A new treatment for neurogenic inflammation caused by EV71 with CR2-targeted complement inhibitor

BACKGROUND: Enterovirus 71 (EV71), one of the most important neurotropic EVs, has caused death and long-term neurological sequelae in hundreds of thousands of young children in the Asia-Pacific region in the past decade. The neurological diseases are attributed to infection by EV71 inducing an extensive peripheral and central nervous system (CNS) inflammatory response with abnormal cytokine production and lymphocyte depletion induced by EV71 infection. In the absence of specific antiviral agents or vaccines, an effective immunosuppressive strategy would be valuable to alleviate the severity of the local inflammation induced by EV71 infection. PRESENTATION OF THE HYPOTHESIS: The complement system plays a pivotal role in the inflammatory response. Inappropriate or excessive activation of the complement system results in a severe inflammatory reaction or numerous pathological injuries. Previous studies have revealed that EV71 infection can induce complement activation and an inflammatory response of the CNS. CR2-targeted complement inhibition has been proved to be a potential therapeutic strategy for many diseases, such as influenza virus-induced lung tissue injury, postischemic cerebral injury and spinal cord injury. In this paper, a mouse model is proposed to test whether a recombinant fusion protein consisting of CR2 and a region of Crry (CR2-Crry) is able to specifically inhibit the local complement activation induced by EV71 infection, and to observe whether this treatment strategy can alleviate or even cure the neurogenic inflammation. TESTING THE HYPOTHESIS: CR2-Crry is expressed in CHO cells, and its biological activity is determined by complement inhibition assays. 7-day-old ICR mice are inoculated intracranially with EV71 to duplicate the neurological symptoms. The mice are then divided into two groups, in one of which the mice are treated with CR2-Crry targeted complement inhibitor, and in the other with phosphate-buffered saline. A group of mice deficient in complement C3, the breakdown products of which bind to CR2, are also infected with EV71 virus. The potential bioavailability and efficacy of the targeted complement inhibitor are evaluated by histology, immunofluorescence staining and radiolabeling. IMPLICATIONS OF THE HYPOTHESIS: CR2-Crry-mediated targeting complement inhibition will alleviate the local inflammation and provide an effective treatment for the severe neurological diseases associated with EV71 infection

Acidosis Activation of the Proton-Sensing GPR4 Receptor Stimulates Vascular Endothelial Cell Inflammatory Responses Revealed by Transcriptome Analysis

Acidic tissue microenvironment commonly exists in inflammatory diseases, tumors, ischemic organs, sickle cell disease, and many other pathological conditions due to hypoxia, glycolytic cell metabolism and deficient blood perfusion. However, the molecular mechanisms by which cells sense and respond to the acidic microenvironment are not well understood. GPR4 is a proton-sensing receptor expressed in endothelial cells and other cell types. The receptor is fully activated by acidic extracellular pH but exhibits lesser activity at the physiological pH 7.4 and minimal activity at more alkaline pH. To delineate the function and signaling pathways of GPR4 activation by acidosis in endothelial cells, we compared the global gene expression of the acidosis response in primary human umbilical vein endothelial cells (HUVEC) with varying level of GPR4. The results demonstrated that acidosis activation of GPR4 in HUVEC substantially increased the expression of a number of inflammatory genes such as chemokines, cytokines, adhesion molecules, NF-κB pathway genes, and prostaglandin-endoperoxidase synthase 2 (PTGS2 or COX-2) and stress response genes such as ATF3 and DDIT3 (CHOP). Similar GPR4-mediated acidosis induction of the inflammatory genes was also noted in other types of endothelial cells including human lung microvascular endothelial cells and pulmonary artery endothelial cells. Further analyses indicated that the NF-κB pathway was important for the acidosis/GPR4-induced inflammatory gene expression. Moreover, acidosis activation of GPR4 increased the adhesion of HUVEC to U937 monocytic cells under a flow condition. Importantly, treatment with a recently identified GPR4 antagonist significantly reduced the acidosis/GPR4-mediated endothelial cell inflammatory response. Taken together, these results show that activation of GPR4 by acidosis stimulates the expression of a wide range of inflammatory genes in endothelial cells. Such inflammatory response can be suppressed by GPR4 small molecule inhibitors and hold potential therapeutic value

Association of white matter hyperintensity burden and infarct volume in the anterior choroidal artery territory with early neurological progression: a dual-center retrospective study

ObjectiveTo investigate the associations of white matter hyperintensity (WMH) burden and infarct volume with early neurological progression in anterior choroidal artery (AChA) territory infarction, and to identify potential imaging-based predictive thresholds.MethodsThis retrospective cohort study consecutively enrolled AChA infarct patients admitted to two comprehensive stroke centers between September 2018 and September 2024. WMH burden and infarct volume were assessed using the Fazekas visual rating scale and an automated volumetric quantification method based on lesion prediction algorithm, respectively. The primary outcome was early neurological progression. Multivariate logistic regression models with stepwise adjustment for confounders were used to evaluate the associations of WMH burden and infarct volume with early progression. Restricted cubic spline regression was performed to explore non-linear relationships and to determine thresholds. Continuous variables were standardized, and piecewise regression analysis was conducted based on the identified thresholds. Subgroup analyses with interaction tests were performed to assess the consistency of these associations across different populations.ResultsA total of 216 patients were included, of whom 82 (38.0%) experienced early neurological progression. After adjustment for potential confounders, WMH burden showed a significant non-linear association with progression risk. For WMH volumes <66.1 mL, each standard deviation increase was associated with a 74% higher risk of progression (standardized OR: 1.74, 95% CI: 1.29–2.40, p < 0.001). Compared with the lowest quartile, patients in the highest WMH quartile showed significantly increased risk (adjusted OR: 5.32, 95% CI: 1.48–13.88, p = 0.009). This association was confirmed by Fazekas scale analysis, with grade 3 patients showing substantially higher risk than grade 0 (adjusted OR: 6.22, 95% CI: 1.74–25.42, p = 0.007). Infarct volume demonstrated a similar non-linear pattern; for volumes <1.1 mL, each standard deviation increase was associated with 59% higher progression risk (standardized OR: 1.59, 95% CI: 1.04–2.47, p = 0.036). Quartile analysis revealed the highest risk in the third quartile compared to the lowest (adjusted OR: 5.63, 95% CI: 2.06–15.40, p < 0.001).ConclusionThis study revealed non-linear associations of WMH and infarct volume with early progression in AChA infarct patients

Raffinose degradation-related gene GhAGAL3 was screened out responding to salinity stress through expression patterns of GhAGALs family genes

A-galactosidases (AGALs), the oligosaccharide (RFO) catabolic genes of the raffinose family, play crucial roles in plant growth and development and in adversity stress. They can break down the non-reducing terminal galactose residues of glycolipids and sugar chains. In this study, the whole genome of AGALs was analyzed. Bioinformatics analysis was conducted to analyze members of the AGAL family in Gossypium hirsutum, Gossypium arboreum, Gossypium barbadense, and Gossypium raimondii. Meanwhile, RT-qPCR was carried out to analyze the expression patterns of AGAL family members in different tissues of terrestrial cotton. It was found that a series of environmental factors stimulated the expression of the GhAGAL3 gene. The function of GhAGAL3 was verified through virus-induced gene silencing (VIGS). As a result, GhAGAL3 gene silencing resulted in milder wilting of seedlings than the controls, and a significant increase in the raffinose content in cotton, indicating that GhAGAL3 responded to NaCl stress. The increase in raffinose content improved the tolerance of cotton. Findings in this study lay an important foundation for further research on the role of the GhAGAL3 gene family in the molecular mechanism of abiotic stress resistance in cotton

Characterization and gene expression patterns analysis implies BSK family genes respond to salinity stress in cotton

Identification, evolution, and expression patterns of BSK (BR signaling kinase) family genes revealed that BSKs participated in the response of cotton to abiotic stress and maintained the growth of cotton in extreme environment. The steroidal hormone brassinosteroids (BR) play important roles in different plant biological processes. This study focused on BSK which were downstream regulatory element of BR, in order to help to decipher the functions of BSKs genes from cotton on growth development and responses to abiotic stresses and lean the evolutionary relationship of cotton BSKs. BSKs are a class of plant-specific receptor-like cytoplasmic kinases involved in BR signal transduction. In this study, bioinformatics methods were used to identify the cotton BSKs gene family at the cotton genome level, and the gene structure, promoter elements, protein structure and properties, gene expression patterns and candidate interacting proteins were analyzed. In the present study, a total of 152 BSKs were identified by a genome-wide search in four cotton species and other 11 plant species, and phylogenetic analysis revealed three evolutionary clades. It was identified that BSKs contain typical PKc and TPR domains, the N-terminus is composed of extended chains and helical structures. Cotton BSKs genes show different expression patterns in different tissues and organs. The gene promoter contains numerous cis-acting elements induced by hormones and abiotic stress, the hormone ABA and Cold-inducing related elements have the highest count, indicating that cotton BSK genes may be regulated by various hormones at different growth stages and involved in the response regulation of cotton to various stresses. The expression analysis of BSKs in cotton showed that the expression levels of GhBSK06, GhBSK10, GhBSK21 and GhBSK24 were significantly increased with salt-inducing. This study is helpful to analyze the function of cotton BSKs genes in growth and development and in response to stress

Row End Detection and Headland Turning Control for an Autonomous Banana-Picking Robot

A row-following system based on machine vision for a picking robot was designed in our previous study. However, the visual perception could not provide reliable information during headland turning according to the test results. A complete navigation system for a picking robot working in an orchard needs to support accurate row following and headland turning. To fill this gap, a headland turning method for an autonomous picking robot was developed in this paper. Three steps were executed during headland turning. First, row end was detected based on machine vision. Second, the deviation was further reduced before turning using the designed fast posture adjustment algorithm based on satellite information. Third, a curve path tracking controller was developed for turning control. During the MATLAB simulation and experimental test, different controllers were developed and compared with the designed method. The results show that the designed turning method enabled the robot to converge to the path more quickly and remain on the path with lower radial errors, which eventually led to reductions in time, space, and deviation during headland turning