Coronavirus disease 2019 (COVID-19) is an emerging disease that was first reported in Wuhan city, the capital of Hubei province in China, and has subsequently spread worldwide. Risk factors for ...mortality have not been well summarized. Current meta-analysis of retrospective cohort studies was done to summarize available findings on the association between age, gender, comorbidities and risk of death from COVID-19 infection.
Online databases including Web of Science, PubMed, Scopus, Cochrane Library and Google scholar were searched to detect relevant publications up to 1 May 2020, using relevant keywords. To pool data, random-effects model was used. Furthermore, sensitivity analysis and publication bias test were also done.
In total, 14 studies with 29,909 COVID-19 infected patients and 1445 cases of death were included in the current meta-analysis. Significant associations were found between older age (≥65 vs <65 years old) (pooled ORs = 4.59, 95%CIs = 2.61-8.04, p < .001), gender (male vs female) (pooled ORs = 1.50, 95%CIs = 1.06-2.12, p = .021) and risk of death from COVID-19 infection. In addition, hypertension (pooled ORs = 2.70, 95%CIs = 1.40-5.24, p = .003), cardiovascular diseases (CVDs) (pooled ORs = 3.72, 95%CIs = 1.77-7.83, p = .001), diabetes (pooled ORs = 2.41, 95%CIs = 1.05-5.51, p = .037), chronic obstructive pulmonary disease (COPD) (pooled ORs = 3.53, 95%CIs = 1.79-6.96, p < .001) and cancer (pooled ORs = 3.04, 95%CIs = 1.80-5.14, p < .001), were associated with higher risk of mortality.
Older age (≥65 years old), male gender, hypertension, CVDs, diabetes, COPD and malignancies were associated with greater risk of death from COVID-19 infection. These findings could help clinicians to identify patients with poor prognosis at an early stage.
Abstract Hepatitis B virus (HBV) remains a major human pathogen, with over 240 million individuals suffering from chronic HBV infections. These can persist for decades due to the lack of therapies ...that can effectively target the stable viral covalently closed circular (ccc) DNA molecules present in infected hepatocytes. Using lentiviral transduction of a bacterial Cas9 gene and single guide RNAs (sgRNAs) specific for HBV, we observed effective inhibition of HBV DNA production in in vitro models of both chronic and de novo HBV infection. Cas9/sgRNA combinations specific for HBV reduced total viral DNA levels by up to ~1000-fold and HBV cccDNA levels by up to ~10-fold and also mutationally inactivated the majority of the residual viral DNA. Together, these data provide proof of principle for the hypothesis that CRISPR/Cas systems have the potential to serve as effective tools for the depletion of the cccDNA pool in chronically HBV infected individuals.
Viruses must balance their reliance on host cell machinery for replication while avoiding host defense. Influenza A viruses are zoonotic agents that frequently switch hosts, causing localized ...outbreaks with the potential for larger pandemics. The host range of influenza virus is limited by the need for successful interactions between the virus and cellular partners. Here we used immunocompetitive capture-mass spectrometry to identify cellular proteins that interact with human- and avian-style viral polymerases. We focused on the proviral activity of heterogenous nuclear ribonuclear protein U-like 1 (hnRNP UL1) and the antiviral activity of mitochondrial enoyl CoA-reductase (MECR). MECR is localized to mitochondria where it functions in mitochondrial fatty acid synthesis (mtFAS). While a small fraction of the polymerase subunit PB2 localizes to the mitochondria, PB2 did not interact with full-length MECR. By contrast, a minor splice variant produces cytoplasmic MECR (cMECR). Ectopic expression of cMECR shows that it binds the viral polymerase and suppresses viral replication by blocking assembly of viral ribonucleoprotein complexes (RNPs). MECR ablation through genome editing or drug treatment is detrimental for cell health, creating a generic block to virus replication. Using the yeast homolog Etr1 to supply the metabolic functions of MECR in MECR-null cells, we showed that specific antiviral activity is independent of mtFAS and is reconstituted by expressing cMECR. Thus, we propose a strategy where alternative splicing produces a cryptic antiviral protein that is embedded within a key metabolic enzyme.
The host restriction factor TRIM5a mediates species-specific, early blocks to retrovirus infection; susceptibility to these blocks is determined by viral capsid sequences. Here we demonstrate that ...TRIM5α variants from Old World monkeys specifically associate with the HIV type 1 (HIV-1) capsid and that this interaction depends on the TRIM5α B30.2 domain. Human and New World monkey TRIM5α proteins associated less efficiently with the HIV-1 capsid, accounting for the lack of restriction in cells of these species. After infection, the expression of a restricting TRIM5α in the target cells correlated with a decrease in the amount of particulate capsid in the cytosol. In some cases, this loss of particulate capsid was accompanied by a detectable increase in soluble capsid protein. Inhibiting the proteasome did not abrogate restriction. Thus, TRIM5α restricts retroviral infection by specifically recognizing the capsid and promoting its rapid, premature disassembly.
ABSTRACT
Early prediction of human clearance is often challenging, in particular for the growing number of low-clearance compounds. Long-term
in vitro
models have been developed which enable ...sophisticated hepatic drug disposition studies and improved clearance predictions. Here, the cell line HepG2, iPSC-derived hepatocytes (iCell®), the hepatic stem cell line HepaRG™, and human hepatocyte co-cultures (HμREL™ and HepatoPac®) were compared to primary hepatocyte suspension cultures with respect to their key metabolic activities. Similar metabolic activities were found for the long-term models HepaRG™, HμREL™, and HepatoPac® and the short-term suspension cultures when averaged across all 11 enzyme markers, although differences were seen in the activities of CYP2D6 and non-CYP enzymes. For iCell® and HepG2, the metabolic activity was more than tenfold lower. The micropatterned HepatoPac® model was further evaluated with respect to clearance prediction. To assess the
in vitro
parameters, pharmacokinetic modeling was applied. The determination of intrinsic clearance by nonlinear mixed-effects modeling in a long-term model significantly increased the confidence in the parameter estimation and extended the sensitive range towards 3% of liver blood flow,
i.e
., >10-fold lower as compared to suspension cultures. For
in vitro
to
in vivo
extrapolation, the well-stirred model was used. The micropatterned model gave rise to clearance prediction in man within a twofold error for the majority of low-clearance compounds. Further research is needed to understand whether transporter activity and drug metabolism by non-CYP enzymes, such as UGTs, SULTs, AO, and FMO, is comparable to the
in vivo
situation in these long-term culture models.
Objective
Vitamin D deficiency has been reported to be associated with the incidence of type 1 and type 2 diabetes and worsening of diabetes complications. This study was designed to investigate the ...effect of vitamin D treatment on the expression of five key genes involved in the development of diabetic cardiomyopathy.
Methods
Twenty‐four male Sprague–Dawley rats were randomly divided into three groups. The first group served as control and the other two groups received an intraperitoneal injection of 45 mg/kg streptozotocin (STZ) to develop diabetes. Then groups were treated for 4 weeks either with placebo or vitamin D (two injections of 20,000 IU/kg). Serum levels of glucose, insulin, HbA1c, and advanced glycation end products (AGEs), as well as the gene expression of AGE cellular receptor (RAGE), glyoxalase, aldose reductase, O‐GlcNAc transferase (OGT), and glutamine‐fructose‐6‐phosphate aminotransferase (GFAT) and nuclear factor‐kB (NF‐kB) activity of nuclear extracts were assessed at the end of experiment.
Results
Increment in serum cholecalciferol could improve hyperglycaemia and hypoinsulinemia in diabetic rats. In addition, a significant reduction was observed in RAGE, OGT, and GFAT gene expression and NF‐kB activity in cardiac myocytes.
Conclusions
Vitamin D might contribute in reducing diabetic cardiomyopathy not only by improving blood glucose and insulin levels but also via downregulating AGE and hexosamine pathways and decreasing NF‐kB activity in heart tissue.
Vitamin D may ameliorate cardiac complications of diabetes by suppressing hexosamine and advanced glycation end‐products pathways.
Adipokines are mediators of body composition and are involved in obesity-related complications such as cardiovascular disease. Omega-3 supplementation has not been studied in the setting of body ...composition and follistatin-like 1 (FSTL1) levels in patients with coronary artery disease (CAD). This study aimed to investigate the effect of omega-3 polyunsaturated fatty acid (ω-3 PUFA) supplementation on body composition indices and serum levels of FSTL1 in CAD patients. A total of 42 male (aged 45–65 years) subjects with angiographically confirmed CAD were included in this randomized, double-blind, placebo-controlled trial study. The subjects were randomly divided into omega-3 and placebo groups. During the 8-week intervention, the omega-3 group received 1,200 mg of omega-3 daily, while the placebo group received paraffin. Before and after the study, anthropometric measurements and body composition components were taken; serum FSTL1 levels were assessed by an enzyme-linked immunosorbent assay (ELISA) kit. In the omega-3 group, a significant 27.6% increase in serum FSTL1 was seen after 8 weeks of intervention (p = .001), but no significant difference in posttreatment levels of FSTL1 was observed between the two groups (p > .05). At the end of the study, a significant decrease in low-density lipoprotein cholesterol (LDL-C; 94.29 ± 22.04 vs. 112.24 ± 24.5; p = .01) and high-sensitivity C-reactive protein (hs-CRP; 1.92 ± 0.79 vs. 3.19 ± 2.51; p = .03) concentration was detected between the two groups. Changes in fasting blood sugar, fasting insulin, body composition, and anthropometric parameters were not significant within and between the groups. Oral omega-3 might increase FSTL1 and decrease LDL-C and hs-CRP concentrations in CAD patients. However, omega-3 supplementation did not have any effect on FSTL1 levels between the groups.
Hepatitis B virus (HBV) infection can cause chronic liver disease, which is associated with increased risk of liver cirrhosis, liver failure, and liver cancer. Clearance of HBV infection requires ...effective HBV-specific immunity; however, the immunological mechanisms that determine the development of effective HBV-specific immunity are poorly understood. Dendritic cells (DC) play a pivotal role in the regulation of antiviral immunity. Here, we investigated the interaction between HBV surface antigen (HBsAg), the main envelope glycoprotein of HBV, and BDCA1(+) myeloid dendritic cells (mDC). Exposure of peripheral blood-derived BDCA1(+) mDC to HBsAg resulted in strong DC maturation, cytokine production, and enhanced capacity to activate antigen-specific cytotoxic T cells (CTLs). By using neutralizing antibodies, crucial roles for CD14 and Toll-like receptor 4 (TLR4) in HBsAg-mediated BDCA1(+) mDC maturation were identified. Concordantly, HBsAg-mediated DC maturation required fetal calf serum (FCS) or human plasma, naturally containing soluble CD14 (sCD14). Intriguingly, HBsAg-induced DC maturation was significantly reduced in umbilical cord blood plasma, which contained less sCD14 than adult plasma, indicating that sCD14 is an important host factor for recognition of HBsAg by DC and subsequent DC activation. A direct interaction between sCD14 and HBsAg was demonstrated by using enzyme-linked immunosorbent assay (ELISA). Moreover, sCD14-HBsAg complexes were detected both in vitro and in sera of HBV-infected patients. The abundance of sCD14-HBsAg complexes varied between chronic HBV disease stages and correlated with activation of BDCA1(+) mDC in vivo We conclude that HBsAg activates BDCA1(+) DC via an sCD14-dependent mechanism. These findings provide important novel insights into the initiation of HBV-specific immunity and facilitate development of effective immunotherapeutic interventions for HBV.
Hepatitis B virus (HBV) infection is a significant health problem, as it causes progressive liver injury and liver cancer in patients with chronic HBV infection, which affects approximately 250 million individuals worldwide. Some of the infected adults and the majority of neonates fail to mount an effective immune response and consequently develop chronic infection. The viral and host factors involved in the initiation of effective HBV-specific immune responses remain poorly understood. Here we identified CD14 and TLR4 as receptors for HBsAg, the main HBV envelope antigen. HBsAg induced strong maturation of dendritic cells (DC), which have a central role in regulation of virus-specific immunity. These results provide essential novel insights into the mechanisms underlying the initiation of HBV-specific immunity. Intriguingly, since neonates have naturally low sCD14, the finding that serum-derived sCD14 is a crucial host factor for recognition of HBsAg by DC may have implications for immunity of neonates to HBV infection.
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