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We study the coupled Choquard type system with lower critical exponents {−Δu+λ1(x)u=μ1(Iα∗|u|N+αN)|u|αN−1u+β(Iα∗|v|N+αN)|u|αN−1u,x∈RN,−Δv+λ2(x)v=μ2(Iα∗|v|N+αN)|v|αN−1v+β(Iα∗|u|N+αN)|v|αN−1v,x∈RN,u,v∈H1(RN), where N≥3, μ1,μ2,β>0, and λ1(x), λ2(x) are nonnegative functions. The existence of at least one positive ground state of this system is proved under certain assumptions on λ1, λ2.

The existence, nonexistence, and multiplicity of vector solutions of the linearly coupled Choquard type equations −Δu+V1xu=Iα∗uN+α/Nuα/N−1u+λv,x∈ℝN,−Δv+V2xv=Iα∗vN+α/Nvα/N−1v+λu,x∈ℝN,u,v∈H1ℝN, are proved, where α∈0,N, N≥3, V1xV2x∈L∞ℝN are positive functions, and Iα denotes the Riesz potential.

Macrophage-derived exosomes (Mφ-Exo) have multidimensional involvement in tumor initiation, progression, and metastasis, but their regulation in hepatocellular carcinoma (HCC) is not fully understood. RBPJ has been implicated in macrophage activation and plasticity. In this study we assess the role of exosomes derived from RBPJ-overexpressed macrophages (RBPJ +/+ Mφ-Exo) in HCC. The circular RNA (circRNA) profiles in RBPJ +/+ Mφ-Exo and THP-1-like macrophages (WT Mφ)-Exo was evaluated using circRNA microarray. CCK-8, Transwell, and flow cytometry analyses were used to evaluate the function of Mφ-Exo-circRNA on HCC cells. Luciferase reporter assays, RNA immunoprecipitation, and Pearson’s correlation analysis were used to confirm interactions. A nude mouse xenograft model was used to further analyze the functional significance of Mφ-Exo-cirRNA in vivo. Our results shown that hsa_circ_0004658 is upregulated in RBPJ +/+ Mφ-Exo compared to WT Mφ-Exo. RBPJ +/+ Mφ-Exo and hsa_circ_0004658 inhibits proliferation and promotes apoptosis in HCC cells, whereas hsa_circ_0004658 knockdown stimulated cell proliferation and migration but restrained apoptosis in vitro and promotes tumor growth in vivo. The effects of RBPJ +/+ Mφ-Exo on HCC cells can be reversed by the hsa_circ_0004658 knockdown. Mechanistic investigations revealed that hsa_circ_0004658 acts as a ceRNA of miR-499b-5p, resulting in the de-repression of JAM3. These results indicate that exosome circRNAs secreted from RBPJ +/+ Mφ inhibits tumor progression through the hsa_circ_0004658/miR-499b-5p/JAM3 pathway and hsa_circ_0004658 may be a diagnostic biomarker and potential target for HCC therapy.

Postprandial hyperglycemia induces inflammation and endothelial dysfunction resulting in vascular complications in patients with diabetes. Toll-like receptors (TLRs) are central to the regulation of inflammatory responses through activation of nuclear factor-kappa B (NF-ĸB). This study examined the role of TLR2 and 4 in regulating inflammation and endothelial dysfunction when exposed to fluctuating glucose concentrations. HMEC-1 cells (a human microvascular endothelial cell line) were exposed to control (5 mM), 30 mM (high), fluctuating (5/30 mM) and 11.2 mM glucose (approximate glycaemic criteria for the diagnosis of diabetes mellitus) for 72 h. Cells were assessed for TLR2, 4, high mobility group box -1 (HMGB1), NF-ĸB, monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Fluctuating glucose concentrations maximally upregulated TLR4 but not TLR2 expression with increased NF-ĸB activation, IL-8 and ICAM-1 expression. HMGB1 was increased in the supernatants of cells exposed to 30 mM and 11.2 mM glucose compared to control. The addition of recombinant HMGB1 induced NF-ĸB activation and synthesis of proinflammatory cytokines and chemokines, which were prevented by TLR2 or 4 signalling inhibition. An additive effect when both TLR2 and 4 signalling pathways were inhibited was observed. However, only inhibition of TLR4 signalling suppressed the synthesis of MCP-1, IL-8 and ICAM-1. In vivo, streptozotocin-induced diabetic mice exhibited an increase in glomerular ICAM-1 which was not evident in TLR2(-/-) or TLR4(-/-) diabetic mice. Collectively, our results suggest that targeting the signalling pathway of TLR2 and 4 may be of therapeutic benefit in attenuating vascular inflammation in diabetic microangiopathy.

The role of the pro-inflammatory cytokine IL-17 in the pathogenesis of numerous inflammatory disorders is well-documented, but conflicting results are reported for its role in diabetic nephropathy. Here we examined the role of IL-17 signalling in a model of streptozotocin-induced diabetic nephropathy through IL-17 knockout mice, administration of neutralising monoclonal anti-IL-17 antibody and in vitro examination of gene expression of renal tubular cells and podocytes under high glucose conditions with or without recombinant IL-17. IL-17 deficient mice were protected against progression of diabetic nephropathy, exhibiting reduced albuminuria, glomerular damage, macrophage accumulation and renal fibrosis at 12 weeks and 24 weeks. Administration of anti-IL-17 monoclonal antibody to diabetic wild-type mice was similarly protective. IL-17 deficiency also attenuated up-regulation of pro-inflammatory and pro-fibrotic genes including IL-6, TNF-α, CCL2, CXCL10 and TGF-β in diabetic kidneys. In vitro co-stimulation with recombinant IL-17 and high glucose were synergistic in increasing the expression of pro-inflammatory genes in both cultured renal tubular cells and podocytes. We conclude that absence of IL-17 signalling is protective against streptozotocin-induced diabetic nephropathy, thus implying a pro-inflammatory role of IL-17 in its pathogenesis. Targeting the IL-17 axis may represent a novel therapeutic approach in the treatment of this disorder.

It remained prevalent in the past years to obtain the precommitment strategies for Markowitz's mean-variance portfolio optimization problems, but not much is known about their time-consistent strategies. This paper takes a step to investigate the time-consistent Nash equilibrium strategies for a multiperiod mean-variance portfolio selection problem. Under the assumption that the risk aversion is, respectively, a constant and a function of current wealth level, we obtain the explicit expressions for the time-consistent Nash equilibrium strategy and the equilibrium value function. Many interesting properties of the time-consistent results are identified through numerical sensitivity analysis and by comparing them with the classical pre-commitment solutions.

Secretory IgA is a key mucosal component ensuring host-microbiota mutualism. Here we use nutritional geometry modelling in mice fed 10 different macronutrient-defined, isocaloric diets, and identify dietary protein as the major driver of secretory IgA production. Protein-driven secretory IgA induction is not mediated by T-cell-dependent pathways or changes in gut microbiota composition. Instead, the microbiota of high protein fed mice produces significantly higher quantities of extracellular vesicles, compared to those of mice fed high-carbohydrate or high-fat diets. These extracellular vesicles activate Toll-like receptor 4 to increase the epithelial expression of IgA-inducing cytokine, APRIL, B cell chemokine, CCL28, and the IgA transporter, PIGR. We show that succinate, produced in high concentrations by microbiota of high protein fed animals, increases generation of reactive oxygen species by bacteria, which in turn promotes extracellular vesicles production. Here we establish a link between dietary macronutrient composition, gut microbial extracellular vesicles release and host secretory IgA response. Secretory IgA plays vital roles interfacing between the host immune system and the resident microbiota at the mucosal surface. Here the authors explore the effect of dietary protein on the production of secretory IgA, driven by the production of extracellular vesicles by the intestinal microbiota.

Background Blood metabolites are important to various aspects of our health. However, currently, there is little evidence about the role of circulating metabolites in the process of skin aging. Objectives To examine the potential effects of circulating metabolites on the process of skin aging. Method In the primary analyses, we applied several MR methods to study the associations between 249 metabolites and facial skin aging risk. In the secondary analyses, we replicated the analyses with another array of datasets including 123 metabolites. MR Bayesian model averaging (MR-BMA) method was further used to prioritize the metabolites for the identification of predominant metabolites that are associated with skin aging. Results In the primary analyses, only the unsaturation degree of fatty acids was found significantly associated with skin aging with the IVW method after multiple testing (odds ratio = 1.084, 95% confidence interval = 1.049–1.120, p  = 1.737 × 10 −06 ). Additionally, 11 out of 17 unsaturation-related biomarkers showed a significant or suggestively significant causal effect [ p  < 0.05 and > 2 × 10 −4 (0.05/249 metabolites)]. In the secondary analyses, seven metabolic biomarkers were found significantly associated with skin aging [ p  < 4 × 10 −4 (0.05/123)], while six of them were related to the unsaturation degree. MR-BMA method validated that the unsaturation degree of fatty acids plays a dominant role in facial skin aging. Conclusions Our study used systemic MR analyses and provided a comprehensive atlas for the associations between circulating metabolites and the risk of facial skin aging. Genetically proxied unsaturation degree of fatty acids was highlighted as a dominant factor correlated with the risk of facial skin aging.

In recent years, the impact of global climate change and human activities on vegetation has become increasingly prominent. Understanding vegetation change and its response to climate variables and human activities are key tasks in predicting future environmental changes, climate changes and ecosystem evolution. This paper aims to explore the impact of Three Gorges Reservoir (TGR) water impoundment on the vegetation–climate response relationship in the Three Gorges Reservoir Region (TGRR) and its surrounding region. Firstly, based on the SPOT/VEGETATION NDVI and ERA5 reanalysis datasets, the correlation between climatic factors (temperature and precipitation) and NDVI was analyzed by using partial correlation coefficient method. Secondly, nonlinear fitting method was used to fit the mapping relationship between NDVI and climatic factors. Then, the residual analysis was conducted to evaluate the impact of TGR impoundment on vegetation–climate response relationship. Finally, sensitivity index (SI), sensitivity variation index (SVI) and difference index (DI) were defined to quantify the variation of vegetation–climate response relationship before and after water impoundment. The results show that water impoundment might have some impacts on the response of vegetation–climate, which gradually reduced with increasing distance from the channel; comparing with the residual analysis method, the SI and DI index methods are more intuitive, and combining these two methods may provide new ideas for the study of the impact of human activities on vegetation.

Toll like receptor (TLR) 4 has been reported to promote inflammation in diabetic nephropathy. However the role of TLR4 in the complicated pathophysiology of diabetic nephropathy is not understood. In this study, we report elevated expression of TLR4, its endogenous ligands and downstream cytokines, chemokines and fibrogenic genes in diabetic nephropathy in WT mice with streptozotocin (STZ) diabetes. Subsequently, we demonstrated that TLR4-/- mice were protected against the development of diabetic nephropathy, exhibiting less albuminuria, inflammation, glomerular hypertrophy and hypercellularity, podocyte and tubular injury as compared to diabetic wild-type controls. Marked reductions in interstitial collagen deposition, myofibroblast activation (α-SMA) and expression of fibrogenic genes (TGF-β and fibronectin) were also evident in TLR4 deficient mice. Consistent with our in vivo results, high glucose directly promoted TLR4 activation in podocytes and tubular epithelial cells in vitro, resulting in NF-κB activation and consequent inflammatory and fibrogenic responses. Our data indicate that TLR4 activation may promote inflammation, podocyte and tubular epithelial cell injury and interstitial fibrosis, suggesting TLR4 is a potential therapeutic target for diabetic nephropathy.