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Wei-Yi Ye,1,2 Jia Li,2 Xiang Li,2 Xue-Zhi Yang,2 Yi-Yun Weng,2 Wei-Wei Xiang,3 Ou Zhang,2 Bo-Xi Ke,4,* Xu Zhang2,* 1Shaoxing People’s Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Zhejiang, People’s Republic of China; 2Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 3School of Mental Health, Wenzhou Medical University, Wenzhou, People’s Republic of China; 4Taizhou Central Hospital (Taizhou University Hospital), Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xu ZhangDepartment of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, People’s Republic of ChinaTel +86 577 5557 9372Fax +86 577 5557 9318Email 1102805261@qq.comBo-Xi KeTaizhou Central Hospital (Taizhou University Hospital), Zhejiang 318000, People’s Republic of ChinaTel +86 139 5769 8220Email keboxi@163.comPurpose: Red blood cell (RBC) distribution width (RDW) is known to reflect the heterogeneity of RBC volume, which may be associated with cardiovascular events or mortality after myocardial infarction. However, the association between RDW and stroke, especially regarding endpoints such as death, remains ambiguous. This study aimed to explore the prognostic value of RDW and its effect on mortality among patients with acute ischemic stroke (AIS) undergoing intravenous thrombolysis (IVT) after one year.Patients and Methods: We retrospectively reviewed patients with AIS treated with IVT between January 2016 and March 2018. We grouped the patients according to modified ranking scale (MRS) scores as follows:0– 2, favorable functional outcome group; and 3– 6, unfavorable functional outcome. Predictors were determined using multivariate logistic regression (MVLR). The area under receiver-operating characteristic curve (AUC) was used to evaluate the predictive capability of variables. Furthermore, the Cox proportional hazard model was used to assess the contribution of risk factors to the outcome of death at one year later.Results: MVLR analysis showed that RDW (odds ratio [OR], 1.179; 95% confidence interval [CI], 0.900– 1.545; p = 0.232) was not an independent predictor of unfavorable functional outcome, but it (OR 1.371; 95% CI 1.109– 1.696; p = 0.004) was an independent biomarker for all-cause mortality. The optimal RDW cut-off value to predict mortality was 14.65% (sensitivity: 42%, specificity: 88.3%, AUC: 0.649, p < 0.001). Furthermore, higher RDW (hazard ratio, 2.860; 95% CI, 1.724– 4.745; p < 0.001) indicated a greater risk of death.Conclusion: The baseline RDW is a potential predictor of mortality in patients with AIS undergoing IVT, but RDW might not be associated with worse survival function among stroke survivors, which will help us to improve treatments and the management of patients with AIS.Keywords: red blood cells, death, inflammatory, cerebrovascular accident, fibrinolytic therapy, predictor

This study explores the effects and mechanisms of Modified Xiaoyao Powder on the intestinal barrier and intestinal flora in mice with metabolic associated fatty liver disease(MAFLD) based on the &quot; gut-liver axis&quot;. Sixty male C57BL/6 mice were randomly divided into the normal group, model group, bifidobacterium tetrad tablet group(SQ), and Modified Xiaoyao Powder groups with low,medium and high doses(XL, XM, XH), with 10 mice in each group. All the mice were administrated with a high-fat diet to build the MAFLD model except the normal group and then treated with related drugs for 12 weeks. Body mass, liver wet weight, and liver index were detected. Serum aspartate aminotransferase(AST), alanine aminotransferase(ALT), total cholesterol(TC), triacylglycerol(TG), low density lipoprotein cholesterol(LDL-C), high density lipoprotein cholesterol(HDL-C), and lipopolysaccharide(LPS)levels were detected using the biochemical kits. The contents of tumor necrosis factor-α(TNF-α) and interleukin(IL-6) in the liver were tested simultaneously. The morphological changes of the liver and intestine were observed using hematoxylin-eosin(HE) staining and oil red O staining. The goblet cells in the ileum were detected by periodic acid Schiff and alcian blue stain(AB-PAS) staining.The expression of zonula occludens-1(ZO-1), recombinant occludin(occludin), and recombinant claudin 1(claudin-1) in ileum and colon were detected by immunohistochemistry and Western blot. The changes of intestinal flora in mice were analyzed by 16S rRNA gene sequencing. The results showed that compared with the normal group, body weight, liver wet weight and liver index in the model group increased. The contents of TC, TG, ALT, AST, LDL-C, and LPS in the serum of the model group increased, while HDL-C decreased. Meanwhile, the contents of TNF-α and IL-6 in liver tissue increased and liver lipid accumulation increased, indicating successful model induction. Compared with the model group, body weight, liver wet weight, and liver index were decreased in XM,XH groups and SQ group. Serum levels of TC, TG, LDL-C, ALT and AST in XM group and SQ group were significantly decreased,and HDL-C levels were increased. The levels of IL-6, TNF-α in liver tissue and serum LPS in the XL, XM groups and SQ group were significantly decreased. The protein expression of claudin-1, occludin and ZO-1 in XL, XM groups and SQ group were increased. The analysis of intestinal flora showed that compared with the model group, Modified Xiaoyao Powder with a medium dose could significantly improve the richness and diversity of intestinal flora in mice. At the phylum level, the Firmicutes/Bacteroidetes(F/B) ratio decreased; at the genus level, Lactobacillus, Brautella, Bacteroides, and Ackermannia increased, while Prevotella, Desulfovibrio and Turicibacter decreased. The main differential species were Odorbacteraceaeae and Peptostreptococcaceae. In conclusion, Modified Xiaoyao Powder could inhibit inflammation, regulate intestinal flora homeostasis, and promote the repair of the intestinal mucosal barrier in mice with MAFLD.

Our objective was to examine differences in cytokine/chemokine response in chronic hepatitis B(CHB) patients to understand the immune mechanism of HBsAg loss (functional cure) during antiviral therapy. We used an unbiased machine learning strategy to unravel the immune pathways in CHB nucleo(t)side analogue-treated patients who achieved HBsAg loss with peg-interferon-α(peg-IFN-α) add-on or switch treatment in a randomised clinical trial. Cytokines/chemokines from plasma were compared between those with/without HBsAg loss, at baseline, before and after HBsAg loss. Peg-IFN-α treatment resulted in higher levels of IL-27, IL-12p70, IL-18, IL-13, IL-4, IL-22 and GM-CSF prior to HBsAg loss. Probabilistic network analysis of cytokines, chemokines and soluble factors suggested a dynamic dendritic cell driven NK and T cell immune response associated with HBsAg loss. Bayesian network analysis showed a dominant myeloid-driven type 1 inflammatory response with a MIG and I-TAC central module contributing to HBsAg loss in the add-on arm. In the switch arm, HBsAg loss was associated with a T cell activation module exemplified by high levels of CD40L suggesting T cell activation. Our findings show that more than one immune pathway to HBsAg loss was found with peg-IFN-α therapy; by myeloid-driven Type 1 response in one instance, and T cell activation in the other.

Background: Prognostic genes in the tumor microenvironment play an important role in immune biological processes and the response of cancer to immunotherapy. Thus, we aimed to assess new biomarkers that are associated with immune/stromal cells in lung adenocarcinomas (LUAD) using the ESTIMATE algorithm, which also significantly affects the prognosis of cancer., Methods: The RNA sequencing (RNA-Seq) and clinical data of LUAD were downloaded from the the Cancer Genome Atlas (TCGA ). The immune and stromal scores were calculated for each sample using the ESTIMATE algorithm. The LUAD gene chip expression profile data and the clinical data (GSE37745, GSE11969, and GSE50081) were downloaded from the Gene Expression Omnibus (GEO) for subsequent validation analysis. Differentially expressed genes were calculated between high and low score groups. Univariate Cox regression analysis was performed on differentially expressed genes (DEGs) between the two groups to obtain initial prognosis genes. These were verified by three independent LUAD cohorts from the GEO database. Multivariate Cox regression was used to identify overall survival-related DEGs. UALCAN and the Human Protein Atlas were used to analyze the mRNA /protein expression levels of the target genes. Immune cell infiltration was evaluated using the Tumor Immune Estimation Resource (TIMER) and CIBERSORT methods, and stromal cell infiltration was assessed using xCell., Results: In this study, immune scores and stromal scores are significantly associated with the clinical characteristics of LUAD, including T stage, M stage, pathological stage, and overall survival time. 530 DEGs (18 upregulated and 512 downregulated) were found to coexist in the difference analysis with the immune scores and stromal scores subgroup. Univariate Cox regression analysis showed that 286 of the 530 DEGs were survival-related genes ( p  < 0.05). Of the 286 genes initially identified, nine prognosis-related genes (CSF2RB, ITK, FLT3, CD79A, CCR4, CCR6, DOK2, AMPD1, and IGJ) were validated from three separate LUAD cohorts. In addition, functional analysis of DEGs also showed that various immunoregulatory molecular pathways, including regulation of immune response and the chemokine signaling pathways, were involved. Five genes (CCR6, ITK, CCR4, DOK2, and AMPD1) were identified as independent prognostic indicators of LUAD in specific data sets. The relationship between the expression levels of these genes and immune genes was assessed. We found that CCR6 mRNA and protein expression levels of LUAD were greater than in normal tissues. We evaluated the infiltration of immune cells and stromal cells in groups with high and low levels of expression of CCR6 in the TCGA LUAD cohort. In summary, we found a series of prognosis-related genes that were associated with the LUAD tumor microenvironment., Competing Interests: The authors declare there are no competing interests., (©2020 Xu et al.)

A complex interaction of anabolic and catabolic metabolism underpins the ability of leukocytes to mount an immune response. Their capacity to respond to changing environments by metabolic reprogramming is crucial to effector function. However, current methods lack the ability to interrogate this network of metabolic pathways at single-cell level within a heterogeneous population. We present Met-Flow, a flow cytometry-based method capturing the metabolic state of immune cells by targeting key proteins and rate-limiting enzymes across multiple pathways. We demonstrate the ability to simultaneously measure divergent metabolic profiles and dynamic remodeling in human peripheral blood mononuclear cells. Using Met-Flow, we discovered that glucose restriction and metabolic remodeling drive the expansion of an inflammatory central memory T cell subset. This method captures the complex metabolic state of any cell as it relates to phenotype and function, leading to a greater understanding of the role of metabolic heterogeneity in immune responses.

Mechanical damage or infection to the endometrium can lead to the formation of adhesions in the uterine cavity, which may result in reduced reproductive outcome and/or pregnancy complications. The prognosis of this disease is poor due to few effective treatments and the complex environment of endometrium. Heparin-Poloxamer Hydrogel (HP hydrogel) is a nontoxic and biodegradable biomaterial, which has been commonly used as a sustained-release delivery system. In this study, we applied a mini-endometrial curette to scrape the endometrium of rats to mimic the process of curettage in patients. After the establishment of IUA model in rats, we injected the thermo-sensitive hydrogel(E 2 -HP hydrogel) into the injured uterine cavity and evaluated the therapeutic effect of E 2 -HP hydrogel on the recovery of IUA. Our results showed that E 2 -HP hydrogel can significantly facilitate the regeneration of injured endometrium along with inhibiting the cell apoptosis in IUA model. Furthermore, we revealed that E 2 -HP hydrogel on the recovery of IUA was closely associated with the upregulation of kisspeptin through activating the ERK1/2 and MAPKs p38 pathways. In conclusion, E 2 -HP hydrogel can effectively transfer E 2 into the injured endometrium and it can be considered as a promising therapeutic method for the women with intrauterine adhesions., (© 2019 Federation of American Societies for Experimental Biology.)

Objective: To evaluate causes and impact of delay in the door-to-balloon (D2B) time for patients undergoing primary percutaneous coronary intervention (PPCI)., Subjects and Methods: From January 2009 to December 2012, 1268 patients (86% male, mean age of 58 ± 12 years) presented to our hospital for ST-elevation myocardial infarction (STEMI) and underwent PPCI. They were divided into two groups: Non-delay defined as D2B time ≤ 90 mins and delay group defined as D2B time > 90 mins. Data were collected retrospectively on baseline clinical characteristics, mode of presentation, angiographic findings, therapeutic modality and inhospital outcome., Results: 202 patients had delay in D2B time. There were more female patients in the delay group. They were older and tend to self-present to hospital. They were less likely to be smokers and have a higher prevalence of prior MI. The incidence of posterior MI was higher in the delay group. They also had a higher incidence of triple vessel disease. The 3 most common reasons for D2B delay was delay in the emergency department (39%), atypical clinical presentation (37.6%) and unstable medical condition requiring stabilisation/computed tomographic imaging (26.7%). The inhospital mortality was numerically higher in the delay group (7.4% versus 4.8%, p = 0.12)., Conclusions: Delay in D2B occurred in 16% of our patients undergoing PPCI. Several key factors for delay were identified and warrant further intervention.

Objective: To evaluate the clinical characteristics and in-hospital outcomes of elderly South-East Asian patients undergoing primary percutaneous coronary intervention (PPCI)., Methods: From January 2009 to December 2012, 1268 patients (86.4% male, mean age of 58.4 ± 12.2 years) presented to our hospital for ST-elevation myocardial infarction (STEMI) and underwent PPCI. They were divided into two groups: elderly group defined as age ≥ 70 years and non-elderly group defined as age < 70 years. Data were collected retrospectively on baseline clinical characteristics, door-to-balloon (D2B) time, angiographic findings, therapeutic modality and hospital course., Results: The elderly group constituted 19% of the study population with mean age 76.6 ± 5.0 years. There was a higher proportion of female gender and ethnic Chinese patients in the elderly group when compared with the non-elderly group. The former was less likely to be smokers and have a significantly higher prevalence of hypertension. The mean D2B time was significantly longer in the elderly group. They also had a significantly higher incidence of triple vessel disease and obstructive left main disease. The use of radial artery access, glycoprotein 2b/3a inhibitors and drug-eluting stents during PPCI were also significantly lower. In-hospital mortality was significantly higher in the elderly group. The rate of cardiogenic shock and inhospital complications were also significantly higher., Conclusions: Our registry showed that in-hospital mortality rate in elderly South-East Asian patients undergoing PPCI for STEMI was high. Further studies into the optimal STEMI management strategy for these elderly patients are warranted.

We recently cloned MtVP1, a type I vacuolar-type H(+)-translocating inorganic pyrophosphatase from Medicago truncatula. In the present study, we investigated the cellular location and the function of this H(+)-PPase in Arabidopsis and potato (Solanum tuberosum L.). An MtVP1::enhanced green fluorescent protein fusion was constructed, which localized to the plasma membrane of onion epidermal cells. Transgenic Arabidopsis thaliana overexpressing MtVP1 had more robust root systems and redder shoots than wild-type (WT) plants under conditions of cold stress. Furthermore, overexpression of MtVP1 in potato accelerated the formation and growth of vegetative organs. The tuber buds and stem base of transgenic potatoes became redder than those of WT plants, but flowering was delayed by approximately half a month. Interestingly, anthocyanin biosynthesis was promoted in transgenic Arabidopsis seedlings and potato tuber buds. The sucrose concentration of transgenic potato tubers and tuber buds was enhanced compared with that of WT plants. Furthermore, sucrose concentration in tubers was higher than that in tuber buds. Although there was no direct evidence to support Fuglsang's hypothetical model regarding the effects of H(+)-PPase on sucrose phloem loading, we speculated that sucrose concentration was increased in tuber buds owing to the increased concentration in tubers. Therefore, overexpressed MtVP1 enhanced sucrose accumulation of source organs, which might enhance sucrose transport to sink organs, thus affecting anthocyanin biosynthesis.