Human Leukocyte Antigen Polymorphism HLA-A*24:02 is Associated with Acute Liver Disease in HBV-Infected Han Chinese Adults.

BACKGROUND: Whether polymorphic Human Leukocyte Antigen (HLA)-A, HLA-B and HLA-DRB1 alleles were associated with acute liver disease after hepatitis B virus (HBV) infections was investigated. METHODS: In this study, from initially 100 participants in each group, HLA-A, HLA-B and HLA-DRB1 sequences were available from 86 acute hepatitis B (AHB) patients and from 84 HBV-resistant individuals (controls), using sequencing-based typing allele groups and alleles that exhibited differences in distribution between the case and control groups were subjected to chi-squared and logistic regression analyses to identify those associated with AHB. A dose response analysis was also performed on the effect of HLA-A*24:02 allele number on acute liver disease following HBV infection. RESULTS: The frequency distribution of HLA-B and HLA-DRB1 alleles in the control group were in Hardy-Weinberg Equilibrium (P > .05). HLA-A*24:02 (χ2 = 6.949, P = .008) occurred most frequently in the AHB and HLA-DRB1*12:02 (χ2 = 7.768, P = .005) in the control group. With adjustment for sex, the logistic regression model showed that the HLA-A*24:02 allele was significantly associated with AHB liver injury (P = .0326, OR = 2.270, 95% CI: 1.070-4.816), whereas the other HLA-A, HLA-B, and HLA-DRB1 alleles were not (P > .05). A linear response was observed for the association between HLA-A*24:02 allele number and acute liver disease after HBV infections (χ2 = 4.428, P = .025). CONCLUSION: The HLA-A*24:02 allele may influence the severity of the cellular response to HBV infection, increasing the elimination of HBV-infected hepatocytes. The HLA-A*24:02 allele may be a potential screening marker for identifying people or regional populations in China at higher risk of acute liver disease following HBV infection.

TLR8 agonist partially improves IFN-γ deficiency of NK cells in chronic hepatitis B through the synergy of monocytes.

BACKGROUND: Natural killer (NK) cells exhibit a selective deficiency of IFN-γ production in chronic hepatitis B (CHB). Toll-like receptor 8 (TLR8) agonists could induce IFN-γ production in immune cells, although their effects on the deficiency in NK cells remain unclear. AIMS: To investigate TLR8 expression in NK cells and the effect of TLR8 agonists in patients with CHB METHODS: We enrolled 32 patients with CHB and 19 healthy controls to assess TLR8 expression and IFN-γ production in NK cells. The sorted NK cells and monocytes were co-cultured to compare the extent of IFN-γ and IL-10 production after TLR8 agonist ssRNA40 stimulation. The synergic effect of NK cells and monocytes was assessed by blocking IL-12 and IL-18. We recruited another 22 patients with CHB undergoing nucleotide analogue (NA) therapy to explore the impact of antiviral treatment on the ssRNA40-mediated response of NK cells. RESULTS: In patients with CHB, TLR8 expression in NK cells was up-regulated, accompanied by insufficient IFN-γ production. The enhanced IFN-γ secretion by ssRNA40 in NK cells depended on monocyte-derived IL-12 and IL-18. NK cells displayed an imbalanced response to ssRNA40 in patients with CHB with a weak increase in IFN-γ despite a higher IL-10 production. The response was improved in patients with CHB undergoing NA therapy. CONCLUSIONS: In patients with CHB, targeting TLR8 partially rescues the IFN-γ insufficiency in NK cells. However, NK cells show an inhibitory response to TLR8 agonist stimulation. TLR8 agonist combined with NA may enhance the antiviral effect of NK cells.

The risk of COVID-19 can be predicted by a nomogram based on m6A-related genes.

BACKGROUND: The expression of m6A-related genes and their significance in COVID-19 patients are still unknown. METHODS: The GSE177477 and GSE157103 datasets of the Gene Expression Omnibus were used to extract RNA-seq data. The expression of 26 m6A-related genes and immune cell infiltration in COVID-19 patients were analyzed. Finally, we built and validated a nomogram model to predict the risk of COVID-19 infection. RESULTS: There were significant differences in 11 m6A regulatory factors between patients with COVID-19 and healthy individuals. The classification of disease subtypes based on m6A-related gene levels can be distinguished. COVID-19 patients in GSE177477 were classified into two categories based on m6A-related genes. The patients in cluster A were all symptomatic, while those in cluster B were asymptomatic. A significant correlation was also found between immune cells and m6A-related genes. Finally, seven m6A-related disease-characteristic genes, HNRNPA2B1, ELAVL1, RBM15, RBM15B, YTHDC1, HNRNPC, and WTAP, were screened to construct a nomogram model for predicting risk. The calibration curve, decision curve analysis, and clinical impact curve analysis were used to show that the nomogram model was effective and had a high net efficacy for risk prediction. CONCLUSIONS: m6A-related genes were correlated with immune cells. The nomogram model effectively predicted COVID-19 risk. Moreover, m6A-related genes may be associated with the presence or absence of symptoms in COVID-19 patients.

Meta-analysis of transcriptome datasets: An alternative method to study IL-6 regulation in coronavirus disease 2019.

In coronavirus disease 2019 (COVID-19) patients, interleukin (IL)-6 is one of the leading factors causing death through cytokine release syndrome. Hence, identification of IL-6 downstream from clinical patients' transcriptome is very valid for analyses of its mechanism. However, clinical study is conditional and time consuming to collect optional size of samples, as patients have the clinical heterogeneity. A possible solution is to deeply mine the relative existing data. Several transcriptome-based studies on other diseases or treatments have revealed different genes to be regulated by IL-6. Through our meta-analysis of these transcriptome datasets, 352 genes were suggested to be regulated by IL-6 in different biological conditions, some of which were related to virus infection and cardiovascular disease. Among them, 232 genes were not identified by current transcriptome studies from clinical research. ICAM1 and PFKFB3 were the most significantly upregulated genes in our meta-analysis and could be employed as biomarkers in patients with severe COVID-19. In general, a meta-analysis of transcriptome datasets could be an alternative way to analyze the immune response and complications of patients suffering from severe COVID-19 and other emergency diseases.

Inhibition of Shh Signaling through MAPK Activation Controls Chemotherapy-Induced Alopecia.

Chemotherapy-induced hair loss (alopecia) (CIA) remains a major unsolved problem in clinical oncology. CIA is often considered to be a consequence of the antimitotic and apoptosis-promoting properties of chemotherapy drugs acting on rapidly proliferating hair matrix keratinocytes. Here, we show that in a mouse model of CIA, the downregulation of Shh signaling in the hair matrix is a critical early event. Inhibition of Shh signaling recapitulated key morphological and functional features of CIA, whereas recombinant Shh protein partially rescued hair loss. Phosphoproteomics analysis revealed that activation of the MAPK pathway is a key upstream event, which can be further manipulated to rescue CIA. Finally, in organ-cultured human scalp hair follicles as well as in patients undergoing chemotherapy, reduced expression of SHH gene correlates with chemotherapy-induced hair follicle damage or the degree of CIA, respectively. Our work revealed that Shh signaling is an evolutionarily conserved key target in CIA pathobiology. Specifically targeting the intrafollicular MAPK-Shh axis may provide a promising strategy to manage CIA.

Structural Insights for Anti-Influenza Vaccine Design.

Influenza A virus are a persistent and significant threat to human health, and current vaccines do not provide sufficient protection due to antigenic drift, which allows influenza viruses to easily escape immune surveillance and antiviral drug activity. Influenza hemagglutinin (HA) is a glycoprotein needed for the entry of enveloped influenza viruses into host cells and is a potential target for anti-influenza humoral immune responses. In recent years, a number of broadly neutralizing antibodies (bnAbs) have been isolated, and their relative structural information obtained from the crystallization of influenza antigens in complex with bnAbs has provided some new insights into future influenza vaccine research. Here, we review the current knowledge of the HA-targeted bnAbs and the structure-based mechanisms contributing to neutralization. We also discuss the potential for this structure-based approach to overcome the challenge of obtaining a highly desired "universal" influenza vaccine, especially on small proteins and peptides.

Quantitative Comparative Proteomics Reveal Biomarkers for Dengue Disease Severity.

Dengue fever (DF) could develop into dengue haemorrhagic fever (DHF) with increased mortality rate. Since the clinical characteristics and pathogen are same in DF and DHF. It's important to identify different molecular biomarkers to predict DHF patients from DF. We conducted a clinical plasma proteomics study using quantification (TMT)-based quantitative proteomics methodology to found the differential expressed protein in DF patients before they developed into DHF. In total 441 proteins were identified up or down regulated. There proteins are enriched in diverse biological processes such as proteasome pathway, Alanine, aspartate, and glutamate metabolism and arginine biosynthesis. Several proteins such as PLAT, LAMB2, and F9 were upregulated in only DF patients which developed into DHF cases, not in DF, compared with healthy-control. In another way, FGL1, MFAP4, GLUL, and VCAM1 were upregulated in both DHF and DF cases compare with healthy-control. RT-PCR and ELISA were used to validate these upregulated gene expression and protein level in 54 individuals. Results displayed the same pattern as proteomics analysis. All including PLAT, LAMB2, F9, VCAM1, FGL1, MFAP4, and GLUL could be considered as potential markers of predicting DHF since the levels of these proteins vary between DF and DHF. These new founding identified potential molecular biomarkers for future development in precision prediction of DHF in DF patients.

Biochemical Characterization and Phylogenetic Analysis of the Virulence Factor Lysine Decarboxylase From Vibrio vulnificus.

Cadaverine is produced in organisms from the amino acid lysine in a decarboxylation reaction catalyzed by lysine decarboxylase (EC 4.1.1.18). The inducible lysine decarboxylase CadA plays a vital role in acid stress response for enteric bacteria. Vibrio vulnificus is an extremely virulent human pathogen causing gastroenteritis when the acid conditions that prevent survival of V. vulnificus in the stomach or small intestine are overcome. A gene encoding CadA was identified from V. vulnificus. Subsequent analyses showed that CadA from V. vulnificus (VvCadA) is a decamer with a 82-kDa subunit. Homogenous VvCadA was purified from Escherichia coli and used for lysine decarboxylation with an optimal pH of 6.0 and optimal temperature of 37°C. The apparent V max and K m for lysine were 9.45 ± 0.24 µM/min and 0.45 ± 0.05 mM, respectively. Mutation analysis suggested that the amino-acid-binding pyridoxal phosphate, the cofactor of the enzyme, plays a vital role in the reaction. Mutation of the negatively charged residues interacting with lysine also affected the activity of the enzyme to some extent. Quantitative RT-PCR showed that expression of VvcadA was up-regulated under low pH, low salinity, and oxidative stresses. Furthermore, the concentration of cadaverine released to the cell exterior also increased under these stresses. Protein sequence similarity network (SSN) analysis indicated that lysine decarboxylases with ornithine decarboxylases and arginine decarboxylases shared a common ancestor, and that lysine decarboxylases are more conserved during evolution. Our data provide evidence for the biochemical characteristics and important roles of VvCadA under stress conditions.

E-Cadherin-Mediated Cell Contact Controls the Epidermal Damage Response in Radiation Dermatitis.

Radiotherapy is a primary oncological treatment modality that also damages normal tissue, including the skin, and causes radiation dermatitis (RD). Here, we explore the mechanism of acute epidermal damage in radiation dermatitis. Two distinctive phases in the damage response were identified: an early destructive phase, where a burst of reactive oxygen species induces loss of E-cadherin-mediated cell contact, followed by a regenerative phase, during which Wnt and Hippo signaling are activated. A blocking peptide, as well as a neutralizing antibody to E-cadherin, works synergistically with ionizing radiation to promote the epidermal damage. In addition, ROS disassembles adherens junctions in epithelial cells via posttranslational mechanisms, that is, activation of Src/Abl kinases and degradation of ß-catenin/E-cadherin. The key role of tyrosine kinases in this process is further substantiated by the rescue effect of the tyrosine kinase inhibitor genistein, and the more specific Src/Abl kinase inhibitor dasatinib: both reduced ROS-induced degradation of ß-catenin/E-cadherin in vitro and ameliorated skin damage in rodent models. Finally, we confirm that the same key molecular events are also seen in human radiation dermatitis. Therefore, we propose that loss of cell contact in epidermal keratinocytes through reactive oxygen species-mediated disassembly of adherens junctions is pivotal for the acute epidermal damage in radiation dermatitis.