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1.  Fatty Acid Oxidation Disorders in a Chinese Population in Taiwan 
JIMD Reports  2013;11:165-172.
Background: Fatty acid oxidation (FAO) disorders are a heterogeneous group of inborn errors in the transportation and oxidation of fatty acids. FAO disorders were thought to be very rare in the Chinese population. Newborn screening for FAO disorders beginning in 2002 in Taiwan may have increased the diagnosis of this group of diseases.
Materials and Methods: Till 2012, the National Taiwan University Hospital Newborn Screening Center screened more than 800,000 newborns for FAO disorders. Both patients diagnosed through screening and patients detected after clinical manifestations were included in this study.
Results: A total of 48 patients with FAO disorders were identified during the study period. The disorders included carnitine palmitoyltransferase I deficiency, carnitine acylcarnitine translocase deficiency, carnitine palmitoyltransferase II deficiency, very long-chain acyl-CoA dehydrogenase deficiency, medium-chain acyl-CoA dehydrogenase deficiency, multiple acyl-CoA dehydrogenase deficiency, short-chain defects, and carnitine uptake defect. Thirty-nine patients were diagnosed through newborn screening. Five false-negative newborn screening cases were noted during this period, and four patients who were not screened were diagnosed based on clinical manifestations. The ages of all patients ranged from 6 months to 22.9 years (mean age 6.6 years). Except for one case of postmortem diagnosis, there were no other mortalities.
Conclusions: The combined incidence of FAO disorders estimated by newborn screening in the Chinese population in Taiwan is 1 in 20,271 live births. Newborn screening also increases the awareness of FAO disorders and triggers clinical diagnoses of these diseases.
PMCID: PMC3755561  PMID: 23700290
3.  Development of a Canadian socioeconomic status index for the study of health outcomes related to environmental pollution 
BMC Public Health  2015;15:714.
Socioeconomic status (SES) is an important determinant of health and potential modifier of the effects of environmental contaminants. There has been a lack of comprehensive indices for measuring overall SES in Canada. Here, a more comprehensive SES index is developed aiming to support future studies exploring health outcomes related to environmental pollution in Canada.
SES variables (n = 22, Census Canada 2006) were selected based on: cultural identities, housing characteristics, variables identified in Canadian environmental injustice studies and a previous deprivation index (Pampalon index). Principal component analysis with a single varimax rotation (factor loadings ≥ │60│) was performed on SES variables for 52974 census dissemination areas (DA). The final index was created by averaging the factor scores per DA according to the three components retained. The index was validated by examining its association with preterm birth (gestational age < 37 weeks), term low birth weight (LBW, <2500 g), small for gestational age (SGA, <10 percentile of birth weight for gestational age) and PM2.5 (particulate matter ≤ 2.5 μm) exposures in Edmonton, Alberta (1999–2008).
Index values exhibited a relatively normal distribution (median = 0.11, mean = 0.0, SD = 0.58) across Canada. Values in Alberta tended to be higher than in Newfoundland and Labrador, Northwest Territories and Nunavut (Pearson chi-square p < 0.001 across provinces). Lower quintiles of our index and the Pampalon’s index confirmed know associations with a higher prevalence of LBW, SGA, preterm birth and PM2.5 exposure. Results with our index exhibited greater statistical significance and a more consistent gradient of PM2.5 levels and prevalence of pregnancy outcomes.
Our index reflects more dimensions of SES than an earlier index and it performed superiorly in capturing gradients in prevalence of pregnancy outcomes. It can be used for future research involving environmental pollution and health in Canada.
Electronic supplementary material
The online version of this article (doi:10.1186/s12889-015-1992-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4517649  PMID: 26215141
Socioeconomic status; Environment; Health
4.  Hepatitis B surface antigen levels of cessation of nucleos(t)ide analogs associated with virological relapse in hepatitis B surface antigen-negative chronic hepatitis B patients 
AIM: To investigate the virological relapse rate in hepatitis B e antigen (HBeAg)-negative patients after antiviral therapy discontinuation and analyze the factors associated with virological relapse.
METHODS: Among patients diagnosed with chronic hepatitis B infection between May 2005 and July 2010, 204 were eligible for analysis. The Kaplan-Meier method and log-rank test were used to calculate the cumulative rate of relapse and compare cumulative relapse rates between groups. The Cox proportional hazards regression model was used to evaluate the predictive factor of virological relapse.
RESULTS: The 2 and 1 year cumulative risks of virological relapse after antiviral therapy discontinuation were 79.41% (162/204) and 43.82% (71/162), respectively. Multivariate analysis revealed that only post treatment hepatitis B surface antigen (HBsAg) level was associated with virological relapse (P = 0.011). The cumulative risk of virological relapse was higher in the patients with HBsAg levels ≥ 1500 IU/L than in those with HBsAg levels < 1500 IU/L (P = 0.0013). The area under the curve was 0.603 (P = 0.033). The cutoff HBsAg value for predicting virological relapse was 1443 IU/L.
CONCLUSION: We found that the virological relapse rate remained high after antiviral therapy discontinuation in the HBeAg-negative patients and that the post treatment HBsAg levels predicted virological relapse.
PMCID: PMC4515846
Chronic hepatitis B; Virological relapse; Hepatitis B surface antigen
5.  De Novo Assembly and Annotation of the Chinese Chive (Allium tuberosum Rottler ex Spr.) Transcriptome Using the Illumina Platform 
PLoS ONE  2015;10(7):e0133312.
Chinese chive (A. tuberosum Rottler ex Spr.) is one of the most widely cultivated Allium species in China. However, minimal transcriptomic and genomic data are available to reveal its evolution and genetic diversity. In this study, de novo transcriptome sequencing was performed to produce large transcript sequences using an Illumina HiSeq 2000 instrument. We produced 51,968,882 high-quality clean reads and assembled them into 150,154 contigs. A total of 60,031 unigenes with an average length of 631 bp were identified. Of these, 36,523 unigenes were homologous to existing database sequences, 35,648 unigenes were annotated in the NCBI non-redundant (Nr) sequence database, and 23,509 unigenes were annotated in the Swiss-Prot database. A total of 26,798 unigenes were assigned to 57 Gene Ontology (GO) terms, and 13,378 unigenes were assigned to Cluster of Orthologous Group categories. Using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database, we mapped 21,361 unigenes onto 128 pathways. Furthermore, 2,125 sequences containing simple sequence repeats (SSRs) were identified. This new dataset provides the most comprehensive resource currently available for gene expression, gene discovery, and future genomic research on Chinese chive. The sequence resources developed in this study can be used to develop molecular markers that will facilitate further genetic research on Chinese chive and related species.
PMCID: PMC4512717  PMID: 26204518
6.  Pulsed Electron Paramagnetic Resonance Study of Domain Docking in Neuronal Nitric Oxide Synthase: The Calmodulin and Output State Perspective 
The Journal of Physical Chemistry. a  2014;118(34):6864-6872.
The binding of calmodulin (CaM) to neuronal nitric oxide synthase (nNOS) enables formation of the output state of nNOS for nitric oxide production. Essential to NOS function is the geometry and dynamics of CaM docking to the NOS oxygenase domain, but little is known about these details. In the present work, the domain docking in a CaM-bound oxygenase/FMN (oxyFMN) construct of nNOS was investigated using the relaxation-induced dipolar modulation enhancement (RIDME) technique, which is a pulsed electron paramagnetic resonance technique sensitive to the magnetic dipole interaction between the electron spins. A cysteine was introduced at position 110 of CaM, after which a nitroxide spin label was attached at the position. The RIDME study of the magnetic dipole interaction between the spin label and the ferric heme centers in the oxygenase domain of nNOS revealed that, with increasing [Ca2+], the concentration of nNOS·CaM complexes increases and reaches a maximum at [Ca2+]/[CaM] ≥ 4. The RIDME kinetics of CaM-bound nNOS represented monotonous decays without well-defined oscillations. The analysis of these kinetics based on the structural models for the open and docked states has shown that only about 15 ± 3% of the CaM-bound nNOS is in the docked state at any given time, while the remaining 85 ± 3% of the protein is in the open conformations characterized by a wide distribution of distances between the bound CaM and the oxygenase domain. The results of this investigation are consistent with a model that the Ca2+–CaM interaction causes CaM docking with the oxygenase domain. The low population of the docked state indicates that the CaM-controlled docking between the FMN and heme domains is highly dynamic.
PMCID: PMC4148148  PMID: 25046446
7.  Effects of Nt-truncation and coexpression of isolated Nt domains on the membrane trafficking of electroneutral Na+/HCO3– cotransporters 
Scientific Reports  2015;5:12241.
The SLC4 genes are all capable of producing multiple variants by alternative splicing or using alternative promoters. The physiological consequences of such diversity are of great interest to investigators. Here, we identified two novel variants of the electroneutral Na+/ cotransporter NBCn1, one full-length starting with “MIPL” and the other Nt-truncated starting with “MDEL”. Moreover, we identified a new promoter of Slc4a10 encoding NBCn2 and a novel type of Nt-truncated NBCn2 starting with “MHAN”. When heterologously expressed, the new NBCn1 variants were well localized to the plasma membrane and exhibited characteristic NBCn1 activity. However, MHAN-NBCn2 was poorly localized on the plasma membrane. By deletion mutations, we identified the Nt regions important for the surface localization of NBCn2. Interestingly, coexpressing the full-length NBCn2 greatly enhances the surface abundance of the Nt-truncated NBCn2. Co-immunoprecipitation and bimolecular fluorescence complementation studies showed that the full-length and Nt-truncated NBCn2 interact with each other to form heterodimers in neuro-2A cells. Finally, we showed that the isolated Nt domain interacts with and enhances the surface abundance of the Nt-truncated NBCn2. The present study expands our knowledge of the NBCn1 and NBCn2 transcriptome, and provides insights into how the Nt domain could affect transporter function by regulating its membrane trafficking.
PMCID: PMC4507446  PMID: 26192895
8.  The THERMOSENSITIVE MALE STERILE 1 Interacts with the BiPs via DnaJ Domain and Stimulates Their ATPase Enzyme Activities in Arabidopsis 
PLoS ONE  2015;10(7):e0132500.
The Arabidopsis TMS1 encodes a heat shock protein identical to the Hsp40 protein AtERdj3A and plays important roles in the thermotolerance of pollen tubes and other plant tissues. Despite its importance to plant growth and reproduction, little has been known about its mechanisms underlying thermotolerance of plants. In this study, the relationship between TMS1 and the Hsp70 proteins, Binding Immunoglobulin Proteins (BiPs) was explored to understand the molecular mechanisms of TMS1 in thermotolerance of plants. The expression of TMS1 was induced not only by heat shock, but also by dithiothreitol (DTT) and L-azetidine-2-carboxylic acid (AZC), similarly to the three BiP genes, indicating that TMS1 may be involved in unfolded protein response (UPR). The firefly luciferase complementary imaging (LCI), GST pull-down and ATPase enzyme activity assays demonstrated that the DnaJ domain of TMS1 could interact with BiP1 and BiP3, and could stimulate their ATPase enzyme activities. In addition, the expression level of TMS1 was reduced in the bzip28 bzip60 double mutant. These results suggest that TMS1 may function at the downstream of bZIP28 and bZIP60 and be involved in termotolerance of plants, possibly by participating in refolding or degradation of unfolded and misfolded proteins through interaction with the BiPs.
PMCID: PMC4505944  PMID: 26186593
9.  Effect of Intravenous Iron Supplementation on Acute Mountain Sickness: A Preliminary Randomized Controlled Study 
The aim of this study was to assess the role of intravenous iron supplementation in the prevention of AMS.
This was a randomized, double-blinded, placebo-controlled study. Forty-one (n=41) healthy Chinese low-altitude inhabitants living in Beijing, China (altitude of about 50 meters) were randomly assigned into intravenous iron supplementation (ISS group; n=21) and placebo (CON group; n=20) groups. Participants in the ISS group received iron sucrose supplement (200 mg) before flying to Lhasa, China (altitude of 4300 meters). Acute mountain sickness (AMS) severity was assessed with the Lake Louise scoring (LLS) system within 5 days after landing on the plateau (at high altitude). Routine check-ups, clinical biochemistry, and blood tests were performed before departure and 24 h after arrival.
A total of 38 participants completed the study (ISS group: n=19; CON group: n=19). The rate of subjects with AMS (LLS>3) was lower in the ISS group compared with the CON group, but no significant differences were obtained (P>0.05). There were no differences in patients’ baseline characteristics. The physiological indices were similar in both groups except for serum iron concentrations (19.44±10.02 vs. 85.10±26.78 μmol/L) and transferrin saturation rates (28.20±12.14 vs. 68.34±33.12%), which were significantly higher in the ISS group (P<0.05). Finally, heart rate was identified as a contributing factor of LLS.
These preliminary findings suggest that intravenous iron supplementation has no significant protective effect on AMS in healthy Chinese low-altitude inhabitants.
PMCID: PMC4515939  PMID: 26175087
Administration, Intravenous; Altitude Sickness; Randomized Controlled Trial
10.  The Semen pH Affects Sperm Motility and Capacitation 
PLoS ONE  2015;10(7):e0132974.
As the chemical environment of semen can have a profound effect on sperm quality, we examined the effect of pH on the motility, viability and capacitation of human sperm. The sperm in this study was collected from healthy males to avoid interference from other factors. The spermatozoa cultured in sperm nutrition solution at pH 5.2, 6.2, 7.2 and 8.2 were analyzed for sperm total motility, progressive motility (PR), hypo-osmotic swelling (HOS) rate, and sperm penetration. Our results showed that these parameters were similar in pH 7.2 and 8.2 sperm nutrition solutions, but decreased in pH 5.2 and 6.2 solutions. The HOS rate exhibited positive correlation with the sperm total motility and PR. In addition, the sperm Na+/K+-ATPase activity at different pHs was measured, and the enzyme activity was significantly lower in pH 5.2 and 6.2 media, comparing with that in pH 8.2 and pH 7.2 solutions. Using flow cytometry (FCM) and laser confocal scanning microscopy (LCSM) analysis, the intracellular Ca2+ concentrations of sperm cultured in sperm capacitation solution at pH 5.2, 6.2, 7.2 and 8.2 were determined. Compared with that at pH 7.2, the mean fluorescence intensity of sperm in pH 5.2 and 6.2 media decreased significantly, while that of pH 8.2 group showed no difference. Our results suggested that the declined Na+/K+-ATPase activity at acidic pHs result in decreased sperm movement and capacitation, which could be one of the mechanisms of male infertility.
PMCID: PMC4501804  PMID: 26173069
11.  Genome-wide identification and Phylogenic analysis of kelch motif containing ACBP in Brassica napus 
BMC Genomics  2015;16(1):512.
Acyl-coA binding proteins (ACBPs) bind long chain acyl-CoA esters with very high affinity. Their possible involvement in fatty acid transportation from the plastid to the endoplasmic reticulum, prior to the formation of triacylglycerol has been suggested. Four classes of ACBPs were identified in Arabidopsis thaliana: the small ACBPs, the large ACBPs, the ankyrin repeats containing ACBPs and the kelch motif containing ACBPs. They differed in structure and in size, and showed multiple important functions. In the present study, Brassica napus ACBPs were identified and characterized.
Eight copies of kelch motif ACBPs were cloned, it showed that B. napus ACBPs shared high amino acid sequence identity with A. thaliana, Brassica rapa and Brassica oleracea. Furthermore, phylogeny based on domain structure and comparison map showed the relationship and the evolution of ACBPs within Brassicaceae family: ACBPs evolved into four separate classes with different structure. Chromosome locations comparison showed conserved syntenic blocks.
ACBPs were highly conserved in Brassicaceae. They evolved from a common ancestor, but domain duplication and rearrangement might separate them into four distinct classes, with different structure and functions. Otherwise, B. napus inherited kelch motif ACBPs from ancestor conserving chromosomal location, emphasizing preserved synteny block region. This study provided a first insight for exploring ACBPs in B. napus, which supplies a valuable tool for crop improvement in agriculture.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1735-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4497377  PMID: 26156054
Acyl-coA binding proteins; kelch motif; Brassica; Evolution; Phylogeny; Chromosome map
12.  Gemcitabine Plus Cisplatin for Advanced Biliary Tract Cancer: A Systematic Review 
Evidence suggests that combined gemcitabine-cisplatin chemotherapy extends survival in patients with advanced biliary tract cancer (BTC). We conducted a systematic review in order to collate this evidence and assess whether gemcitabine-cisplatin efficacy is influenced by primary tumor site, disease stage, or geographic region, and whether associated toxicities are related to regimen. MEDLINE (1946-search date), EMBASE (1966-search date), ClinicalTrials. gov (2008-search date), and abstracts from major oncology conferences (2009- search date) were searched (5 Dec 2013) using terms for BTC, gemcitabine, and cisplatin. All study types reporting efficacy (survival, response rates) or safety (toxicities) outcomes of gemcitabine-cisplatin in BTC were eligible for inclusion; efficacy data were extracted from prospective studies only. Evidence retrieved from one meta-analysis (abstract), four randomized controlled trials, 12 nonrandomized prospective studies, and three retrospective studies supported the efficacy and safety of gemcitabine-cisplatin for BTC. Median overall survival ranged from 4.6 to 11.7 months, and response rate ranged from 17.1% to 36.6%. Toxicities were generally acceptable and manageable. Heterogeneity in study designs and data collected prevented formal meta-analysis, however exploratory assessments suggested that efficacy did not vary with primary tumor site (gallbladder vs. others), disease stage (metastatic vs. locally advanced), or geographic origin (Asia vs. other). Incidence of grade 3/4 toxicities was not related to gemcitabine dose or cisplatin frequency. Despite individual variation in study designs, the evidence presented suggests that gemcitabine-cisplatin is effective in patients from a diverse range of countries and with heterogeneous disease characteristics. No substantial differences in toxicity were observed among the different dosing schedules of gemcitabine and cisplatin.
PMCID: PMC4509359  PMID: 25989801
Biliary tract neoplasms; Cholangiocarcinoma; Cisplatin; Gallbladder neoplasms; Gemcitabine
13.  Optimization and Validation of the TZM-bl Assay for Standardized Assessments of Neutralizing Antibodies Against HIV-1 
The TZM-bl assay measures antibody-mediated neutralization of HIV-1 as a function of reductions in HIV-1 Tat-regulated firefly luciferase (Luc) reporter gene expression after a single round of infection with Env-pseudotyped viruses. This assay has become the main endpoint neutralization assay used for the assessment of preclinical and clinical trial samples by a growing number of laboratories worldwide. Here we present the results of the formal optimization and validation of the TZM-bl assay, performed in compliance with Good Clinical Laboratory Practice (GCLP) guidelines. The assay was evaluated for specificity, accuracy, precision, limits of detection and quantitation, linearity, range and robustness. The validated manual TZM-bl assay was also adapted, optimized and qualified to an automated 384-well format.
PMCID: PMC4040342  PMID: 24291345
Neutralizing Antibody; Assay Validation; HIV; TZM-bl cells; GCLP
14.  NADPH oxidase NOX4 supports renal tumorigenesis by promoting the expression and nuclear accumulation of HIF2α 
Cancer research  2014;74(13):3501-3511.
Most sporadically occurring renal tumors include a functional loss of the tumor suppressor VHL. Development of VHL-deficient renal cell carcinoma (RCC) relies upon activation of the hypoxia-inducible factor HIF-2α, a master transcriptional regulator of genes that drive diverse processes including angiogenesis, proliferation and anaerobic metabolism. In determining the critical functions for HIF-2α expression in RCC cells, the NADPH oxidase NOX4 has been identified, but the pathogenic contributions of NOX4 to RCC have not been evaluated directly. Here we report that NOX4 silencing in VHL-deficient RCC cells abrogates cell branching, invasion, colony formation and growth in a murine xenograft model RCC. These alterations were phenocopied by treatment of the superoxide scavenger, TEMPOL, or by overexpression of manganese superoxide dismutase or catalase. Notably, NOX4 silencing or superoxide scavenging was sufficient to block nuclear accumulation of HIF-2α in RCC cells. Our results offer direct evidence that NOX4 is critical for renal tumorigenesis and they show how NOX4 suppression and VHL re-expression in VHL-deficient RCC cells are genetically synonymous, supporting development of therapeutic regimens aimed at NOX4 blockade.
PMCID: PMC4079760  PMID: 24755467
Nox4; HIF-2α; superoxide scavenger; renal cell carcinoma
15.  A Meta-Analysis of Acupuncture Use in the Treatment of Cognitive Impairment After Stroke 
Objective: This meta-analysis was conducted to evaluate the efficacy of acupuncture on cognitive impairment (function) after a stroke.
Design: Randomized controlled trials (RCTs) comparing acupuncture with no acupuncture in addition to medicine or rehabilitation were identified from databases (PubMed, Cochrane Central Register of Controlled Trials, Chinese National Knowledge Infrastructure, VIP Chinese Periodical Database, Wangfang Chinese Periodical Database, Chinese Bio-medicine Database, Cochrane Library, and Chinese medical literature databases) and two relevant journals (Chinese Acupuncture and Moxibustion and the Journal of Shanghai Acupuncture and Moxibustion). Meta-analyses were conducted for the eligible RCTs.
Results: Twenty-one trials with a total of 1421 patients met inclusion criteria. Pooled random-effects estimates of the change in the Mini-Mental State Examination were calculated for the comparison of acupuncture with no acupuncture in addition to medicine or rehabilitation. Following 4 weeks and 8 weeks of intervention with acupuncture, the merged mean difference was 3.14 (95% confidence interval [CI], 2.06–4.21; p<.00001) and 2.03 (95% CI, 0.26–3.80; p=0.02), respectively. For the comparison of 3–4 weeks of acupuncture with no acupuncture in addition to medicine or rehabilitation groups, the merged MD in Neurobehavioral Cognitive State Examination total scores was 5.63 (95% CI, 3.95–7.31; p<.00001). For the comparison of 8–12 weeks of acupuncture with no acupuncture in addition to medicine or rehabilitation groups, the P300 latency merged MD was −12.80 (95% CI, −21.08 to −4.51; p<.00001), while the P300 amplitude merged MD was 1.38 (95% CI, 0.93–1.82; p<.00001). Overall, the study quality was rated as moderate on the basis of the Cochrane Handbook for Systematic Reviews of Interventions (part 2: 8.5).
Conclusions: This meta-analysis suggests that acupuncture had positive effects on cognitive function after stroke and supports the need for additional research on the potential benefits of this therapeutic approach.
PMCID: PMC4086349  PMID: 24915606
16.  Efficient in vivo deletion of a large imprinted lncRNA by CRISPR/Cas9 
RNA Biology  2014;11(7):829-835.
Recent genome-wide studies have revealed that the majority of the mouse genome is transcribed as non-coding RNAs (ncRNAs) and growing evidence supports the importance of ncRNAs in regulating gene expression and epigenetic processes. However, the low efficiency of conventional gene targeting strategies has hindered the functional study of ncRNAs in vivo, particularly in generating large fragment deletions of long non-coding RNAs (lncRNAs) with multiple expression variants. The bacterial clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) system has recently been applied as an efficient tool for engineering site-specific mutations of protein-coding genes in the genome. In this study, we explored the potential of using the CRISPR/Cas9 system to generate large genomic deletions of lncRNAs in mice. We developed an efficient one-step strategy to target the maternally expressed lncRNA, Rian, on chromosome 12 in mice. We showed that paired sgRNAs can precisely generate large deletions up to 23kb and the deletion efficiency can be further improved up to 33% by combining multiple sgRNAs. The deletion successfully abolished the expression of Rian from the maternally inherited allele, validating the biological relevance of the mutations in studying an imprinted locus. Mutation of Rian has differential effects on expression of nearby genes in different somatic tissues. Taken together, we have established a robust one-step method to engineer large deletions to knockout lncRNA genes with the CRISPR/Cas9 system. Our work will facilitate future functional studies of other lncRNAs in vivo.
PMCID: PMC4179957  PMID: 25137067
CRISPR/Cas9; large fragment deletion; Rian; imprinting; lncRNA
17.  Targeting Nrf2 by dihydro-CDDO-trifluoroethyl amide enhances autophagic clearance and viability of β-cells in a setting of oxidative stress 
FEBS letters  2014;588(12):2115-2124.
Nrf2 appears to be a critical regulator of diabetes in rodents. However, the underlying mechanisms as well as the clinical relevance of the Nrf2 signaling in human diabetes remain to be fully understood. Herein, we report that islet expression of Nrf2 is upregulated at an earlier stage of diabetes in both human and mice. Activation of Nrf2 suppresses oxidative stress and oxidative stress-induced β-cell apoptosis while enhancing autophagic clearance in isolated rat islets. Additionally, oxidative stress per se activated autophagy in β-cells. Thus, these results reveal that Nrf2 drives a novel antioxidant independent autophagic clearance for β-cell protection in the setting of diabetes.
PMCID: PMC4486285  PMID: 24815692
Nrf2; β-Cells; Oxidative stress; Ubiquitination; Autophagy; Diabetes
18.  Complete Genome Sequence of Elizabethkingia meningoseptica, Isolated from a T-Cell Non-Hodgkin’s Lymphoma Patient 
Genome Announcements  2015;3(3):e00673-15.
An Elizabethkingia meningoseptica infection was detected at the end stage of a patient with T-cell non-Hodgkin’s lymphoma. The complete genome of this isolated strain, FMS-007, was generated in one contig with a total size of 3,938,967 bp. A preliminary screening indicated that the genome contains drug resistance genes to aminoglycosides and β-lactams. A clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated proteins (CRISPR/Cas) system with 16 direct repeats and 15 spacers was identified.
PMCID: PMC4481284  PMID: 26112786
19.  C-Peptide Is Independently Associated with an Increased Risk of Coronary Artery Disease in T2DM Subjects: A Cross-Sectional Study 
PLoS ONE  2015;10(6):e0127112.
C-peptide has been reported to be a marker of subclinical atherosclerosis in type 2 diabetes mellitus (T2DM) patients, whereas its role in coronary artery disease (CAD) has not been clarified, especially in diabetics with differing body mass indices (BMIs).
Design and Methods
This cross-sectional study included 501 patients with T2DM. First, all subjects were divided into the following two groups: CAD and non-CAD. Then, binary logistic regression was used to determine the risk factors for CAD for all patients. To clarify the role of obesity, we re-divided all subjects into two additional groups (obese and non-obese) based on BMI. Finally, binary logistic regression was used to determine the risk factors for CAD for each weight group.
The patients with CAD showed a higher BMI and fasting C-peptide level in addition to an increased prevalence of traditional risk factors for CAD, such as hypertension, insulin resistance, higher cholesterol, cysteine-C (Cys-C) and lower estimated glomerular filtration rate (eGFR). Logistic regression analysis showed that fasting C-peptide (OR=1.513, p=0.005), insulin treatment (OR=1.832, p=0.027) hypertension (OR=1.987, p=0.016) and hyperlipidemia (OR=4.159, p<0.001) significantly increased the risk of clinical CAD in the T2DM patients independent of age, gender, diabetes duration, smoking and alcohol statuses, fasting insulin and glucose, hypoglycemic episodes, UA and eGFR. Additionally, in both of the obese (OR=1.488, p=0.049) and non-obese (OR=1.686, p=0.037) DM groups, C-peptide was associated with an increased risk of CAD after multiple adjustments.
C-peptide is associated with an increased CAD risk in T2DM patients, no matter whether they are obese or not.
PMCID: PMC4476669  PMID: 26098780
20.  Response to Kaufman and Harper Letter 
The American journal of psychiatry  2012;169(10):1118-1119.
PMCID: PMC4474188  PMID: 23032391
21.  Functional Operons in Secondary Metabolic Gene Clusters in Glarea lozoyensis (Fungi, Ascomycota, Leotiomycetes) 
mBio  2015;6(3):e00703-15.
Operons are multigene transcriptional units which occur mostly in prokaryotes but rarely in eukaryotes. Protein-coding operons have not been reported in the Fungi even though they represent a very diverse kingdom of organisms. Here, we report a functional operon involved in the secondary metabolism of the fungus Glarea lozoyensis belonging to Leotiomycetes (Ascomycota). Two contiguous genes, glpks3 and glnrps7, encoding polyketide synthase and nonribosomal peptide synthetase, respectively, are cotranscribed into one dicistronic mRNA under the control of the same promoter, and the mRNA is then translated into two individual proteins, GLPKS3 and GLNRPS7. Heterologous expression in Aspergillus nidulans shows that the GLPKS3-GLNRPS7 enzyme complex catalyzes the biosynthesis of a novel pyrrolidinedione-containing compound, xenolozoyenone (compound 1), which indicates the operon is functional. Although it is structurally similar to prokaryotic operons, the glpks3-glnrps7 operon locus has a monophylogenic origin from fungi rather than having been horizontally transferred from prokaryotes. Moreover, two additional operons, glpks28-glnrps8 and glpks29-glnrps9, were verified at the transcriptional level in the same fungus. This is the first report of protein-coding operons in a member of the Fungi.
Operons are multigene transcriptional units which occur mostly in prokaryotes but rarely in eukaryotes. Three operon-like gene structures for secondary metabolism that were discovered in the filamentous fungus Glarea lozoyensis are the first examples of protein-coding operons identified in a member of the Fungi. Among them, the glpks3-glnrps7 operon is responsible for the biosynthesis of xenolozoyenone, which is a novel tetramic acid-containing compound. Although structurally similar to prokaryotic operons, the glpks3-glnrps7 operon locus did not result from horizontal gene transfer from prokaryotes. In addition, operonlike structures have been predicted in silico to be common in other fungi. The common occurrence and operonlike structure in fungi provide evolutionary insight and essential data for eukaryotic gene transcription.
PMCID: PMC4471562  PMID: 26081635
22.  Identification of Influenza A/PR/8/34 Donor Viruses Imparting High Hemagglutinin Yields to Candidate Vaccine Viruses in Eggs 
PLoS ONE  2015;10(6):e0128982.
One of the important lessons learned from the 2009 H1N1 pandemic is that a high yield influenza vaccine virus is essential for efficient and timely production of pandemic vaccines in eggs. The current seasonal and pre-pandemic vaccine viruses are generated either by classical reassortment or reverse genetics. Both approaches utilize a high growth virus, generally A/Puerto Rico/8/1934 (PR8), as the donor of all or most of the internal genes, and the wild type virus recommended for inclusion in the vaccine to contribute the hemagglutinin (HA) and neuraminidase (NA) genes encoding the surface glycoproteins. As a result of extensive adaptation through sequential egg passaging, PR8 viruses with different gene sequences and high growth properties have been selected at different laboratories in past decades. The effect of these related but distinct internal PR8 genes on the growth of vaccine viruses in eggs has not been examined previously. Here, we use reverse genetics to analyze systematically the growth and HA antigen yield of reassortant viruses with 3 different PR8 backbones. A panel of 9 different HA/NA gene pairs in combination with each of the 3 different lineages of PR8 internal genes (27 reassortant viruses) was generated to evaluate their performance. Virus and HA yield assays showed that the PR8 internal genes influence HA yields in most subtypes. Although no single PR8 internal gene set outperformed the others in all candidate vaccine viruses, a combination of specific PR8 backbone with individual HA/NA pairs demonstrated improved HA yield and consequently the speed of vaccine production. These findings may be important both for production of seasonal vaccines and for a rapid global vaccine response during a pandemic.
PMCID: PMC4465931  PMID: 26068666
23.  Unusual apocrine carcinoma with neuroendocrine differentiation: a cutaneous neoplasm may be analogous to neuroendocrine carcinoma with apocrine differentiation of breast 
Diagnostic Pathology  2015;10:64.
Cutaneous apocrine carcinoma (AC) is a rare adnexal neoplasm that histologically can mimic breast carcinoma metastatic to the skin or apocrine carcinoma arising in ectopic breast tissue. As extremely rare condition, neuroendocrine differentiation may be observed in AC although its etiology and pathogenesis is still unclear. We report here a case of unusual AC with neuroendocrine differentiation in right labium majus pudenda. A 43-year-old woman presented with a 6-month history of an asymptomatic pea-sized brownish nodule in right labium majus pudenda without enlargement of inguinal lymph nodes and bilateral breast nodules. The mass was totally resected. Microscopically, the tumor was solitary and located in the deep dermis without epidermal connection. Tumor cells were arranged in a micronodular or formed massive solid nests separated by densely fibroblastic stroma. Scattered glandular or rosette-like structures were identified within the tumor nodules. Immunohistochemically, the tumor cells were diffusely positive to CK7, CEA, GCDFP-15, synaptophysin, estrogen and progesterone receptors. Part of tumor cells expressed androgen receptor, but they were negative to CK20, CK5/6, p63 and S-100. Because of its rarity and histogenesis complexity, there exist diagnostic challenges for pathologists to differentiate cutaneous AC with neuroendocrine differentiation from other carcinomas with apocrine or neuroendocrine features. Our case demonstrates that the tumor shares some features with mammary carcinoma and might originate from mammary-like sweat gland in anogenital region. The results suggest that, for the first time, primary cutaneous AC with neuroendocrine differentiation may be analogous to the mammary neuroendocrine carcinoma with apocrine differentiation in histological feature and biological behavior.
Virtual Slides: The virtual slide(s) for this article can be found here:
PMCID: PMC4460766  PMID: 26055980
Apocrine carcinoma; Neuroendocrine tumor; Neuroendocrine differentiation; Histogenesis; Differential diagnosis
24.  Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors 
Cancer discovery  2014;4(2):216-231.
Despite gains in survival, outcomes for patients with metastatic or recurrent rhabdomyosarcoma (RMS) remain dismal. In a collaboration between the National Cancer Institute, Children's Oncology Group, and Broad Institute, we performed whole-genome, whole-exome and transcriptome sequencing to characterize the landscape of somatic alterations in 147 tumor/normal pairs. Two genotypes are evident in RMS tumors; those characterized by the PAX3 or PAX7 fusion and those that lack these fusions but harbor mutations in key signaling pathways. The overall burden of somatic mutations in RMS is relatively low, especially in tumors that harbor a PAX3/7 gene fusion. In addition to previously reported mutations of NRAS, KRAS, HRAS, FGFR4, PIK3CA, CTNNB1, we found novel recurrent mutations in FBXW7, and BCOR providing potential new avenues for therapeutic intervention. Furthermore, alteration of the receptor tyrosine kinase/RAS/PIK3CA axis affects 93% of cases providing a framework for genomics directed therapies that might improve outcomes for RMS patients.
PMCID: PMC4462130  PMID: 24436047
Rhabdomyosarcoma; whole genome sequencing; whole exome sequencing; RNAseq
25.  Enhanced Antifungal Activity by Ab-Modified Amphotericin B-Loaded Nanoparticles Using a pH-Responsive Block Copolymer 
Fungal infections are an important cause of morbidity and mortality in immunocompromised patients. Amphotericin B (AMB), with broad-spectrum antifungal activity, has long been recognized as a powerful fungicidal drug, but its clinical toxicities mainly nephrotoxicity and poor solubility limit its wide application in clinical practice. The fungal metabolism along with the host immune response usually generates acidity at sites of infection, resulting in loss of AMB activity in a pH-dependent manner. Herein, we developed pH-responsive AMB-loaded and surface charge-switching poly(d,l-lactic-co-glycolic acid)-b-poly(l-histidine)-b-poly(ethylene glycol) (PLGA-PLH-PEG) nanoparticles for resolving the localized acidity problem and enhance the antifungal efficacy of AMB. Moreover, we modified AMB-encapsulated PLGA-PLH-PEG nanoparticles with anti-Candida albicans antibody (CDA) (CDA-AMB-NPs) to increase the targetability. Then, CDA-AMB-NPs were characterized in terms of physical characteristics, in vitro drug release, stability, drug encapsulation efficiency, and toxicity. Finally, the targetability and antifungal activity of CDA-AMB-NPs were investigated in vitro/in vivo. The result demonstrated that CDA-AMB-NPs significantly improve the targetability and bioavailability of AMB and thus improve its antifungal activity and reduce its toxicity. These NPs may become a good drug carrier for antifungal treatment.
PMCID: PMC4486495  PMID: 26061446
Amphotericin B; Targetability; C. albicans; Nanocarrier

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