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Hepatitis B (HB) vaccination effectively reduces the risks of chronic infection with the hepatitis B virus (HBV). It is unknown whether there is a common genetic determinant for response to the HB vaccine and susceptibility to chronic HBV infection. This case-control study, which included 193 chronic HBV carriers and 495 non-carriers, aimed to explore the effects of the most significant single nucleotide polymorphisms (SNPs) in response to the HB vaccine on the risks of chronic HBV infection. Out of 13 tested SNPs, the genotype distributions of four SNPs at the human leukocyte antigen (HLA) class II region, including rs34039593, rs614348, rs7770370, and rs9277535, were significantly different between HBV carriers and non-carriers. The age-sex-adjusted odds ratios (OR) of chronic HBV infection for rs34039593 TG, rs614348 TC, rs7770370 AA, and rs9277535 AA genotypes were 0.51 (95% confidence interval [CI], 0.33–0.79; p = 0.0028), 0.49 (95% CI, 0.32–0.75; p = 6.5 × 10−4), 0.33 (95% CI, 0.18–0.63; p = 7.4 × 10−4), and 0.31 (95% CI, 0.14–0.70; p = 0.0043), respectively. Multivariable analyses showed that rs614348 TC and rs7770370 AA genotypes were significantly independent protectors against chronic HBV infection. The multivariable-adjusted ORs for subjects with none, either one, or both of the protective genotypes were 1.00 (referent), 0.47 (95% CI: 0.32–0.71; p = 3.0 × 10−4), and 0.16 (95% CI: 0.05–0.54; p = 0.0032), respectively. Among eight HBeAg-positive carriers, only one of them carried a protective genotype. This study shows that response to the HB vaccine and susceptibility to chronic HBV infection share common genetic determinants and indicates that HLA class II members are the main responsible host genetic factors.

Reactive oxygen species impair the blood vessels, leading to the initiation of atherosclerosis, and migration and proliferation of vascular smooth muscle cells and neovascularization by endothelial cells of vasa vasorum are essential for atherosclerosis development. Obg-like ATPase 1 (OLA1), a negative regulator in cellular responses to oxidative stress, binds to breast cancer susceptibility gene 1 (BRCA1), which protects vascular endothelial and smooth muscle cells against reactive oxygen species. However, it is not known whether OLA1 is genetically correlated with atherosclerosis. Here, we conducted two independent population-based case-control studies to explore the effects of variants in

Bone morphogenetic proteins (BMP) 2 and 4 are implicated in the development of atherosclerosis. However, the relationships between the proteins, their main receptors and carotid intima-media thickness (cIMT), a predictive preclinical phenotype of atherosclerosis, have not been established. Methods and Results: We screened and validated the relationships of single-nucleotide polymorphisms (SNPs) on BMP2, BMP4, BMPR1A, BMPR1B, and BMPR2 with thicker cIMT by 2 independent case-control studies that used different subject selection methods. Among 200 screened SNPs, 12 on BMPR1B were regarded as candidate genetic markers (P-value5.0×10We identified 2 SNPs on BMPR1B showing significantly independent correlations with thicker cIMT. The study provides invaluable evidence supporting that BMPR1B is closely related to carotid atherosclerosis and a potential target for the development of therapeutic agents for atherosclerotic disease.

No report explored the combined effects of HLA-DPA1 and -DPB1 with long-term response to hepatitis B (HB) vaccination (HBVac). The specific aims of the study were to assess the combined effects and relative contributions of DPA1 and DPB1 genes.The cases were 152 adolescents who had undetectable (1.0 mIU/mL) post-booster anti-HBs titers and the controls were adolescents who had residual anti-HBs ≥ 10 mIU/mL at aged 16 years (n = 207) or had detectable (≥1.0 mIU/mL) anti-HBs titers after booster HBVac (n = 481). HLA-DPA1 and -DPB1 genotypes were determined by sequence-based typing.HLA-DPA1*01:03:01 was correlated with lower ORs of undetectable anti-HBs titers, while -DPA1*02:02:02 and -DPB1*05:01:01 were correlated with higher ORs. The ORs for HLA-DPA1*01:03:01-DPB1*05:01:01 and DPA1*02:02:02-DPB1*protective combinatory types were significantly less than 1.0. As compared with subjects who had no protective allele, the adjusted ORs (95% CI) were 0.545 (0.328-0.906), 0.350 (0.174-0.702), and 0.122 (0.058-0.257), for subjects who had protective alleles on DPA1only, DPB1 only, and both genes, respectively. Analyses of amino acid polymorphisms showed that subjects who carried Arg81-Pro158-Val191-Pro259α + Met234β and Gln62-Arg82α + Met234β combinations had 4.3-to-4.6 folds of risks.Both DPA1 and DPB1 genes contribute to the persistence of immunological response to primary infantile HBVac. The effects of HLA-DP risk alleles were dominated by the protective alleles and there were significant gene-gene interactions. Our findings provide evidences for the design of more potent HB vaccine.

Background and Aim Hepatitis B (HB) vaccination is highly effective in reducing the risk of hepatitis B virus infection. However, breakthrough and chronic hepatitis B virus infections in vaccinated subjects raised concern about its long-term efficacy. The specific aim of the study was to explore the host genetic determinants of long-term immunological memory against HB vaccination. Methods We conducted a case–control study nested in a cohort of HB booster recipients who had received primary HB vaccination during infancy but failed to reside an anti-HBs titers ≥ 10 mIU/mL at the age of 15–18 years. We used a genome-wide single nucleotide polymorphism (SNP) array plate to scan autosomal chromosomes and assayed the human leukocyte antigen (HLA)-DPB1 genotype by sequence-based techniques. Results We found that 10 of the 112 candidate SNPs (P-value

a Department of Medicine, Mackay Medical College, New Taipei City, Taiwan b Laboratory for Epidemiology, Department of Health Care Management, and Healthy Aging Research Center, Chang Gung University, Tao-Yuan City, Taiwan c Department of Public Health, Taipei Medical University, Taipei City, Taiwan d Institute of Biomedical Sciences, Mackay Medical College, New Taipei City, Taiwan e Section of Cardiology, Department of Internal Medicine, Mackay Memorial Hospital, Mackay Medical College, Taipei, Taiwan

Hepatitis B virus (HBV) infection is a global health issue. Universal infantile hepatitis B (HB) vaccination is very efficacious. However, HBV infections among those immunized subjects have been reported. The long-term efficacy of postnatal passive-active HB vaccination in high-risk subjects is not well explored. A total of 8,733 senior high school students who were born after July 1987 were assayed for hepatitis B surface antigen (HBsAg) and antibodies to HBsAg (anti-HBs). The overall HBsAg and anti-HBs-positive rates were 1.9% and 48.3%, respectively. The HBsAg-positive rate was 15% in HB immunoglobulin (HBIG) recipients (adjusted odds ratio [OR]: 15.63; 95% confidence interval [CI]: 10.99-22.22). Among students who did not receive HBIG, there was a significantly negative association between HB vaccination dosage and HBsAg-positive rate (P for trend = 0.011). Adjusted ORs for those who received 4, 3, and 1 to 2 doses were 1.00, 1.52 (95% CI: 0.91-2.53), and 2.85 (95% CI: 1.39-5.81), respectively. Among HBIG recipients, the HBsAg-positive rate was significantly higher in subjects with maternal hepatitis B e antigen (HBeAg) positivity and who received HBIG off-schedule. A booster dose of HB vaccination was administered to 1974 HBsAg- and anti-HBs-negative subjects. Prebooster and a postbooster blood samples were drawn for anti-HBs quantification. The proportions of postbooster anti-HBs titer

Background and Aim: Carotid intima-media thickness (IMT) is a well-studied phenotype of atherosclerosis in developed countries, however, there was only a few studies in developing countries. The aim of the study was to explore the relationships between carotid IMTs and prevalent cardio-metabolic diseases in Chinese. Methods: 1579 residents aged 40-74 years from three communities in northern Taiwan were recruited in 2010-2012. The far-wall intima-media thickness (IMTs) of the right and left common carotid arteries (CCAs), internal carotid arteries (ICA), and carotid bifurcation (BIF) were measured by B mode ultrasound. All participants were assessed for cardio-metabolic profiles and 10-year general cardiovascular risks by the Framingham Risk Score. Results: Correlation analyses showed that there were significant linear trends with age and estimated 10-year general cardiovascular risks for all segmental carotid IMTs. The linear trends were the strongest for CCA IMTs, followed by BIF IMTs, and the least for ICA IMTs, and stronger for the average IMTs of the right and left carotid arteries than one-sided IMTs alone. Male sex, central obesity, high BMI, high LDL-/HLD-C ratio, high blood pressure, and high blood sugar were significantly correlated with thicker carotid IMTs. Subjects affected with hypertension, diabetes mellitus (DM), metabolic syndrome, and cardiovascular diseases (CVDs) had significantly thicker carotid IMTs. After adjustment for traditional cardio-metabolic risk factors, subjects who had mean or maximum CCA or mean BIF IMTs >= the 3rd quartiles had significantly higher likelihoods of having prevalent CVDs. The adjusted ORs were 2.13 (95% CI: 1.30-3.49), 1.73 (95% CI: 1.06-2.82), and 1.59 (95% CI: 1.01-2.51), respectively. The adjusted ORs were not significant for subjects who had elevated mean or maximum ICA or maximum BIF IMTs. Conclusions: Carotid IMTs were significantly correlated with most traditional cardio-metabolic risk factors. Among different segmental carotid IMTs, CCA IMTs demonstrated stronger associations with prevalent CVDs and DM. Carotid IMTs may be used as an intermediate marker of advanced vascular diseases in Chinese.

Polarized epithelia, such as hepatocytes, target their integral membrane proteins to specific apical or basolateral membrane domains during or after biogenesis. The roles played by protein glycosylation in this sorting process remain controversial. We report here that deglycosylation treatments in well-polarized hepatic cells by deglycosylation drugs, or by site-directed mutagenesis of the N-linked-glycosylation residues, all cause the Na+/K+-ATPase β-subunit to traffic from the native basolateral to the apical/canalicular domain. Deglycosylated β-subunits are still able to bind and therefore transport the catalytic α-subunits to the aberrant apical location. Such apical targeting is mediated via the indirect transcytosis pathway. Cells containing apical Na+/K+-ATPase appear to be defective in maintaining the ionic gradient across the plasma membrane and in executing hepatic activities that are dependent upon the ionic homeostasis such as canalicular excretion.

Estrogen receptor (ER) mediated neuroprotection has been demonstrated in both in vitro and in vivo model systems. However, the relative contribution by either ER subtype, ERalpha or ERbeta, to estrogen-induced neuroprotection remains unresolved. To address this question, we investigated the impact of selective ER agonists for either ERalpha, PPT, or ERbeta, DPN, to prevent neurodegeneration in cultured hippocampal neurons exposed to excitotoxic glutamate. Using three indicators of neuronal viability and survival, we demonstrated that both the ERalpha selective agonist PPT and the ERbeta selective agonist DPN protected hippocampal neurons against glutamate-induced cell death in a dose-dependent manner, with the maximal response occurring at 100 pM. Further analyses showed that both PPT and DPN enhanced Bcl-2 expression in hippocampal neurons, with an efficacy comparable to their neuroprotective capacity. Collectively, the present data indicate that activation of either ERalpha or ERbeta can promote neuroprotection in hippocampal neurons, suggesting that both receptor subtypes could be involved in estrogen neuroprotection. As ERbeta is highly expressed in the brain and has little or no expression in the breast or uterus, discovery and design of ERbeta selective molecules could provide a strategy for activating the beneficial effects of estrogen in the brain without activating untoward effects of estrogen in reproductive organs.

Hepatitis B (HB) vaccination is highly effective in reducing the risk of hepatitis B virus infection. However, breakthrough and chronic hepatitis B virus infections in vaccinated subjects raised concern about its long-term efficacy. The specific aim of the study was to explore the host genetic determinants of long-term immunological memory against HB vaccination.We conducted a case-control study nested in a cohort of HB booster recipients who had received primary HB vaccination during infancy but failed to reside an anti-HBs titers ≥ 10 mIU/mL at the age of 15-18 years. We used a genome-wide single nucleotide polymorphism (SNP) array plate to scan autosomal chromosomes and assayed the human leukocyte antigen (HLA)-DPB1 genotype by sequence-based techniques.We found that 10 of the 112 candidate SNPs (P-value 5.0 × 10(-5) ) clustered within a 47-Kb region of the HLA-DP loci. All the minor alleles of these HLA-DP candidate SNPs were correlated with lower likelihoods of nonresponse to HB vaccine. There was a significant linkage disequilibrium between these HLA-DP candidate SNPs and HLA-DPB1 protective alleles. Multivariate analyses showed that rs7770370 was the most significant genetic factor. As compared with rs7770370 GG homozygotes, adjusted odds ratios were 0.524 (95% confidence interval, 0.276-0.993) and 0.095 (95% confidence interval, 0.030-0.307) for AG heterozygotes and AA homozygotes, respectively.Our results showed that rs7770370 was the most significant genetic factor of response to HB booster. The rs7770370 and nearby SNPs may also contribute to the long-term immunological memory against HB vaccination.

Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) near the human leukocyte antigen (HLA)-DP loci that were significantly correlated with outcomes of hepatitis B virus (HBV) infection. We performed a case–control study nested in a well-characterized cohort of booster recipients to assess whether genetic variants of HLA-DPB1 are also associated with response to hepatitis B (HB) vaccination. The cases and controls were 171 and 510 booster recipients whose post-booster titers of antibodies against HBV surface antigen (anti-HBs) were undetectable and detectable, respectively. The HLA-DPB1 genotype was determined using sequence-based techniques. The frequencies of HLA-DPB1 alleles were significantly different between cases and controls (p = 1.7 × 10−8). The HLA-DPB1 05:01 and 09:01 alleles were significantly more frequent in the cases, and 02:01:02, 02:02, 03:01:01, 04:01:01, and 14:01, were significantly more frequent in the controls. The adjusted odds ratio (OR) of undetectable post-booster anti-HBs titers was significantly correlated with the number of risk alleles (p for trend = 3.8 × 10−5). For the number of protective alleles, the trend was significantly inversed (p for trend = 1.3 × 10−5). As compared with subjects with two risk alleles, adjusted OR were 0.34 (95 % confidence interval [CI] 0.21–0.55) and 0.20 (95 % CI 0.08–0.48) for subjects with 1 and 2 protective alleles, respectively. The HLA-DPB1 02:02, 04:01:01, 05:01 and 09:01 alleles were also significantly correlated with the likelihoods of undetectable pre-booster anti-HBs titers. Our results indicated that HLA-DPB1 is significantly correlated with response to booster HB vaccination in adolescent who had received postnatal active HB vaccination. HLA-DBP1 may also determine the long-term persistence of response to HB vaccination.

Previously we demonstrated that 17β-Estradiol (E2) induced rapid Ca 2+ influx via L-type calcium channel activation, which was required for activation of Src/ERK/CREB/Bcl2 signaling cascade and subsequent induction of neuroprotective and neurotrophic responses in rat hippocampal and cortical neurons (Wu et al., 2005; Zhao et al., 2005). The current study determined the presence and specificity of membrane E2 binding sites and the functional consequence of E2 binding to membrane receptors in individual neurons. Using E2-BSA-FITC (fluorescein isothiocyanate) macromolecular complex, membrane E2 binding sites were observed in hippocampal neurons. Punctate FITC signal was observed on plasma membrane of soma and neuronal processes in E2-BSA-FITC binding neurons. No membrane binding was observed with BSA-FITC. Specificity of binding was demonstrated by competition with excess un-conjugated E2. An ERa specific agonist, PPT, and an ERb agonist, DPN, partially competed for E2-BSA-FITC binding. Imaging of intracellular Ca 2+ ([Ca 2+ ]i) in live neurons, revealed rapid Ca 2+ responses in E2-BSA-FITC binding neurons within minutes that culminated in a greater [Ca 2+ ]i rise and [Ca 2+ ]i spikes at > 20 min. The same neurons in which E2-BSA-FITC induced a [Ca 2+ ]i rise also exhibited activated pERK (extracellular signal-regulated kinase) that was translocated to the nucleus. Immunofluorescent analyses demonstrated that both excitatory and inhibitory neuronal markers labeled subpopulations of E2-BSA-FITC binding neurons. All E2-BSA-FITC binding neurons expressed L-type calcium channels. These results demonstrate, at a single cell level, that E2 membrane receptors mediate the rapid signaling cascades required for E2 neuroprotective and neurotrophic effects in hippocampal neurons. These results are discussed with respect to therapeutic targets of estrogen therapy in brain.

TDP-43 is a multifunctional DNA/RNA-binding factor that has been implicated in the regulation of neuronal plasticity. TDP-43 has also been identified as the major constituent of the neuronal cytoplasmic inclusions (NCIs) that are characteristic of a range of neurodegenerative diseases, including the frontotemporal lobar degeneration with ubiquitin+ inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). We have generated a FTLD-U mouse model (CaMKII-TDP-43 Tg) in which TDP-43 is transgenically overexpressed in the forebrain resulting in phenotypic characteristics mimicking those of FTLD-U. In particular, the transgenic (Tg) mice exhibit impaired learning/memory, progressive motor dysfunction, and hippocampal atrophy. The cognitive and motor impairments are accompanied by reduced levels of the neuronal regulators phospho–extracellular signal-regulated kinase and phosphorylated cAMP response element-binding protein and increased levels of gliosis in the brains of the Tg mice. Moreover, cells with TDP-43+, ubiquitin+ NCIs and TDP-43–deleted nuclei appear in the Tg mouse brains in an age-dependent manner. Our data provide direct evidence that increased levels of TDP-43 protein in the forebrain is sufficient to lead to the formation of TDP-43+, ubiquitin+ NCIs and neurodegeneration. This FTLD-U mouse model should be valuable for the mechanistic analysis of the role of TDP-43 in the pathogenesis of FTLD-U and for the design of effective therapeutic approaches of the disease.

Adaptive variable structure controller was proposed to increase the robustness and decrease the influence of the disturbance for active magnetic bearings suspended turbomolecular pump in this paper. The model reference adaptive tuner was aimed to overcome the estimation error that is caused by the parameter uncertainty and the model uncertainty. The simulation results indicated that the turbomolecular pump suspended by active magnetic bearings with adaptive variable structure controller was successfully operated in wide rang, well resisted the unbalance or external disturbance during the rotational speed raising, and the amplitude of the displacement of system could quickly reach the center nearby when disturbance force was applied to the system suddenly.

Optical fiber current sensors have certain privileges that the traditional sensors couldn't support. However, when the fiber is deployed, a large degree of linear birefringence is induced in the fiber. This induced birefringence significantly reduces the sensitivity of the system and quenches the weak Faraday effect signal. We demonstrate that twisted the single mode fiber before it is annealed can largely eliminates the residual linear birefringence. It dramatically improves the possibility to employ the twisted single mode fiber that intrinsically had large residual linear birefringence for constructing an optical twisted electric current sensor. We design a new electric current sensor employing the twisted single mode optical fiber. This sensing system has been verified with good performance. The minimum detectable current was measured to be 1 A and the maximum measurable current up to 2kA with linearity lower than 0.1%, and dynamic range approaches 40 dB. Because of the advantages of high sensitivity, considerable wide dynamic range, and free from electric shock, this novel optic electric current sensor may open a new era in the applications of the electric power system.

We have used human hepatoma cell lines as an in vitro model to study the development of hepatic bile canaliculi (BC). Well-differentiated hepatoma cells cultured for 72 hours could develop characteristic spheroid structures at sites of cell-cell contact that contained tight junctions and various membrane protein markers, resembling BC found in vivo. Intact cytoskeleton was essential for this differentiation process. In the coculture experiments in which cells of different origins were populated together, BC only formed between hepatic cells and preferentially among well-differentiated cells. Poorly differentiated hepatoma cells never formed BC among themselves, but could be induced to undergo canalicular differentiation by interacting with well-differentiated cells. During BC morphogenesis, integral canalicular membrane proteins were gradually delivered and accumulated at the developing BC. Among them, targeting of aminopeptidase N (APN) seemed to correlate with activation of certain secretory functions. Specifically, only APN-positive BC supported excretion of fluorescein diacetate (FDA) and 70-kd dextran, but had no relationship with secretion of horseradish peroxidase (HRP). Targeting of another BC protein, dipeptidyl peptidase IV (DPPIV), on the other hand, bore no association with any secretory activity examined. In addition, inhibition of enzymatic activity of APN could perturb canalicular differentiation without affecting cell proliferation. Our results suggest that targeting of APN proteins may reflect or even play an important role in the development and functional maturation of the canalicular structures.