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1.  Preserving Differential Privacy in Degree-Correlation based Graph Generation 
Transactions on data privacy  2013;6(2):127-145.
Enabling accurate analysis of social network data while preserving differential privacy has been challenging since graph features such as cluster coefficient often have high sensitivity, which is different from traditional aggregate functions (e.g., count and sum) on tabular data. In this paper, we study the problem of enforcing edge differential privacy in graph generation. The idea is to enforce differential privacy on graph model parameters learned from the original network and then generate the graphs for releasing using the graph model with the private parameters. In particular, we develop a differential privacy preserving graph generator based on the dK-graph generation model. We first derive from the original graph various parameters (i.e., degree correlations) used in the dK-graph model, then enforce edge differential privacy on the learned parameters, and finally use the dK-graph model with the perturbed parameters to generate graphs. For the 2K-graph model, we enforce the edge differential privacy by calibrating noise based on the smooth sensitivity, rather than the global sensitivity. By doing this, we achieve the strict differential privacy guarantee with smaller magnitude noise. We conduct experiments on four real networks and compare the performance of our private dK-graph models with the stochastic Kronecker graph generation model in terms of utility and privacy tradeoff. Empirical evaluations show the developed private dK-graph generation models significantly outperform the approach based on the stochastic Kronecker generation model.
PMCID: PMC3979555  PMID: 24723987
Differential Privacy; Graph Generation; dK-graph; Kronecker Graph
2.  During the Long Way to Mars: Effects of 520 Days of Confinement (Mars500) on the Assessment of Affective Stimuli and Stage Alteration in Mood and Plasma Hormone Levels 
PLoS ONE  2014;9(4):e87087.
For future interplanetary manned spaceflight, mental issues, as well as physiological problems, must inevitably be considered and solved. Mars500 is a high-fidelity ground simulation experiment that involved 520 days of confined isolation for six multinational crewmembers. This experiment provided a good opportunity to perform psycho-physiological and psycho-social researches on such missions. To investigate emotional responses and psychological adaptation over long-term confinement, the International Affective Pictures System (IAPS) was selected as the visual emotional stimuli in this study. Additional data collected and analyzed included the Profile of Mood States (POMS) questionnaire and the levels of four types of plasma hormones: cortisol, 5-hydroxy tryptamine, dopamine, and norepinephrine. The results demonstrated an obvious bias on valence rating for unpleasant stimuli with time (p<0.05), and the correlation between psychological and biochemical data was identified (p<0.05). Overall, we concluded that the confined crew tended to assign positive ratings to negative pictures with time, which might be driven by a defensive system. There was a stage-changing pattern of psychological adaptation of the Mars500 crew, which is similar to the third-quarter phenomenon.
PMCID: PMC3973648  PMID: 24695321
3.  Comparison of Circulating, Hepatocyte Specific Messenger RNA and microRNA as Biomarkers for Chronic Hepatitis B and C 
PLoS ONE  2014;9(3):e92112.
Circulating microRNAs have been widely recognized as a novel category of biomarker in a variety of physiological and pathological conditions. Other reports revealed that fragments of organ specific messenger RNAs are also detectable in serum/plasma and can be utilized as sensitive indicators of liver pathology and cancer. In order to assess the sensitivity and reliability of these two class of RNAs as marker of hepatitis B or C induced chronic liver disease, we collected plasma samples from 156 chronic hepatitis B or C patients (HBV active n = 112, HBV carrier n = 19, hepatitis C n = 25) and 22 healthy donors and quantified their circulating mRNA for albumin, HP (haptoglobin), CYP2E1 (cytochrome P450, family 2, subfamily E) and ApoA2 (Apolipoprotein A2) in conjunction with microRNA-122, a well established marker for acute and chronic liver injury. We found that plasma microRNA-122 level is significantly elevated in patients with active HBV but not in HBV carriers. Furthermore, microRNA-122 is not elevated in HCV patients even though their median serum alanine aminotransferase (sALT) was three fold of the healthy donors. Nevertheless, circulating mRNAs, especially albumin mRNA, showed much more sensitivity in distinguishing active hepatitis B, hepatitis B carrier or HCV patientsfrom healthy control. Correlation and multiple linear regression analysis suggested that circulating mRNAs and miRNAs are much more related to HBsAg titre than to sALT. Immunoprecipitation of HBsAg in HBV patients’ plasma resulted in enrichment of albumin and HP mRNA suggesting that fragments of liver specific transcripts can be encapsidated into HBsAg particles. Taken together, our results suggest that hepatocyte specific transcripts in plasma like albumin mRNA showed greater sensitivity and specificity in differentiating HBV or HCV induced chronic liver disease than microRNA-122. Circulating mRNA fragments merit more attention in the quest of next generation biomarkers for various maladies.
PMCID: PMC3958472  PMID: 24643113
4.  Enhancement of Antitumor Immunity Using a DNA-Based Replicon Vaccine Derived from Semliki Forest Virus 
PLoS ONE  2014;9(3):e90551.
A DNA-based replicon vaccine derived from Semliki Forest virus, PSVK-shFcG-GM/B7.1 (Fig. 1a) was designed for tumor immunotherapy as previously constructed. The expression of the fusion tumor antigen (survivin and hCGβ-CTP37) and adjuvant molecular protein (Granulocyte-Macrophage Colony-Stimulating Factor/ GM-CSF/B7.1) genes was confirmed by Immunofluorescence assay in vitro, and immunohistochemistry assay in vivo. In this paper, the immunological effect of this vaccine was determined using immunological assays as well as animal models. The results showed that this DNA vaccine induced both humoral and cellular immune responses in C57BL/6 mice after immunization, as evaluated by the ratio of CD4+/CD8+ cells and the release of IFN-γ. Furthermore, the vaccination of C57BL/6 mice with PSVK-shFcG-GM/B7.1 significantly delayed the in vivo growth of tumors in animal models (survivin+ and hCGβ+ murine melanoma, B16) when compared to vaccination with the empty vector or the other control constructs (Fig. 1b). These data indicate that this type of replicative DNA vaccine could be developed as a promising approach for tumor immunotherapy. Meanwhile, these results provide a basis for further study in vaccine pharmacodynamics and pharmacology, and lay a solid foundation for clinical application.
PMCID: PMC3946523  PMID: 24608380
5.  Role of berberine in anti-bacterial as a high-affinity LPS antagonist binding to TLR4/MD-2 receptor 
Berberine is an isoquinoline alkaloid mainly extracted from Rhizoma Coptidis and has been shown to possess a potent inhibitory activity against bacterial. However, the role of berberine in anti-bacterial action has not been extensively studied.
The animal model was established to investigate the effects of berberine on bacterial and LPS infection. Docking analysis, Molecular dynamics simulations and Real-time RT-PCR analysis was adopted to investigate the molecular mechanism.
Treatment with 40 mg/kg berberine significantly increased the survival rate of mice challenged with Salmonella typhimurium (LT2), but berberine show no effects in bacteriostasis. Further study indicated that treatment with 0.20 g/kg berberine markedly increased the survival rate of mice challenged with 2 EU/ml bacterial endotoxin (LPS) and postpone the death time of the dead mice. Moreover, pretreatment with 0.05 g/kg berberine significantly lower the increasing temperature of rabbits challenged with LPS. The studies of molecular mechanism demonstrated that Berberine was able to bind to the TLR4/MD-2 receptor, and presented higher affinity in comparison with LPS. Furthermore, berberine could significantly suppressed the increasing expression of NF-κB, IL-6, TNFα, and IFNβ in the RAW264.7 challenged with LPS.
Berberine can act as a LPS antagonist and block the LPS/TLR4 signaling from the sourse, resulting in the anti-bacterial action.
PMCID: PMC3946165  PMID: 24602493
6.  ADAM17 cleaves CD16b (FcγRIIIb) in human neutrophils 
Biochimica et biophysica acta  2012;1833(3):680-685.
CD16b (FcγRIIIb) is exclusively expressed by human neutrophils and binds IgG in immune complexes. Cell surface CD16b undergoes efficient ectodomain shedding upon neutrophil activation and apoptosis. Indeed, soluble CD16b is present at high levels in the plasma of healthy individuals, which appears to be maintained by the daily turnover of apoptotic neutrophils. At this time, the principal protease responsible for CD16b shedding is not known. We show that CD16b plasma levels were significantly decreased in patients administered a selective inhibitor targeting the metalloproteases ADAM10 and ADAM17. Additional analysis with inhibitors selective for ADAM10 or ADAM17 revealed that only inhibition of ADAM17 significantly blocked the cleavage of CD16b following neutrophil activation and apoptosis. CD16b shedding by ADAM17 was further demonstrated using a unique ADAM17 function-blocking mAb and a cell-based ADAM17 reconstitution assay. Unlike human CD16, however, mouse CD16 did not undergo efficient ectodomain shedding upon neutrophil stimulation or apoptosis, indicating that this mechanism cannot be modeled in normal mice. Taken together, our findings are the first to directly demonstrate that ADAM17 cleaves CD16 in human leukocytes.
PMCID: PMC3556181  PMID: 23228566
Neutrophil; metalloprotease; ADAM17; apoptosis; Fc receptor
7.  ABCC4 is required for cell proliferation and tumorigenesis in non-small cell lung cancer 
OncoTargets and therapy  2014;7:343-351.
Multidrug resistance protein 4 (MRP4), also known as ATP-cassette binding protein 4 (ABCC4), is a member of the MRP/ABCC subfamily of ATP-binding cassette transporters, which are capable of pumping a wide variety of drugs out of the cell. However, little is known about the function of ABCC4 in the proliferation of lung cancer cells.
ABCC4 mRNA and protein levels in lung cancer cell lines were measured by real-time polymerase chain reaction and Western blot, respectively. A lentivirus-mediated RNA interference technique was used to inhibit ABCC4 mRNA expression in A549 and 801D cells. The function of ABCC4 in cell growth was investigated by MTS and colony formation assays. The role of ABCC4 in cell cycle progression was evaluated by flow cytometry and Western blot analysis. ABCC4 mRNA levels in 30 pairs of tumors and corresponding matched adjacent normal tissues from non-small cell lung cancer patients were detected by real-time polymerase chain reaction.
ABCC4 was highly expressed in lung cancer cell lines. ABCC4 expression was markedly downregulated in A549 and 801D cells using the RNA interference technique. Suppression of ABCC4 expression inhibited cell growth. The percentage of cells in G1 phase was increased when ABCC4 expression was suppressed. Phosphorylation of retinoblastoma protein was weakened, originating in the downregulation of ABCC4. ABCC4 mRNA was highly expressed in lung cancer tissue and lung cancer cell lines.
ABCC4 may play an important role in the control of A549 and 801D cell growth. ABCC4 is a potential target for lung cancer therapy.
PMCID: PMC3937249  PMID: 24591841
ABCC4; cell proliferation; lung cancer; cell cycle
8.  Interleukin-33 Increases Antibacterial Defense by Activation of Inducible Nitric Oxide Synthase in Skin 
PLoS Pathogens  2014;10(2):e1003918.
Interleukin-33 (IL-33) is associated with multiple diseases, including asthma, rheumatoid arthritis, tissue injuries and infections. Although IL-33 has been indicated to be involved in Staphylococcus aureus (S. aureus) wound infection, little is known about how IL-33 is regulated as a mechanism to increase host defense against skin bacterial infections. To explore the underlying intricate mechanism we first evaluated the expression of IL-33 in skin from S. aureus-infected human patients. Compared to normal controls, IL-33 was abundantly increased in skin of S. aureus-infected patients. We next developed a S. aureus cutaneous infection mouse model and found that IL-33 was significantly increased in dermal macrophages of infected mouse skin. The expression of IL-33 by macrophages was induced by staphylococcal peptidoglycan (PGN) and lipoteichoic acid (LTA) via activation of toll-like receptor 2(TLR2) –mitogen-activated protein kinase (MAPK)-AKT-signal transducer and activator of transcription 3(STAT3) signaling pathway as PGN and LTA failed to induce IL-33 in Tlr2-deficient peritoneal macrophages, and MAPK,AKT, STAT3 inhibitors significantly decreased PGN- or LTA-induced IL-33. IL-33, in turn, acted on macrophages to induce microbicidal nitric oxygen (NO) release. This induction was dependent on inducible nitric oxide synthase (iNOS) activation, as treatment of macrophages with an inhibitor of iNOS, aminoguanidine, significantly decreased IL-33-induced NO release. Moreover, aminoguanidine significantly blocked the capacity of IL-33 to inhibit the growth of S. aureus, and IL-33 silencing in macrophages significantly increased the survival of S. aureus in macrophages. Furthermore, the administration of IL-33-neutralizing antibody into mouse skin decreased iNOS production but increased the survival of S. aureus in skin. These findings reveal that IL-33 can promote antimicrobial capacity of dermal macrophages, thus enhancing antimicrobial defense against skin bacterial infections.
Author Summary
Interleukin-33 (IL-33) is associated with multiple diseases, including asthma, rheumatoid arthritis, tissue injuries and infections. Although IL-33 has been indicated to be involved in wound infections, little is known about how IL-33 is regulated as a mechanism to increase host defense against skin bacterial infections. Here we have shown that Staphylococcus aureus (S. aureus) cutaneous infection increases IL-33 expression in dermal macrophages in the skin. The expression of IL-33 by macrophages is induced by staphylococcal peptidoglycan (PGN) and lipoteichoic acid (LTA) via activation of toll-like receptor 2(TLR2) –mitogen-activated protein kinase (MAPK)-AKT-signal transducer and activator of transcription 3(STAT3) signaling pathway. IL-33 in turn acts on macrophages to inhibit the growth of S. aureus by binding to its receptor ST2 followed by activation of the AKT-β-catenin pathway, thus inducing and activating inducible nitric oxygen synthase (iNOS) to release microbiocidal nitric oxygen (NO). These findings reveal that IL-33 can promote antimicrobial capacity of dermal macrophages, thus enhancing antimicrobial defense against skin bacterial infections.
PMCID: PMC3930573  PMID: 24586149
9.  Serum IL-21 levels associated with chronic hepatitis B and hepatitis B-related liver failure 
The aim of the present study was to investigate the role of interleukin (IL)-21 in chronic hepatitis B virus (HBV) infection. IL-21 stimulates T and B cell responses and plays a role in the control of chronic viral infections. Serum IL-21 levels were measured by enzyme immunoassay in 109 patients with chronic HBV infection at various clinical stages, as well as in 19 healthy controls (HCs). The proportion of T cells producing IL-21 in the peripheral blood was assessed by intracellular cytokine staining and flow cytometry. Mean serum IL-21 levels in patients with chronic hepatitis B (CHB) and the HCs were 303.54±152.77 pg/ml and 68.24±9.06 pg/ml, respectively (P=0.003). In addition, the mean serum IL-21 level in patients with hepatitis B-related acute-on-chronic liver failure (HB-ACLF) was 455.38±412.38 pg/ml, which exhibited a statistically significant difference when compared with the HCs (P=0.000). Serum IL-21 levels were highest in the patients with HB-ACLF (455.38±412.38 pg/ml) and exhibited a significant difference when compared with the CHB patients (P=0.04). The mean serum IL-21 levels in patients with cirrhosis also increased, but there was no statistically significant difference when compared with the HCs (P=0.82). The frequency of IL-21+CD4+ cells also increased compared with the HCs and correlated with the number and percentage of lymphocytes in the peripheral blood. Serum IL-21 levels increased in CHB and HB-ACLF patients. Relatively low serum IL-21 levels in CHB may have a causal role in the persistence of HBV infection. Higher serum levels in HB-ACLF may activate T and B cells to eliminate the virus or injure the liver via the release of inflammatory cytokines.
PMCID: PMC3964921  PMID: 24669269
interleukin-21; hepatitis B virus; clinical stages; peripheral blood mononuclear cells
10.  Association of Cholecystectomy with Metabolic Syndrome in a Chinese Population 
PLoS ONE  2014;9(2):e88189.
An association between cholecystectomy and metabolic syndrome has not been fully established. Here we analyzed the association between cholecystectomy and metabolic syndrome in a Chinese population of 5672 subjects who undergone annual health checkups at the First Affiliated Hospital, College of Medicine, Zhejiang University between January 2011 and December 2012. The prevalences of gallstones, cholecystectomy and metabolic syndrome were 6.0%, 3.6%, and 32.5%, respectively. The prevalence of metabolic syndrome was significantly higher in subjects with a history of cholecystectomy (63.5%) than in those with gallstones (47.0%) or in those without gallstone disease (30.3%; P<0.01 for both). Multivariate logistic regression analysis showed that cholecystectomy was significantly associated with increased risk of metabolic syndrome (OR = 1.872; 95% CI: 1.193–2.937). However, the association of gallstones with metabolic syndrome was not statistically significant (OR = 1.267; 95% CI: 0.901–1.782). Altogether, our results suggest that cholecystectomy significantly increases the risk of metabolic syndrome.
PMCID: PMC3914934  PMID: 24505425
11.  BioHackathon series in 2011 and 2012: penetration of ontology and linked data in life science domains 
Katayama, Toshiaki | Wilkinson, Mark D | Aoki-Kinoshita, Kiyoko F | Kawashima, Shuichi | Yamamoto, Yasunori | Yamaguchi, Atsuko | Okamoto, Shinobu | Kawano, Shin | Kim, Jin-Dong | Wang, Yue | Wu, Hongyan | Kano, Yoshinobu | Ono, Hiromasa | Bono, Hidemasa | Kocbek, Simon | Aerts, Jan | Akune, Yukie | Antezana, Erick | Arakawa, Kazuharu | Aranda, Bruno | Baran, Joachim | Bolleman, Jerven | Bonnal, Raoul JP | Buttigieg, Pier Luigi | Campbell, Matthew P | Chen, Yi-an | Chiba, Hirokazu | Cock, Peter JA | Cohen, K Bretonnel | Constantin, Alexandru | Duck, Geraint | Dumontier, Michel | Fujisawa, Takatomo | Fujiwara, Toyofumi | Goto, Naohisa | Hoehndorf, Robert | Igarashi, Yoshinobu | Itaya, Hidetoshi | Ito, Maori | Iwasaki, Wataru | Kalaš, Matúš | Katoda, Takeo | Kim, Taehong | Kokubu, Anna | Komiyama, Yusuke | Kotera, Masaaki | Laibe, Camille | Lapp, Hilmar | Lütteke, Thomas | Marshall, M Scott | Mori, Takaaki | Mori, Hiroshi | Morita, Mizuki | Murakami, Katsuhiko | Nakao, Mitsuteru | Narimatsu, Hisashi | Nishide, Hiroyo | Nishimura, Yosuke | Nystrom-Persson, Johan | Ogishima, Soichi | Okamura, Yasunobu | Okuda, Shujiro | Oshita, Kazuki | Packer, Nicki H | Prins, Pjotr | Ranzinger, Rene | Rocca-Serra, Philippe | Sansone, Susanna | Sawaki, Hiromichi | Shin, Sung-Ho | Splendiani, Andrea | Strozzi, Francesco | Tadaka, Shu | Toukach, Philip | Uchiyama, Ikuo | Umezaki, Masahito | Vos, Rutger | Whetzel, Patricia L | Yamada, Issaku | Yamasaki, Chisato | Yamashita, Riu | York, William S | Zmasek, Christian M | Kawamoto, Shoko | Takagi, Toshihisa
The application of semantic technologies to the integration of biological data and the interoperability of bioinformatics analysis and visualization tools has been the common theme of a series of annual BioHackathons hosted in Japan for the past five years. Here we provide a review of the activities and outcomes from the BioHackathons held in 2011 in Kyoto and 2012 in Toyama. In order to efficiently implement semantic technologies in the life sciences, participants formed various sub-groups and worked on the following topics: Resource Description Framework (RDF) models for specific domains, text mining of the literature, ontology development, essential metadata for biological databases, platforms to enable efficient Semantic Web technology development and interoperability, and the development of applications for Semantic Web data. In this review, we briefly introduce the themes covered by these sub-groups. The observations made, conclusions drawn, and software development projects that emerged from these activities are discussed.
PMCID: PMC3978116  PMID: 24495517
BioHackathon; Bioinformatics; Semantic Web; Web services; Ontology; Visualization; Knowledge representation; Databases; Semantic interoperability; Data models; Data sharing; Data integration
12.  Phosphoregulation of Nap1 Plays a Role in Septin Ring Dynamics and Morphogenesis in Candida albicans 
mBio  2014;5(1):e00915-13.
Nap1 has long been identified as a potential septin regulator in yeasts. However, its function and regulation remain poorly defined. Here, we report functional characterization of Nap1 in the human-pathogenic fungus Candida albicans. We find that deletion of NAP1 causes constitutive filamentous growth and changes of septin dynamics. We present evidence that Nap1’s cellular localization and function are regulated by phosphorylation. Phos-tag gel electrophoresis revealed that Nap1 phosphorylation is cell cycle dependent, exhibiting the lowest level around the time of bud emergence. Mass spectrometry identified 10 phosphoserine and phosphothreonine residues in a cluster near the N terminus, and mutation of these residues affected Nap1’s localization to the septin ring and cellular function. Nap1 phosphorylation involves two septin ring-associated kinases, Cla4 and Gin4, and its dephosphorylation occurs at the septin ring in a manner dependent on the phosphatases PP2A and Cdc14. Furthermore, the nap1Δ/Δ mutant and alleles carrying mutations of the phosphorylation sites exhibited greatly reduced virulence in a mouse model of systemic candidiasis. Together, our findings not only provide new mechanistic insights into Nap1’s function and regulation but also suggest the potential to target Nap1 in future therapeutic design.
Septins are conserved filament-forming GTPases involved in a wide range of cellular events, such as cytokinesis, exocytosis, and morphogenesis. In Candida albicans, the most prevalent human fungal pathogen, septin functions are indispensable for its virulence. However, the molecular mechanisms by which septin structures are regulated are poorly understood. In this study, we deleted NAP1, a gene encoding a putative septin regulator, in C. albicans and found that cells lacking NAP1 showed abnormalities in morphology, invasive growth, and septin ring dynamics. We identified a conserved N-terminal phosphorylation cluster on Nap1 and demonstrated that phosphorylation at these sites regulates Nap1 localization and function. Importantly, deletion of NAP1 or mutation in the N-terminal phosphorylation cluster strongly reduced the virulence of C. albicans in a mouse model of systemic infection. Thus, this study not only provides mechanistic insights into septin regulation but also suggests Nap1 as a potential antifungal target.
PMCID: PMC3950511  PMID: 24496790
13.  Inhibition of HSP90 attenuates porcine reproductive and respiratory syndrome virus production in vitro 
Virology Journal  2014;11:17.
Porcine reproductive and respiratory syndrome virus (PRRSV) infection leads to substantial economic losses to the swine industry worldwide. However, no effective countermeasures exist to combat this virus infection so far. The most common antiviral strategy relies on directly inhibiting viral proteins. However, this strategy invariably leads to the emergence of drug resistance due to the error-prone nature of viral ploymerase. Targeting cellular proteins required for viral infection for developing new generation of antivirals is gaining concern. Recently, heat shock protein 90 (HSP90) was found to be an important host factor for the replication of multiple viruses and the inhibition of HSP90 showed significant antiviral effects. It is thought that the inhibition of HSP90 could be a promising broad-range antiviral approach. However, the effects of HSP90 inhibition on PRRSV infection have not been evaluated. In the current research, we tried to inhibit HSP90 and test whether the inhibition affect PRRSV infection.
We inhibit the function of HSP90 with two inhibitors, geldanamycin (GA) and 17- allylamono-demethoxygeldanamycin (17-AAG), and down-regulated the expression of endogenous HSP90 with specific small-interfering RNAs (siRNAs). Cell viability was measured with alamarBlue. The protein level of viral N was determined by western blotting and indirect immunofluorescence (IFA). Besides, IFA was employed to examine the level of viral double-stranded RNA (dsRNA). The viral RNA copy number and the level of IFN-β mRNA were determined by quantitative real-time PCR (qRT-PCR).
Our results indicated that both HSP90 inhibitors showed strong anti-PRRSV activity. They could reduce viral production by preventing the viral RNA synthesis. These inhibitory effects were not due to the activation of innate interferon response. In addition, we observed that individual knockdown targeting HSP90α or HSP90β did not show dramatic inhibitory effect. Combined knockdown of these two isoforms was required to reduce viral infection.
Our results shed light on the possibility of developing potential therapeutics targeting HSP90 against PRRSV infection.
PMCID: PMC3942275  PMID: 24490822
Porcine reproductive and respiratory syndrome virus; PRRSV; HSP90; Geldanamycin; 17-AAG; Antiviral
14.  Gene Expression of Glutamate Metabolizing Enzymes in the Hippocampal Formation in Human Temporal Lobe Epilepsy 
Epilepsia  2012;54(2):228-238.
Increased interictal concentrations of extracellular hippocampal glutamate have been implicated in the pathophysiology of temporal lobe epilepsy (TLE) in humans. Recent studies suggest that perturbations of the glutamate metabolizing enzymes glutamine synthetase (GS) and phosphate activated glutaminase (PAG) may underlie the glutamate excess in TLE. However, the molecular mechanism of the enzyme perturbations remains unclear. A better understanding of the regulatory mechanisms of GS and PAG could facilitate the discovery of novel therapeutics for TLE.
We used in situ hybridization on histological sections to assess the distribution and quantity of mRNA for GS and PAG in subfields of hippocampal formations from: (a) patients with TLE and concomitant hippocampal sclerosis, (b) patients with TLE and no hippocampal sclerosis, and (c) non-epilepsy autopsy subjects.
GS mRNA was increased by approximately 50% in the CA3 in TLE patients without hippocampal sclerosis vs. in TLE patients with sclerosis and in non-epilepsy subjects. PAG mRNA was increased by more than 100% in the subiculum in both TLE patient categories vs. in non-epilepsy subjects. PAG mRNA was also increased in the CA1, CA2, CA3 and dentate hilus in TLE without hippocampal sclerosis vs. in TLE with sclerosis. Finally, PAG mRNA was increased in the dentate gyrus in TLE with sclerosis vs. in non-epilepsy subjects, and also increased in the hilus in TLE without sclerosis vs. in TLE with sclerosis.
These findings demonstrate complex changes in the expression of mRNAs for GS and PAG in the hippocampal formation in TLE, and raise the possibility that both transcriptional and post-transcriptional mechanisms may underlie the regulation of GS and PAG proteins in the epileptic brain.
PMCID: PMC3578420  PMID: 23384343
Astrocytes; brain; glutamine synthetase; glutamate-glutamine cycle; phosphate activated glutaminase
15.  In vitro antioxidant activity and potential inhibitory action against α-glucosidase of polysaccharides from fruit peel of tea (Camellia sinensis L.)* #  
The conditions for extracting polysaccharides from tea (Camellia sinensis L.) fruit peel (TFPPs) were studied. Three parameters (temperature, time, and liquid/solid ratio) affecting the extraction of TFPP were optimized using response surface methodology (RSM). Under the optimized conditions, the yield of TFPP was predicted to be 4.98%. The physicochemical properties, in vitro antioxidant activities, and inhibitory effects on α-glucosidase of fractionated TFPPs (TFPP-0, TFPP-20, TFPP-40, and TFPP-60) were investigated. We found that the TFPPs were all acid protein-bound heteropolysaccharides, although with different chemical compositions. They had not only remarkable scavenging activity on 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) and reducing activity, but also excellent inhibitory potential against α-glucosidase in vitro. Our results suggest that tea fruit peel could be treated as a potential bioresource for the development of polysaccharide antioxidants.
PMCID: PMC3924393  PMID: 24510710
Polysaccharides; Tea (Camellia sinensis L.) fruit peel; Physicochemical properties; Antioxidant activity; α-Glucosidase inhibition
16.  HuR and TIA1/TIAL1 Are Involved in Regulation of Alternative Splicing of SIRT1 Pre-mRNA 
SIRT1 is a pleiotropic protein that plays critical and multifunctional roles in metabolism, senescence, longevity, stress-responses, and cancer, and has become an important therapeutic target across a range of diseases. Recent research demonstrated that SIRT1 pre-mRNA undergoes alternative splicing to produce different isoforms, such as SIRT1 full-length and SIRT1-ΔExon8 variants. Previous studies revealed these SIRT1 mRNA splice variants convey different characteristics and functions to the protein, which may in turn explain the multifunctional roles of SIRT1. However, the mechanisms underlying the regulation of SIRT1 alternative splicing remain to be elucidated. Our objective is to search for new pathways that regulate of SIRT1 alternative splicing. Here we describe experiments showing that HuR and TIA1/TIAL1, two kinds of RNA-binding proteins, were involved in the regulation of alternative splicing of SIRT1 pre-mRNA under normal and stress circumstances: HuR increased SIRT1-ΔExon8 by promoting SIRT1 exon 8 exclusion, whereas TIA1/TIAL1 inhibition of the exon 8 exclusion led to a decrease in SIRT1-ΔExon8 mRNA levels. This study provides novel insight into how the alternative splicing of SIRT1 pre-mRNA is regulated, which has fundamental implications for understanding the critical and multifunctional roles of SIRT1.
PMCID: PMC3958892  PMID: 24566137
SIRT1; alternative splicing; SIRT1-ΔExon8; Hu antigen R; T-cell-restricted intracellular antigen 1; TIA1-like 1
17.  Tracking Socioeconomic Vulnerability Using Network Analysis: Insights from an Avian Influenza Outbreak in an Ostrich Production Network 
PLoS ONE  2014;9(1):e86973.
The focus of management in many complex systems is shifting towards facilitation, adaptation, building resilience, and reducing vulnerability. Resilience management requires the development and application of general heuristics and methods for tracking changes in both resilience and vulnerability. We explored the emergence of vulnerability in the South African domestic ostrich industry, an animal production system which typically involves 3–4 movements of each bird during its lifetime. This system has experienced several disease outbreaks, and the aim of this study was to investigate whether these movements have contributed to the vulnerability of this system to large disease outbreaks.
Methodology/Principal Findings
The ostrich production system requires numerous movements of birds between different farm types associated with growth (i.e. Hatchery to juvenile rearing farm to adult rearing farm). We used 5 years of movement records between 2005 and 2011 prior to an outbreak of Highly Pathogenic Avian Influenza (H5N2). These data were analyzed using a network analysis in which the farms were represented as nodes and the movements of birds as links. We tested the hypothesis that increasing economic efficiency in the domestic ostrich industry in South Africa made the system more vulnerable to outbreak of Highly Pathogenic Avian Influenza (H5N2). Our results indicated that as time progressed, the network became increasingly vulnerable to pathogen outbreaks. The farms that became infected during the outbreak displayed network qualities, such as significantly higher connectivity and centrality, which predisposed them to be more vulnerable to disease outbreak.
Taken in the context of previous research, our results provide strong support for the application of network analysis to track vulnerability, while also providing useful practical implications for system monitoring and management.
PMCID: PMC3909050  PMID: 24498004
18.  A Systematic Review and Meta-Analysis of the Association between Serotonergic Gene Polymorphisms and Obstructive Sleep Apnea Syndrome 
PLoS ONE  2014;9(1):e86460.
5-Hydroxytryptamine receptor (5-HTR) and 5-hydroxytryptamine transporter (5-HTT) gene polymorphisms have been reported to be associated with susceptibility to obstructive sleep apnea syndrome (OSAS). The associations, derived from sporadic, inconsistent, small-sample-size studies, need to be evaluated further in a meta-analysis.
Relevant studies were identified by searching PubMed, Embase, The Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang, and Weipu. Eligible data were extracted from each included study. Odds ratios (ORs) were calculated using a fixed-effects or a random-effects model. The ORs and 95% confidence interval (CI) were used to assess the strength of the association between serotonergic gene polymorphisms and OSAS in the dominant and recessive models, as well as alleles. The Q statistic was used to evaluate homogeneity and Begg’s test was used to assess publication bias.
Eight studies were finally included in the meta-analysis of the association between 5-HTR2A gene variants (including 102T/C and 1438G/A), 5-HTT gene polymorphisms (including 5-HTT gene-linked promoter region (5-HTTLRP), and serotonin transporter intron 2 variable number tandem repeat (STin2VNTR) and OSAS risk. The G allele of 5-HTR2A 1438G/A, long 5-HTTLPR, and 10-tandem-repeats STin2VNTR were shown to increase OSAS susceptibility, with ORs of 2.33 (A vs. G, 95% CI 1.48–3.66), 1.24 (L vs. S, 95% CI: 1.04–1.49), and 2.87 (10 vs. 12, 95% CI: 1.38–5.97), respectively. These significant differences were determined in both dominant and recessive models. Of the 5-HTR2A 1438G/A gene polymorphism, the AA genotype increased the OSAS risk, with an OR of 4.21 (95% CI: 2.83–6.25) in a recessive model in male OSAS patients, but no significant association was found in females.
Our meta-analysis demonstrated that polymorphisms in the 5-HTR2A 1438G/A and 5-HTT genes contributed to susceptibility to OSAS. The A allele of the 1438G/A gene polymorphism is predominantly distributed in males and increased the OSAS risk significantly.
PMCID: PMC3903532  PMID: 24475124
19.  Autophagy Is Involved in the Cardioprotection Effect of Remote Limb Ischemic Postconditioning on Myocardial Ischemia/Reperfusion Injury in Normal Mice, but Not Diabetic Mice 
PLoS ONE  2014;9(1):e86838.
Recent animal study and clinical trial data suggested that remote limb ischemic postconditioning (RIPostC) can invoke potent cardioprotection. However, during ischemia reperfusion injury (IR), the effect and mechanism of RIPostC on myocardium in subjects with or without diabetes mellitus (DM) are poorly understood. Autophagy plays a crucial role in alleviating myocardial IR injury. The aim of this study was to determine the effect of RIPostC on mice myocardial IR injury model with or without DM, and investigate the role of autophagy in this process.
Methodology and Results
Streptozocin (STZ) induced DM mice model and myocardial IR model were established. Using a noninvasive technique, RIPostC was induced in normal mice (ND) and DM mice by three cycles of ischemia (5 min) and reperfusion (5 min) in the left hindlimb. In ND group, RIPostC significantly reduced infarct size (32.6±3.0% in ND-RIPostC vs. 50.6±2.4% in ND-IR, p<0.05) and improved cardiac ejection fraction (49.70±3.46% in ND-RIPostC vs. 31.30±3.95% in ND-IR, p<0.05). However, in DM group, no RIPostC mediated cardioprotetion effect was observed. To analyze the role of autophagy, western blot and immunohistochemistry was performed. Our data showed that a decreased sequestosome 1 (SQSTM1/p62) level, an increased Beclin-1 level, and higher ratio of LC3-II/LC3-I were observed in ND RIPostC group, but not DM RIPostC group.
The current study suggested that RIPostC exerts cardioprotection effect on IR in normal mice, but not DM mice, and this difference is via, at least in part, the up-regulation of autophagy.
PMCID: PMC3900658  PMID: 24466263
20.  The GG Genotype of Telomerase Reverse Transcriptase at Genetic Locus rs2736100 Is Associated with Human Atherosclerosis Risk in the Han Chinese Population 
PLoS ONE  2014;9(1):e85719.
A single nucleotide polymorphism (SNP) in the second intron of human TERT (hTERT), rs2736100, acts as a critical factor in hTERT synthesis and activation. The rs2736100 SNP was found to be associated with susceptibility to many cancers. Recently, inhibition of telomerase and marked telomere shortening were determined to be closely associated with the increasing severity of atherosclerosis. The association between the SNP of rs2736100 and the presence of atherosclerosis was evaluated in 84 atherosclerosis patients and 257 healthy controls using multivariate logistic regression analyses. The proportion of the GG genotype in atherosclerosis patients (17.9%) was significantly higher than in the control group (9.7%). Eight variables, including age, gender, cholesterol, high density lipoprotein, homocysteine, total bilirubin, indirect bilirubin, and rs2736100 GG genotype, were associated with atherosclerosis with odds ratios of 1.88, 2.11, 1.66, 0.23, 1.27, 1.29, 1.53, and 1.74, respectively, using multivariate logistic regression analyses. Homozygous GG was demonstrated to be associated with the presence of atherosclerosis in our population.
PMCID: PMC3897494  PMID: 24465664
21.  Downregulation of PAX6 by shRNA Inhibits Proliferation and Cell Cycle Progression of Human Non-Small Cell Lung Cancer Cell Lines 
PLoS ONE  2014;9(1):e85738.
The transcription factor PAX6 is primarily expressed in embryos. PAX6 is also expressed in several tumors and plays an oncogenic role. However, little is known about the role of PAX6 in lung cancer.
The function of PAX6 in lung cancer cells was evaluated by small interfering RNA-mediated depletion of the protein followed by analyses of cell proliferation, anchorage-independent growth, and cell cycle arrest. The changes of cyclin D1, pRB, ERK1/2, p38 expression caused by PAX6 inhibition were detected using western-blotting. The PAX6 mRNA level in 52 pairs of tumors and corresponding matched adjacent normal tissues from non-small cell lung cancer patients and lung cancer cell lines was detected by real-time PCR.
Suppression of PAX6 expression inhibited cell growth and colony formation in A549 and H1299 cells. The percentage of cells in G1-phase increased when PAX6 expression was inhibited. The cyclin D1 protein level, as well as the pRB phosphorylation level, decreased as a result of PAX6 down-regulation. The activity of ERK1/2 and p38 was also suppressed in PAX6 knock-down cells. The PAX6 mRNA was highly expressed in lung cancer tissue and lung cancer cell lines. In most patients (about 65%), the relative ratio of PAX6 mRNA in primary NSCLC versus adjacent tissues exceeded 100.
Our data implicated that PAX6 accelerates cell cycle progression by activating MAPK signal pathway. PAX6 mRNA levels were significantly elevated in primary lung cancer tissues compared to their matched adjacent tissues.
PMCID: PMC3893268  PMID: 24454925
22.  On Learning Cluster Coefficient of Private Networks 
Enabling accurate analysis of social network data while preserving differential privacy has been challenging since graph features such as clustering coefficient or modularity often have high sensitivity, which is different from traditional aggregate functions (e.g., count and sum) on tabular data. In this paper, we treat a graph statistics as a function f and develop a divide and conquer approach to enforce differential privacy. The basic procedure of this approach is to first decompose the target computation f into several less complex unit computations f1, …, fm connected by basic mathematical operations (e.g., addition, subtraction, multiplication, division), then perturb the output of each fi with Laplace noise derived from its own sensitivity value and the distributed privacy threshold εi, and finally combine those perturbed fi as the perturbed output of computation f. We examine how various operations affect the accuracy of complex computations. When unit computations have large global sensitivity values, we enforce the differential privacy by calibrating noise based on the smooth sensitivity, rather than the global sensitivity. By doing this, we achieve the strict differential privacy guarantee with smaller magnitude noise. We illustrate our approach by using clustering coefficient, which is a popular statistics used in social network analysis. Empirical evaluations on five real social networks and various synthetic graphs generated from three random graph models show the developed divide and conquer approach outperforms the direct approach.
PMCID: PMC3889125  PMID: 24429843
23.  The Associations of Uric Acid, Cardiovascular and All-Cause Mortality in Peritoneal Dialysis Patients 
PLoS ONE  2014;9(1):e82342.
To investigate whether uric acid (UA) is an independent predictor of cardiovascular (CV) and all-cause mortality in peritoneal dialysis (PD) patients after controlling for recognized CV risk factors.
A total of 2264 patients on chronic PD were collected from seven centers affiliated with the Socioeconomic Status on the Outcome of Peritoneal Dialysis (SSOP) Study. All demographic and laboratory data were recorded at baseline. Multivariate Cox regression was used to calculate the hazard ratio (HR) of CV and all-cause mortality with adjustments for recognized traditional and uremia-related CV factors.
There were no significant differences in baseline characteristics between patients with (n = 2193) and without (n = 71) UA measured. Each 1 mg/dL of increase in UA was associated with higher all-cause mortality with 1.05(1.00∼1.10) of HR and higher CV mortality with 1.12 (1.05∼1.20) of HR after adjusting for age, gender and center size. The highest gender-specific tertile of UA predicted higher all-cause mortality with 1.23(1.00∼1.52) of HR and higher CV mortality with 1.69 (1.21∼2.38) of HR after adjusting for age, gender and center size. The predictive value of UA was stronger in patients younger than 65 years without CV disease or diabetes at baseline. The prognostic value of UA as both continuous and categorical variable weakened or disappeared after further adjusted for uremia-related and traditional CV risk factors.
The prognostic value of UA in CV and all-cause mortality was weak in PD patients generally, which was confounded by uremia-related and traditional CV risk factors.
PMCID: PMC3885378  PMID: 24416142
24.  Identification and Chronological Analysis of Genomic Signatures in Influenza A Viruses 
PLoS ONE  2014;9(1):e84638.
An increase in the availability of data on the influenza A viruses (IAV) has enabled the identification of the potential determinants of IAV host specificity using computational approaches. In this study, we proposed an alternative approach, based on the adjusted Rand index (ARI), for the evaluation of genomic signatures of IAVs and their ability to distinguish hosts they infected. Our experiments showed that the host-specific signatures identified using the ARI were more characteristic of their hosts than those identified using previous measures. Our results provided updates on the host-specific genomic signatures in the internal proteins of the IAV based on the sequence data as of February 2013 in the National Center for Biotechnology Information (NCBI). Unlike other approaches for signature recognition, our approach considered not only the ability of signatures to distinguish hosts (according to the ARI), but also the chronological relationships among proteins. We identified novel signatures that could be mapped to known functional domains, and introduced a chronological analysis to investigate the changes in host-specific genomic signatures over time. Our chronological analytical approach provided results on the adaptive variability of signatures, which correlated with previous studies’ findings, and indicated prospective adaptation trends that warrant further investigation.
PMCID: PMC3885579  PMID: 24416256
25.  Exploring Candidate Genes for Pericarp Russet Pigmentation of Sand Pear (Pyrus pyrifolia) via RNA-Seq Data in Two Genotypes Contrasting for Pericarp Color 
PLoS ONE  2014;9(1):e83675.
Sand pear (Pyrus pyrifolia) russet pericarp is an important trait affecting both the quality and stress tolerance of fruits. This trait is controlled by a relative complex genetic process, with some fundamental biological questions such as how many and which genes are involved in the process remaining elusive. In this study, we explored differentially expressed genes between the russet- and green-pericarp offspring from the sand pear (Pyrus pyrifolia) cv. ‘Qingxiang’ × ‘Cuiguan’ F1 group by RNA-seq-based bulked segregant analysis (BSA). A total of 29,100 unigenes were identified and 206 of which showed significant differences in expression level (log2fold values>1) between the two types of pericarp pools. Gene Ontology (GO) analyses detected 123 unigenes in GO terms related to ‘cellular_component’ and ‘biological_process’, suggesting developmental and growth differentiations between the two types. GO categories associated with various aspects of ‘lipid metabolic processes’, ‘transport’, ‘response to stress’, ‘oxidation-reduction process’ and more were enriched with genes with divergent expressions between the two libraries. Detailed examination of a selected set of these categories revealed repressed expressions of candidate genes for suberin, cutin and wax biosynthesis in the russet pericarps.Genes encoding putative cinnamoyl-CoA reductase (CCR), cinnamyl alcohol dehydrogenase (CAD) and peroxidase (POD) that are involved in the lignin biosynthesis were suggested to be candidates for pigmentation of sand pear russet pericarps. Nine differentially expressed genes were analyzed for their expressions using qRT-PCR and the results were consistent with those obtained from Illumina RNA-sequencing. This study provides a comprehensive molecular biology insight into the sand pear pericarp pigmentation and appearance quality formation.
PMCID: PMC3882208  PMID: 24400075

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