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1.  Effects of Mitochondrial Translocation of Telomerase on Drug Resistance in Hepatocellular Carcinoma Cells 
Journal of Cancer  2015;6(2):151-159.
Hepatocellular carcinoma (HCC) cells exhibit multidrug resistance (MDR), but the underlying mechanisms remain unclear. Cancer cells that overexpress telomerase are resistant to chemotherapeutic drugs. This study aimed to determine the effects of mitochondrial translocation of telomerase on MDR in HCC cells. HepG2 cells were transfected with negative plasmid and PTPN11 (Shp-2) short hairpin RNA (ShRNA) plasmid to establish HepG2-negative (HepG2 transfected with negative plasmid) and HepG2-ShShp-2 (HepG2 transfected with Shp-2 ShRNA plasmid) cells. Sensitivity to chemotherapeutic drugs was assessed by Cell Counting Kit-8 (CCK-8) assays. Distribution of human telomerase reverse transcriptase (hTERT) within mitochondria was detected by western blotting and immunofluorescence combined with laser scanning confocal microscopy. Mitochondrial reactive oxygen species (ROS) generation was demonstrated by flow cytometry with the mitochondrial superoxide (Mito-Sox) indicator. The frequency of damaged mitochondrial DNA (mtDNA) was illustrated by quantitative real-time polymerase chain reaction (Q-PCR). Expression of mitochondrial respiratory chain complex subunits ND1 and COXII were also demonstrated by western blotting. Knockdown of Shp-2 in HepG2 cells resulted in upregulation of mitochondrial TERT expression and increased resistance to cisplatin (CDDP) and 5-fluorouracil (5-FU) (resistance indices, 2.094 and 1.863, respectively). In addition, both the mitochondrial ROS and the frequency of mtDNA damage were decreased, and COXII expression was upregulated. Our results suggest that Mitochondrial translocation of hTERT may lead to chemotherapeutic resistance in HCC cells. Mitochondrial hTERT contributes to the drug resistance of tumor cells by reducing ROS production and mtDNA damage, and exerting a protective effect on the mitochondrial respiratory chain.
PMCID: PMC4280398  PMID: 25561980
telomerase; mitochondria; multidrug resistance; hepatocellular carcinoma.
2.  Adenosine A2A receptor deficiency alleviates blast-induced cognitive dysfunction 
Traumatic brain injury (TBI), particularly explosive blast-induced TBI (bTBI), has become the most prevalent injury among military personnel. The disruption of cognitive function is one of the most serious consequences of bTBI because its long-lasting effects prevent survivors fulfilling their active duty and resuming normal civilian life. However, the mechanisms are poorly understood and there is no treatment available. This study investigated the effects of adenosine A2A receptor (A2AR) on bTBI-induced cognitive deficit, and explored the underlying mechanisms. After being subjected to moderate whole-body blast injury, mice lacking the A2AR (A2AR knockout (KO)) showed less severity and shorter duration of impaired spatial reference memory and working memory than wild-type mice did. In addition, bTBI-induced cortical and hippocampal lesions, as well as proinflammatory cytokine expression, glutamate release, edema, cell loss, and gliosis in both early and prolonged phases of the injury, were significantly attenuated in A2AR KO mice. The results suggest that early injury and chronic neuropathological damages are important mechanisms of bTBI-induced cognitive impairment, and that the impairment can be attenuated by preventing A2AR activation. These findings suggest that A2AR antagonism is a potential therapeutic strategy for mild-to-moderate bTBI and consequent cognitive impairment.
PMCID: PMC3824177  PMID: 23921902
adenosine; brain trauma; cognitive impairment; experimental; neuroprotection
3.  An Immunochip-based interrogation of scleroderma susceptibility variants identifies a novel association at DNASE1L3 
The aim of the study was to interrogate the genetic architecture and autoimmune pleiotropy of scleroderma susceptibility in the Australian population.
We genotyped individuals from a well-characterized cohort of Australian scleroderma patients with the Immunochip, a custom array enriched for single nucleotide polymorphisms (SNPs) at immune loci. Controls were taken from the 1958 British Birth Cohort. After data cleaning and adjusting for population stratification the final dataset consisted of 486 cases, 4,458 controls and 146,525 SNPs. Association analyses were conducted using logistic regression in PLINK. A replication study was performed using 833 cases and 1,938 controls.
A total of eight loci with suggestive association (P <10-4.5) were identified, of which five showed significant association in the replication cohort (HLA-DRB1, DNASE1L3, STAT4, TNP03-IRF5 and VCAM1). The most notable findings were at the DNASE1L3 locus, previously associated with systemic lupus erythematosus, and VCAM1, a locus not previously associated with human disease. This study identified a likely functional variant influencing scleroderma susceptibility at the DNASE1L3 locus; a missense polymorphism rs35677470 in DNASE1L3, with an odds ratio of 2.35 (P = 2.3 × 10−10) in anti-centromere antibody (ACA) positive cases.
This pilot study has confirmed previously reported scleroderma associations, revealed further genetic overlap between scleroderma and systemic lupus erythematosus, and identified a putative novel scleroderma susceptibility locus.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-014-0438-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4230517  PMID: 25332064
4.  Whole-Exome Sequencing to Decipher the Genetic Heterogeneity of Hearing Loss in a Chinese Family with Deaf by Deaf Mating 
PLoS ONE  2014;9(10):e109178.
Inherited deafness has been shown to have high genetic heterogeneity. For many decades, linkage analysis and candidate gene approaches have been the main tools to elucidate the genetics of hearing loss. However, this associated study design is costly, time-consuming, and unsuitable for small families. This is mainly due to the inadequate numbers of available affected individuals, locus heterogeneity, and assortative mating. Exome sequencing has now become technically feasible and a cost-effective method for detection of disease variants underlying Mendelian disorders due to the recent advances in next-generation sequencing (NGS) technologies. In the present study, we have combined both the Deafness Gene Mutation Detection Array and exome sequencing to identify deafness causative variants in a large Chinese composite family with deaf by deaf mating. The simultaneous screening of the 9 common deafness mutations using the allele-specific PCR based universal array, resulted in the identification of the 1555A>G in the mitochondrial DNA (mtDNA) 12S rRNA in affected individuals in one branch of the family. We then subjected the mutation-negative cases to exome sequencing and identified novel causative variants in the MYH14 and WFS1 genes. This report confirms the effective use of a NGS technique to detect pathogenic mutations in affected individuals who were not candidates for classical genetic studies.
PMCID: PMC4188603  PMID: 25289672
5.  Effect of stable transfection with PHD3 on growth and proliferation of HepG2 cells in vitro and in vivo 
Objective: To establish a human hepatoma HepG2 cell line with stable expression of Prolyl hydroxylase domain 3 (PHD3) gene and study its effect of growth and proliferation in nude mice xenograft tumor. Methods: Eukaryotic expression vectors of pcDNA 3.1-PHD3 was constructed. HepG2 cells were transfected with recombinant plasmid pcDNA 3.1-PHD3 and empty vector plasmid pcDNA 3.1 by lipofectamine 2000 as transfected group, control group respectively, while the HepG2 cell without any operation was considered as parental group. Steady expression cells were gotten by G418 selecting. RT-PCR and agarose gel electrophoresis were used to confirm the expression of PHD3 in HepG2 cells and transfection successfully. The growth of these cells in vivo were also observed by injecting three groups of cell into nude mice, and volume were measured and compared. Results: The recombinant plasmid pcDNA 3.1-PHD3 and empty vector plasmid pcDNA 3.1 were successfully transfected into human hepatoma HepG2 cell line and showed stable expression in this cell line. Tumors were observed in nude mice when the transfectant cells were xenografted successfully, The average tumor size of PCDNA (3.1)-PHD3 groups are significant different compared with other two groups (P < 0.001). Conclusion: The PHD3 gene may have negative influence of growth and proliferation on HepG2 cells in vitro. The PHD3 may be a potentially tumor suppressor.
PMCID: PMC4161567  PMID: 25232407
Prolyl hydroxylase domain 3 (PHD3); hypoxia inducible factor (HIF); hepatocellular cancer (HCC); transfection
6.  Regional Hypothermia Inhibits Spinal Cord Somatosensory-Evoked Potentials without Neural Damage in Uninjured Rats 
Journal of Neurotrauma  2013;30(15):1325-1333.
Both the therapeutic effects of regional hypothermia (RH) and somatosensory-evoked potentials (SSEP) have been intensively studied; however, the in vivo relationship between the two remains unknown. The primary focus of the current study was to investigate the impact of RH on SSEP in uninjured rats, as well as the neural safety of RH on neuronal health. An epidural perfusion model was used to keep local temperature steady by adjusting perfusion speed at 30°C, 26°C, 22°C, and 18°C for 30 min, respectively. Total hypothermic duration lasted up to 3 h. Neural signals were recorded at the end of each hypothermic period, as well as before cooling and after spontaneous rewarming. In addition, the Basso, Beattie, and Bresnahan (BBB) Locomotor Rating Scale was used to evaluate the effects of RH pre- and post-operative, combined with hematoxylin and eosin (H&E) and Fluoro-Jade C (FJC) staining. The results showed a marked declining trend in SSEP amplitude, as well as a significant prolongation in latency only during profound hypothermia (18°C). The BBB scale remained consistent at 21 throughout the entire process, signifying that no motor function injury was caused by RH. In addition, H&E and FJC staining did not show obvious histological injury. These findings firmly support the conclusion that RH, specifically profound RH, inhibits spinal cord SSEP in both amplitude and latency without neural damage in uninjured rats.
PMCID: PMC3727526  PMID: 22916828
RH; spinal cord; SSEP; uninjured rat
7.  Genetic variants in STAT4 and HLA-DQ genes confer risk of hepatitis B virus–related hepatocellular carcinoma 
Nature genetics  2012;45(1):72-75.
To identify genetic susceptibility loci for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) in the Chinese population, we carried out a genome-wide association study (GWAS) in 2,514 chronic HBV carriers (1,161 HCC cases and 1,353 controls) followed by a 2-stage validation among 6 independent populations of chronic HBV carriers (4,319 cases and 4,966 controls). The joint analyses showed that HCC risk was significantly associated with two independent loci: rs7574865 at STAT4, Pmeta = 2.48 × 10−10, odds ratio (OR) = 1.21; and rs9275319 at HLA-DQ, Pmeta = 2.72 × 10−17, OR = 1.49. The risk allele G at rs7574865 was significantly associated with lower mRNA levels of STAT4 in both the HCC tissues and nontumor tissues of 155 individuals with HBV-related HCC (Ptrend = 0.0008 and 0.0002, respectively). We also found significantly lower mRNA expression of STAT4 in HCC tumor tissues compared with paired adjacent nontumor tissues (P = 2.33 × 10−14).
PMCID: PMC4105840  PMID: 23242368
8.  Intracellular Clusterin Interacts with Brain Isoforms of the Bridging Integrator 1 and with the Microtubule-Associated Protein Tau in Alzheimer's Disease 
PLoS ONE  2014;9(7):e103187.
Sporadic or late-onset Alzheimer's disease (AD) is expected to affect 50% of individuals reaching 85 years of age. The most significant genetic risk factor for late-onset AD is the e4 allele of APOE gene encoding apolipoprotein E, a lipid carrier shown to modulate brain amyloid burden. Recent genome-wide association studies have uncovered additional single nucleotide polymorphisms (SNPs) linked to AD susceptibility, including those in the CLU and BIN1 genes encoding for clusterin (CLU) and the bridging integrator 1 (BIN1) proteins, respectively. Because CLU has been implicated in brain amyloid-β (Aβ) clearance in mouse models of amyloid deposition, we sought to investigate whether an AD-linked SNP in the CLU gene altered Aβ42 biomarker levels in the cerebrospinal fluid (CSF). Instead, we found that the CLU rs11136000 SNP modified CSF levels of the microtubule-associated protein Tau in AD patients. We also found that an intracellular form of CLU (iCLU) was upregulated in the brain of Tau overexpressing Tg4510 mice, but not in Tg2576 amyloid mouse model. By overexpressing iCLU and Tau in cell culture systems we discovered that iCLU was a Tau-interacting protein and that iCLU associated with brain-specific isoforms of BIN1, also recently identified as a Tau-binding protein. Through expression analysis of CLU and BIN1 variants, we found that CLU and BIN1 interacted via their coiled-coil motifs. In co-immunoprecipitation studies using human brain tissue, we showed that iCLU and the major BIN1 isoform expressed in neurons were associated with modified Tau species found in AD. Finally, we showed that expression of certain coding CLU variants linked to AD risk led to increased levels of iCLU. Together, our findings suggest that iCLU and BIN1 interaction might impact Tau function in neurons and uncover potential new mechanisms underlying the etiology of Tau pathology in AD.
PMCID: PMC4106906  PMID: 25051234
9.  Tumor suppressor TSLC1 inhibits growth, proliferation, invasiveness and angiogenesis in nude mice xenografted tumor of Eca109 cells 
Tumor suppressor in lung cancer 1 (TSLC1) is a novel tumor suppressor gene whose inactivation is implicated in the occurrence, invasion, metastasis and prognosis of esophageal cancer. TSLC1 was studied by comparing the tumor formation of TSLC1 transfectant and control cells in nude mice. Compared with blank group and mock group, tumor size and infiltrating range of transfected group was less, differentiation of tumor tissue was slightly better, and differences of tumor angiogenesis was worse. There was no obvious difference between blank group and mock group. We have shown TSLC1 gene inhibited the growth proliferation, infiltration and angiogenesis of Eca109 cells.
PMCID: PMC4100959  PMID: 25035773
Tumor suppressor gene; tumor suppressor in lung cancer -1 (TSLC1); esophageal cancer; tumorigenicity; nude mice
10.  Expression of leucine aminopeptidase 3 (LAP3) correlates with prognosis and malignant development of human hepatocellular carcinoma (HCC) 
Leucine aminopeptidases (LAPs) were associated with tumor cell proliferation, invasion and/or angiogenesis. LAP3 is one important member of this family. However, its clinical significance and biological function in hepatocellular carcinoma (HCC) remains unknown. In the present study, we demonstrated that LAP3 expression was significantly up-regulated in HCC tissues as well as cells and was closely correlated with lower differentiation, positive lymph node metastasis and high Ki-67 expression, indicating a poor prognosis. Then cell viability assays, flow cytometry assays, wound-healing assays and matrigel invasion assays were performed to demonstrate that LAP3 promoted HCC cells proliferation by regulating G1/S checkpoint in cell cycle and advanced HCC cells migration. Furthermore, we discovered that knockdown LAP3 will enhance the sensitivity of HCC cells to cisplatin, thus promoting the cell death of HCC cells. Collectively, our results indicated that up-regulated expression of LAP3 might contribute to the proliferation and metastasis of HCC. Our data gains greater insight into the cancer-promoting role of LAP3 and its functions in HCC cells, possibly providing potential therapeutic strategies for clinical trials.
PMCID: PMC4128986  PMID: 25120751
Hepatocellular carcinoma (HCC); LAP3; prognosis; proliferation; migration
11.  Extranodal Rosai-Dorfman disease involving the right atrium in a 60-year-old male 
Diagnostic Pathology  2014;9:115.
Rosai-Dorfman disease (RDD) involving the cardiovascular system is extremely rare; to our knowledge, there are only 9 cases in the literature. Here, a case of a 60-year-old male with RDD involving the right atrium is presented. A comprehensive literature review was undertaken to summarize the clinical and pathologic features of this disorder.
Virtual Slides
The virtual slide(s) for this article can be found here:
PMCID: PMC4067074  PMID: 24916611
Rosai-Dorfman disease; Right atrium; Differential diagnosis
12.  Adrenergic β2-Receptors Mediates Visceral Hypersensitivity Induced by Heterotypic Intermittent Stress in Rats 
PLoS ONE  2014;9(4):e94726.
Chronic visceral pain in patients with irritable bowel syndrome (IBS) has been difficult to treat effectively partially because its pathophysiology is not fully understood. Recent studies show that norepinephrine (NE) plays an important role in the development of visceral hypersensitivity. In this study, we designed to investigate the role of adrenergic signaling in visceral hypersensitivity induced by heterotypical intermittent stress (HIS). Abdominal withdrawal reflex scores (AWRs) used as visceral sensitivity were determined by measuring the visceromoter responses to colorectal distension. Colon-specific dorsal root ganglia neurons (DRGs) were labeled by injection of DiI into the colon wall and were acutely dissociated for whole-cell patch-clamp recordings. Blood plasma level of NE was measured using radioimmunoassay kits. The expression of β2-adrenoceptors was measured by western blotting. We showed that HIS-induced visceral hypersensitivity was attenuated by systemic administration of a β-adrenoceptor antagonist propranolol, in a dose-dependent manner, but not by a α-adrenoceptor antagonist phentolamine. Using specific β–adrenoceptor antagonists, HIS-induced visceral hypersensitivity was alleviated by β2 adrenoceptor antagonist but not by β1- or β3-adrenoceptor antagonist. Administration of a selective β2-adrenoceptor antagonist also normalized hyperexcitability of colon-innervating DRG neurons of HIS rats. Furthermore, administration of β-adrenoceptor antagonist suppressed sustained potassium current density (IK) without any alteration of fast-inactivating potassium current density (IA). Conversely, administration of NE enhanced the neuronal excitability and produced visceral hypersensitivity in healthy control rats, and blocked by β2-adrenoceptor antagonists. In addition, HIS significantly enhanced the NE concentration in the blood plasma but did not change the expression of β2-adrenoceptor in DRGs and the muscularis externa of the colon. The present study might provide a potential molecular target for therapy of visceral hypersensitivity in patents with IBS.
PMCID: PMC3986230  PMID: 24733123
13.  Heterozygous alleles restore male fertility to cytoplasmic male-sterile radish (Raphanus sativus L.): a case of overdominance 
Journal of Experimental Botany  2013;64(7):2041-2048.
The practice of hybridization has greatly contributed to the increase in crop productivity. A major component that exploits heterosis in crops is the cytoplasmic male sterility (CMS)/nucleus-controlled fertility restoration (Rf) system. Through positional cloning, it is shown that heterozygous alleles (RsRf3-1/RsRf3-2) encoding pentatricopeptide repeat (PPR) proteins are responsible for restoring fertility to cytoplasmic male-sterile radish (Raphanus sativus L.). Furthermore, it was found that heterozygous alleles (RsRf3-1/RsRf3-2) show higher expression and RNA polymerase II occupancy in the CMS cytoplasmic background compared with their homozygous alleles (RsRf3-1/RsRf3-1 or RsRf3-2/RsRf3-2). These data provide new insights into the molecular mechanism of fertility restoration to cytoplasmic male-sterile plants and illustrate a case of overdominance.
PMCID: PMC3638831  PMID: 23630327
Cytoplasmic male sterility; fertility restoration; heterozygous alleles; overdominance; radish.
14.  Elevated Interleukin-32 Expression Is Associated with Helicobacter pylori-Related Gastritis 
PLoS ONE  2014;9(3):e88270.
Interleukin-32 (IL-32) is a recently discovered proinflammatory cytokine involved in inflammatory diseases. We investigated the expression of IL-32 and its regulation mechanism in the inflammatory response of patients with Helicobacter pylori (H. pylori) infection.
Design and Methods
IL-32 mRNA and protein expression in gastric tissues was detected by quantitative real-time PCR and immunohistochemistry. The regulation of IL-32 in human gastric epithelia cell line AGS was investigated by different cytokine stimulation and different H. pylori strain infection.
Gastric IL-32 mRNA and protein expression were elevated in patients with H. pylori infection and positively correlated with gastritis. In H. pylori-infected patients, the mRNA level of IL-32 was also correlated with that of proinflammatory cytokines IL-1β and TNF-α. In vitro IL-1β and TNF-α could upregulate IL-32 mRNA and protein level in AGS cells, which was dependent on NF-κB signal pathway. The regulation of IL-32 expression in response to H. pylori-infection could be weakened by using neutralizing antibodies to block IL-1β and TNF-α. Moreover, H. pylori-infected AGS cells also induced IL-32 mRNA and protein expression, which was dependent on CagA.
IL-32 level is elevated in patients with H. pylori infection and its expression is regulated by proinflammatory stimuli, suggesting that IL-32 may play a role in the pathogenesis of H. pylori-related gastritis.
PMCID: PMC3954549  PMID: 24633341
15.  Impaired social decision making in patients with major depressive disorder 
BMC Psychiatry  2014;14:18.
Abnormal decision-making processes have been observed in patients with major depressive disorder (MDD). However, it is unresolved whether MDD patients show abnormalities in decision making in a social interaction context, in which decisions have actual influences on both the self-interests of the decision makers per se and those of their partners.
Using a well-studied ultimatum game (UG), which is frequently used to investigate social interaction behavior, we examined whether MDD can be associated with abnormalities in social decision-making behavior by comparing the acceptance rates of MDD patients (N = 14) with those of normal controls (N = 19).
The acceptance rates of the patients were lower than those of the normal controls. Additionally, unfair proposals were accepted at similar rates from computer partners and human partners in the MDD patients, unlike the acceptance rates in the normal controls, who were able to discriminatively treat unfair proposals from computer partners and human partners.
Depressed patients show abnormal decision-making behavior in a social interaction context. Several possible explanations, such as increased sensitivity to fairness, negative emotional state and disturbed affective cognition, have been proposed to account for the abnormal social decision-making behavior in patients with MDD. This aberrant social decision-making behavior may provide a new perspective in the search to find biomarkers for the diagnosis and prognosis of MDD.
PMCID: PMC3904421  PMID: 24450703
Ultimatum game; Major depressive disorder; Decision making; Fairness
16.  The neural correlates of risk propensity in males and females using resting-state fMRI 
Men are more risk prone than women, but the underlying basis remains unclear. To investigate this question, we developed a trait-like measure of risk propensity which we correlated with resting-state functional connectivity to identify sex differences. Specifically, we used short- and long-range functional connectivity densities to identify associated brain regions and examined their functional connectivities in resting-state functional magnetic resonance imaging (fMRI) data collected from a large sample of healthy young volunteers. We found that men had a higher level of general risk propensity (GRP) than women. At the neural level, although they shared a common neural correlate of GRP in a network centered at the right inferior frontal gyrus, men and women differed in a network centered at the right secondary somatosensory cortex, which included the bilateral dorsal anterior/middle insular cortices and the dorsal anterior cingulate cortex. In addition, men and women differed in a local network centered at the left inferior orbitofrontal cortex. Most of the regions identified by this resting-state fMRI study have been previously implicated in risk processing when people make risky decisions. This study provides a new perspective on the brain-behavioral relationships in risky decision making and contributes to our understanding of sex differences in risk propensity.
PMCID: PMC3904110  PMID: 24478649
functional connectivity; functional magnetic resonance imaging; resting state; risk propensity; sex difference
17.  Money talks: neural substrate of modulation of fairness by monetary incentives 
A unique feature of the human species is compliance with social norms, e.g., fairness, even though this normative decision means curbing self-interest. However, sometimes people prefer to pursue wealth at the expense of moral goodness. Specifically, deviations from a fairness-related normative choice have been observed in the presence of a high monetary incentive. The neural mechanism underlying this deviation from the fairness-related normative choice has yet to be determined. In order to address this issue, using functional magnetic resonance imaging we employed an ultimatum game (UG) paradigm in which fairness and a proposed monetary amount were orthogonally varied. We found evidence for a significant modulation by the proposed amount on fairness in the right lateral prefrontal cortex (PFC) and the bilateral insular cortices. Additionally, the insular subregions showed dissociable modulation patterns. Inter-individual differences in the modulation effects in the left inferior frontal gyrus (IFG) accounted for inter-individual differences in the behavioral modulation effect as measured by the rejection rate, supporting the concept that the PFC plays a critical role in making fairness-related normative decisions in a social interaction condition. Our findings provide neural evidence for the modulation of fairness by monetary incentives as well as accounting for inter-individual differences.
PMCID: PMC4017157  PMID: 24834034
fairness; insula; lateral prefrontal cortex; normative decision; ultimatum game
18.  Decreasing ventromedial prefrontal cortex deactivation in risky decision making after simulated microgravity: effects of −6° head-down tilt bed rest 
Space is characterized by risk and uncertainty. As humans play an important role in long-duration space missions, the ability to make risky decisions effectively is important for astronauts who spend extended time periods in space. The present study used the Balloon Analog Risk Task to conduct both behavioral and fMRI experiments to evaluate the effects of simulated microgravity on individuals' risk-taking behavior and the neural basis of the effect. The results showed that participants' risk-taking behavior was not affected by bed rest. However, we found that the ventromedial prefrontal cortex (VMPFC) showed less deactivation after bed rest and that the VMPFC activation in the active choice condition showed no significant difference between the win outcome and the loss outcome after bed rest, although its activation was significantly greater in the win outcome than in the loss outcome before bed rest. These results suggested that the participants showed a decreased level of value calculation after the bed rest. Our findings can contribute to a better understanding of the effect of microgravity on individual higher-level cognitive functioning.
PMCID: PMC4034329  PMID: 24904338
risk; BART; fMRI; bed rest; ventromedial prefrontal cortex
19.  Disrupted resting-state functional architecture of the brain after 45-day simulated microgravity 
Long-term spaceflight induces both physiological and psychological changes in astronauts. To understand the neural mechanisms underlying these physiological and psychological changes, it is critical to investigate the effects of microgravity on the functional architecture of the brain. In this study, we used resting-state functional MRI (rs-fMRI) to study whether the functional architecture of the brain is altered after 45 days of −6° head-down tilt (HDT) bed rest, which is a reliable model for the simulation of microgravity. Sixteen healthy male volunteers underwent rs-fMRI scans before and after 45 days of −6° HDT bed rest. Specifically, we used a commonly employed graph-based measure of network organization, i.e., degree centrality (DC), to perform a full-brain exploration of the regions that were influenced by simulated microgravity. We subsequently examined the functional connectivities of these regions using a seed-based resting-state functional connectivity (RSFC) analysis. We found decreased DC in two regions, the left anterior insula (aINS) and the anterior part of the middle cingulate cortex (MCC; also called the dorsal anterior cingulate cortex in many studies), in the male volunteers after 45 days of −6° HDT bed rest. Furthermore, seed-based RSFC analyses revealed that a functional network anchored in the aINS and MCC was particularly influenced by simulated microgravity. These results provide evidence that simulated microgravity alters the resting-state functional architecture of the brains of males and suggest that the processing of salience information, which is primarily subserved by the aINS–MCC functional network, is particularly influenced by spaceflight. The current findings provide a new perspective for understanding the relationships between microgravity, cognitive function, autonomic neural function, and central neural activity.
PMCID: PMC4046318  PMID: 24926242
anterior insula; cingulate cortex; head-down tilt bed rest; functional magnetic resonance imaging (fMRI); functional connectivity; resting state
20.  Baseline Prognostic Factors and Statistic Model to Predict Early Virological Response in Telbivudine-Treated Patients With Chronic Hepatitis B 
Hepatitis Monthly  2013;13(12):e15573.
Hepatitis B virus (HBV) infection is still a worldwide disease, which may cause liver cirrhosis or even hepatocellular carcinoma. Telbivudine is a potent nucleoside analogue used in the treatment of chronic hepatitis B (CHB); however, drug resistance has remained a challenge. As early virological response can predict long-term efficacy of nucleotide analogue treatment, numerous studies have been conducted in this area.
The aim of this study was to establish baseline prognostic factors and a statistical model to predict early virological response in telbivudine-treated CHB patients.
Patients and Methods:
One hundred and eight CHB patients without any experience of nucleotide analogue therapy were assigned to receive telbivudine (600 mg, once daily) for at least 24 weeks, and then were followed up every two weeks. Cox proportional hazard regression model analyses were employed to evaluate baseline variables, and further developing a statistical model to predict early virological response.
Negative family history of HBV infection (P = 0.000235), baseline higher serum TBIL (P = 0.038714) and AST (P = 0.020684) concentrations, and lower level of HBV-DNA (P = 0.0034784) were identified to be associated with higher possibility of early virological response. A model was established based on these variables to calculate the risk scores (R) for CHB patients. R > -0.38 suggested early virological response to telbivudine. The model was validated among an independent set of 20 patients.
Family history as well as baseline bilirubin, AST and HBV DNA levels can predict early virological response. The model provides a better tool for response prediction based on the four prognostic factors.
PMCID: PMC3877653  PMID: 24403918
Hepatitis B, Chronic; Telbivudine; Proportional Hazards Models; Virology
21.  Differential Nrf2 expression between glioma stem cells and non-stem-like cells in glioblastoma 
Oncology Letters  2013;7(3):693-698.
Glioblastoma multiforme (GBM), the most commonly occurring primary intracranial tumor, is associated with a negative outcome, regardless of the availability of multimodal therapies. However, the identification of glioma stem cells (GSCs), which are small groups of cells within the GBM, has resulted in novel avenues for research. GSCs are resistant to numerous types of environmental stress, such as irradiation, antitumor drugs and hypoxia. Nuclear factor erythroid 2-related factor 2 (Nrf2) has a significant role the cellular response to oxidative stress and previous studies have supported the significance of Nrf2 in GBM; however, the role of Nrf2 in GSCs remains unclear. In the present study, Nrf2 in CD133− GBM cells and CD133+ GSCs from GBM were compared. GSCs from GBM, which express the surface marker CD133, were separated by magnetic cell sorting and analyzed by immunofluorescence in 24-well clusters and cell counting using flow cytometry. The expression of Nrf2 was detected at the transcriptional and translational levels in CD133+ and CD133− cells, and the result indicated that GSCs were successfully isolated from the GBM. The percentage of tumor stem cells in total cells was between 0.49 and 0.91%. Nrf2 was overexpressed in CD133+ GSCs when compared with CD133− GBM cells, which indicated that the expression of Nrf2 in GSCs was closely correlated with malignant proliferation and differentiation of the GBM. Therefore, it was concluded that Nrf2 may be a potential biomarker and rational therapeutic target in GBM.
PMCID: PMC3919893  PMID: 24527074
glioblastoma; glioma stem cell; nuclear factor erythroid 2-related factor 2
22.  Structural Propensities of Human Ubiquitination Sites: Accessibility, Centrality and Local Conformation 
PLoS ONE  2013;8(12):e83167.
The existence and function of most proteins in the human proteome are regulated by the ubiquitination process. To date, tens of thousands human ubiquitination sites have been identified from high-throughput proteomic studies. However, the mechanism of ubiquitination site selection remains elusive because of the complicated sequence pattern flanking the ubiquitination sites. In this study, we perform a systematic analysis of 1,330 ubiquitination sites in 505 protein structures and quantify the significantly high accessibility and unexpectedly high centrality of human ubiquitination sites. Further analysis suggests that the higher centrality of ubiquitination sites is associated with the multi-functionality of ubiquitination sites, among which protein-protein interaction sites are common targets of ubiquitination. Moreover, we demonstrate that ubiquitination sites are flanked by residues with non-random local conformation. Finally, we provide quantitative and unambiguous evidence that most of the structural propensities contain specific information about ubiquitination site selection that is not represented by the sequence pattern. Therefore, the hypothesis about the structural level of the ubiquitination site selection mechanism has been substantially approved.
PMCID: PMC3859641  PMID: 24349449
23.  Plasma glutamate–modulated interaction of A2AR and mGluR5 on BMDCs aggravates traumatic brain injury–induced acute lung injury 
Activation of adenosine A2A receptor aggravates lung damage in a neurogenic mouse model of acute lung injury (ALI) but protects against nonneurogenic ALI.
The bone marrow–derived cell (BMDC)–associated inflammatory response plays a key role in the development of acute lung injury (ALI). Activation of adenosine A2A receptor (A2AR) is generally considered to be antiinflammatory, inhibiting BMDC activities to protect against ALI. However, in the present study, we found that in a mouse model of neurogenic ALI induced by severe traumatic brain injury (TBI), BMDC A2AR exerted a proinflammatory effect, aggravating lung damage. This is in contrast to the antiinflammatory effect observed in the mouse oleic acid–induced ALI model (a nonneurogenic ALI model.) Moreover, the A2AR agonist CGS21680 aggravated, whereas the antagonist ZM241385 attenuated, the severe TBI-induced lung inflammatory damage in mice. Further investigation of white blood cells isolated from patients or mouse TBI models and of cultured human or mouse neutrophils demonstrated that elevated plasma glutamate after severe TBI induced interaction between A2AR and the metabotropic glutamate receptor 5 (mGluR5) to increase phospholipase C–protein kinase C signaling, which mediated the proinflammatory effect of A2AR. These results are in striking contrast to the well-known antiinflammatory and protective role of A2AR in nonneurogenic ALI and indicate different therapeutic strategies should be used for nonneurogenic and neurogenic ALI treatment when targeting A2AR.
PMCID: PMC3620361  PMID: 23478188
24.  Molecular and phylogenetic analysis of the porcine kobuvirus VP1 region using infected pigs from Sichuan Province, China 
Virology Journal  2013;10:281.
Porcine kobuvirus (PKoV) is a member of the Kobuvirus genus within the Picornaviridae family. PKoV is distributed worldwide with high prevalence in clinically healthy pigs and those with diarrhea.
Fecal and intestinal samples (n = 163) from pig farms in Sichuan Province, China were obtained to determine the presence of PKoV using reverse transcription polymerase chain reaction assays. Specific primers were used for the amplification of the gene encoding the PKoV VP1 protein sequence. Sequence and phylogenetic analyses were conducted to clarify evolutionary relationships with other PKoV strains.
Approximately 53% (87/163) of pigs tested positive for PKoV. PKoV was widespread in asymptomatic pigs and those with diarrhea. A high prevalence of PKoV was observed in pigs younger than 4 weeks and in pigs with diarrhea. Phylogenetic analysis of 36 PKoV VP1 protein sequences showed that Sichuan PKoV strains formed four distinct clusters. Two pigs with diarrhea were found to be co-infected with multiple PKoV strains. Sequence and phylogenetic analyses revealed diversity within the same host and between different hosts. Significant recombination breakpoints were observed between the CHN/SC/31-A1 and CHN/SC/31-A3 strains in the VP1 region, which were isolated from the same sample.
PKoV was endemic in Sichuan Province regardless of whether pigs were healthy or suffering from diarrhea. Based on our statistical analyses, we suggest that PKoV was the likely causative agent of high-mortality diarrhea in China from 2010. For the first time, we provide evidence for the co-existence of multiple PKoV strains in one pig, and possible recombination events in the VP1 region. Our findings provide further insights into the molecular properties of PKoV, along with its epidemiology.
PMCID: PMC3847588  PMID: 24025093
Porcine kobuvirus; VP1 protein; Diarrhea; Phylogenetic analysis; Co-infection; Recombination
25.  Function and expression of prolyl hydroxylase 3 in cancers 
Hypoxia inducible factor (HIF) is a product of tumor cells that plays an important role in protecting tumor cells and adjusting to low oxygen tension through driving the progression and aggressiveness of tumors and changing the growth, angiogenesis, differentiation and metastasis of tumors. Prolyl hydroxylase 3 (PHD3) is a member of PHDs that are induced in hypoxia. Many studies have shown that PHD3 not only can hydroxylate HIF-1α, but also has various other biological functions. Thus PHD3 plays significant roles in suppressing the growth, angiogenesis, differentiation and metastasis of tumors and promoting apoptosis of tumors under hypoxic conditions. It may become a new tumor suppressor gene and also may become a new approach to investigate tumors.
PMCID: PMC3776186  PMID: 24049515
prolyl hydroxylase 3; cancer; hypoxia inducible factors

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