, and biocontainment systems. Full article

Abiotic stresses, such as heat, cold, drought, and salt, pose severe challenges to global agriculture, with climate change exacerbating these threats and intensifying risks to crop productivity and food security. Strigolactones (SLs), a class of phytohormones, play pivotal roles in mediating plant development and enhancing stress resilience. This review highlights the multifaceted mechanisms through which SLs regulate plant responses to abiotic stresses, integrating molecular, physiological, biochemical, and morphological dimensions. Molecularly, SLs regulate the expression of stress-responsive genes, such as those encoding antioxidant enzymes and mitogen-activated protein kinase (MAPK), to enhance plant acclimation and survival under abiotic stress conditions. Moreover, genes involved in SL biosynthesis and signaling pathways are indispensable in these processes. Physiologically and biochemically, SLs improve resilience by modulating photosynthesis, stomatal closure, reactive oxygen species (ROS) metabolism, and osmotic adjustment. Morphologically, SLs modulate leaf morphology, shoot development, and root architecture, enhancing plant stress tolerance. Collectively, SLs emerge as key regulators of plant tolerance to abiotic stresses, offering promising strategies for advancing crop improvement and securing agricultural sustainability in the face of climate change. Full article

Maximal safe surgical resection remains a critical component of glioblastoma (GBM) management, improving both survival and quality of life. However, complete tumor removal is hindered by the infiltrative nature of GBM and its proximity to eloquent brain regions. Fluorescence-guided surgery (FGS) has emerged as a valuable tool to enhance intraoperative tumor visualization and optimize resection outcomes. Currently used fluorophores such as 5-aminolevulinic acid (5-ALA), fluorescein sodium (FS), and indocyanine green (ICG) have distinct advantages but are limited by suboptimal specificity, shallow tissue penetration, and technical constraints. 5-ALA and SF often yield unreliable signals in low-grade tumors or infiltrative regions and also pose challenges such as phototoxicity and poor depth resolution. In contrast, near-infrared (NIR) fluorescence imaging represents a promising next-generation approach, providing superior tissue penetration, reduced autofluorescence, and real-time delineation of tumor margins. This review explores the mechanisms, clinical applications, and limitations of currently approved FGS agents and highlights future directions in image-guided neurosurgery. Full article

Glioblastoma (GBM) is the most aggressive primary brain tumor, characterized by rapid proliferation, invasiveness, therapeutic resistance, and an immunosuppressive tumor microenvironment. A subpopulation of glial stem-like cells (GSCs) within GBM tumors contributes significantly to tumor initiation, progression, and relapse, displaying remarkable adaptability to oxidative stress and metabolic reprogramming. Recent evidence implicates the atypical kinases RIOK1 and RIOK2 in promoting GBM growth and proliferation through their interaction with oncogenic pathways such as AKT and c-Myc. Concurrently, the redox-sensitive Nrf2/Keap1 axis regulates antioxidant defenses and supports GSC survival and chemoresistance. Additionally, aberrant activation of the canonical Wnt/β-catenin pathway in GSCs enhances their self-renewal, immune evasion, and resistance to standard therapies, particularly under oxidative stress conditions. This review integrates current knowledge on how redox homeostasis and key signaling pathways converge to sustain GSC maintenance and GBM malignancy. Finally, we discuss emerging redox-based therapeutic strategies designed to target GSC resilience, modulate the tumor immune microenvironment, and surmount treatment resistance. Full article

In aquaculture, Pacific white shrimp (Litopenaeus vannamei) growth in low-salinity waters is limited by osmoregulatory stress; therefore, improving resistance to low-salinity stress via nutritional modulation is key. In the present study, shrimp postlarvae were provided with a taurine supplement under low-salinity stress, and then the survival rate, the histology, the Na⁺/K⁺-ATPase (NKA) expression pattern and transcriptomic sequencing were investigated to evaluate the postlarval responses. The results showed that the postlarva survival rate in low-salinity water was only 61.11%, which is significantly lower than that for postlarvae reared in saline water (92.67%). However, taurine supplementation significantly increased the postlarva survival rate in low-salinity culture to 76.67% and also increased the shrimp body length. Moreover, immunofluorescence and enzyme activity assays indicated that taurine alleviated NKA overactivation in the shrimp postlarvae under low-salinity stress. Furthermore, a GO enrichment analysis of differentially expressed genes suggested that the overactivation of hormone and receptor signaling under low-salinity stress was significantly downregulated after taurine supplementation. On the other hand, taurine supplementation may promote epithelial cell proliferation in shrimp postlarvae by negatively regulating the Wnt signaling pathway. These findings suggest that taurine may enhance the shrimp postlarval osmoregulatory capacity, thereby improving their ability to acclimatize to low-salinity environments. Full article

As large language model (LLM) tutors evolve from scripted helpers into adaptive educational partners, their capacity for self-regulation, ethical decision-making, and internal monitoring will become increasingly critical. This paper introduces the Needs-Driven Consciousness Framework (NDCF) as a novel, integrative architecture that combines Dennett’s multiple drafts model, Damasio’s somatic marker hypothesis, and Tulving’s tripartite memory system into a unified motivational design for synthetic consciousness. The NDCF defines three core regulators, specifically Survive (system stability and safety), Thrive (autonomy, competence, relatedness), and Excel (creativity, ethical reasoning, long-term purpose). In addition, there is a proposed supervisory Protect layer that detects value drift and overrides unsafe behaviours. The core regulators compute internal need satisfaction states and urgency gradients, feeding into a softmax-based control system for context-sensitive action selection. The framework proposes measurable internal signals (e.g., utility gradients, conflict intensity Ω), behavioural signatures (e.g., metacognitive prompts, pedagogical shifts), and three falsifiable predictions for educational AI testbeds. By embedding these layered needs directly into AI governance, the NDCF offers (i) a psychologically and biologically grounded model of emergent machine consciousness, (ii) a practical approach to building empathetic, self-regulating AI tutors, and (iii) a testable platform for comparing competing consciousness theories through implementation. Ultimately, the NDCF provides a path toward the development of AI tutors that are capable of transparent reasoning, dynamic adaptation, and meaningful human-like relationships, while maintaining safety, ethical coherence, and long-term alignment with human well-being. Full article