Clinical Significance and Properties of IFN-γ+IL-17+ Th17 Cells in Liver Injury Associated with Chronic Hepatitis B Virus Infection.

INTRODUCTION: Our previous study demonstrated that intrahepatic Th17 cells exacerbated the progression of chronic hepatitis B virus (HBV) infection. Meanwhile, we found a small group of IFN-γ and IL-17 double-positive Th17 cells (IFN-γ+IL-17+ Th17 cells) in liver tissues. This study aimed to investigate the clinical significance and properties of IFN-γ+IL-17+ Th17 cells in liver injury associated with chronic HBV infection. METHODS: The frequencies of CD4+ Th cells, Tregs, and CD4+ T cells expressing specific chemokine receptors in the blood and liver tissues were detected using flow cytometry. The chemotaxis of C C chemokine receptor 5 (CCR5) and C-X-C chemokine receptor 3 (CXCR3) toward IFN-γ+IL-17+ Th17 cells and Tregs was evaluated by transwell chemotactic assay. Analyses of different variables were performed using GraphPad Prism v 5.01 and IBM SPSS Statistics 23.0. HBV-specific IFN-γ+IL-17+ Th17 cells were investigated using a cell stimulation assay with HBV antigens in vitro. RESULTS: The frequencies of IFN-γ+IL-17+ Th17, Th17 cells, and Tregs in the blood were increased from normal controls to chronic hepatitis B (CHB) and acute-on-chronic liver failure (ACLF). The same trend could also be observed in CHB liver tissues compared to those in CHB blood specimens. Furthermore, the frequencies of IFN-γ+IL-17+ Th17 cells were positively associated with Th17 cells, Th17 cell-related cytokines (IL-17 and IL-6), HBV DNA load, and the levels of HBsAg, HBeAg, and ALT. The ratios of IFN-γ+IL-17+ Th17 cells to Tregs extremely decreased in ACLF blood specimens compared with those in CHB blood specimens. Additionally, CCR5 and CXCR3 were conducive to the recruitment of IFN-γ+IL-17+ Th17 cells and Tregs to liver tissue. CONCLUSIONS: IFN-γ+IL-17+ Th17 cells have Th17 cell-like properties in the progression of chronic HBV infection. CCR5 and CXCR3 facilitated the recruitment of IFN-γ+IL-17+ Th17 cells and Tregs to the liver. Importantly, the ratio of IFN-γ+IL-17+ Th17 cells to Tregs might be an effective assessment indicator of the severity of liver injury.

Characteristics of coagulation alteration in patients with COVID-19.

Abnormal blood coagulation often occurs in critically ill patients, which seriously affects their prognosis. This retrospective study investigated the implications of changes in blood coagulation in patients with coronavirus disease 2019 (COVID-19). Records were reviewed for patients admitted with COVID-19 between February 4 and 16, 2020. The primary outcome was in-hospital death. A total of 85 patients were included, of whom 12 died in the hospital. The admission prothrombin time (PT), international normalized ratio (INR), and levels of D-dimer and fibrin/fibrinogen degradation products (FDP) were significantly higher in non-survivors than in survivors, while the reverse was true for prothrombin time activity (PT-act) and PaO2/FiO2. Multivariate logistic regression showed that PT-act < 75% was independently associated with mortality. The area under the receiver operating characteristic curves for PT-act, D-dimer, and FDP at admission could significantly predict mortality. The AUCs for PT-act were larger than those for D-dimer and FDP; however, there was no significant difference. After 2 weeks of treatment, the coagulation parameters of the surviving patients improved. COVID-19 is often accompanied by abnormal coagulation. PT-act at admission is able to predict mortality in patients with COVID-19 as can D-dimer and FDP levels. PT-act < 75% is independently associated with mortality.

The water droplet with huge charge density excited by triboelectric nanogenerator for water sterilization.

Water is one of the most essential resources for the survival of human beings and all other living things. For the point of daily use, water sterilization has enormous social and economic significance, especially for remote and undeveloped areas. Here, we developed a self-powered water sterilization device, which consists of a rotating-disk freestanding triboelectric-layer mode triboelectric nanogenerator (RF-TENG), a voltage-multiplying circuit, and a water droplet control system. The output voltage of the RF-TENG is boosted by a voltage-multiplying circuit and then utilized to charge water droplet. When the rotation rate of the RF-TENG is 300 rpm, the output voltage of a six-fold voltage-multiplying circuit can reach 9319 V, and a 62.50µl water droplet can be positively charged to 6320 nC at the flow rate of 0.31 ml min-1. The charge density and electric filed of the water droplet can reach 101.12 nCµl-1and 11.28 kV cm-1, respectively. The charged water droplet can killE. coliandS. aureusquickly and efficiently through electroporation mechanism. With the advantages of low cost, simple in fabrication and usage, portability, and etc, the self-powered water sterilization device has wide application prospects in remote and undeveloped areas.

Intrahepatic T helper 17 cells recruited by hepatitis B virus X antigen-activated hepatic stellate cells exacerbate the progression of chronic hepatitis B virus infection.

Immunopathological injury induced by persistent hepatitis B virus (HBV) infection contributes to the progression from chronic hepatitis B (CHB) to hepatic cirrhosis and hepatocellular carcinoma (HCC). Regulatory T cells (Tregs), CD4+ T helper (Th) cells, and hepatic stellate cells (HSCs) are considered to be the pivotal factors during this progression. In this study, our aim was to investigate the molecular mechanisms of liver immunopathological injury associated with Tregs, CD4+ Th cells, and HSCs. Liver tissues were collected to assay the cytokines and distribution and frequencies of CD4+ Th cells and Tregs. The chemotaxis of Th17 cells towards the liver and the interactions between IL-22, IL-17A, and HSCs were explored. The data showed the frequencies of Th17 cells, and their effector molecules IL-22 and IL-17A were increased along with the severity of chronic liver diseases. However, the frequencies of Tregs were decreased in HBV-associated cirrhotic tissues compared with those in CHB tissues and HCC tissues. hepatitis B virus X antigen (HBxAg)-activated HSCs recruited more Th17 cells into the liver and conduced to the secretion of IL-17A and IL-22 that could in turn stimulate the proliferation and fibrotic marker secretion of the HSCs. Therefore, we suggest that the interactions between Th17 cells, IL-17A, IL-22, and HSCs form a positive feedback loop that aggravated the progression of chronic liver disease with HBV infection through the phosphoinositide-3-kinase/protein kinase B (PI3K/AKT) signalling pathway. Our findings indicated the IL-17A/IL-22 pathway might become a new treatment target for liver cirrhosis and HCC.

Interleukin-34 Ameliorates Survival and Bacterial Clearance in Polymicrobial Sepsis.

OBJECTIVES: Sepsis is a devastating condition with a high mortality rate and limited treatments. Sepsis is characterized by a failed host immune response to contain the infection, resulting in organ dysfunction. Interleukin-34 is new cytokine involved in infection and immunity. Whether interleukin-34 is beneficial or deleterious to sepsis and the underlying mechanisms remains unknown. DESIGN: Prospective randomized animal investigation and in vitro studies. SETTING: Research laboratory at a university hospital. SUBJECTS: Wild-type C57BL/6 mice were used for in vivo studies, and septic human patients and healthy human subjects were used to obtain blood for in vitro studies. INTERVENTIONS: Interleukin-34 concentrations were measured in human sepsis patients and healthy individuals. The effects of interleukin-34 administration on survival, bacterial burden, organ injury, and inflammatory response were assessed in a murine model of cecal ligation and puncture-induced polymicrobial sepsis. MEASUREMENTS AND MAIN RESULTS: Interleukin-34 levels were significantly elevated in human sepsis and cecal ligation and puncture-induced experimental sepsis. Interleukin-34 administration improved survival and bacterial clearance, although suppressed vascular leakage and organ injury after cecal ligation and puncture-induced polymicrobial sepsis. Neutralization of interleukin-34 increased mortality rate and decreased bacterial clearance in septic mice. An increased neutrophil and macrophage influx were developed in interleukin-34-treated mice at the site of infection, accompanied by elevated production of neutrophil chemokine chemokine (C-X-C motif) ligand 1 and macrophage chemokine C-C motif chemokine ligand 2 in the peritoneal cavity. Depletion of neutrophils or macrophages reversed interleukin-34-mediated protection against polymicrobial sepsis. CONCLUSIONS: We reported for the first time a potential therapeutic role for interleukin-34 in sepsis and suggested that interleukin-34 is a novel target for the development of therapeutic agents against sepsis.

Interleukin 36α Attenuates Sepsis by Enhancing Antibacterial Functions of Macrophages.

Background: Sepsis is newly defined as life-threatening organ dysfunction caused by a dysregulated host response to infection with a high mortality rate and limited effective treatments. The role of interleukin 36α (IL-36α) in host response during sepsis remains unknown. Methods: An experimental sepsis model of cecal ligation and puncture was established to investigate the effects of IL-36α on host response to sepsis. Results: IL-36α production was significantly up-regulated during sepsis. IL-36α treatment reduced the mortality rate in mice with severe sepsis by cecal ligation and puncture. IL-36α-treated mice had more efficient bacterial clearance, inhibited tissue inflammation, improved organ injury, and reduced immune cell apoptosis. The therapeutic implication of these observations was also highlighted by the finding that specific blockade of IL-36α led to an increased mortality rate in mice with nonsevere sepsis. Furthermore, we found that IL-36α enhanced bacterial phagocytosis and killing by macrophages, thereby allowing local and systemic bacterial clearance. Importantly, macrophage depletion before the onset of sepsis eliminated IL-36α-mediated protection against sepsis. Conclusions: Our results demonstrate that IL-36α plays an important role in the host defense response to sepsis and suggest a potential therapeutic role for IL-36α in sepsis.

Haplotype-based case-control study of DNA repair gene XRCC3 and hepatocellular carcinoma risk in a Chinese population.

Previous studies indicated that the human X-ray repair complementing group 3 gene (XRCC3) plays an important role in hepatocellular carcinoma (HCC) susceptibility. We aimed to investigate the association of XRCC3 genetic polymorphism with HCC risk. This study was conducted in a Chinese Han population consisting of 300 HCC cases and 300 sex- and age-matched cancer-free controls. Three genetic variants (rs861539, rs12432907, and rs861537) were genotyped by the TaqMan® SNP Genotyping Assay. Our findings suggested that the TT genotype and T allele from rs861539 genetic variants were statistically associated with HCC risk. The TT genotype was statistically associated with the increased risk of HCC compared to CC wild genotype (P < 0.001). And the T allele was more common in the HCC patients than that in the control subjects. (OR = 1.97, 95% confidence interval (CI) 1.457 ~ 2.659, P < 0.001). Haplotype-based case-control study analysis indicated that TTG haplotype was more frequent in HCC groups than in the control group (odds ratio (OR) = 1.967, 95% CI 1.456 ~ 2.658); however, the CTG haplotype is more common in the control group than that in the HCC group (OR = 0.550, 95 % CI 0.430 ~ 0.703; P < 0.001). Our data indicated that genetic variants of the XRCC3 gene were statistically associated with HCC risk in a Chinese population.

Detection of HBV DNA integration in plasma cell-free DNA of different HBV diseases utilizing DNA capture strategy.

The landscape of hepatitis B virus (HBV) integration in the plasma cell-free DNA (cfDNA) of HBV-infected patients with different stages of liver diseases [chronic hepatitis B (CHB), liver cirrhosis (LC), and hepatocellular carcinoma (HCC)] remains unclear. In this study, we developed an improved strategy for detecting HBV DNA integration in plasma cfDNA, based on DNA probe capture and next-generation sequencing. Using this optimized strategy, we successfully detected HBV integration events in chimeric artificial DNA samples and HBV-infected HepG2-NTCP cells at day one post infection, with high sensitivity and accuracy. The characteristics of HBV integration events in the HBV-infected HepG2-NTCP cells and plasma cfDNA from HBV-infected individuals (CHB, LC, and HCC) were further investigated. A total of 112 and 333 integration breakpoints were detected in the HepG2-NTCP cells and 22 out of 25 (88%) clinical HBV-infected samples, respectively. In vivo analysis showed that the normalized number of support unique sequences (nnsus) in HCC was significantly higher than in CHB or LC patients (P values â€‹< â€‹0.05). All integration breakpoints are randomly distributed on human chromosomes and are enriched in the HBV genome around nt 1800. The majority of integration breakpoints (61.86%) are located in the gene-coding region. Both non-homologous end-joining (NHEJ) and microhomology-mediated end-joining (MMEJ) interactions occurred during HBV integration across the three different stages of liver diseases. Our study provides evidence that HBV DNA integration can be detected in the plasma cfDNA of HBV-infected patients, including those with CHB, LC, or HCC, using this optimized strategy.

An Electromagnetic Microwave Stealth Photothermal Soft Actuator with Lightweight and Hydrophobic Properties.

Electromagnetic (EM) microwave stealth soft robots are in urgent need in military application. Photothermal soft actuators with photomechanical energy conversion have attracted significant interest owing to their remote control, flexibility, and contactless operation. The innovative combination of an electromagnetic microwave absorption (EMA) function with a photothermal actuator paves the way for this aspect. Here, a composite with unique dual three-dimensional foam is fabricated based on graphene and hollow carbon spheres (HCSs). When exposed to 1 sun illumination, the temperature could increase to 50 °C within 1 min and plateaus at 80 °C for hollow carbon spheres-graphene foam-polydimethylsiloxane (HCSs-GF-PDMS), which shows great photothermal performance. A wormlike crawling robot has been constructed based on this composite material, which could move forward under only 1 sun illumination. Remarkably, the EM stealth could be successfully realized because the composite material exhibits great EMA performance with a minimum reflection loss of -56.99 dB at a thickness of 2.5 mm, and the maximum effective absorption bandwidth is 8.65 GHz. In addition, the HCSs-GF exhibits hydrophobic and lightweight functions as well, which lighten the weight of soft robots and lead to self-cleaning and energy saving. This work provides a promising direction of multifunctional EM stealth soft robots.

Adjustable Graphene/Polyolefin Elastomer Epsilon-near-Zero Metamaterials at Radiofrequency Range.

While epsilon-near-zero (ENZ) metamaterials have marvelously shown various application prospects, the way to construct intrinsic ENZ metamaterials and adjust their ENZ properties precisely is still uncovered. The realization of stable and broadband ENZ properties at the radiofrequency range is of great significance. Herein graphene/polyolefin elastomer (POE) intrinsic ENZ metamaterials are initially constructed via the nanohybrid process. The metamaterials possess excellent adjustable ENZ properties by adjusting the content and reduction methods of graphene. The permittivities maintain between -1 and 1 steadily with increasing graphene content, which is attributed to the moderated carrier concentration of the conductive networks in the nanohybrids. Besides, different reduction methods also have significant impacts on ENZ properties. The hydrazine hydrate reduction method increases the maximum ENZ frequency region to 126 MHz. Lorentz type resonance is reasonable for the positive-negative transition in the ENZ frequency regions. As a significant indicator of the emergence of ENZ property, the sudden peak of dielectric loss tangent is observed. This work offers novel routes to construct intrinsic ENZ metamaterials with excellent adjustability in both values of permittivity and ENZ frequency regions.

Comparison of admission serum albumin and hemoglobin as predictors of outcome in children with moderate to severe traumatic brain injury: A retrospective study.

Hypoalbuminemia and anemia are frequent among in patients with traumatic brain injury (TBI). We assess whether serum albumin and hemoglobin at admission can predict outcome in children with moderate to severe TBI.This retrospective study was conducted in a tertiary pediatric hospital between May 2012 and Jun 2018 included children with an admission Glasgow Coma Scale of ≤13.A total of 213 patients were included of whom 45 died in hospital. Multivariate logistic regression showed that hypoalbuminemia (serum albumin <30 g/L) was independently associated with mortality (adjusted odds ratio [OR] = 3.059; 95% confidence interval [CI]: 1.118-8.371; P = .030) in children with moderate to severe TBI, while anemia (hemoglobin <90 g/L) was not independently associated with mortality (adjusted OR = 1.742; 95% CI: 0.617-4.916; P = .295). Serum albumin was significantly superior to hemoglobin (area under the curve [AUC] 0.738 vs AUC 0.689, P < .05) under receiver operating characteristic curve analysis. Hypoalbuminemia was also associated with reduced 14-day ventilation-free days, 14-day intensive care unit (ICU)-free days, and 28-day hospital-free days.Serum albumin at admission was superior to hemoglobin in predicting the mortality in children with moderate to severe TBI and also associated with reduced ventilator-free, ICU-free, and hospital-free days.

Up-regulated Reg proteins induced by Interleukin-22 treatment ameliorate acute liver injury in rat model.

BACKGROUND: The regenerating gene (Reg), encoding lectin-related protein, was originally isolated from a rat regenerating pancreatic islets. Interleukin-22 (IL-22), a recently identified cytokine, is produced by Th 17 cells and natural killer cells. Both of them have been shown to play an important role in controlling tissue repair. But, it is unclear whether the IL-22/Reg axis is involved in liver regeneration and the improvement of liver function in a rat model of acute liver injury. AIMS: We investigated the expression levels of Reg proteins after IL-22 stimulation in a rat model of acute liver injury, and estimated the effects of Reg proteins ameliorating acute liver injury. METHODS: Western blot was used to measure the expressions of Reg I, Reg III, Reg IV proteins after treatment with recombinant lentivirus IL-22. At the same time, the expression levels of TB, ALT, AST, endotoxin (ETM), superoxide dismutase (SOD), malondialdehyde (MDA) were detected by related reagents. RESULTS: In a rat model of acute liver injury, the expression levels of Reg I, Reg III, Reg IV proteins were increased after treatment with IL-22 recombinant lentivirus compared with treatment with lentivirus-empty vector, especially, Reg IV protein expression. Meanwhile, treatment with IL-22 recombinant lentivirus reduced serum levels of TB, ALT, AST, ETM, and decreased MAD levels in rat liver tissues, but increased SOD levels in rat liver tissues. CONCLUSION: IL-22 stimulation enhanced the expressions of Reg proteins in liver cell, especially, Reg IV protein, and ameliorated liver injury in a rat model of acute liver injury. Reg protein, especially Reg IV protein, might act as a biological mediator of immune cell-derived IL-22 in the recovering mechanism of liver injury.

Epigenetic silencing of miRNA-9 is correlated with promoter-proximal CpG island hypermethylation in gastric cancer in vitro and in vivo.

Silencing of protein-coding tumor suppressor genes (TSGs) by CpG island hypermethylation is a common occurrence in gastric cancer (GC). Here, we examine if tumor suppressor microRNAs (miRNAs) are silenced in a similar manner. Real-time quantitative PCR (RTQ-PCR) was employed to investigate the expression level of four candidate miRNAs in GC tissues (n=30) and cell lines. Basing on RTQ-PCR results and bioinformatics approach, miR-9 was chosen for further study on epigenetic regulation. Bisulfite genomic sequencing PCR (BSP) was performed to assess the methylation status of miR-9 in GC tissues. In both GC cell lines and animal models, demethylation was performed either by treatment with 5-aza-2'-deoxycytidine (5-AZA-CdR) or by siRNA targeting DNMT1. We also analyzed the relationship between miRNAs and several clinicopathological features. Candidate miRNAs (miR-9, miR-433, miR-19b, and miR-370) were found strongly downregulated in GC tissues and cell lines. Their expression was increased following 5-AZA-CdR treatment. CpG island methylation of miR-9 was significantly higher in GC tissues compared to normal controls. After two demethylation treatments, miR-9 methylation degree was significantly decreased and miR-9 expression was ob-viously restored in GC cells and animal models. Deregulation of miR-9 was positively correlated with tumor lesion size. Three other miRNAs, miR-19b, miR-433, and miR-370 were assοciated with lymph node metastasis, decreased curvature, and poorly differentiated carcinoma. miR-19b and miR-433 were positively correlated with male gender. Of four candidate miRNAs downregulated in GC, miR-9 is epigenetically regulated by DNA methylation both in vitro and in vivo.

Down-regulated miR-9 and miR-433 in human gastric carcinoma.

BACKGROUND: MircoRNAs(miRNAs) are short, endogenously non-coding RNAs. The abnormal expression of miRNAs may be valuable for the diagnosis and treatment of tumors. METHODS: To screening the special miRNAs in gastric carcinoma, expression level of miRNAs in gastric carcinoma and normal gaster samples were detected by miRNA gene chip. Then, the expressions of miR-9 and miR-433 in gastric carcinoma tissue and SGC7901 cell line were validated by qRT-PCR. GRB2 and RAB34, targets of miR-433 and miR-9 respectively, were detected by Western blot. RESULTS: We found 19 miRNAs and 7 miRNAs were down-regulated and up-regulated respectively. Compared with normal gaster samples, our data showed that miR-9 and miR-433 were down-regulated in gastric carcinoma. Meanwhile, we also found that miR-433 and miR-9 regulated the expression levels of GRB2 and RAB34 respectively. CONCLUSION: Our data show miR-9 and miR-433 was down-regulated in gastric carcinoma. The targets of miR-433 and miR-9 were tumor-associated proteins GRB2 and RAB34 respectively. This result provided the related information of miRNAs in gastric carcinoma.