Tanshinone IIA Protects against Dextran Sulfate Sodium- (DSS-) Induced Colitis in Mice by Modulation of Neutrophil Infiltration and Activation

Neutrophils play a critical role in the initiation and maintenance of intestinal inflammation. However, conventional neutrophil-targeted therapies can impair normal host defense. Tanshinone IIA has been recently revealed to act directly on neutrophils. Hence, we aimed at investigating whether Tanshinone IIA can protect against experimental colitis through modulation of neutrophils. We induced colitis in C57BL/6 mice by giving 3% dextran sulfate sodium (DSS) orally, and meanwhile, we treated mice daily with Tanshinone IIA intraperitoneally. The severity of colitis was evaluated by calculating disease activity index (DAI) and histological parameters. Neutrophil infiltration and activation in the colons of mice were measured. Moreover, whether Tanshinone IIA has direct effects on neutrophil migration and activation was determined in vitro. Our data showed that Tanshinone IIA significantly ameliorated the severity of DSS-induced colitis in mice, evidenced by the reduced DAI and improved colonic inflammation. In addition, Tanshinone IIA decreased neutrophil infiltration of intestinal mucosa and activation and reduced colonic inflammatory cytokines in DSS-treated mice. Furthermore, Tanshinone IIA was demonstrated to significantly suppress neutrophil migration and activation. These results provide compelling evidence that Tanshinone IIA has a therapeutic potential for alleviating inflammatory colitis in mice, which is possibly mediated by the immunomodulation of neutrophils

Simultaneous Mutations in Multi-Viral Proteins Are Required for Soybean mosaic virus to Gain Virulence on Soybean Genotypes Carrying Different R Genes

BACKGROUND: Genetic resistance is the most effective and sustainable approach to the control of plant pathogens that are a major constraint to agriculture worldwide. In soybean, three dominant R genes, i.e., Rsv1, Rsv3 and Rsv4, have been identified and deployed against Soybean mosaic virus (SMV) with strain-specificities. Molecular identification of virulent determinants of SMV on these resistance genes will provide essential information for the proper utilization of these resistance genes to protect soybean against SMV, and advance knowledge of virus-host interactions in general. METHODOLOGY/PRINCIPAL FINDINGS: To study the gain and loss of SMV virulence on all the three resistance loci, SMV strains G7 and two G2 isolates L and LRB were used as parental viruses. SMV chimeras and mutants were created by partial genome swapping and point mutagenesis and then assessed for virulence on soybean cultivars PI96983 (Rsv1), L-29 (Rsv3), V94-5152 (Rsv4) and Williams 82 (rsv). It was found that P3 played an essential role in virulence determination on all three resistance loci and CI was required for virulence on Rsv1- and Rsv3-genotype soybeans. In addition, essential mutations in HC-Pro were also required for the gain of virulence on Rsv1-genotype soybean. To our best knowledge, this is the first report that CI and P3 are involved in virulence on Rsv1- and Rsv3-mediated resistance, respectively. CONCLUSIONS/SIGNIFICANCE: Multiple viral proteins, i.e., HC-Pro, P3 and CI, are involved in virulence on the three resistance loci and simultaneous mutations at essential positions of different viral proteins are required for an avirulent SMV strain to gain virulence on all three resistance loci. The likelihood of such mutations occurring naturally and concurrently on multiple viral proteins is low. Thus, incorporation of all three resistance genes in a soybean cultivar through gene pyramiding may provide durable resistance to SMV

Mechanisms by which spinal cord stimulation intervenes in atrial fibrillation: The involvement of the endothelin-1 and nerve growth factor/p75NTR pathways

Can the spinal cord stimulation (SCS) regulate the autonomic nerves through the endothelin-1 (ET-1) and nerve growth factor (NGF)/p75NTR pathways and thus inhibit the occurrence of atrial fibrillation (AF)? In our research, 16 beagles were randomly divided into a rapid atrial pacing (RAP) group (n = 8) and a RAP + SCS group (n = 8), and the effective refractory period (ERP), ERP dispersion, AF induction rate, and AF vulnerability window (WOV) at baseline, 6 h of RAP, 6 h of RAP + SCS were measured. The atrial tissue was then taken for immunohistochemical analysis to determine the localization of ET-1, NGF, p75NTR, NF-kB p65, and other genes. Our results showed that SCS attenuated the shortening of ERP in all parts caused by RAP, and after 6 h of SCS, the probability of AF in dogs was reduced compared with that in the RAP group. Moreover, the expression of ET-1, NGF, and p75NTR in the atrial tissues of dogs in the RAP + SCS group was significantly increased, but the expression of NF-kB p65 was reduced. In conclusion, SCS promotes the positive remodeling of cardiac autonomic nerves by weakening NFκB p65-dependent pathways to interfere with the ET-1 and NGF/p75NTR pathways to resist the original negative remodeling and inhibit the occurrence of AF

Incorporation of Pilot Factors into Risk Analysis of Civil Aviation Accidents from 2008 to 2020: A Data-Driven Bayesian Network Approach

Pilot factor is worth considering when analyzing the causes of civil aviation accidents. This study introduces a data-driven Bayesian network (BN) approach to investigating the joint causal effects of pilot and other factors on civil aviation safety. A total number of 163 individual pilot-related accidents in the National Transportation Safety Board (NTSB) aviation accident database from 2008 to 2020 are analyzed, focusing on eliciting the causal effects of various potential risk factors, including pilot factors, on civil aviation accidents. The modeling of the interdependency among the risk influencing factors (RIFs) and their causal contributory effect on the accident outcome is structured by a tree augmented network (TAN) and validated by sensitivity analysis. The novelty of this study is to incorporate pilot factors derived from the civil aviation accident database into risk analysis, combined with other external factors. The results indicate that weather conditions and flight phases are more correlated with casualty types of civil aviation accidents than pilot action and decision, and three other pilot factors only contribute to fatal injury in civil aviation accidents

Comparison of nine growth curve models to describe growth of partridges(Alectoris chukar)

In this study, nine non linear growth curve models were used to determine the goodness of fit by the body weight measurements of the total number of 178 partridges(Alectoris chukar), 93 females, and 85 males, respectively. The R2(coefficients of determination) values for the total partridges, females and males in Brody, Gompertz, Logistic, von Bertalanffy, asymptote regression,exponential, Monomolecular, Richards and Weibull-type were 0.985, 0.980 and 0.984, 0.997, 0.998 and 0.998, 0.996, 0.999 and 0.999, 0.995, 0.995 and 0.996, 0.985, 0.980 and 0.984, 0.891, 0.871 and 0.892, 0.985, 0.980 and 0.984, 0.997, 0.999 and 0.999, 0.997, 0.999 and 0.999, respectively. The R2 values for Gompertz, Logistic, von Bertalanffy, Richards and Weibull-type were >0.99, while the exponential (<0.90) had the lowest. What’s more, the Gompertz, Logistic, Richards and Weibull-type models best described the data because of lower MSE (mean square error), AIC(Akaike’s information criteria) and BIC(Schwarz Bayesian information criterion), higher adj. R2(Adjusted coefficient of determination) and r(the correlation coefficient between measured body weight and estimated body weight) and there was not an autocorrelation between the residual values. As a result, based on goodness of fit criteria; R2, adj.R2, MSE, r, AIC, BIC values, the Weibull-type model best described live weight data of the Partridges(Alectoris chukar)

ST2/IL-33-Dependent Microglial Response Limits Acute Ischemic Brain Injury

ST2, a member of the interleukin (IL) 1 receptor family, and its ligand IL-33 play critical roles in immune regulation and inflammatory responses. This study explores the roles of endogenous IL-33/ST2 signaling in ischemic brain injury and elucidates the underlying mechanisms of action. The expression of IL-33 rapidly increased in oligodendrocytes and astrocytes after 60 min transient middle cerebral artery occlusion (tMCAO). ST2 receptor deficiency exacerbated brain infarction 3 d after tMCAO as well as distal permanent MCAO. ST2 deficiency also aggravated neurological deficits up to 7 d after tMCAO. Conversely, intracerebroventricular infusions of IL-33 after tMCAO attenuated brain infarction. Flow cytometry analyses demonstrated high levels of ST2 expression on microglia, and this expression was dramatically enhanced after tMCAO. The absence of ST2 enhanced the expression of M1 polarization markers on microglia/macrophages, and impaired the expression of M2 polarization markers after tMCAO. studies on various types of cultures and coculture systems confirmed that IL-33/ST2 signaling potentiated expression of and other M2 genes in primary microglia. The activation of ST2 on microglia led to a protective phenotype that enhanced neuronal survival against oxygen glucose deprivation. Further studies revealed that IL-33-activated microglia released IL-10, and that this was critical for their neuroprotective effects. Similarly, intracerebroventricular infusions of IL-33 into knock-out mice failed to provide neuroprotection against tMCAO These results shed new light on the IL-33/ST2 axis as an immune regulatory mechanism that serves as a natural brake on the progression of ischemic brain injury. This is the first study to identify the function of interleukin (IL) 33/ST2 signaling in poststroke microglial responses and neuroprotection against ischemia. Using two models of ischemic stroke, we demonstrate here that ST2 deficiency shifted microglia/macrophages toward a M1-like phenotype, thereby expanding brain infarcts and exacerbating long-term behavioral deficits after stroke. Using stroke models and various culture and coculture systems, we further characterized a previously undefined mechanism whereby IL-33/ST2 engagement stimulates the production of IL-10 from microglia, which, in turn, enhances neuronal survival upon ischemic challenge. These results shed light on endogenous IL-33/ST2 signaling as a potential immune regulatory mechanism that serves to promote beneficial microglial responses and mitigate ischemic brain injury after stroke