Zoonotic Hantaviridae with Global Public Health Significance.

Hantaviridae currently encompasses seven genera and 53 species. Multiple hantaviruses such as Hantaan virus, Seoul virus, Dobrava-Belgrade virus, Puumala virus, Andes virus, and Sin Nombre virus are highly pathogenic to humans. They cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome or hantavirus pulmonary syndrome (HCPS/HPS) in many countries. Some hantaviruses infect wild or domestic animals without causing severe symptoms. Rodents, shrews, and bats are reservoirs of various mammalian hantaviruses. Recent years have witnessed significant advancements in the study of hantaviruses including genomics, taxonomy, evolution, replication, transmission, pathogenicity, control, and patient treatment. Additionally, new hantaviruses infecting bats, rodents, shrews, amphibians, and fish have been identified. This review compiles these advancements to aid researchers and the public in better recognizing this zoonotic virus family with global public health significance.

Transcriptional regulation of Glis2 in hepatic fibrosis.

The role of Gli-similar 2 (Glis2) in hepatic fibrosis (HF) is controversial. In this study, we focused on the functional and molecular mechanisms involved in the Glis2-mediated activation of hepatic stellate cells (HSCs)-a milestone event leading to HF. The expression levels of Glis2 mRNA and protein were significantly decreased in the liver tissues of patients with severe HF and in mouse fibrotic liver tissues as well as HSCs activated by TGFß1. Functional studies indicated that upregulated Glis2 significantly inhibited HSC activation and alleviated BDL-induced HF in mice. Downregulation of Glis2 was found to correlate significantly with DNA methylation of the Glis2 promoter mediated by methyltransferase 1 (DNMT1), which restricted the binding of hepatic nuclear factor 1-α (HNF1-α), a liver-specific transcription factor, to Glis2 promoters. In addition, the enrichment of DNMT1 in the Glis2 promoter region was mediated by metastasis-associated lung adenocarcinoma transcriptor-1 (MALAT1) lncRNA, leading to transcriptional silencing of Glis2 and activation of HSCs. In conclusion, our findings reveal that the upregulation of Glis2 can maintain the resting state of HSCs. The decreased expression of Glis2 under pathological conditions may lead to the occurrence and development of HF with the expression silencing of DNA methylation mediated by MALAT1 and DNMT1.

Epidemiology-based analysis of the risks and elimination strategies of the monkeypox outbreak in 2022.

Human monkeypox, caused by monkeypox virus, has spread unprecedentedly to more than 100 countries since May 2022. Here we summarized the epidemiology of monkeypox through a literature review and elucidated the risks and elimination strategies of this outbreak mainly based on the summarized epidemiology. We demonstrated that monkeypox virus became more contagious and less virulent in 2022, which could result from the fact that the virus entered a special transmission network favoring close contacts (i.e., sexual behaviors of men who have sex with men outside Africa) and the possibility that the virus accumulated a few adaptive mutations. We gave the reasons to investigate whether cattle, goats, sheep, and pigs are susceptible to monkeypox virus and whether infection with monkeypox virus could be latent in some primates. We listed six potential scenarios for the future of the outbreak (e.g., the outbreak could lead to endemicity outside Africa with increased transmissibility or virulence). We also listed multiple factors aiding or impeding the elimination of the outbreak. We showed that the control measures strengthened worldwide after the World Health Organization declared the outbreak a public health emergency of international concern (PHEIC) could eliminate the outbreak in 2022. We clarified eight strategies, i.e., publicity and education, case isolation, vaccine stockpiling, risk-based vaccination or ring vaccination, importation quarantine, international collaboration, and laboratory management, for the elimination of the outbreak.

A highly powerful nonspecific strategy to reduce COVID-19 deaths.

The coronavirus disease 2019 (COVID-19) pandemic caused by the coronavirus severe acute respiratory syndrome coronavirus 2 remains risky worldwide. We elucidate here that good IDM (isolation, disinfection, and maintenance of health) is powerful to reduce COVID-19 deaths based on the striking differences in COVID-19 case fatality rates among various scenarios. IDM means keeping COVID-19 cases away from each other and from other people, disinfecting their living environments, and maintaining their health through good nutrition, rest, and treatment of symptoms and pre-existing diseases (not through specific antiviral therapy). Good IDM could reduce COVID-19 deaths by more than 85% in 2020 and more than 99% in 2022. This is consistent with the fact that good IDM can minimize co-infections and maintain body functions and the fact that COVID-19 has become less pathogenic (this fact was supported with three novel data in this report). Although IDM has been frequently implemented worldwide to some degree, IDM has not been highlighted sufficiently. Good IDM is relative, nonspecific, flexible, and feasible in many countries, and can reduce deaths of some other relatively mild infectious diseases. IDM, vaccines, and antivirals aid each other to reduce COVID-19 deaths. The IDM concept and strategy can aid people to improve their health behavior and fight against COVID-19 and future pandemics worldwide.

Highly adaptive Phenuiviridae with biomedical importance in multiple fields.

The newly established virus family Phenuiviridae in Bunyavirales harbors viruses infecting three kingdoms of host organisms (animals, plants, and fungi), which is rare in known virus families. Many phenuiviruses are arboviruses and replicate in two distinct hosts (e.g., insects and humans or rice). Multiple phenuivirid species, such as Dabie bandavirus, Rift Valley fever phlebovirus, and Rice stripe tenuivirus, are highly pathogenic to humans, animals, or plants. They impose heavy global burdens on human health, livestock industry, and agriculture and are research hotspots. In recent years the taxonomy of Phenuiviridae has been expanded greatly, and research on phenuiviruses has made significant progress. With these advances, this review drew a novel panorama regarding the biomedical significance, distribution, morphology, genomics, taxonomy, evolution, replication, transmission, pathogenesis, and control of phenuiviruses, to aid researchers in various fields to recognize this highly adaptive and important virus family and conduct relevant risk analysis.

11ß­hydroxysteroid dehydrogenase­1 is associated with the activation of hepatic stellate cells in the development of hepatic fibrosis.

Hepatic fibrosis (HF) is a common complication of numerous chronic liver diseases, but predominantly results from persistent liver inflammation or injury. If left untreated, HF can progress and develop into liver cirrhosis and even hepatocellular carcinoma. However, the underlying molecular mechanisms of HF remain unknown. The present study aimed to investigate the role of 11ß­hydroxysteroid dehydrogenase­1 (11ß­HSD1) during the development of hepatic fibrosis. An experimental rat model of liver fibrosis was induced using porcine serum. 11ß­HSD1 gene expression levels and enzyme activity during hepatic fibrogenesis were assessed. 11ß­HSD1 gene knockdown using small interfering RNA and overexpression were performed in LX2­human hepatic stellate cells (HSCs). HSCs were stimulated with transforming growth factor­ß1 (TGF­ß1). Cell cycle distribution, proliferation, collagen secretion and 11ß­HSD1 gene activity in HSCs were compared before and after stimulation. As hepatic fibrosis progressed, 11ß­HSD1 gene expression and activity increased, indicating a positive correlation with typical markers of liver fibrosis. 11ß­HSD1 inhibition markedly reduced the degree of fibrosis. The cell proliferation was increased, the number of cells in the G0/G1 phase decreased and the number of cells in the S and G2/M phases increased in the pSuper transfected group compared with the N group. In addition, the overexpression of 11ß­HSD1 enhanced the TGF­ß1­induced activation of LX2­HSCs and enzyme activity of connective tissue growth factor. 11ß­HSD1 knockdown suppressed cell proliferation by blocking the G0/G1 phase of the cell cycle, which was associated with HSC stimulation and inhibition of 11ß­HSD1 enzyme activity. In conclusion, increased 11ß­HSD1 expression in the liver may be partially responsible for hepatic fibrogenesis, which is potentially associated with HSC activation and proliferation.

Early hepatitis B viral DNA clearance predicts treatment response at week 96.

AIM: To investigate whether hepatitis viral DNA load at 24 wk of treatment predicts response at 96 wk in patients with chronic hepatitis B. METHODS: A total of 172 hepatitis B envelope antigen (HBeAg)-positive chronic hepatitis B patients who received initial treatment at 16 tertiary hospitals in Hunan Province, China were enrolled in this study. All patients received conventional doses of lamivudine and adefovir dipivoxil, telbivudine, entecavir dispersible tablets, or entecavir tablets for 96 wk. Patients who used other antiviral drugs or antitumor and immune regulation therapy were excluded. Patients were stratified into three groups according to their viral DNA load at 24 wk: < 10 IU/mL (group 1), 10-103 IU/mL (group 2), and > 103 IU/mL (group 3). Correlations of 24-wk DNA load with HBeAg negative status and HBeAg seroconversion at 96 wk were analyzed. Receiver operating characteristic curve analysis was used to test the predictive value of the HBV DNA load at 24 wk for long-term response. RESULTS: The rates of conversion to HBeAg negative status and HBeAg seroconversion rates were 53.7% and 51.9%, respectively, in group 1; 35.21% and 32.39% in group 2; and 6.38% and 6.38% in group 3. The receiver operating characteristic curves for the three subgroups revealed that the lowest DNA load (< 10 IU/mL) was better correlated with response at 96 wk than a higher DNA load (10-103 IU/mL). Nested PCR was used for amplifying and sequencing viral DNA in patients with a viral DNA load > 200 IU/mL at 96 wk; resistance mutations involving different loci were present in 26 patients, and three of these patients had a viral DNA load 10-103 IU/mL at 96 wk. CONCLUSION: Hepatitis B viral DNA load at 24 wk of antiviral treatment in patients with chronic hepatitis B is a predictor of the viral load and response rate at 96 wk.

Novel HBV mutations and their value in predicting efficacy of conventional interferon.

BACKGROUND: Accumulating studies assessing the impacts of hot spot mutations on conventional interferon (IFN) efficacy come to discrepant conclusions; studies regarding the mutations in S and RT regions are also unclear. The present study aimed to evaluate the impacts of HBV mutations on the efficacy of conventional IFN. METHODS: A total of 126 patients who received conventional IFN treatment for 48 weeks were enrolled. Biochemical and serological parameters were routinely tested. The sequences of HBV from 78 serum samples were amplified by nested-PCR; mutations were identified with sequence scanner V1.0 after ABI 3730xl direct sequencing, HBV genotypes were determined according to RT gene sequences utilizing NCBI Genotyping Tool which was based on phylogenetic analysis. RESULTS: The baseline DNA levels of virological response (VR) group were significantly lower than those of no VR group [7.13+/-0.76 vs 7.69+/-0.56 lg (copies/mL), P=0.001]. The baseline ALT levels were significantly higher in the HBeAg clearance group (204.72+/-88.65 vs 162.80+/-85.81 IU/L, P<0.05) and HBeAg seroconversion group (204.89+/-95.68 vs 166.75+/-84.43 IU/L, P<0.05). Females and lower BMI levels (20.01+/-2.33 vs 21.65+/-3.66 kg/m2, P<0.05) were prone to acquired biochemical response (BR). PC-W28STOP (ntG1896A) was significantly higher in the combined response (CR) group than that in the no CR group (91.7% vs 39.7%, P=0.001). Multivariate logistic regression analysis showed that baseline DNA, PC-P159T (ntC2288A), BCP-N118T (ntA1726C) and BCP-L134L (ntA1775C/G/T) influenced VR independently. PC-G182C (ntG2357T), PC-S64A/T (ntT2003G/A) and BMI were independent influence factors for HBeAg clearance, HBeAg seroconversion and BR, respectively. The new predicting model concluded that baseline DNA and new mutations for VR were established successfully, and ROC analysis showed that AUC was 0.842 (P<0.001) with a sensitivity of 0.652 and a specificity of 0.933. CONCLUSIONS: PC-P159T (ntC2288A), BCP-N118T (ntA1726C), BCP-L134L (ntA1775C/G/T), PC-G182C (ntG2357T) and PC-S64A/T (ntT2003G/A) were novel identified mutations that impacted IFN therapeutic efficacy. These novel mutations could serve as important predictors before conventional IFN treatment.

Results of a phase III clinical trial with an HBsAg-HBIG immunogenic complex therapeutic vaccine for chronic hepatitis B patients: experiences and findings.

BACKGROUND & AIMS: Even though various experimental therapeutic approaches for chronic hepatitis B infection have been reported, few of them have been verified by clinical trials. We have developed an antigen-antibody (HBsAg-HBIG) immunogenic complex therapeutic vaccine candidate with alum as adjuvant (YIC), aimed at breaking immune tolerance to HBV by modulating viral antigen processing and presentation. A double-blind, placebo-controlled, phase II B clinical trial of YIC has been reported previously, and herein we present the results of the phase III clinical trial of 450 patients. METHODS: Twelve doses of either YIC or alum alone as placebo were administered randomly to 450 CHB patients and they were followed for 24weeks after the completion of immunization. The primary end point was HBeAg seroconversion, and the secondary end points were decrease in viral load, improvement of liver function, and histology. RESULTS: In contrast to the previous phase II B trial using six doses of YIC and alum as placebo, six more injections of YIC or alum resulted in a decrease of the HBeAg seroconversion rate from 21.8% to 14.0% in the YIC group, but an increase from 9% to 21.9% in the alum group. Decrease in serum HBV DNA and normalization of liver function were similar in both groups (p>0.05). CONCLUSIONS: Overstimulation with YIC did not increase but decreased its efficacy due to immune fatigue in hosts. An appropriate immunization protocol should be explored and is crucial for therapeutic vaccination. Multiple injections of alum alone could have stimulated potent inflammatory and innate immune responses contributing to its therapeutic efficacy, and needs further investigation.

[Analysis of the prophylactic effect of nucleosides against reactivation of HBV in HBsAg-positive patients with non-hepatic tumors after chemotherapy].

OBJECTIVE: To investigate the efficacy of nucleosides as a prophylactic agent against reactivation of hepatitis B virus (HBV) in HBsAg-positive patients with non-hepatic tumors after chemotherapy. METHODS: Fifty-eight patients with non-hepatic tumors were divided into prevention group and control group. The patients of prevention group received nucleosides as a prophylactic agent before chemotherapy and were compared with the control ones about the clinical manifestation of HBV reactivation. Then, the patients of the control group were divided into three groups according to antiviral drugs, use or not and time of the use. The patients having HBV reactivation but never received nucleosides were included in the group A, the patients receiving nucleosides after having HBV reactivation were divided into the group B, and the patients receiving nucleosides before HBV reactivation were divided into the group C. The progression, prognosis and curative effect among the three groups were compared. RESULTS: The rate of HBV reactivation, incidence of severe hepatitis, mortality rate of the control group (61.1%, 27.8%, 16.7%) were significantly higher than those of the prevention group (13.6%, 0, 0), and liver dysfunction was more serious than that in the prevention group. In the control group, all the 5 patients of group A died of liver failure. Of the 13 patients in the group B, 4 cases suffered from severe hepatitis and 1 of them died of the disease. Of the 18 patients in the group C, 4 cases suffered from HBV reactivation, but the clinical manifestation was milder than that of the group B. CONCLUSION: Nucleosides can be used as a prophylactic measure to prevent HBV reactivation. If chemotherapy had begun, the use of nucleosides may reduce the risk of HBV reactivation. Even if patients had suffered from HBV reactivation, the use of nucleosides may still help the recovery of liver function and improve prognosis.

[Analysis of antibiotics treatment in 86 cases of liver transplant recipients].

OBJECTIVE: To analyze the characteristic of bacterial infections, and the relationship between antibiotics treatment and bacterial infections after liver transplantation, and to prevent antibiotic-resistant bacterial infections. METHODS: 86 liver transplant recipients were retrospected. Different indexes including limited daily dose, the frequency of medication, drug use index were used to evaluate the rationality of the use of antibiotics, three-dimensional test was used to explore extended-spectrum beta-lactamase and AmpC enzyme of Gram-negative bacteria. RESULTS: The major pathogens of infection after liver transplantation were Enterococcus faecalis, Enterobacter cloacae, fungi and E. coli. Pre-operative antibiotic utilization rate was 83.7%, it was mainly a single use of antibiotics; After- operative antibiotic usage was 100.0%, it was mainly joint use of two or three antibiotics; The top 3 antibiotics used were cephalosporins, the combined enzyme inhibitors and penicillin. Antibiotics with drug utilization index (DUI) more than 1.1 included ampicillin and Lalin proxy. 43.3% and 31.8% of Gram -Negative bacteria produced ESBLs and AmpC, respectively, while 21.3% Gram -Negative bacteria produced two enzymes. CONCLUSION: There is high incidence of bacterial infections after liver transplantation. The use of antibiotics is high dose, high-frequency and reasonable; High resistance of bacterial infections was prone to develop and the prevention of the high resistance of bacterial infections is very important.

Involvement of dimethylarginine dimethylaminohydrolase-2 in visfatin-enhanced angiogenic function of endothelial cells.

BACKGROUND: Visfatin, a new adipocytokine, was reported to promote angiogenesis. Dimethylarginine dimethylaminohydrolase (DDAH), which could regulate vascular endothelial growth factor (VEGF) expression in endothelial cells, is thought as a novel modulator of angiogenesis. The aim of the study was to investigate the role of DDAH2 in visfatin-induced angiogenesis in human umbilical vein endothelial cells (HUVECs). METHODS AND RESULTS: Visfatin could concentration- and time-dependently enhance cell migration and tube formation reflecting angiogenic capability of HUVECs. Moreover, visfatin upregulated both mRNA and protein expressions of DDAH2 and VEGF. Angiogenic effects of visfatin were attenuated by DDAH2 small interfering RNA. Visfatin-induced protein kinase B (Akt) phosphorylation and phosphoinositide 3 kinase (PI3K) inhibitors could suppress visfatin-induced upregulation of DDAH2 and VEGF expressions. CONCLUSIONS: Taken together, our results demonstrate that PI3K/Akt-mediated upregulation of DDAH2 expression plays a critical role in visfatin-promoted angiogenesis via regulating VEGF-dependent pathway.

[Immortalization of embryonic fibroblasts in heat shock transcription factor 1 knockout mouse].

OBJECTIVE: To establish immortalized embryonic fibroblast lines in heat shock transcription factor 1 (HSF1) HSF1-/- and HSF1+/+ mice and to provide experimental models to study the function of HSF1. METHODS: A mammalian expression vector (pSV3neo) containing the SV40 large T antigen was used to transfect the HSF1-/- and HSF1+/+ mouse embryonic fibroblast using Lipofectamine 2000. Colonies were screened by G418 and expanded to immortalized cell lines. PCR was used to detect the integration of the large T antigen with genome in the mouse embryonic fibroblast. Expression of SV40 large T antigen gene in expanded cells was identified by RT-PCR. HSP70 expression was examined by Western blot in the embryonic fibroblast lines. RESULTS: The stable growth and serial propagation were observed in the HSF1-/- and HSF1+/+ cell lines for six months. The mRNA of SV40 T antigen gene expressed in the two cell lines. HSP70 expression could not be induced in the heat-treated HSF1-/- mouse embryo fibroblasts. CONCLUSION: The immortalized cells of HSF1+/+ and HSF1-/- mouse embryo fibroblasts are successfully established.