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1.  The tyrosine kinase Itk suppresses CD8+ memory T cell development in response to bacterial infection 
Scientific Reports  2015;5:7688.
Vaccine efficacy depends on strong long-term development of immune memory and the formation of memory CD8+ T cells is critical for recall responses to infection. Upon antigen recognition by naïve T cells, the strength of the TcR signal influences the subsequent effector and memory cells differentiation. Here, we have examined the role of Itk, a tyrosine kinase critical for TcR signaling, in CD8+ effector and memory T cell differentiation during Listeria monocytogenes infection. We found that the reduced TcR signal strength in Itk deficient naïve CD8+ T cells enhances the generation of memory T cells during infection. This is accompanied by increased early Eomesodermin, IL-7Rα expression and memory precursor effector cells. Furthermore, Itk is required for optimal cytokine production in responding primary effector cells, but not secondary memory responses. Our data suggests that Itk-mediated signals control the expression of Eomesodermin and IL-7Rα, thus regulating the development of memory CD8+ T cells, but not subsequent response of memory cells.
doi:10.1038/srep07688
PMCID: PMC4286740  PMID: 25567129
2.  HOP2-MND1 modulates RAD51 binding to nucleotides and DNA 
Nature communications  2014;5:4198.
The HOP2-MND1 heterodimer is required for progression of homologous recombination in eukaryotes. In vitro, HOP2-MND1 stimulates the DNA strand exchange activities of RAD51 and DMC1. We demonstrate that HOP2-MND1 induces changes in the conformation of RAD51 that profoundly alter the basic properties of RAD51. HOP2-MND1 enhances the interaction of RAD51 with nucleotide cofactors and modifies its DNA binding specificity in a manner that stimulates DNA strand exchange. It enables RAD51 DNA strand exchange in the absence of divalent metal ions required for ATP binding and offsets the effect of the K133A mutation that disrupts ATP binding. During nucleoprotein formation HOP2-MND1 helps to load RAD51 on ssDNA restricting its dsDNA-binding and during the homology search it promotes dsDNA binding removing the inhibitory effect of ssDNA. The magnitude of the changes induced in RAD51 defines HOP2-MND1 as a “molecular trigger” of RAD51 DNA strand exchange.
doi:10.1038/ncomms5198
PMCID: PMC4279451  PMID: 24943459
3.  Efficacy of Neonatal HBV Vaccination on Liver Cancer and Other Liver Diseases over 30-Year Follow-up of the Qidong Hepatitis B Intervention Study: A Cluster Randomized Controlled Trial 
PLoS Medicine  2014;11(12):e1001774.
In a 30-year follow-up of the Qidong Hepatitis B Intervention Study, Yawei Zhang and colleagues examine the effects of neonatal vaccination on liver diseases.
Please see later in the article for the Editors' Summary
Background
Neonatal hepatitis B vaccination has been implemented worldwide to prevent hepatitis B virus (HBV) infections. Its long-term protective efficacy on primary liver cancer (PLC) and other liver diseases has not been fully examined.
Methods and Findings
The Qidong Hepatitis B Intervention Study, a population-based, cluster randomized, controlled trial between 1985 and 1990 in Qidong, China, included 39,292 newborns who were randomly assigned to the vaccination group in which 38,366 participants completed the HBV vaccination series and 34,441 newborns who were randomly assigned to the control group in which the participants received neither a vaccine nor a placebo. However, 23,368 (67.8%) participants in the control group received catch-up vaccination at age 10–14 years. By December 2013, a total of 3,895 (10.2%) in the vaccination group and 3,898 (11.3%) in the control group were lost to follow-up. Information on PLC incidence and liver disease mortality were collected through linkage of all remaining cohort members to a well-established population-based tumor registry until December 31, 2013. Two cross-sectional surveys on HBV surface antigen (HBsAg) seroprevalence were conducted in 1996–2000 and 2008–2012. The participation rates of the two surveys were 57.5% (21,770) and 50.7% (17,204) in the vaccination group and 36.3% (12,184) and 58.6% (17,395) in the control group, respectively. Using intention-to-treat analysis, we found that the incidence rate of PLC and the mortality rates of severe end-stage liver diseases and infant fulminant hepatitis were significantly lower in the vaccination group than the control group with efficacies of 84% (95% CI 23%–97%), 70% (95% CI 15%–89%), and 69% (95% CI 34%–85%), respectively. The estimated efficacy of catch-up vaccination on HBsAg seroprevalence in early adulthood was 21% (95% CI 10%–30%), substantially weaker than that of the neonatal vaccination (72%, 95% CI 68%–75%). Receiving a booster at age 10–14 years decreased HBsAg seroprevalence if participants were born to HBsAg-positive mothers (hazard ratio [HR] = 0.68, 95% CI 0.47–0.97). Limitations to consider in interpreting the study results include the small number of individuals with PLC, participants lost to follow-up, and the large proportion of participants who did not provide serum samples at follow-up.
Conclusions
Neonatal HBV vaccination was found to significantly decrease HBsAg seroprevalence in childhood through young adulthood and subsequently reduce the risk of PLC and other liver diseases in young adults in rural China. The findings underscore the importance of neonatal HBV vaccination. Our results also suggest that an adolescence booster should be considered in individuals born to HBsAg-positive mothers and who have completed the HBV neonatal vaccination series.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Hepatitis B is a life-threatening liver infection caused by the hepatitis B virus (HBV). HBV, which is transmitted through contact with the blood or other bodily fluids of an infected person, can cause both acute (short-term) and chronic (long-term) liver infections. Acute infections rarely cause any symptoms and more than 90% of adults who become infected with HBV (usually through sexual intercourse with an infected partner or through the use of contaminated needles) are virus-free within 6 months. However, in sub-Saharan Africa, East Asia, and other regions where HBV infection is common, HBV is usually transmitted from mother to child at birth or between individuals during early childhood and, unfortunately, most infants who are infected with HBV during the first year of life and many children who are infected before the age of 6 years develop a chronic HBV infection. Such infections can cause liver cancer, liver cirrhosis (scarring of the liver), and other fatal liver diseases. In addition, HBV infection around the time of birth can cause infant fulminant hepatitis, a rare but frequently fatal condition.
Why Was This Study Done?
HBV infections kill about 780,000 people worldwide annually but can be prevented by neonatal vaccination—immunization against HBV at birth. A vaccine against HBV became available in 1982 and many countries now include HBV vaccination at birth followed by additional vaccine doses during early childhood in their national vaccination programs. But, although HBV vaccination has greatly reduced the rate of chronic HBV infection, the protective efficacy of neonatal HBV vaccination against liver diseases has not been fully examined. Here, the researchers investigate how well neonatal HBV vaccination protects against primary liver cancer and other liver diseases by undertaking a 30-year follow-up of the Qidong Hepatitis B intervention Study (QHBIS). This cluster randomized controlled trial of neonatal HBV vaccination was conducted between 1983 and 1990 in Qidong County, a rural area in China with a high incidence of HBV-related primary liver cancer and other liver diseases. A cluster randomized controlled trial compares outcomes in groups of people (towns in this study) chosen at random to receive an intervention or a control treatment (here, vaccination or no vaccination; this study design was ethically acceptable during the 1980s when HBV vaccination was unavailable in rural China but would be unethical nowadays).
What Did the Researchers Do and Find?
The QHBIS assigned nearly 80,000 newborns to receive either a full course of HBV vaccinations (the vaccination group) or no vaccination (the control group); two-thirds of the control group participants received a catch-up vaccination at age 10–14 years. The researchers obtained data on how many trial participants developed primary liver cancer or died from a liver disease during the follow-up period from a population-based tumor registry. They also obtained information on HBsAg seroprevalence—the presence of HBsAg (an HBV surface protein) in the blood of the participants, an indicator of current HBV infection—from surveys undertaken in1996–2000 and 2008–2012. The researchers estimate that the protective efficacy of vaccination was 84% for primary liver cancer (vaccination reduced the incidence of liver cancer by 84%), 70% for death from liver diseases, and 69% for the incidence of infant fulminant hepatitis. Overall, the efficacy of catch-up vaccination on HBsAg seroprevalence in early adulthood was weak compared with neonatal vaccination (21% versus 72%). Notably, receiving a booster vaccination at age 10–14 years decreased HBsAg seroprevalence among participants who were born to HBsAg-positive mothers.
What Do These Findings Mean?
The small number of cases of primary liver cancer and other liver diseases observed during the 30-year follow-up, the length of follow-up, and the availability of incomplete data on seroprevalence all limit the accuracy of these findings. Nevertheless, these findings indicate that neonatal HBV vaccination greatly reduced HBsAg seroprevalence (an indicator of current HBV infection) in childhood and young adulthood and subsequently reduced the risk of liver cancer and other liver diseases in young adults. These findings therefore support the importance of neonatal HBV vaccination. In addition, they suggest that booster vaccination during adolescence might consolidate the efficacy of neonatal vaccination among individuals who were born to HBsAg-positive mothers, a suggestion that needs to be confirmed in randomized controlled trials before booster vaccines are introduced into vaccination programs.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001774.
The World Health Organization provides a fact sheet about hepatitis B (available in several languages) and information about hepatitis B vaccination
The World Hepatitis Alliance (an international not-for-profit, non-governmental organization) provides information about viral hepatitis, including some personal stories about hepatitis B from Bangladesh, Pakistan, the Philippines, and Malawi
The UK National Health Service Choices website provides information about hepatitis B
The not-for-profit British Liver Trust provides information about hepatitis B, including Hepatitis B: PATH B, an interactive educational resource designed to improve the lives of people living with chronic hepatitis B
MedlinePlus provides links to other resources about hepatitis B (in English and Spanish)
Information about the Qidong Hepatitis B intervention Study is available
Chinese Center for Disease Control and Prevention provides links about hepatitis B prevention in Chinese
doi:10.1371/journal.pmed.1001774
PMCID: PMC4280122  PMID: 25549238
4.  Improving protein order-disorder classification using charge-hydropathy plots 
BMC Bioinformatics  2014;15(Suppl 17):S4.
Background
The earliest whole protein order/disorder predictor (Uversky et al., Proteins, 41: 415-427 (2000)), herein called the charge-hydropathy (C-H) plot, was originally developed using the Kyte-Doolittle (1982) hydropathy scale (Kyte & Doolittle., J. Mol. Biol, 157: 105-132(1982)). Here the goal is to determine whether the performance of the C-H plot in separating structured and disordered proteins can be improved by using an alternative hydropathy scale.
Results
Using the performance of the CH-plot as the metric, we compared 19 alternative hydropathy scales, with the finding that the Guy (1985) hydropathy scale (Guy, Biophys. J, 47:61-70(1985)) was the best of the tested hydropathy scales for separating large collections structured proteins and intrinsically disordered proteins (IDPs) on the C-H plot. Next, we developed a new scale, named IDP-Hydropathy, which further improves the discrimination between structured proteins and IDPs. Applying the C-H plot to a dataset containing 109 IDPs and 563 non-homologous fully structured proteins, the Kyte-Doolittle (1982) hydropathy scale, the Guy (1985) hydropathy scale, and the IDP-Hydropathy scale gave balanced two-state classification accuracies of 79%, 84%, and 90%, respectively, indicating a very substantial overall improvement is obtained by using different hydropathy scales. A correlation study shows that IDP-Hydropathy is strongly correlated with other hydropathy scales, thus suggesting that IDP-Hydropathy probably has only minor contributions from amino acid properties other than hydropathy.
Conclusion
We suggest that IDP-Hydropathy would likely be the best scale to use for any type of algorithm developed to predict protein disorder.
doi:10.1186/1471-2105-15-S17-S4
PMCID: PMC4304195  PMID: 25559583
Intrinsically disordered proteins; natively unstructured or unfolded proteins; structure and disorder prediction; support vector machines
5.  miR-101 suppresses tumor proliferation and migration, and induces apoptosis by targeting EZH2 in esophageal cancer cells 
Aim: To investigate the role of miR-101 in the regulation of tumor proliferation, invasion, apoptosis and to its target gene in human ESCC. Methods: The expression level of miR-101 in Eca109 cell line was determined by real-time polymerase chain reaction (PCR). After transfected with miR-101 mimics and inhibitor, proliferation, migration and apoptosis in ESCC cell line (Eca109) were detected by MTT, cell wound healing assay and flow cytometry, respectively. The expression of EZH2 in Eca109 cell was examined by immunohistochemical staining. Results: We found that miR-101 was significantly down-regulated in ESCC cell than in matched normal esophageal epithelium cell. The expression level of miR-101 was inversely correlated to EZH2 protein expression in ESCC cell. In Eca109 cells, over-expression of miR-101 significantly inhibited the migration and invasion of ESCC cells, and promotes cell apoptosis. Conclusions: These findings suggest that decreased expression of miR-101 might promote metastasis of human ESCC by inducing accumulation of EZH2 protein.
PMCID: PMC4230090  PMID: 25400732
MiR-101; ESCC; proliferation; invasion; EZH2
6.  Astragalosides from Radix Astragali benefits experimental autoimmune encephalomyelitis in C57BL /6 mice at multiple levels 
Background
Radix Astragali is famous for its beneficial effect on inflammation associated diseases. This study was to assess the efficacy of astragalosides (AST) extracted from Radix Astragali, on the progression of experimental autoimmune encephalomyelitis (EAE), and explore its possible underlying molecular mechanisms.
Methods
EAE was induced by subcutaneous immunization of MOG35–55. Infiltration of inflammatory cells was examined by HE staining. ROS level was detected by measuring infiltrated hydroethidine. Leakage of blood brain barrier (BBB) was assessed using Evan’s blue dye extravasation method. Levels of inflammatory cytokines were measured using ELISA kits. Activities of total-SOD, GSH-Px, and iNOS and MDA concentration were measured using biochemical analytic kits. Gene expression was detected using real-time PCR method. Protein expression was assayed using western blotting approach.
Results
AST administration attenuated the progression of EAE in mice remarkably. Further studies manifested that AST treatment inhibited infiltration of inflammatory cells, lessened ROS production and decreased BBB leakage. In peripheral immune-systems, AST up-regulated mRNA expression of transcriptional factors T-bet and Foxp3 but decreased that of RORγt to modulate T cell differentiation. In CNS, AST stopped BBB leakage, reduced ROS production by up-regulation of T-SOD, and reduced neuroinflammation by inhibition of iNOS and other inflammatory cytokines. Moreover, AST inhibited production of p53 and phosphorylation of tau by modulation of the Bcl-2/Bax ratio.
Conclusions
AST orchestrated multiple pathways, including immuno-regulation, anti-oxidative stress, anti-neuroinflammation and anti-neuroapoptosis involved in the MS pathogenesis, to prevent the deterioration of EAE, which paves the way for the application of it in clinical prevention/therapy of MS.
doi:10.1186/1472-6882-14-313
PMCID: PMC4155103  PMID: 25150364
Astragalosides; Experimental autoimmune encephalomyelitis; Multiple sclerosis; Neuroinflammation; Oxidative stress; Apoptosis
7.  Dramatic reduction of liver cancer incidence in young adults: 28 year follow-up of etiological interventions in an endemic area of China 
Carcinogenesis  2013;34(8):1800-1805.
Qidong City, China, has had high liver cancer incidence from endemic hepatitis B virus (HBV) infection and dietary exposure to aflatoxin. Based on etiologic studies, we began interventions in 1980 to reduce dietary aflatoxin and initiate neonatal HBV vaccination. We studied trends in liver cancer incidence rates in the 1.1 million inhabitants of Qidong and examined trends in aflatoxin exposure, staple food consumption, HBV infection markers and annual income. Aflatoxin exposure declined greatly in association with economic reform, increased earnings and educational programs to shift staple food consumption in the total population from moldy corn to fresh rice. A controlled neonatal HBV vaccination trial began in 1983 and ended in November, 1990, when vaccination was expanded to all newborns. Liver cancer incidence fell dramatically in young adults. Compared with 1980–83, the age-specific liver cancer incidence rates in 2005–08 significantly decreased 14-fold at ages 20–24, 9-fold at ages 25–29, 4-fold at ages 30–34, 1.5-fold at ages 35–39, 1.2-fold at ages 40–44 and 1.4-fold at ages 45–49, but increased at older ages. The 14-fold reduction at ages 20–24 might reflect the combined effects of reduced aflatoxin exposure and partial neonatal HBV vaccination. Decrease incidence in age groups >25 years could mainly be attributable to rapid aflatoxin reduction. Compared with 1980–83, liver cancer incidence in 1990–93 significantly decreased 3.4-fold at ages 20–24, and 1.9-fold at ages 25–29 when the first vaccinees were <11 years old.
doi:10.1093/carcin/bgt007
PMCID: PMC3731800  PMID: 23322152
8.  A Small Molecule Inhibitor of Human RAD51 Potentiates Breast Cancer Cell Killing by Therapeutic Agents in Mouse Xenografts 
PLoS ONE  2014;9(6):e100993.
The homologous recombination pathway is responsible for the repair of DNA double strand breaks. RAD51, a key homologous recombination protein, promotes the search for homology and DNA strand exchange between homologous DNA molecules. RAD51 is overexpressed in a variety of cancer cells. Downregulation of RAD51 by siRNA increases radio- or chemo-sensitivity of cancer cells. We recently developed a specific RAD51 small molecule inhibitor, B02, which inhibits DNA strand exchange activity of RAD51 in vitro. In this study, we used human breast cancer cells MDA-MB-231 to investigate the ability of B02 to inhibit RAD51 and to potentiate an anti-cancer effect of chemotherapeutic agents including doxorubicin, etoposide, topotecan, and cisplatin. We found that the combination of B02 with cisplatin has the strongest killing effect on the cancer cells. We then tested the effect of B02 and cisplatin on the MDA-MB-231 cell proliferation in mouse xenografts. Our results showed that B02 significantly enhances the therapeutic effect of cisplatin on tumor cells in vivo. Our current data demonstrate that use of RAD51-specific small molecule inhibitor represents a feasible strategy of a combination anti-cancer therapy.
doi:10.1371/journal.pone.0100993
PMCID: PMC4074124  PMID: 24971740
9.  Dual IGF-1R/InsR Inhibitor BMS-754807 Synergizes with Hormonal Agents in Treatment of Estrogen-Dependent Breast Cancer 
Cancer research  2011;71(24):7597-7607.
Insulin-like growth factor (IGF) signaling has been implicated in the resistance to hormonal therapy in breast cancer. Using a model of postmenopausal, estrogen-dependent breast cancer, we investigated the antitumor effects of the dual IGF-1R/InsR tyrosine kinase inhibitor BMS-754807 alone and in combination with letrozole or tamoxifen. BMS-754807 exhibited antiproliferative effects in vitro that synergized strongly in combination with letrozole or 4-hydroxytamoxifen and fulvestrant. Similarly, combined treatment of BMS-754807 with either tamoxifen or letrozole in vivo elicited tumor regressions not achieved by single-agent therapy. Notably, hormonal therapy enhanced the inhibition of IGF-1R/InsR without major side effects in animals. Microarray expression analysis revealed downregulation of cell-cycle control and survival pathways and upregulation of erbB in response to BMS-754807 plus hormonal therapy, particularly tamoxifen. Overall, these results offer a preclinical proof-of-concept for BMS-754807 as an antitumor agent in combination with hormonal therapies in hormone-sensitive breast cancer. Cooperative cell-cycle arrest, decreased proliferation, and enhanced promotion of apoptosis may contribute to antitumor effects to be gauged in future clinical investigations justified by our findings.
doi:10.1158/0008-5472.CAN-11-1080
PMCID: PMC4004036  PMID: 22042792
10.  Comparison of the free and bound phenolic profiles and cellular antioxidant activities of litchi pulp extracts from different solvents 
Background
The phenolic contents and antioxidant activities of fruits could be underestimated if the bound phenolic compounds are not considered. In the present study, the extraction efficiencies of various solvents were investigated in terms of the total content of the free and bound phenolic compounds, as well as the phenolic profiles and antioxidant activities of the extracts.
Methods
Five different solvent mixtures were used to extract the free phenolic compounds from litchi pulp. Alkaline and acidic hydrolysis methods were compared for the hydrolysis of bound phenolic compounds from litchi pulp residue. The phenolic compositions of the free and bound fractions from the litchi pulp were identified using HPLC-DAD. The antioxidant activities of the litchi pulp extracts were determined by oxygen radical absorbance capacity (ORAC) and cellular antioxidant activity (CAA) assays.
Results
Of the solvents tested, aqueous acetone extracted the largest amount of total free phenolic compounds (210.7 mg GAE/100 g FW) from litchi pulp, followed sequentially by aqueous mixtures of methanol, ethanol and ethyl acetate, and water itself. The acid hydrolysis method released twice as many bound phenolic compounds as the alkaline hydrolysis method. Nine phenolic compounds were detected in the aqueous acetone extract. In contrast, not all of these compounds were found in the other four extracts. The classification and content of the bound phenolic compounds released by the acid hydrolysis method were higher than those achieved by the alkaline hydrolysis. The aqueous acetone extract showing the highest ORAC value (3406.9 μmol TE/100 g FW) for the free phenolic extracts. For the CAA method, however, the aqueous acetone and methanol extracts (56.7 and 55.1 μmol QE/100 g FW) showed the highest levels of activity of the five extracts tested. The ORAC and CAA values of the bound phenolic compounds obtained by acid hydrolysis were 2.6- and 1.9-fold higher than those obtained using the alkaline hydrolysis method.
Conclusions
The free and bound phenolic contents and profiles and antioxidant activities of the extracts were found to be dependent on the extraction solvent used. Litchi exhibited good cellular antioxidant activity and could be a potentially useful natural source of antioxidants.
doi:10.1186/1472-6882-14-9
PMCID: PMC3893551  PMID: 24405977
11.  VE-cadherin Signaling Induces EB3 Phosphorylation to Suppress Microtubule Growth and Assemble Adherens Junctions 
Molecular cell  2012;48(6):914-925.
Summary
Vascular Endothelial (VE)-cadherin homophilic adhesion controls endothelial barrier permeability through assembly of adherens junctions (AJs). We observed that loss of VE-cadherin-mediated adhesion induced the activation of Src and phospholipase C (PLC)γ2, which mediated Ca2+ release from endoplasmic reticulum (ER) stores resulting in activation of calcineurin (CaN), a Ca2+-dependent phosphatase. Downregulation of CaN activity induced phosphorylation of serine 162 in End Binding (EB) protein 3. This phospho-switch was required to destabilize the EB3 dimer, suppress microtubule (MT) growth, and assemble AJs. The phospho-defective S162A EB3 mutant, in contrast, induced MT growth in confluent endothelial monolayers and disassembled AJs. Thus, VE-cadherin outside-in signaling regulates cytosolic Ca2+ homeostasis and EB3 phosphorylation, which are required for assembly of AJs. These results identify a pivotal function of VE-cadherin homophilic interaction in modulating endothelial barrier through the tuning of MT dynamics.
doi:10.1016/j.molcel.2012.10.011
PMCID: PMC3627495  PMID: 23159740
12.  Space-Time Clustering Characteristics of Tuberculosis in China, 2005-2011 
PLoS ONE  2013;8(12):e83605.
Objectives
China is one of the 22 tuberculosis (TB) high-burden countries in the world. As TB is a major public health problem in China, spatial analysis could be applied to detect geographic distribution of TB clusters for targeted intervention on TB epidemics.
Methods
Spatial analysis was applied for detecting TB clusters on county-based TB notification data in the national notifiable infectious disease case reporting surveillance system from 2005 to 2011. Two indicators of TB epidemic were used including new sputum smear-positive (SS+) notification rate and total TB notification rate. Global Moran’s I by ArcGIS was used to assess whether TB clustering and its trend were significant. SaTScan software that used the retrospective space-time analysis and Possion probability model was utilized to identify geographic areas and time period of potential clusters with notification rates on county-level from 2005 to 2011.
Results
Two indicators of TB notification had presented significant spatial autocorrelation globally each year (p<0.01). Global Moran’s I of total TB notification rate had positive trend as time went by (t=6.87, p<0.01). The most likely clusters of two indicators had similar spatial distribution and size in the south-central regions of China from 2006 to 2008, and the secondary clusters in two regions: northeastern China and western China. Besides, the secondary clusters of total TB notification rate had two more large clustering centers in Inner Mongolia, Gansu and Qinghai provinces and several smaller clusters in Shanxi, Henan, Hebei and Jiangsu provinces.
Conclusion
The total TB notification cases clustered significantly in some special areas each year and the clusters trended to aggregate with time. The most-likely and secondary clusters that overlapped among two TB indicators had higher TB burden and risks of TB transmission. These were the focused geographic areas where TB control efforts should be prioritized.
doi:10.1371/journal.pone.0083605
PMCID: PMC3868653  PMID: 24367604
13.  Signal Transduction via the T cell Antigen Receptor in naïve and effector/memory T cells 
T cells play an indispensable role in immune defense against infectious agents, but can also be pathogenic. These T cells develop in the thymus, are exported into the periphery as naïve cells and participate in immune responses. Upon recognition of antigen, they are activated and differentiate into effector and memory T cells. While effector T cells carry out the function of the immune response, memory T cells can last up to the life time of the individual, and are activated by subsequent antigenic exposure. Throughout this life cycle, the T cell uses the same receptor for antigen, the T cell Receptor, a complex multi-subunit receptor. Recognition of antigen presented by peptide/MHC complexes on antigen presenting cells unleashes signaling pathways that control T cell activation at each stage. In this review, we discuss the signals regulated by the T cell receptor in naïve and effector/memory T cells.
doi:10.1016/j.biocel.2012.08.023
PMCID: PMC3532926  PMID: 22981631
14.  Amelioration of carbon tetrachloride-induced cirrhosis and portal hypertension in rat using adenoviral gene transfer of Akt 
AIM: To investigate whether a virus constitutively expressing active Akt is useful to prevent cirrhosis induced by carbon tetrachloride (CCl4).
METHODS: Using cre-loxp technique, we created an Ad-myr-HA-Akt virus, in which Akt is labeled by a HA tag and its expression is driven by myr promoter. Further, through measuring enzyme levels and histological structure, we determined the efficacy of this Ad-myr-HA-Akt virus in inhibiting the development of cirrhosis induced by CCl4 in rats. Lastly, using western blotting, we examined the expression levels and/or phosphorylation status of Akt, apoptotic mediators, endothelial nitric oxide synthase (eNOS), and markers for hepatic stellate cells activation to understand the underlying mechanisms of protective role of this virus.
RESULTS: The Ad-myr-HA-Akt virus was confirmed using polymerase chain reaction amplification of inserted Akt gene and sequencing for full length of inserted fragment, which was consistent with the sequence reported in the GenBank. The concentrations of Ad-myr-HA-Akt and adenoviral enhanced green fluorescent protein (Ad-EGFP) virus used in the current study were 5.5 × 1011 vp/mL. The portal vein diameter, peak velocity of blood flow, portal blood flow and congestion index were significantly increased in untreated, saline and Ad-EGFP cirrhosis groups when compared to normal control after the virus was introduced to animal through tail veil injection. In contrast, these parameters in the Akt cirrhosis group were comparable to normal control group. Compared to the normal control, the liver function (Alanine aminotransferase, Aspartate aminotransferase and Albumin) was significantly impaired in the untreated, saline and Ad-EGFP cirrhosis groups. The Akt cirrhosis group showed significant improvement of liver function when compared to the untreated, saline and Ad-EGFP cirrhosis groups. The Hyp level and portal vein pressure in Akt cirrhosis groups were also significantly lower than other cirrhosis groups. The results of HE and Van Gieson staining indicated that Akt group has better preservation of histological structure and less fibrosis than other cirrhosis groups. The percentage of apoptotic cell was greatly less in Akt cirrhosis group than in other cirrhosis groups. Akt group showed positive HA tag and an increased level of phosphorylated Akt as well as decreased levels of Fas. In contrast, Caspase-3 and Caspase-9 levels in Akt group were significantly lower than other cirrhosis groups. Noticeable decrease of DR5 and α-SMA and increase of phosphorylated eNOS were observed in the Akt group when compared to other cirrhosis groups. The NO level in liver was significantly higher in Akt group than other cirrhosis groups, which was consistent with the level of phosphorylated eNOS in these groups.
CONCLUSION: This study suggest that Ad-myr-HA-Akt virus is a useful tool to prevent CCl4-induced cirrhosis in rat model and Akt pathway may be a therapeutic target for human cirrhosis.
doi:10.3748/wjg.v19.i43.7778
PMCID: PMC3837279  PMID: 24431897
Adenovirus; Akt; Gene transfer; Apoptosis; Cirrhosis; Carbon tetrachloride; Rat
15.  DHA Inhibits Protein Degradation More Efficiently than EPA by Regulating the PPARγ/NFκB Pathway in C2C12 Myotubes 
BioMed Research International  2013;2013:318981.
This study was conducted to evaluate the mechanism by which n-3 PUFA regulated the protein degradation in C2C12 myotubes. Compared with the BSA control, EPA at concentrations from 400 to 600 µM decreased total protein degradation (P < 0.01). However, the total protein degradation was decreased when the concentrations of DHA ranged from 300 µM to 700 µM (P < 0.01). DHA (400 µM, 24 h) more efficiently decreased the IκBα phosphorylation and increased in the IκBα protein level than 400 µM EPA (P < 0.01). Compared with BSA, 400 µM EPA and DHA resulted in a 47% or 68% induction of the NFκB DNA binding activity, respectively (P < 0.01). Meanwhile, 400 µM EPA and DHA resulted in a 1.3-fold and 2.0-fold induction of the PPARγ expression, respectively (P < 0.01). In C2C12 myotubes for PPARγ knockdown, neither 400 µM EPA nor DHA affected the levels of p-IκBα, total IκBα or NFκB DNA binding activity compared with BSA (P > 0.05). Interestingly, EPA and DHA both still decreased the total protein degradation, although PPARγ knockdown attenuated the suppressive effects of EPA and DHA on the total protein degradation (P < 0.01). These results revealed that DHA inhibits protein degradation more efficiently than EPA by regulating the PPARγ/NF-κB pathway in C2C12 myotubes.
doi:10.1155/2013/318981
PMCID: PMC3745922  PMID: 23984342
16.  Role and Functional Domain of Hepatitis B Virus X Protein in Regulating HBV Transcription and Replication in Vitro and in Vivo 
Viruses  2013;5(5):1261-1271.
The role of hepatitis B virus (HBV) X protein (HBx) in the regulation of HBV replication remains controversial. In the present study, the role of HBx in regulating HBV replication was initially investigated in both HepG2 and Huh7 in vitro cell lines with a transient transfection system. Next, the regions of HBx responsible for transcriptional transactivation and promotion of HBV replication were mapped in an HBV replication mouse model by in vivo transfection of a series of HBx expression plasmids. In an in vitro setting, HBx deficiency had little effect on HBV replication in Huh7 cells, but impaired HBV replication in HepG2 cells. In an in vivo setting, HBx had a strong enhancing effect on HBV transcription and replication. For the C-terminal two-thirds of the protein (amino acids [aa] 51 to 154) was required for this function of HBx, and the regions spanning aa 52 to 72 and 88 to 154 were found to be important for the stimulatory function of HBx on HBV replication. In conclusion, the role of HBx in HBV replication regulation is affected by host cell type, and HBx has an important role in stimulating HBV transcription and replication in hepatocytes in vivo. Further, the transcriptional transactivation function of HBx may be crucial for its stimulatory effect on HBV transcription and replication.
doi:10.3390/v5051261
PMCID: PMC3712307  PMID: 23698398
hepatitis B virus; HBx protein; transcription and replication; cell culture; mouse model
17.  Active Smoking, Passive Smoking, and Risk of Nonalcoholic Fatty Liver Disease (NAFLD): A Population-Based Study in China 
Journal of Epidemiology  2013;23(2):115-121.
Background
The effect of active smoking on development of nonalcoholic fatty liver disease (NAFLD) is controversial, and there are limited clinical data on the relationship between passive smoking and NAFLD. We investigated whether active and passive smoking are associated with NAFLD.
Methods
A total of 8580 subjects (2691 men) aged 40 years or older participated in a community-based survey in Shanghai, China. Information on active and passive smoking was collected using a validated questionnaire. NAFLD was diagnosed by abdominal B-mode ultrasound testing and serum liver enzymes.
Results
NAFLD prevalence was 29.4% in never smokers, 34.2% in former smokers, 27.8% in light smokers (<20 cigarettes/day), 30.8% in moderate smokers (20–39 cigarettes/day), and 43.5% in heavy smokers (≥40 cigarettes/day). Fully adjusted logistic regression analyses revealed that, as compared with never smoking, former and heavy smoking were associated with increased risk of prevalent NAFLD, with odds ratios of 1.45 (95% CI 1.05–2.00) and 2.29 (95% CI 1.30–4.03), respectively. Active smoking and body mass index (BMI) had a synergistic effect on the risk of prevalent NAFLD; the combination of these risk factors was associated with the highest observed odds ratio for NAFLD: 8.58. In never-smoking women, passive smoking during both childhood and adulthood was associated with a 25% increase in the risk of prevalent NAFLD (OR = 1.25, 95% CI 1.05–1.50) as compared with no passive smoking.
Conclusions
Passive smoking and heavy active smoking are associated with prevalent NAFLD in middle-aged and elderly Chinese. Active smoking and BMI have a synergistic effect on prevalent NAFLD.
doi:10.2188/jea.JE20120067
PMCID: PMC3700247  PMID: 23399520
active tobacco smoking; passive tobacco smoking; fatty liver
18.  Impaired Lung Function Is Associated with Increased Carotid Intima-Media Thickness in Middle-Aged and Elderly Chinese 
PLoS ONE  2013;8(2):e53153.
Background
Impairment of lung function was reported to be associated with cardiovascular disease (CVD). The aim of the present study is to evaluate the relationship between lung function and carotid intima-media thickness (cIMT) in participants without chronic pulmonary disease.
Methodology and Principal Findings
A total of 6,423 participants aged 40 years and above were recruited from Jiading District, Shanghai, China. Lung function, evaluated by forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) was measured with standard spirometry. CIMT was measured with high-resolution ultrasonography by trained physicians. Mean values of FVC (% pred) and FEV1 (% pred) in participants with elevated cIMT were significantly lower than in those without (0.92±0.20 vs. 0.99±0.19, 0.83±0.24 vs. 0.90±0.22; both p-values < 0.0001). The levels of cIMT in the lowest quartile of FVC (% pred) and FEV1 (% pred) were markedly higher than in the second, third and fourth quartile, respectively (p < 0.0001 for all). The lowest quartile of FVC (% pred) and FEV1 (% pred) was associated with increased odds of elevated cIMT, with the fully adjusted odds ratio of 1.34 and 1.41 (95% confidence interval (CI) 1.09–1.65, p  =  0.006, 95% CI 1.15–1.72, p  =  0.0008), respectively.
Conclusions and Significance
Impaired lung function is associated with elevated cIMT in middle-aged and elderly Chinese. These findings suggest the need to screen impairment of lung function in people without respiratory disease for the presence of subclinical atherosclerosis in CVD prevention.
doi:10.1371/journal.pone.0053153
PMCID: PMC3574141  PMID: 23457443
19.  Autonomic Test by EZSCAN in the Screening for Prediabetes and Diabetes 
PLoS ONE  2013;8(2):e56480.
Background
Autonomic neuropathy is common in diabetics and may occur in prediabetes. A new and noninvasive autonomic test-EZSCAN evaluates sudomotor function precisely. No generally accepted EZSCAN thresholds to screen for prediabetes and diabetes have been defined.
Methodology and Principal Findings
Cross-sectional study of 5, 824 Chinese adults aged 40 and older was conducted in Shanghai, China. We used EZSCAN to evaluate autonomic function in different glucose status and screen for prediabetes and diabetes. The prevalence of prediabetes and diabetes were 21.9% and 17.5% respectively. Compared with the lowest quintile, the highest quintile of EZSCAN value had odds ratios for having dysglycemia (prediabetes or diabetes) of 2.08 (95% CI 1.67–2.58) in total population, 2.89 (95% CI 2.06–4.05) in men and 1.70 (95% CI 1.28–2.25) in women after adjustment for confounding factors. EZSCAN value improved the areas under ROC curve for detection of dysglycemia or diabetes beyond the contribution of conventional risk factors by 0.8% and 12.9%. The cut-off point of EZSCAN value higher than 30% provided reasonable sensitivities (70.3–83.7%) to detect dysglycemia not only in total population regardless of sex but also in individuals with high risk of developing diabetes.
Conclusions and Significance
EZSCAN value higher than 30% indicate an increased risk of prevalent prediabetes and diabetes, suggesting that subjects with EZSCAN ≥30% should be further evaluated by oral glucose tolerance test. The improvement of EZSCAN for diabetes detection was still of limited clinical relevance. Thus the clinical application value of EZSCAN is needed to be explored in future studies.
doi:10.1371/journal.pone.0056480
PMCID: PMC3570410  PMID: 23424665
20.  Growth and differentiation of neural stem cells in a three-dimensional collagen gel scaffold★ 
Neural Regeneration Research  2013;8(4):313-319.
Collagen protein is an ideal scaffold material for the transplantation of neural stem cells. In this study, rat neural stem cells were seeded into a three-dimensional collagen gel scaffold, with suspension cultured neural stem cells being used as a control group. Neural stem cells, which were cultured in medium containing epidermal growth factor and basic fibroblast growth factor, actively expanded and formed neurospheres in both culture groups. In serum-free medium conditions, the processes extended from neurospheres in the collagen gel group were much longer than those in the suspension culture group. Immunofluorescence staining showed that neurospheres cultured in collagen gels were stained positive for nestin and differentiated cells were stained positive for the neuronal marker βIII-tubulin, the astrocytic marker glial fibrillary acidic protein and the oligodendrocytic marker 2’,3’-cyclic nucleotide 3’-phosphodiesterase. Compared with neurospheres cultured in suspension, the differentiation potential of neural stem cells cultured in collagen gels increased, with the formation of neurons at an early stage. Our results show that the three-dimensional collagen gel culture system is superior to suspension culture in the proliferation, differentiation and process outgrowth of neural stem cells.
doi:10.3969/j.issn.1673-5374.2013.04.003
PMCID: PMC4107534  PMID: 25206671
neural regeneration; stem cells; neural stem cells; collagen gel; scaffold; central nervous system; proliferation; differentiation; neurosphere; photographs-containing paper; neuroregeneration
21.  Both Serum Apolipoprotein B and the Apolipoprotein B/Apolipoprotein A-I Ratio Are Associated with Carotid Intima-Media Thickness 
PLoS ONE  2013;8(1):e54628.
Background
Previous studies indicated that apolipoprotein measurements predicted cardiovascular disease (CVD) risk; however, associations between apolipoproteins and carotid intima-media thickness (CIMT) were less explored.
Methodology and Principal Findings
The cross-sectional study included 6069 participants aged 40 years or older with NGT from Shanghai, China. Serum fasting traditional lipids (total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C] and triglycerides [TG]), apoA-I and apoB were assessed. A high-resolution B-mode ultrasonography was performed to measure CIMT. We found CIMT increased progressively across the quartiles of serum apoB (p for trend <0.0001). In logistic regression, concentrations of apoB (odds ratio [OR] 1.27, 95% confidence interval [CI] 1.18–1.36), TC (OR 1.23, 95% CI 1.14–1.32), LDL-C (OR 1.25, 95% CI 1.16–1.34) and TG (OR 1.11, 95% CI 1.04–1.20) were significantly related to elevated CIMT after adjusted for age and sex. Meanwhile, the apoB/apoA-I ratio (OR 1.25, 95% CI 1.17–1.34) related to elevated CIMT. ApoB (OR 1.23, 95% CI 1.00–1.51) and the apoB/apoA-I ratio (OR 1.19, 95% CI 1.04–1.36) remained significantly associated with elevated CIMT, after adjusted for the traditional CVD risk factors including traditional lipids.
Conclusions and Significance
There were significant associations between serum apoB, the apoB/apoA-I ratio and elevated CIMT. Serum apoB and the apoB/apoA-I ratio might be independent predictors of early atherosclerosis in NGT.
doi:10.1371/journal.pone.0054628
PMCID: PMC3554742  PMID: 23359805
22.  Control Self-Assembly of Hydrazide-Based Cyclic Hexamers: In or Out 
Scientific Reports  2013;3:1059.
By moving the alkoxy group on the spacer from position 5 to position 4 to add another protocol for the algorithm for intermolecular and intramolecular hydrogen bonding interactions, highly regioselectivity of noncovalent synthesis of the hydrazide-based cyclic hexamers was achieved: one out of thirteen possible isomeric cyclic hexamers selectively formed and thus precise control of the two hydrazide units in the cyclic hexamers (in or out) was accomplished.
doi:10.1038/srep01059
PMCID: PMC3544009  PMID: 23320140
23.  SRPK1 Dissimilarly Impacts on the Growth, Metastasis, Chemosensitivity and Angiogenesis of Glioma in Normoxic and Hypoxic Conditions 
Journal of Cancer  2013;4(9):727-735.
Glioma is among the ten most common causes of cancer-related death and has no effective treatment for it, so we are trying to find a new target for anticancer treatment. This study investigates the different expression of SRPK1 as a novel protein in glioma, which can influence tumor cells biological characteristics in normoxic and hypoxic environment. The expression levels of SRPK1 protein in glioma cell lines transfected with siSRPK1 or not were examined using immunofluorescence, RT-PCR and Western blot analysis, respectively. The impact of SRPK1 on the biological characteristics of U251 cells was further studied using methylthiazol tetrazolium assays, flow cytometry, and Transwell invasion chamber assays. The results showed that knockdown of SRPK1 inhibited tumor cells growth, invasion and migration in normoxic condition, but portion of the effect could be reversed in hypoxia. SRPK1 expression was induced in glioma cells by DDP treated, but not TMZ, in both normoxia and hypoxia conditions. We propose SRPK1 as a new molecular player contributing to the early treatment of glioma.
doi:10.7150/jca.7576
PMCID: PMC3842442  PMID: 24312143
SRPK1; glioma; growth; metastasis; chemosensitivity.
24.  Biological characteristics of the rtA181T/sW172* mutant strain of Hepatitis B virus in animal model 
Virology Journal  2012;9:280.
Background
The effects of Hepatitis B virus (HBV) rtA181T/sW172* mutation on viral replication and pathogenicity was concerned recently. This study aimed to investigate the biological characteristics of rtA181T/sW172* mutant strain of HBV in animal model.
Methods
The rtA181T/sW172* mutant plasmid was constructed using the pHBV4.1 (wild type HBV) as a template. The wild and mutant HBV replication mouse models were established utilizing a hydrodynamic technique. The titers of hepatitis B surface antigen (HBsAg), hepatitis B e antigen, and HBV DNA in serum, and the levels of HBsAg, hepatitis B core antigen(HBcAg), HBV DNA replication intermediates (HBV DNA RI) and HBV RNA in liver were measured after 1, 3, 5, 7, 10, 12 and 15 days of plasmid injection.
Results
In wild-type HBV replication mouse model, serum HBsAg was high on day 1, 3, and 5, but became lower since day 7; while in mutant HBV mouse model, serum HBsAg was always at very low level. In liver tissues, HBV DNA RI of wild type HBV was detected on day 1 after transfection. The level subsequently peaked on day 3, gradually declined after day 5, and was almost undetectable on day 10. However, the HBV DNA RI levels of the mutant strain were always higher and lasted longer until day 15. Consistently, the expression levels of HBsAg and HBcAg in liver of the mutant group were significantly increased.
Conclusions
In the case of the HBV rtA181T/sW172* mutation, the secretion of serum HBsAg was impaired, whereas HBV DNA replication and HBsAg/HBcAg expression were increased in liver. These results suggest that the mutation can impair HBsAg secretion, and may cause the accumulation of viral core particles in liver.
doi:10.1186/1743-422X-9-280
PMCID: PMC3515399  PMID: 23171829
Hepatitis B virus; rtA181T/sW172* mutation; Transcription and replication; Hepatitis B surface antigen; Secretion defect; Drug sensitivity
25.  Human Initiated Cascading Failures in Societal Infrastructures 
PLoS ONE  2012;7(10):e45406.
In this paper, we conduct a systematic study of human-initiated cascading failures in three critical inter-dependent societal infrastructures due to behavioral adaptations in response to a crisis. We focus on three closely coupled socio-technical networks here: (i) cellular and mesh networks, (ii) transportation networks and (iii) mobile call networks. In crises, changes in individual behaviors lead to altered travel, activity and calling patterns, which influence the transport network and the loads on wireless networks. The interaction between these systems and their co-evolution poses significant technical challenges for representing and reasoning about these systems. In contrast to system dynamics models for studying these interacting infrastructures, we develop interaction-based models in which individuals and infrastructure elements are represented in detail and are placed in a common geographic coordinate system. Using the detailed representation, we study the impact of a chemical plume that has been released in a densely populated urban region. Authorities order evacuation of the affected area, and this leads to individual behavioral adaptation wherein individuals drop their scheduled activities and drive to home or pre-specified evacuation shelters as appropriate. They also revise their calling behavior to communicate and coordinate among family members. These two behavioral adaptations cause flash-congestion in the urban transport network and the wireless network. The problem is exacerbated with a few, already occurring, road closures. We analyze how extended periods of unanticipated road congestion can result in failure of infrastructures, starting with the servicing base stations in the congested area. A sensitivity analysis on the compliance rate of evacuees shows non-intuitive effect on the spatial distribution of people and on the loading of the base stations. For example, an evacuation compliance rate of 70% results in higher number of overloaded base stations than the evacuation compliance rate of 90%.
doi:10.1371/journal.pone.0045406
PMCID: PMC3485300  PMID: 23118847

Results 1-25 (54)