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关键词： Calcium chloride   Calcium ions   Longevity effects   CaMK family   DAF-16  

摘要： Calcium chloride can be used as a food additive and in medicine. The intake of calcium chloride can elevate the intracellular Ca2+ level, which subsequently activates the downstream proteins in the Ca2+/calmodulin-dependent protein kinase (CaMK) family. Based on evidence from the literature, we hypothesized that the calcium chloride supplementation may promote longevity by increasing intracellular Ca2+ levels, thereby activating the UNC-43/DAF-16 pathway, with potential involvement of the CKK-1 and CMK-1. The lifespan assays, health indexes (pharyngeal pumping and body bends), calcium imaging to assess the Ca2+ level, loss-of-function assays for the mutants, DAF-16 nuclear localization, UNC-43 protein localization, and Caenorhabditis elegans RNA interference (RNAi) experiments were conducted. The results showed that the supplementation of calcium chloride significantly extended the lifespan in a dose-dependent manner. At the most effective dose (2000 nmol/plate), calcium chloride increased the mean lifespan by 15.4%, enhanced the calcium-level fluorescence by 2.8 folds, and improved both the health indices. The longevity effects induced by the calcium chloride required the CKK-1, CMK-1, UNC-43, and DAF-16 proteins. Moreover, both the DAF-16 nuclear translocation and the longevity effects were significantly suppressed by the RNAi targeting the CKK-1, CMK-1 and UNC-43. Importantly, the maintenance of the UNC-43 in the cytoplasm was dependent on the CKK-1 and CMK-1, as demonstrated by the RNAi analyses. All of these results indicated that the calcium chloride supplementation can exert the longevity effects in the C. elegans via a CKK-1 and CMK-1-dependent UNC-43/DAF-16 signaling mechanism.

关键词： Cardiac diagnostics   Coronary artery disease   Myocarditis   Cardiomyopathy   Cardiovascular imaging   Cardiac diagnostics   Coronary artery disease   Myocarditis   Cardiomyopathy   Cardiovascular imaging  

摘要： Cardiovascular imaging is an essential component of modern cardiology. Its information is important for diagnosing cardiovascular diseases, for treatment decisions and therapy management, and for assessing individual prognosis. Magnetic resonance imaging (MRI) plays a growing role in this field. It provides information on cardiac anatomy, function, perfusion, viability, inflammation and blood flow. Frequent indications for cardiovascular MRI include the assessment of coronary artery disease, cardiomyopathies, inflammatory heart disease, heart failure, valvular heart disease and congenital heart defects. This two-part article provides a practical overview.

关键词： neurofibromatosis type 1   NF1   sleep   circadian   zebrafish  

摘要： Neurofibromatosis type 1 (NF1) is a common neurodevelopmental disorder that is associated with several developmental and behavioral phenotypes, including reduced and fragmented sleep at night. Here, we describe the role of NF1 in sleep in zebrafish, a diurnal vertebrate whose mechanisms of sleep control are broadly conserved with those of mammals. The zebrafish genome encodes two neurofibromin 1 (nf1) paralogs: nf1a and nf1b, which function in a partially redundant manner. We found that zebrafish with reduced nf1 function exhibit decreased and delayed sleep at night, similar to humans with the NF1 disorder, in a dose-dependent manner. Zebrafish nf1 mutants also exhibit shorter sleep bouts, decreased arousal threshold, and decreased sleep depth, consistent with disrupted sleep, and show increased sleep in the morning. Finally, we found that zebrafish nf1 mutants have intact behavioral circadian rhythms, and the nf1 mutant sleep phenotype does not require entrained circadian rhythms. These results establish a vertebrate nf1 model that recapitulates key aspects of human NF1-associated sleep disturbances and provides a basis to explore mechanisms through which NF1 regulates sleep. This study also suggests that disrupted sleep in the human NF1 disorder is directly due to reduced NF1 function, rather than a secondary symptom of the disorder. Statement of Significance Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder that is associated with several developmental and behavioral phenotypes, including disrupted sleep. Here, we establish zebrafish as a model to study the function of NF1 in sleep in a diurnal vertebrate, and show that zebrafish with reduced neurofibromin 1 (nf1) function exhibit decreased and delayed sleep at night, similar to humans with the NF1 disorder. Our results suggest that disrupted sleep in individuals with the NF1 disorder is directly due to reduced NF1 function, rather than a secondary symptom of the disorder. These results estab

关键词： chronic kidney disease   crosstalk   fibrosis   IGFBP-5   TGF-beta 1  

摘要： Background Renal fibrosis is a common pathological feature of chronic kidney disease (CKD) but its underlying mechanisms remain incompletely understood. Our previous study demonstrated that insulin-like growth factor-binding protein 5 (IGFBP-5) promotes glycolytic reprogramming in vascular endothelial cells (ECs) and exacerbates renal inflammation in diabetic kidney *** Human renal proximal tubular epithelial cells (HK-2) and human umbilical vein endothelial cells (HUVECs) were used. A co-culture system was employed to investigate endothelial cell-tubular epithelial cell (EC-TEC) crosstalk. Unilateral ureteral obstruction (UUO) and aristolochic acid nephropathy (ANN) models were established in wild-type (WT), global IGFBP-5-/- and endothelial-specific Tie-2 Cre;IGFBP-5-/- mice. Expression levels of IGFBP-5, TGF-beta 1 and fibrosis markers were assessed to investigate the role of IGFBP-5 in renal *** Serum IGFBP-5 levels were significantly elevated in patients with CKD. Genetic ablation of IGFBP-5 attenuated renal fibrosis in murine models, demonstrating its critical role in fibrogenesis. IGFBP-5 was predominantly expressed in ECs and endothelial-specific deletion delayed renal fibrosis progression via suppression of the TGF-beta 1/Smad3 pathway. In vitro, endothelial-derived IGFBP-5 promoted a profibrotic phenotypic transformation in TECs through AKT-mediated phosphorylation of the TGF-beta 1/Smad3 axis. Conversely, TGF-beta 1 stimulated IGFBP-5 biosynthesis and secretion in ECs via the ERK signalling pathway, establishing a self-amplifying feedback loop. This reciprocal IGFBP-5/TGF-beta 1 crosstalk between ECs and TECs was confirmed in co-culture *** Our findings reveal a novel EC-TEC crosstalk axis mediated by reciprocal IGFBP-5/TGF-beta 1 signalling, which is a critical driver of renal fibrosis. IGFBP-5 emerges as a promising therapeutic target for inhibiting renal fibrogenesis in CKD.

关键词： cytotoxic T lymphocyte   dendritic cells   LSP1   melanoma  

摘要： Leukocyte-specific protein 1 (LSP1) is an F-actin-binding protein involved in immune cell motility and cytoskeletal rearrangement. Although LSP1 has been extensively studied in neutrophils and macrophages, its role in dendritic cells and tumour surveillance remains poorly understood. Here, we demonstrate that LSP1 deficiency in mice leads to increased growth of B16-OVA melanoma, accompanied by reduced survival. Flow cytometry and histological analysis revealed lower total leukocyte content in the tumour microenvironment (TME) in LSP1 knockout (KO) mice compared to wild-type (WT) mice, and a significant reduction in CD8+ T cells and CD103+ dendritic cells (DCs), as well as in additional immune cell populations, in tumour-draining lymph nodes of LSP1 KO mice. In vivo, DCs from LSP1 KO mice exhibited impaired antigen uptake and transportation to the tumour-draining lymph node and a reduced in vitro capacity to activate na & iuml;ve CD8+ T cells. These defects correlated with diminished in vitro and in vivo CD8+ T cell priming and activation in LSP1-deficient mice. Cytokine profiling of tumour homogenates from LSP1 KO mice revealed a complex inflammatory milieu, with elevated levels of both pro- and anti-tumoural cytokines, including IL-1 beta, TNF-alpha, IL-10, IL-17A, IFN beta IL-23, IL-27 and GM-CSF. Our findings suggest that LSP1 plays a critical, cell-intrinsic role in both DC and CD8+ T cell function, although we cannot exclude the possible role of other leukocyte populations. Its absence promotes tumour progression by disrupting key immune responses in the TME.

关键词： acute ischemic stroke   sLRP1   stroke prognosis   prognostic biomarkers   functional outcome improvement   biomarker-based prediction models  

摘要： Aims Serum soluble low-density lipoprotein receptor-related protein 1 (sLRP1) has been implicated in the severity of ischemia-reperfusion injury in experimental stroke models. Its potential prognostic value in ischemic stroke recovery warrants further investigation. This study aims to explore the association between serum sLRP1 levels and functional outcome improvement from 3 to 12 months following acute ischemic stroke (AIS). Methods We included patients hospitalized for AIS within 24 hours of symptom onset. Serum sLRP1 levels at admission were analyzed for their association with functional outcome improvement, defined as a >= 1-point decrease in the modified Rankin Scale (mRS) score between 3 and 12 months. Multivariate binary logistic regression was employed to adjust for potential confounders. Improvements in predictive performance by including sLRP1 were assessed using the net reclassification index (NRI) and integrated discrimination improvement (IDI). Results A total of 171 patients were enrolled (median age: 65 years;64.9% male). Functional outcome improvement was observed in 53 patients (31.0%). After adjusting for confounding factors, patients in the second and third tertiles of sLRP1 had significantly lower odds of functional outcome improvement compared to those in the lowest tertile (Tertile 2, odds ratio [OR] 0.19, 95% confidence interval [CI]: 0.08-0.49, P = .001;Tertile 3, OR 0.10, 95% CI: 0.03-0.27, P < .001). Incorporating sLRP1 into predictive models alongside conventional factors significantly enhanced reclassification accuracy (NRI = 46%, P = .004;IDI = 4%, P = .014). Conclusions Lower serum sLRP1 levels at admission are independently associated with functional outcome improvement after AIS. These findings suggest that modulating sLRP1 may represent a promising therapeutic strategy to enhance recovery in stroke patients.

关键词： C-H activation   ss-C(sp (2) )-H thiolation & selanylation   Additive free   Cu-catalysis   8-AIP   Late-stage functionalization  

摘要： Diaryl sulfides, diaryl selenides, and their derivatives are crucial scaffolds in the fields of organic chemistry and drug discovery. We report a practical and broadly applicable strategy for additive-free copper(II)-catalyzed ortho-sulfanylation and selanylation of beta-C(sp(2))-H bonds in (hetero)arenes, directed by 8-aminoimidazo[1,2-a]pyridine (8-AIP), a removable 6,5-fused bicyclic N,N-bidentate directing group. This protocol features mild reaction conditions that enable the formation of diverse functionalized thioethers and selenides using thiols, disulfides, and diselenides, with enhanced functional group tolerance and unique site-selectivity. The present protocol is reproducible in gram scale, and, in addition, we have also the showed cleavage of chelating auxiliary.