G protein‐coupled receptor 65 (GPR65), a susceptibility gene for inflammatory bowel diseases (IBD), has been identified to promote Th17 cell pathogenicity and induce T cell apoptosis. However, the potential role of GPR65 in modulating CD4+ T cell immune responses in the pathogenesis of IBD stills not entirely understood. Here, we displayed that GPR65 expression was increased in inflamed intestinal mucosa of IBD patients and positively associated with disease activity. It was expressed in CD4+ T cells and robustly upregulated through the TNF‐α‐caspase 3/8 signalling pathway. Ectopic expression of GPR65 significantly promoted the differentiation of peripheral blood (PB) CD4+ T cells from IBD patients and HC to Th1 and Th17 cells in vitro. Importantly, conditional knockout of Gpr65 in CD4+ T cells ameliorated trinitrobenzene sulfonic acid (TNBS)‐induced acute murine colitis and a chronic colitis in Rag1–/– mice reconstituted with CD45RBhighCD4+ T cells in vivo, characterised by attenuated Th1 and Th17 cell immune response in colon mucosa and decreased infiltration of CD4+ T cells, neutrophils and macrophages. RNA‐seq analysis of Gpr65ΔCD4 and Gpr65flx/flxCD4+ T cells revealed that NUAK family kinase 2 (Nuak2) acts as a functional target of Gpr65 to restrict Th1 and Th17 cell immune response. Mechanistically, GPR65 deficiency promoted NUAK2 expression via the cAMP‐PKA‐C‐Raf‐ERK1/2‐LKB1‐mediated signalling pathway. Consistently, silencing of Nuak2 facilitated the differentiation of Gpr65ΔCD4 and Gpr65flx/flxCD4+ T cells into Th1 and Th17 cells. Therefore, our data point out that GPR65 promotes Th1 and Th17 cell immune response and intestinal mucosal inflammation by suppressing NUAK2 expression, and that targeting GPR65 and NUAK2 in CD4+ T cells may represent a novel therapeutic approach for IBD.

Background Ulcerative colitis (UC) may be exacerbated by Fusobacterium nucleatum (Fn) infection. However, the mechanism underlying Fn-mediated progression of UC has yet to be established. Here, we aimed to establish whether and how Fn-derived extracellular vesicles (Fn-EVs) participate in the development of experimental colitis through microRNAs (miRNAs). Methods EVs were isolated and purified by ultracentrifugation from Fn and Escherichia coli culture supernatants. Differentially expressed miRNAs in control intestinal epithelial cells (IECs) and Fn-EV–treated IECs were identified by miRNA sequencing. EVs were cocultured with IECs or administered to CARD3wt/CARD3–/– mice by gavage to assess inflammatory responses to and the mechanism of action of Fn-EVs. Results Fn-EVs promoted upregulation of proinflammatory cytokines (interleukin [IL]-1β, IL-6, tumor necrosis factor α), downregulation of anti-inflammatory IL-10 and intercellular tight junction proteins ZO-1 and occludin, and epithelial barrier dysfunction in IECs. Fn-EVs significantly aggravated experimental colitis in mice associated with Fn-EV–mediated downregulation of miR-574-5p expression and autophagy activation. Blockade of autophagy using chloroquine alleviates barrier damage exacerbated by Fn-EVs in vitro and in vivo. Inhibition of the miR-574-5p/CARD3 axis reduced the severity of colitis, epithelial barrier damage, and autophagy activation induced by Fn-EVs. Conclusions Here, we describe a new mechanism by which Fn-EVs mediate experimental colitis severity through miR-574-5p/CARD3–dependent autophagy activation, providing a novel target for UC monitoring and targeted therapy.

The pathogenesis of ulcerative colitis (UC) is unclear, while genetic factors have been confirmed to play an important role in its development. P2RY13 is a G protein-coupled receptor (GPCRs), which are involved in the pathogenesis of inflammation and immune disorders. According to GEO database analysis, we first observed that the expression of P2Y13 was increased in UC patients. Therefore, we sought to determine the role of P2Y13 in the development of colitis. Our data showed that P2RY13 was highly expressed in the inflamed intestinal tissues of UC patients. In mice, pharmacological antagonism of P2Y13 can significantly attenuate the intestinal mucosal barrier disruption. In LPS-induced NCM460 cell, knockdown or pharmacological inhibition of P2RY13 increased the expression of intestinal tight junction protein and reduced apoptosis. In addition, we found that the effect of P2Y13 on colitis is related to the activation of the IL-6/STAT3 pathway. Activation of P2Y13 increases IL-6 expression and promotes STAT3 phosphorylation and nuclear transport. Deletion of the STAT3 gene in the intestinal epithelial cells of mice significantly mitigated the exacerbation of colitis due to P2Y13 activation. Thus, P2Y13 can aggravate intestinal mucosal barrier destruction by activating the IL-6/STAT3 pathway. P2Y13 might be a potential drug target for UC.

Pulmonary hypertension (PH) is a severe, progressive vascular disorder characterized by elevation in pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR), finally leading to right heart failure and death. During the rise in PAP and PVR, vascular remodeling is accompanied by accumulation of pulmonary artery smooth muscle cells (PASMCs), endothelial cells (ECs), fibroblasts, myofibroblasts and pericytes in pulmonary arterial wall, which leads to thickening of the inner and outer linings of blood vessels, loss and obstructive remodeling of the pulmonary vascular bed and perivascular inflammation. 1-3 Associated with multiple primary causes, PH encompasses a group of clinical entities. According to the latest classification proposed by the Sixth World Symposium on PH, the disease can develop due to pulmonary arterial disorder, left heart disease, lung disease or hypoxia, chronic thromboembolic disease and other unclear or multifactorial mechanisms. 4 Though current treatments can improve clinical symptoms and hemodynamic abnormality to some extent, it is difficult to target pulmonary vascular remodeling and

Neutrophils are considered as complex innate immune cells and play a critical role in maintaining intestinal mucosal homeostasis. They exert robust pro-inflammatory effects and recruit other immune cells in the acute phase of pathogen infection and intestinal inflammation, but paradoxically, they also limit exogenous microbial invasion and facilitate mucosal restoration. Hyperactivation or dysfunction of neutrophils results in abnormal immune responses, leading to multiple autoimmune and inflammatory diseases including systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel diseases (IBD). As a refractory intestinal inflammatory disease, the pathogenesis and progression of IBD are associated with complicated immune response processes in which neutrophils are profoundly involved. However, the consensus on potential roles of neutrophils in modulating pathogenic and repair processes of IBD remains not fully understood. Accumulated infiltrating neutrophils cross the epithelial barrier and contribute to microbial dysbiosis, aggravated intestinal architectural damage, compromised resolution of intestinal inflammation and increased risk of thrombosis during IBD. Paradoxically, activated neutrophils are also associated with effective elimination of invaded microbiota, promoted angiogenesis and tissue restoration of gut mucosa in IBD. Here, we discuss the beneficial and detrimental roles of neutrophils in the onset and resolution of intestinal mucosal inflammation and provide a precise overview of neutrophil functions in the pathogenesis of IBD.

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SUMMARYA new seismic energy dissipation shear wall structure is proposed in this paper. The new shear wall is one with purposely built-in vertical slits within the wall panel, and rubber belts as seismic energy dissipation devices are installed in the vertical slits. In order to verify this concept, shaking table tests of a 10-storey shear wall model with rubber belts "lled in the vertical slits were carried out, and comparison of seismic behaviour was made between the new shear wall system and a shear wall with reinforced concrete connecting beams as energy dissipation. Furthermore, the seismic behaviour of this new shear wall is analysed by a "nite element time history analysis method. The test and analysis show that the new shear wall system has a very good ability to dissipate seismic energy and is easy to use in engineering practice. INTRODUCTIONIn order to prevent the brittle damages of shear walls and improve their property of dissipating seismic energy, the concept of slit shear wall, a new seismic energy dissipation system, has been proposed during the recent years [1}6]. A slit shear wall is one with purposely built-in vertical slits which divide the shear wall into two narrower wall units connected by shear transfer interfaces (see Figure 1). The shear transfer interfaces between adjacent wall units are generally of three types: (1) reinforced concrete connecting beams; (2) some elastic materials with low elastic modulus and high deformation capacity such as rubber belts; and (3) various dampers, such as rubber dampers, spring dampers, etc. The working mechanism of this shear wall has been described in previous papers [1}6], and a series of static [2}4] and dynamic tests [6] have been carried out at the University of Hong Kong and Tongji University. Lu et al. [7] have introduced the shaking table tests of a 10-storey shear wall model (DM1) which has reinforced concrete connecting beams as shear transfer interfaces. Lu et al. [7] have described the dynamic analysis method for model DM1, and have performed some parametric study for this shear wall system. This paper will describe the shaking table tests of a new 10-storey shear wall model (DM2) which has rubber belts and reinforcements as shear transfer interfaces. Therefore, the objective of this paper is to further study the seismic behaviour and energy dissipation mechanism of the new shear wall system by shaking table tests and "nite element time history analysis method. DESCRIPTION OF SHAKING TABLE TESTIn order to verify the analysis method and to study the seismic energy dissipation mechanism of the new shear wall system, one reinforced-concrete shear wall model was constructed and tested. It was 1/5 scale model of a typical 10-storey shear wall structure having a height/width ratio of 5.6. The model consists of two pieces of 40 mm thick walls connected by slabs at each #oor level and four foundation beams for "xing the model onto the shaking table. Each wall has rubber belts "lled in the vertical slits (see Figure 1) as shear transfer interface...

Background Evidence has shown that the traditional Chinese herbal medicine Wumei decoction (WMD) has a protective effect on ulcerative colitis. Here, we studied the anti-inflammatory effects and potential mechanisms of WMD on chronic colitis in mice. Methods A dextran sulfate sodium (DSS)–induced chronic colitis model and CD45RBhighCD4+ T cell transfer model were established in mice. Body weight, Disease Activity Index, and colon length were assessed, and histopathology was confirmed by hematoxylin and eosin staining. Colon tissue samples were collected to detect the frequencies of various immune cells, expression of cytokines, and tight junction–related proteins using flow cytometry, quantitative real-time polymerase chain reaction, and enzyme-linked immunosorbent assay, respectively. 16S ribosomal DNA sequencing was performed to distinguish differential microbiota of fecal samples. Results Severe chronic colitis was observed in mice after DSS exposure and in Rag1-/- mice reconstituted with CD45RBhighCD4+ T cells, as manifested by weight loss, hematochezia, and shortening and thickening of the colon, which were reversed by WMD treatment. WMD markedly suppressed intestinal mucosal CD4+ T cell differentiation and the secretion of proinflammatory cytokines (eg, tumor necrosis factor α, interleukin-1β, interferon γ, and IL-17A) by flow cytometry, quantitative real-time polymerase chain reaction, and enzyme-linked immunosorbent assay, respectively. Moreover, WMD promoted the expression of occludin, zonula occludens-1, and E-cadherin, thereby maintaining the epithelial barrier function. Additionally, 16S ribosomal DNA sequencing revealed that WMD regulated the dysbiosis of gut microbiota in CD45RBhighCD4+ T cell-reconstituted Rag1-/- mice, evidenced by an increase of Allobaculum and Bacteroides and a decrease of Ileibacterium. Conclusions WMD ameliorates chronic colitis in mice induced by DSS or reconstituted with CD45RBhighCD4+ T cells through suppressing Th1/Th17 cell differentiation and the secretion of proinflammatory cytokines, maintaining epithelial barrier function, and improving the dysbiosis.