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Background and Aims Seroclearance of hepatitis B surface antigen (HBsAg) is regarded as the functional cure of chronic hepatitis B (CHB). The relationship between human leukocyte antigen (HLA) variants, hepatitis B virus genotype, and longitudinal HBsAg serodecline remains to be explored. Methods A total of 2498 HBeAg-seronegative CHB patients of the community-based REVEAL-HBV cohort were genotyped for rs1710 (HLA-G) and rs2770 (HLA-B) using TaqMan assay. Cox proportional hazard regression and generalized linear mixed models were used to analyze the association of HLA genetic variants with the rate of HBsAg seroclearance and longitudinal HBsAg serodecline. Results Rs1710 G allele was differentially associated with the HBsAg seroclearance in genotype B [aRR (95% CI)=0.74 (0.56-0.98)] and genotype C [aRR (95%CI)=1.43 (1.08-1.88)] infection. Rs2770 G allele was associated with HBsAg seroclearance only in genotype B infection [aRR (95% CI)=0.69 (0.52-0.91)]. The alleles associated with HBsAg seroclearance were significant predictors for the serodecline of HBsAg levels in an HBV genotype-dependent manner (genotype B infection: rs1710, p=0.013; rs2770, p=0.0081; genotype C infection: rs1710, P=0.0452). Conclusions Our results suggest both spontaneous HBsAg seroclearance and serodecline are modified by the interaction between HLA variants and HBV genotype.

In chronic hepatitis B virus (HBV) infection, earlier seroclearance of hepatitis B e antigen (HBeAg) is associated with more favorable outcomes. Soluble programmed cell death 1 (sPD-1) has been implicated in higher viral load and hepatocellular carcinoma. We investigated the association between sPD-1 levels and spontaneous HBeAg seroclearance.Baseline serum samples from 488 HBeAg-seropositive patients in the REVEAL-HBV cohort were tested for sPD-1 levels. Among them, 329 with available follow-up serum samples were further assayed. Multivariate Cox regression analysis was used to estimate the adjusted rate ratio (aRR) and 95% confidence interval (CI) with adjustment of host and viral factors. The 66th percentile and an annual reduction of ≥ 10% were used as the cut-off point for baseline sPD-1 levels (high/low) and sPD-1 trajectory (decline/no decline), respectively.Lower baseline sPD-1 levels [aRR (95% CI): 2.19 (1.47-3.27)] and long-term decline in sPD-1 levels [aRR (95% CI): 4.08 (2.79-5.97)] were both independent predictors for HBeAg seroclearance. However, further stratification analysis by HBV genotype showed that lower baseline sPD-1 levels were significantly associated with HBeAg seroclearance only in genotype C infection [aRR (95% CI): 4.47 (2.38-8.37)] but not in genotype B infection. On the other hand, long-term decline in sPD-1 levels was predictive for HBeAg seroclearance regardless of HBV genotype with aRR (95% CI) of 4.62 (2.71-7.88) and 2.95 (1.68-5.17), respectively, for genotypes B and C.Serum sPD-1 levels may serve as a novel immunological predictor for spontaneous HBeAg seroclearance in patients with chronic hepatitis B.

Seven viruses including the Epstein-Barr virus (EBV), hepatitis B virus (HBV), hepatitis C virus (HCV), Kaposi's sarcoma herpes virus (KSHV), human immunodeficiency virus, type-1 (HIV-1), human T cell lymphotrophic virus, type-1 (HTLV-1), and human papillomavirus (HPV) have been classified as Group 1 human carcinogens by the International Agency for Research on Cancer (IARC). The conclusions are based on the findings of epidemiological and mechanistic studies. EBV, HPV, HTLV-1, and KSHV are direct carcinogens; HBV and HCV are indirect carcinogens through chronic inflammation; and HIV-1 is an indirect carcinogen through immune suppression. Some viruses may cause more than one cancer, while some cancers may be caused by more than one virus. However, only a proportion of persons infected by these oncogenic viruses will develop specific cancers. A series of studies have been carried out to assess the viral, host, and environmental cofactors of EBV-associated nasopharyngeal carcinoma, HBV/HCV-associated hepatocellular carcinoma, and HPV-associated cervical carcinoma. Persistent infection, high viral load, and viral genotype are important risk predictors of these virus-caused cancers. Risk calculators incorporating host and viral risk predictors have been developed for the prediction of long-term risk of hepatocellular carcinoma, nasopharyngeal carcinoma and cervical cancer. These risk calculators are useful for the triage and clinical management of infected patients. Both clinical trials and national programs of immunization, antiviral therapy and screening have demonstrated a significant reduction in the incidence of cancers caused by HBV, HCV, and HPV. Future research on gene-gene and gene-environment interactions of oncogenic viruses and the human host using large-scale longitudinal studies with serial measurements of biosignatures are in urgent need.

BACKGROUND: Hepatocarcinogenicity of Aflatoxin B(1) (AFB(1)) has rarely been studied in populations with hepatitis C virus (HCV) infection and those without hepatitis B virus (HBV) and HCV infection (non-B-non-C). This case-control study nested in a community-based cohort aimed to investigate the HCC risk associated with AFB(1) in HCV-infected and non-B-non-C participants. METHODS: Baseline serum AFB(1)-albumin adduct levels were measured in 100 HCC cases and 1767 controls seronegative for anti-HCV and HBsAg (non-B-non-C), and another 103 HCC cases and 176 controls who were anti-HCV-seropositive and HBsAg-seronegative. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated using logistic regression. RESULTS: In 20 years of follow-up, the follow-up time to newly-developed HCC was significantly shorter in participants with higher serum AFB(1)-albumin adduct levels in non-B-non-C (p=0.0162) and HCV-infected participants (p

The relation between aflatoxin B1 (AFB1 ) and cirrhosis in chronic carriers of hepatitis B virus (HBV) remains inconclusive. This case-control study nested in a large community-based cohort aimed to assess the effect of AFB1 exposure on cirrhosis and HCC in chronic HBV carriers. Serum AFB1 -albumin adduct levels at study entry were measured in 232 cirrhosis cases, 262 HCC cases and 577 controls. Multivariate-adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) were estimated using logistic regression. Among all chronic HBV carriers, the time intervals between study entry and diagnosis of HCC, cirrhosis, cirrhotic HCC, and non-cirrhotic HCC were all significantly (p

The resistive switching characteristics of n-type CuAlO x thin films fabricated by rf magnetron sputtering under different gas-flow ratios of O 2 /Ar were examined in this study. The dependence of resistive switching on the O 2 /Ar rate was found. The conduction mechanisms could be described as nearest-neighboring hopping and variable-range hopping conductions. For high or low resistive states (HRS or LRS), the electrical resistance decreases with increasing temperature, indicating semiconducting behavior. The transition from HRS to LRS due to the migration of oxygen vacancies (V O ) is associated with electron hopping mediated through the V O trap sites. The findings show the importance of simultaneous control of the number of oxygen vacancies and film crystallinity in achieving optimization of oxide-based memory devices.

The effect of surface sulfidation of Si on electronic transport of heterojunction diodes based on the p-type Cu2ZnSnS4 (CZTS) and n-type Si is investigated. The temperature-dependent current–voltage (I–V) characteristics of CZTS/Si diodes with and without sulfide treatment are measured in the temperature range of −30 ~ 90 °C. The temperature dependence of forward bias I–V characteristics can be explained on the basis of the thermionic emission theory. Compared with the CZTS/Si diode without sulfide treatment, the CZTS/Si diode with sulfide treatment exhibits a better rectifying behavior. The enhanced device performance is mainly the result of the formation of Si–S bonds that serve to reduce the interfacial potential fluctuations. In order to obtain a greater understanding of the improved rectifying I–V characteristics, the photoresponse measurement is performed. The increased photocurrent density can be interpreted by the device rectifying performance and interface passivation.

The relation between aflatoxin B1 (AFB1) and cirrhosis in chronic carriers of hepatitis B virus (HBV) remains inconclusive. This case-control study nested in a large community-based cohort aimed to assess the effect of AFB1 exposure on cirrhosis and HCC in chronic HBV carriers. Serum AFB1-albumin adduct levels at study entry were measured in 232 cirrhosis cases, 262 HCC cases and 577 controls. Multivariate-adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) were estimated using logistic regression. Among all chronic HBV carriers, the time intervals between study entry and diagnosis of HCC, cirrhosis, cirrhotic HCC, and non-cirrhotic HCC were all significantly (p

Lipopolysaccharides (LPS) are critical components for the fitness of most gram-negative bacteria. Ralstonia solanacearum causes a deadly wilting disease in many crops; however, the pathogenic roles of different forms of LPS and their pathways of biogenesis remain unknown. By screening for phage-resistant mutants of R. solanacearum Pss4, whose genome sequence is unavailable, mutants with various types of structural defects in LPS were isolated. Pathogenesis assays of the mutants revealed that production of rough LPS (R-LPS), which does not contain O-polysaccharides, was sufficient to cause necrosis on Nicotiana benthamiana and induce the hypersensitive response on N. tabacum. However, biosynthesis of smooth LPS (S-LPS), which contains O-polysaccharides, was required for bacterial proliferation at infection sites on N. benthamiana leaves and for proliferation and causing wilt on tomato. Complementation tests confirmed the involvement of the previously unidentified cluster RSc2201 to RSc2204 in the formation of R. solanacearum S-LPS. With these data and the availability of the annotated genomic sequence of strain GMI1000, certain loci involved in key steps of R. solanacearum LPS biosynthesis were identified. The strategy of this work could be useful for similar studies in other bacteria without available genome sequences.

Curcumin is the active ingredient in the herbal medicine and dietary spice, turmeric (Curcuma longa). It has a wide range of biological activities, including anti-inflammatory, antioxidant, chemopreventive, and chemotherapeutic activities. We examined the effects of curcumin on the lifespan and aging in Caenorhabditis elegans, and found that it responded to curcumin with an increased lifespan and reduced intracellular reactive oxygen species and lipofuscin during aging. We analyzed factors that might influence lifespan extension by curcumin. We showed that lifespan extension by curcumin in C. elegans is attributed to its antioxidative properties but not its antimicrobial properties. Moreover, we showed that lifespan extension had effects on body size and the pharyngeal pumping rate but not on reproduction. Finally, lifespan tests with selected stress- and lifespan-relevant mutant strains revealed that the lifespan-extending phenotype was absent from the osr-1, sek-1, mek-1, skn-1, unc-43, sir-2.1, and age-1 mutants, whereas curcumin treatment prolonged the lifespan of mev-1 and daf-16 mutants. Our study has unraveled a diversity of modes of action and signaling pathways to longevity and aging with curcumin exposure in vivo.

Drinking highly arsenic-contaminated groundwater is a likely cause of blackfoot disease in Taiwan, but microorganisms that potentially control arsenic mobility in the subsurface remain unstudied. The objective of this study was to investigate the relevant arsenite-oxidizing and arsenate-reducing microbial community that exists in highly arsenic-contaminated groundwater in Taiwan. We cultured and identified arsenic-transforming bacteria, analyzed arsenic resistance and transformation, and determined the presence of genetic markers for arsenic transformation. In total, 11 arsenic-transforming bacterial strains with different colony morphologies and varying arsenic transformation abilities were isolated, including 10 facultative anaerobic arsenate-reducing bacteria and one strictly aerobic arsenite-oxidizing bacterium. All of the isolates exhibited high levels of arsenic resistance with minimum inhibitory concentrations of arsenic ranging from 2 to 200 mM. Strain AR-11 was able to rapidly oxidize arsenite to arsenate at concentrations relevant to environmental groundwater samples without the addition of any electron donors or acceptors. We provide evidence that arsenic-reduction activity may be conferred by the ars operon(s) that were not amplified by the designed primers currently in use. The 16S rRNA sequence analysis grouped the isolates into the following genera: Pseudomonas, Bacillus, Psychrobacter, Vibrio, Citrobacter, Enterobacter, and Bosea. Among these genera, we present the first report of the genus Psychrobacter being involved in arsenic reduction. Our results further support the hypothesis that bacteria capable of either oxidizing arsenite or reducing arsenate coexist and are ubiquitous in arsenic-contaminated groundwater.

Microbes encounter various environmental factors which frequently cause detrimental effects on their population dynamics. Ralstonia solanacearum is a devastating bacterium causing a deadly and very complex disease of many agronomically important crops. To better control the disease, information about responses of distinct strains of this bacterium to environmental factors is certainly important but still insufficient. In this study, effects of salinity, excess copper, extreme pHs, drought and light on the propagation and survival of a representative of R. solanacearum strains in Taiwan, Pss4, were assessed. Our results showed that salinity negatively affected Pss4 multiplication in rich media at a dose-dependent manner, but resulted in negligent effects on its survival in sand and in water. In the presence of excess copper, similar negative effects on Pss4 culturability in rich media and at a less level on that in sand occurred. Additionally, Pss4 multiplication in rich media was substantially reduced at pH 9.0 and at a less degree at pH 5.0. Moreover, the survival of this bacterium in sand was sensitive to drought, but it sustained under incident light in water. The results were compared with previous studies on distinct R. solanacearum strains prevalent in different geographic regions and discussed in detail. The information gathered from this study would pave to the way for future studies on field samples to advance disease epidemiology and develop feasible strategies for disease control in Taiwan.

Ralstonia solanacearum causes a deadly wilting disease on a wide range of crops. To elucidate pathogenesis of this bacterium in different host plants, we set out to identify R. solanacearum genes involved in pathogenesis by screening random transposon insertion mutants of a highly virulent strain, Pss190, on tomato and Arabidopsis thaliana. Mutants exhibiting various decreased virulence levels on these two hosts were identified. Sequence analysis showed that most, but not all, of the identified pathogenesis genes are conserved among distinct R. solanacearum strains. A few of the disrupted loci were not reported previously as being involved in R. solanacearum pathogenesis. Notably, a group of mutants exhibited differential pathogenesis on tomato and Arabidopsis. These results were confirmed by characterizing allelic mutants in one other R. solanacearum strain of the same phylotype. The significantly decreased mutants' colonization in Arabidopsis was found to be correlated with differential pathogenesis on these two plants. Differential requirement of virulence genes suggests adaptation of this bacterium in different host environments. Together, this study reveals commonalities and differences of R. solanacearum pathogenesis on single solanaceous and nonsolanaceous hosts, and provides important new insights into interactions between R. solanacearum and different host plants.

The sodium taurocholate co-transporting polypeptide (NTCP), encoded by SLC10A1, was recently identified as a receptor for HBV. We assessed the association of the p.Ser267Phe variant (rs2296651) with chronic hepatitis B (CHB) serostatus, cirrhosis and hepatocellular carcinoma (HCC) in patients with CHB.The variant was genotyped in 3801 patients with CHB and 3801 matched hepatitis B surface antigen (HBsAg) seronegative individuals. ORs with 95% CIs for the variant's association with CHB, cirrhosis and HCC were estimated using logistic regression.In patients with CHB, the S267F variant was observed in 515 (18.5%) controls, 40 (17.2%) cirrhosis only cases, 49 (13.2%) non-cirrhotic HCC cases, and 52 (12.7%) cirrhotic-HCC cases. After adjustment for known risk factors, S267F was significantly associated with decreased risk for cirrhosis (OR 0.65 (95% CI 0.49 to 0.86), p=0.002) and HCC (OR 0.55 (95% CI 0.42 to 0.72), p0.001). This association persisted for non-cirrhotic and cirrhotic-HCC. Compared with patients with HBV DNA levels greater than 10(5) copies/mL who carried the GG genotype, patients who had undetectable HBV DNA and the GA or AA genotypes had a 25-fold decreased risk of developing HCC (OR 0.04 (95% CI 0.02 to 0.11), p0.001). The AA genotype was also associated with HBsAg seronegativity (OR 0.13 (95% CI 0.05 to 0.34), p0.001).The SLC10A1 (NTCP) S267F variant is independently associated with decreased risk of cirrhosis and HCC, and resistance to CHB infection. Together with serum HBV DNA levels, S267F may help to identify patients with CHB with very low risk of HCC.

Ralstonia solanacearum causes deadly wilting on many crops worldwide. However, the information on its components important for cell integrity and interactions with phages is limited. By systematically characterizing mutants resistant to a T7-like phage, we showed that the biosynthesis of rough lipopolysaccharides (R-LPS) was crucial for maintaining the membrane integrity, while the production of smooth LPS (S-LPS) was required for the resistance to polymyxin B and phage adsorption. Furthermore, RSc0154/ampG disruption did not affect LPS production and phage adsorption but may have caused aberrant release of peptidoglycan fragments, thus hindering phage DNA injection into or virion release from the cell. Mutations in the RSc2958–RSc2962/mla cluster, although not affecting LPS production, may have caused elevated phospholipid level in the outer leaflet of the outer membrane, consequently sheltering the mutants from phage adsorption on the O-antigen. These results specify important roles of the biogenesis and homeogenesis of envelope components for R. solanacearum-phage interaction.

Arsenic (As) contamination of groundwater is a significant public health concern. In this study, the removal of arsenic from groundwater using biological processes was investigated. The efficiency of arsenite (As(III)) bacterial oxidation and subsequent arsenate (As(V)) removal from contaminated groundwater using bacterial biomass was examined. A novel As(III)-oxidizing bacterium (As7325) was isolated from the aquifer in the blackfoot disease (BFD) endemic area in Taiwan. As7325 oxidized 2300μg/l As(III) using in situ As(III)-contaminated groundwater under aerobic conditions within 1d. After the oxidation of As(III) to As(V), As(V) removal was further examined using As7325 cell pellets. The results showed that As(V) could be adsorbed efficiently by lyophilized As7325 cell pellets, the efficiency of which was related to lyophilized cell pellet concentration. Our study conducted the examination of an alternative technology for the removal of As(III) and As(V) from groundwater, indicating that the oxidation of As(III)-contaminated groundwater by native isolated bacterium, followed by As(V) removal using bacterial biomass is a potentially effective technology for the treatment of As(III)-contaminated groundwater.

Cinnamomum osmophloeum Kaneh is an indigenous tree species in Taiwan. In this study, phytochemical characteristics and antioxidant activities of the essential oils and key constituents from the leaves of two C. osmophloeum clones were investigated. The two trees possess two chemotypes, which were classified as the cinnamaldehyde type and camphor type. We demonstrated that the essential oils from C. osmophloeum leaves exerted in vivo antioxidant activities in Caenorhabditis elegans. In addition, trans-cinnamaldehyde and D-(+)-camphor, which respectively represent the major compounds in the cinnamaldehyde-type and camphor-type trees, exerted significant in vivo antioxidant activities against juglone-induced oxidative stress in C. elegans. Moreover, expressions of antioxidative-related genes, including superoxide dismutase (SOD) and glutathione S-transferase (GST), were significantly induced by trans-cinnamaldehyde and D-(+)-camphor from C. osmophloeum leaves. Our results showed that the essential oils from C. osmophloeum leaves and their major compounds might have good potential for further development as nutraceuticals or antioxidant remedies.

High levels of arsenic in groundwater and drinking water represent a major health problem worldwide. Drinking arsenic-contaminated groundwater is a likely cause of blackfoot disease (BFD) in Taiwan, but mechanisms controlling the mobilization of arsenic present at elevated concentrations within aquifers remain understudied. Microcosm experiments using sediments from arsenic contaminated shallow alluvial aquifers in the blackfoot disease endemic area showed simultaneous microbial reduction of Fe(III) and As(V). Significant soluble Fe(II) (0.23 ± 0.03 mM) in pore waters and mobilization of As(III) (206.7 ± 21.2 nM) occurred during the first week. Aqueous Fe(II) and As(III) respectively reached concentrations of 0.27 ± 0.01 mM and 571.4 ± 63.3 nM after 8 weeks. We also showed that the addition of acetate caused a further increase in aqueous Fe(II) but the dissolved arsenic did not increase. We further isolated an As(V)-reducing bacterium native to aquifer sediments which showed that the direct enzymatic reduction of As(V) to the potentially more-soluble As(III) in pore water is possible in this aquifer. Our results provide evidence that microorganisms can mediate the release of sedimentary arsenic to groundwater in this region and the capacity for arsenic release was not limited by the availability of electron donors in the sediments.