Search Results (1,040)

Opioid analgesics are essential in the management of severe and chronic pain; however, their prolonged use is limited by the onset of analgesic tolerance and opioid-induced hyperalgesia (OIH). Recent studies increasingly implicate both synaptic functional and structural plasticity within nociceptive pathways as crucial mechanisms in OIH and tolerance. This review integrates current mechanistic understanding of how opioids alter synaptic transmission throughout the dorsal root ganglia (DRG), spinal dorsal horn, and supraspinal nociceptive networks. Peripherally, μ-opioid receptor (MOR) activation on TRPV1-positive nociceptors initiates presynaptic long-term potentiation (LTP), forming an early substrate for central sensitization. In the spinal dorsal horn, chronic opioid exposure drives NMDAR-dependent LTP, TRPC-mediated calcium influx, and actin cytoskeleton remodeling, leading to persistent increases in synaptic strength and excitatory connectivity. In supraspinal regions—including the ventral hippocampus, prefrontal cortex, and amygdala—opioids promote experience-dependent plasticity and predictive coding, which link environmental cues to reduced analgesic effectiveness. In addition to synaptic functional plasticity, opioid-induced synaptic structural plasticity within nociceptive pathways has been shown to underlie the long-term nature of opioid analgesic tolerance. Collectively, these data define a distributed network of opioid-responsive synapses whose pathological potentiation underpins the development of tolerance and hyperalgesia. Elucidating these mechanisms underlying OIH and tolerance paves the way for targeted therapeutic strategies that maintain analgesic efficacy while minimizing adverse synaptic remodeling and negative outcomes. Full article

Glucose transporter type 4 (GLUT4), encoded by the SLC2A4 gene, is the final effector of insulin-stimulated glucose uptake in insulin-sensitive tissues: skeletal muscle, adipose tissue, and cardiac muscle. Its dynamic localization, retained intracellularly under basal conditions and extensively translocated to the plasma membrane upon stimulation, makes it a master regulator of glycemic homeostasis. While the canonical insulin pathway (PI3K/Akt/TBC1D4) is the most potent and specific mechanism in the postprandial state, its dysfunction is centrally associated with insulin resistance and type 2 diabetes mellitus (T2DM). Crucially, robust alternative signaling networks function completely independently of insulin to regulate GLUT4 synthesis and translocation. Prominent among these are contraction-mediated pathways in skeletal muscle, which employ calcium signaling (via CaMKII), mechanical/metabolic stress sensors (via p38 MAPK γ/δ), and AMP-activated protein kinase (AMPK). This review critically integrates current knowledge, linking the molecular architecture and post-translational modifications of GLUT4 to the complex, tissue-specific signaling networks that govern its vesicular trafficking. We emphasize the hierarchy, redundancy, and interdependence of these pathways, highlighting differences between acute translocation and chronic transcriptional adaptations. Finally, we discuss how deciphering insulin-independent mechanisms offers promising therapeutic opportunities, particularly in identifying pharmacological targets that mimic the metabolic benefits of physical exercise. Full article

Background: Hyperparathyroidism is a common endocrine disorder, and its diagnosis can be complex. Various indices based on blood biomarkers have been proposed to improve diagnostic accuracy. The objective of this systematic review was to analyze the diagnostic utility of different indices in primary hyperparathyroidism. Methods: A systematic review was performed with searches up to January 2026. Risk of bias was assessed, and a meta-analysis was conducted for indices with two or more studies, calculating sensitivity, specificity, and other accuracy measures. The certainty of the evidence was evaluated using the GRADE system. Results: Twelve studies were included. The calcium–phosphorus ratio demonstrated a sensitivity of 91.6%, specificity of 89.3%, and an area under the curve of 0.957. The parathyroid function index showed a sensitivity of 94.4% and specificity of 94.2%; however, this finding is based on only two studies and requires validation in larger cohorts. The Wisconsin index also showed good performance. Other indices, including the Ca × Cl/P ratio (evaluated in a single study), yielded promising results but with very limited evidence that precludes firm conclusions. All indices performed poorly in cases with normal calcium. Certainty assessment indicated moderate evidence for the main indices and low or very low evidence for the others. Conclusions: The calcium–phosphorus ratio and the parathyroid function index are valid and useful tools for the diagnosis of primary hyperparathyroidism, with excellent performance. The calcium–phosphorus ratio is especially valuable due to its simplicity and accessibility for screening. No index should be used in isolation; integration with clinical evaluation remains essential. Full article

Nitrogen (N) and phosphorus (P) are essential nutrients that play critical roles in plant physiological processes and the accumulation of N and P in broccoli head was significantly correlated with yield. Therefore, there is a need for a rapid, non-destructive diagnosis of crop status by detecting deficiencies in essential nutrients. This study evaluated the effects of N and P deficiency on field grown broccoli (Brassica oleracea L. var. italica Plenk) using a plant-induced electrical signal (PIES) sensor, in which needle electrodes are inserted into the stem to measure electrical conductivity reflecting plant water and ion status. Four treatments were established, including the control (N100P100) with sufficient N and P supply, N deficiency (N0P100), P deficiency (N100P0), and combined N–P deficiency (N0P0). For sufficient supply, urea and fused phosphate (FP) were applied at rates of 122 kg N ha⁻¹ and 71 kg P ha⁻¹, respectively. Soil, stem, and leaf nutrient contents, growth parameters, and stress related indicators were analyzed and their relationship with PIES values were evaluated. PIES was highest in control (N100P100) and lowest under N–P deficiency (N0P0). Higher PIES values were observed during the vegetative stage, whereas values declined during the reproductive stage, reflecting changes in physiological activity. Growth parameters such as shoot and root weight and stem diameter were generally superior in the control (N100P100) treatment, while leaf calcium (Ca), magnesium (Mg), and potassium (K) concentrations showed no significant differences among treatments. Total N content in leaves was higher in N fertilized treatments (control and P deficiency). Photosynthesis-related parameters, including soil plant analysis development (SPAD), Fv/Fm, and chlorophyll content, were lowest under N–P deficiency, which was reflected in the PIES. Principal component analysis (PCA) showed that the PIES was closely associated with growth and photosynthetic parameters and clearly distinguished N sufficient treatments (control and P deficiency) from N deficient treatments (N0P100, N0P0). Overall, these findings suggest that PIES monitoring can serve as a sensitive physiological indicator of nutrient stress and may be applied as an early diagnostic tool before visible growth inhibition occurs in broccoli cultivation. Full article

The safe and precise regulation of therapeutic gene expression remains a major challenge for mammalian synthetic biology and cell-based therapies. Many existing inducible systems rely on non-mammalian regulatory components or ligands with limited clinical compatibility. Designer receptors exclusively activated by designer drugs (DREADDs) offer a human G protein-coupled receptor (GPCR)-based framework for pharmacological control of intracellular signaling, yet their application as clinically relevant gene-regulation platforms remains underexplored. Here, we report a clozapine-responsive gene switch that couples a designer GPCR to signaling-dependent transcriptional control. By linking clozapine-activated receptors to cyclic adenosine monophosphate (cAMP)- or calcium-responsive synthetic promoters, receptor activation is converted into robust transgene expression across a broad dynamic range, with sensitivity to sub-nanomolar to low-nanomolar clozapine concentrations. In vivo, alginate-encapsulated reporter cells implanted in C57BL/6J mice responded to systemic or local clozapine administration with efficient secretion of a reporter protein, achieving robust induction at low daily doses (0.3 mg/kg) following either oral administration or local delivery. Together, these results establish a human GPCR-based clozapine-responsive gene switch that integrates regulation by a clinically used small molecule with modular transcriptional outputs, providing an additional approach for pharmacologically controllable gene expression in mammalian cells and in vivo. Full article

Vitamin K (VK), traditionally recognized for its role in coagulation, is increasingly implicated in extrahepatic processes, including glucose metabolism and calcium regulation. A suboptimal VK status is common in the general population and may limit these functions, yet evidence linking VK to glucose metabolism and other endocrine axes remains heterogeneous and incompletely synthesized. This narrative review integrates mechanistic, observational, and interventional evidence to examine the role of VK across the endocrine system, with particular emphasis on glucose metabolism. Mechanistic studies indicate that VK supports pancreatic β-cell function, modulates peripheral insulin sensitivity, and facilitates proper calcium distribution. Observational studies consistently associate a higher VK status with a lower risk of type 2 diabetes, while interventional studies suggest that VK supplementation may improve glucose metabolism, primarily in metabolically impaired populations. In bone and mineral metabolism, VK acts synergistically with calcitriol, with combined supplementation showing more consistent benefits in skeletal outcomes than either vitamin alone. Evidence for VK involvement in other endocrine axes, including reproductive and inflammatory pathways, remains limited and largely mechanistic. Overall, the available evidence supports a context-dependent role for VK in glucose metabolism, influenced by baseline nutritional and metabolic status and outcome selection, as well as a synergistic interaction with calcitriol and parathormone in calcium regulation. Future clinical studies should incorporate baseline VK status stratification, dynamic measures of insulin sensitivity, and adequately powered designs to clarify the therapeutic relevance of VK across endocrine and metabolic outcomes. Full article

Skeletal muscle differentiation is tightly regulated by membrane potential dynamics and voltage-dependent ion channel activity. Potassium (K⁺) and calcium (Ca²⁺) currents cooperate to orchestrate the transition of myoblasts into fusion-competent myotubes, and alterations in this process are associated with dystrophic phenotypes. Here, we investigated the electrophysiological remodeling accompanying C2C12 myogenesis and the modulatory effects of the polyphenol resveratrol (RES) on calcium voltage-gated channel subunit alpha 1 S (CACNA1S, Cav1.1, L-type) currents. Whole-cell patch-clamp recordings were performed in proliferating and differentiating C2C12 cells to characterize the temporal expression of K⁺ currents and voltage-dependent Ca²⁺ channels (VDCCs). During differentiation, three electrophysiological subpopulations were identified according to K⁺ current profiles: SK4+/EAG−/Kir−, SK4−/EAG+/Kir−, and SK4−/EAG+/Kir+. This sequence paralleled a progressive membrane hyperpolarization from −20 mV to −70 mV, consistent with the physiological maturation of myogenic cells. In C2C12 myocytes, nimodipine-sensitive L-type currents were the only Ca²⁺ conductance observed. Their activation threshold (~−30 mV) and half-activation voltage (V/2 ≈ −12 mV) indicated the co-expression of embryonic and adult Cav1.1 isoforms. Exposure to RES (30 µM, 48 h) produced a depolarizing shift in activation (ΔV/2 ≈ +9 mV) and a reduction in current amplitude across all voltages, consistent with a transition toward the adult splice variant of Cav1.1. These findings suggest that RES promotes electrophysiological maturation of skeletal muscle cells by modulating calcium channel expression and gating behavior. Given its known ability to correct splicing abnormalities in CACNA1S and related genes, resveratrol emerges as a promising pharmacological agent for restoring calcium homeostasis in neuromuscular disorders such as myotonic dystrophy type 1 (DM1). Full article

This study investigates how soil calcium (Ca) and magnesium (Mg) supplementation influence mitragynine accumulation in Mitragyna speciosa (kratom), addressing the lack of quantitative thresholds in previous research. Seedlings from a uniform seed stock were cultivated in a controlled environment using a standardized soil mix (soil:peat moss:earthworm castings, 6:1:1). Following an initial growth phase, Ca and Mg were applied at three concentrations and in fixed Ca:Mg ratios (5:1, 10:1, 20:1) using gypsum and Epsom salt. Over a 45-day treatment period, growth parameters and mitragynine levels were assessed one week after the final application. Seedlings under control had the highest total biomass (102.35 g), significantly exceeding both the Mg-only and Ca:Mg treatments (64–84 g), and values above the typical upper threshold of 20 did not suppress growth, as evidenced by unchanged root-to-shoot ratios across treatments. In contrast, mitragynine accumulation was the highest under moderate Ca:Mg ratios (8–10), exhibiting a 2–14% increase relative to the control, suggesting that production of this alkaloid is more sensitive to nutrient balance than overall growth. These findings underscore the importance of nutrient ratios, rather than individual nutrient concentrations, in regulating both vegetative development and alkaloid production in kratom. Maintaining an appropriate Ca:Mg ratio can support efficient seedling growth as well as maximizing mitragynine levels. Preliminary field trials over a span of one month indicate that field-grown seedlings exhibit a similar result with high growth and mitragynine content in soils having a Ca:Mg ratio of 1:10. Future studies should test these responses under field conditions and over longer growth periods. Full article

Coal-fired power plants can adversely affect aquatic ecosystems through wastewater discharge, waste landfills, and the atmospheric deposition of toxic substances released during coal combustion. These processes degrade the water quality of nearby surface and underground water bodies. The study presents the impact of the coal-fired power plant Contour Global Maritza East 3 on the ecological status of the Sokolitsa River, reflected by changes in the composition and structure of the sensitive phytobenthos and macrozoobenthos communities and supporting environmental variables, including water temperature, pH, dissolved oxygen, conductivity, nutrients, sulfates, calcium, and calcium carbonate hardness. Methods for monitoring and assessing the ecological status of surface water bodies compliant with European and national legislation were applied to the studied biological quality elements and key physicochemical variables. Historical monitoring data from a ten-year period, 2013–2022, together with data collected during the study in 2023 and 2024 were analyzed and evaluated. The results indicated a significant increase in most physicochemical variables downstream of the CFPP compared with the upstream site, including water temperature, conductivity, calcium carbonate hardness, calcium, sulfates and nitrogen (N) nutrients (ammonium N, nitrite N, nitrate N, total N). The ecological status of the river deteriorated, as indicated by the negatively affected aquatic habitats and the changes in the taxonomic richness and abundance of the studied organism groups. Full article

Calcium carbonate is a widely used filler in polymer composites due to its low cost and ability to improve stiffness, dimensional stability, and impact resistance. However, its hydrophilic surface limits compatibility with nonpolar polymer matrices, making surface modification essential to improve filler dispersion and interfacial adhesion. Stearic acid is commonly applied as a surface modifier for calcium carbonate because it readily chemisorbs onto the mineral surface and forms densely packed self-assembled monolayers that improve hydrophobic character. Despite its widespread use, stearic acid exhibits limited thermal and interfacial stability under polymer processing conditions, motivating the development of stabilization strategies. In this work, gamma and electron-beam irradiation were applied to stearic-acid-modified calcium carbonate to modify the surface-bound stearic acid layer with the aim of enhancing its interfacial stability, surface resistance, and hydrophobic performance, and to evaluate the influence of irradiation atmosphere on these effects. The modified materials were characterized in terms of structural integrity, surface wettability, surface free energy, thermal stability, and optical properties. The results demonstrate that ionizing radiation enhances surface hydrophobicity and coating durability while preserving the crystal structure of the CaCO₃ substrate. Gamma irradiation of stearic-acid-modified vaterite exhibited strong atmosphere dependence, with improved hydrophobicity under oxygen-free conditions, whereas electron-beam irradiation showed more robust and oxygen-insensitive behavior. Based on the observed improvements in hydrophobicity, surface free energy, and thermal stability, electron-beam irradiation emerges as a promising and less atmosphere-sensitive approach for producing durable stearic-acid-modified CaCO₃ fillers suitable for polymer composite applications. Full article

During fires, the temperature difference between indoor and outdoor environments induces out-of-plane deformation in steel studs. Due to the differential coefficients of thermal expansion between panels and steel, the panels exert a restraining effect on the studs. However, there remains a lack of systematic experimental and theoretical models addressing the failure modes, restraining mechanisms, and synergistic effects of various panels on steel studs. This study conducted high-temperature bending tests to compare the failure modes, load–displacement curves, and key mechanical parameters (peak load, elastic stiffness) of connections combining steel studs with three types of panels: autoclaved lightweight concrete (ALC) panels, fire-resistant gypsum boards, and medium-density calcium silicate board. The research clarifies the constraining effect and temperature sensitivity of different panels. Based on experimental data, a bending constitutive model was developed to quantify the attenuation of the out-of-plane constraining effect at elevated temperatures. The results indicate that the load–displacement curves exhibit three distinct stages: Elastic Ascending Stage, Elastoplastic Ascending Stage, and Post-Peak Stage. A two-stage bending constitutive model was proposed and formulated. Comparison between numerical simulations and experimental specimens in terms of failure modes and characteristic parameters demonstrated that simplifying the panels as spring elements, with stiffness defined by the proposed bending constitutive model, yields errors within 15%, confirming the accuracy of the model. This study systematically investigates the influence of sheathing panels on the high-temperature out-of-plane mechanical behavior of cold-formed steel studs, innovatively proposes a two-stage bending constitutive model, provides theoretical and data support for cold-formed steel structural fire-resistant design, and offers new perspectives and methodologies for future research. Full article

Background/Objectives: Secondary hyperparathyroidism (SHPT) is a common and clinically significant complication of advanced chronic kidney disease and may require surgical intervention when medical therapy fails. This study aimed to evaluate the association between parathyroid gland burden, defined by gland number and size parameters, and biochemical disease severity in patients undergoing parathyroidectomy for SHPT, and to assess the concordance between preoperative imaging findings and intraoperative observations. Although parathyroid gland enlargement is a hallmark of SHPT, the clinical relevance of parathyroid gland number and overall gland burden in relation to biochemical disease severity and the accuracy of preoperative imaging remains incompletely defined. Methods: This single-center, retrospective observational study included adult patients who underwent parathyroidectomy for secondary hyperparathyroidism between January 2015 and December 2020. Demographic, clinical, laboratory, imaging, intraoperative, and histopathological data were analyzed. Parathyroid gland burden was assessed based on gland number, largest gland diameter, and total gland burden. Associations between gland morphology and biochemical parameters were evaluated using correlation analyses and multivariable logistic regression. Agreement between preoperative imaging and intraoperative findings was assessed using diagnostic performance metrics, contingency analysis, and the weighted kappa coefficient. Results: A total of 101 patients were included. Patients with three or more enlarged parathyroid glands had significantly higher preoperative parathyroid hormone and alkaline phosphatase levels, higher serum phosphorus levels, and lower calcium and vitamin D levels (all p < 0.05). Total gland burden and largest gland diameter were positively correlated with parathyroid hormone and alkaline phosphatase levels. In multivariable analysis, higher parathyroid hormone levels, longer dialysis duration, and vitamin D deficiency were independently associated with high gland burden. Preoperative imaging demonstrated moderate agreement with intraoperative findings (weighted kappa = 0.46; 95% CI, 0.29–0.63). Separate evaluation of imaging modalities showed that both ultrasonography and scintigraphy had relatively high sensitivity but limited specificity for detecting extensive gland involvement. Conclusions: In patients undergoing parathyroidectomy for secondary hyperparathyroidism, increased parathyroid gland burden is associated with greater biochemical disease severity. Preoperative imaging shows limited concordance with intraoperative findings and should be interpreted cautiously, particularly in the presence of multiglandular disease. These findings support the integration of morphological parameters into comprehensive preoperative assessment while highlighting the need for larger prospective, multicenter studies with standardized imaging protocols and long-term follow-up. Full article

Calcium-ion batteries (CIBs) offer several advantages. CIBs are viable alternatives to lithium-based battery systems owing to the natural abundance, low cost, and high volumetric capacity of calcium. However, their development has been severely constrained by electrolyte instability and water sensitivity. We conducted a systematic examination of Ca(ClO₄)₂ and Ca(PF₆)₂ electrolytes, focusing on low-cost salt production, solvent selection, and stringent dehydration procedures. Acetonitrile (ACN) was the ideal solvent for high salt solubility and reversible Ca²⁺ electrochemistry, while carbonate solvents failed rapidly. We found that even a small amount of moisture in the electrolyte significantly affected the electrochemical performance. This study improved the dehydration process by using 3 Å molecular sieve (MS3A) and vacuum drying to reduce moisture to ppm levels, stabilizing the electrolyte. Prussian blue (PB) half cells exhibited reversible capacities of up to ≈95 mAh g⁻¹, whereas PB-hard carbon full cells utilizing dried Ca(ClO₄)₂ showed stable cycling over 240 cycles with a Coulombic efficiency of ≈99% and capacity loss of only ≈17%. This study establishes a moisture-controlled electrolyte as a critical enabler for practical CIBs. Full article

Calmodulin-like proteins (CMLs) serve as core components in plant calcium signal transduction pathways, and they extensively modulate plant growth, development, and adaptive responses to various abiotic stresses. In this study, we cloned the StCML19 gene from potato and generated stable transgenic Arabidopsis thaliana lines constitutively expressing this gene to investigate its functional role under drought stress. Transcriptome analysis revealed that StCML19 was up-regulated under drought conditions. Phenotypic assays showed that overexpressing StCML19 notably increased the seed germination rate and root length of transgenic Arabidopsis under mannitol-induced osmotic stress, and greatly improved the plant survival rate under severe soil drought stress. Physiological analysis showed that when put under drought stress, transgenic plants had higher proline content, better SOD, CAT, and POD activities, and significantly less malondialdehyde (MDA) accumulation than wild-type plants. In addition, overexpression of StCML19 led to greater plant sensitivity to exogenous ABA, with inhibited root growth and delayed seed germination as indicators. Conclusively, this study is the first to make sense of the biological function of potato StCML19 in the drought stress response and views StCML19 as a promising candidate gene for the genetic improvement of drought-tolerant potato varieties. Full article

Background/Objectives: Type 2 diabetes mellitus (T2DM) is characterized by chronic hyperglycemia and insulin resistance, leading to progressive metabolic dysfunction. Flavonoids, such as astragalin, have reported antidiabetic potential; however, their direct effects on pancreatic β-cell ionic mechanisms and insulin secretion remain unclear. This study aimed to investigate the effects of astragalin on glucose uptake, insulin secretion, and membrane ionic currents in pancreatic β-cell lines. Methods: Murine MIN6 and rat INS-1 pancreatic β-cells were used as experimental models. Following astragalin treatment, glucose uptake was quantified by bioluminescence, and insulin secretion was measured by ELISA. Ionic currents were analyzed using the whole-cell patch-clamp technique. Selective pharmacological blockers targeting ATP-sensitive K⁺ channels (KATP), voltage-dependent K⁺ channels (K_v), and L-type voltage-dependent Ca²⁺ channels were applied to elucidate the underlying mechanisms. Results: Astragalin increased glucose uptake in a time-dependent manner, reaching a plateau between 3 and 5 h. Insulin secretion was significantly enhanced after 1 h of exposure to 100 µM astragalin. Patch-clamp recordings demonstrated that astragalin reduced potassium channel currents in pancreatic β-cells. Pharmacological modulation confirmed the involvement of KATP, K_v, and L-type Ca²⁺ channels. Verapamil attenuated the insulinotropic effect, supporting the role of calcium influx in astragalin-induced insulin exocytosis. Conclusions: Astragalin enhances glucose uptake and stimulates insulin secretion in pancreatic β-cells through modulation of potassium and calcium channels, promoting calcium-dependent exocytosis. These findings support its potential as a candidate for antidiabetic therapeutic strategies. Full article