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1.  Transcriptomic basis for drought-resistance in Brassica napus L. 
Scientific Reports  2017;7:40532.
Based on transcriptomic data from four experimental settings with drought-resistant and drought-sensitive cultivars under drought and well-watered conditions, statistical analysis revealed three categories encompassing 169 highly differentially expressed genes (DEGs) in response to drought in Brassica napus L., including 37 drought-resistant cultivar-related genes, 35 drought-sensitive cultivar-related genes and 97 cultivar non-specific ones. We provide evidence that the identified DEGs were fairly uniformly distributed on different chromosomes and their expression patterns are variety specific. Except commonly enriched in response to various stimuli or stresses, different categories of DEGs show specific enrichment in certain biological processes or pathways, which indicated the possibility of functional differences among the three categories. Network analysis revealed relationships among the 169 DEGs, annotated biological processes and pathways. The 169 DEGs can be classified into different functional categories via preferred pathways or biological processes. Some pathways might simultaneously involve a large number of shared DEGs, and these pathways are likely to cross-talk and have overlapping biological functions. Several members of the identified DEGs fit to drought stress signal transduction pathway in Arabidopsis thaliana. Finally, quantitative real-time PCR validations confirmed the reproducibility of the RNA-seq data. These investigations are profitable for the improvement of crop varieties through transgenic engineering.
doi:10.1038/srep40532
PMCID: PMC5238399  PMID: 28091614
2.  Gastroprotective [6]-Gingerol Aspirinate as a Novel Chemopreventive Prodrug of Aspirin for Colon Cancer 
Scientific Reports  2017;7:40119.
A growing body of research suggests daily low-dose aspirin (ASA) reduces heart diseases and colorectal cancers. However, the major limitation to the use of aspirin is its side effect to cause ulceration and bleeding in the gastrointestinal tract. Preclinical studies have shown that ginger constituents ameliorate ASA-induced gastric ulceration. We here report the design and synthesis of a novel prodrug of aspirin, [6]-gingerol aspirinate (GAS). Our data show that GAS exerts enhanced anti-cancer properties in vitro and superior gastroprotective effects in mice. GAS was also able to survive stomach acid and decomposed in intestinal linings or after absorption to simultaneously release ASA and [6]-gingerol. We further present that GAS inactivates both COX-1 and COX-2 equally. Our results demonstrate the enhanced anticancer properties along with gastroprotective effects of GAS, suggesting that GAS can be a therapeutic equivalent for ASA in inflammatory and proliferative diseases without the deleterious effects on stomach mucosa.
doi:10.1038/srep40119
PMCID: PMC5220309  PMID: 28067282
3.  Evolutionary phylogeography and transmission pattern of echovirus 14: an exploration of spatiotemporal dynamics based on the 26-year acute flaccid paralysis surveillance in Shandong, China 
BMC Genomics  2017;18:48.
Background
Echovirus 14 (E-14) causes various clinical recognized syndromes, mostly with gastrointestinal syndrome and paralysis. The current study summarized the Shandong E-14 strains isolated from a 26-year acute flaccid paralysis (AFP) surveillance, and elucidated the characterization of phylogenetic and phylogeographic relationships of E-14 worldwide.
Results
As a predominant serotype circulating in AFP surveillance, phylogenetic analysis showed that E-14 exhibited both time and geographic subdivision worldwide. In order to know the evolutionary history and spatial temporal dynamics of E-14, evolutionary phylogeography was reconstructed using BEAST and SPREAD software based on the VP1 sequences. The time of the most recent common ancestor of E-14 was estimated around 85 years and evolved with 9.17 × 10−3 substitutions/site/year. Phylogeographic analysis suggested that two regional transmissions of E-14 were mainly detected, with one located between Europe and Africa countries and the other was in the Asia-Pacific region.
Conclusions
Our study investigates the molecular evolution and phylogeographic of E-14, and brings new insight to the dispersal of E-14 worldwide. Regional transmission was mainly detected and Australia may be responsible for the spread of E-14 in recent years.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-016-3418-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12864-016-3418-3
PMCID: PMC5219651  PMID: 28061751
Echovirus 14; Acute flaccid paralysis; Phylogeny; Phylogeography
4.  Bone Morphogenetic Protein-9 Enhances Osteogenic Differentiation of Human Periodontal Ligament Stem Cells via the JNK Pathway 
PLoS ONE  2017;12(1):e0169123.
Bone morphogenetic protein-9 (BMP9) shows great osteoinductive potential in bone regeneration. Periodontal ligament stem cells (PDLSCs) with multi-differentiation capability and low immunogenicity are increasingly used as seed cells for periodontal regenerative therapies. In the present study, we investigated the potent osteogenic activity of BMP9 on human PDLSCs (hPDLSCs), in which the c-Jun N-terminal kinase (JNK) pathway is possibly involved. Our results showed that JNK inhibition by the specific inhibitor SP600125 or adenovirus expressing small interfering RNA (siRNA) targeting JNK (AdR-si-JNK) significantly decreased BMP9-induced gene and protein expression of early and late osteogenic markers, such as runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP), osteopontin (OPN), and osteocalcin (OCN), in hPDLSCs. We also confirmed the in-vivo positive effect of JNKs on ectopic bone formation induced by hPDLSCs injected into the musculature of athymic nude mice and BMP9 ex vivo gene delivery. For the cellular mechanism, we found that BMP9 activated the phosphorylation of JNKs and Smad2/3, and that JNKs may engage in cross-talk with the Smad2/3 pathway in BMP9-mediated osteogenesis.
doi:10.1371/journal.pone.0169123
PMCID: PMC5214565  PMID: 28052093
5.  Tequila Regulates Insulin-Like Signaling and Extends Life Span in Drosophila melanogaster  
The aging process is a universal phenomenon shared by all living organisms. The identification of longevity genes is important in that the study of these genes is likely to yield significant insights into human senescence. In this study, we have identified Tequila as a novel candidate gene involved in the regulation of longevity in Drosophila melanogaster. We have found that a hypomorphic mutation of Tequila (Teq f01792), as well as cell-specific downregulation of Tequila in insulin-producing neurons of the fly, significantly extends life span. Tequila deficiency–induced life-span extension is likely to be associated with reduced insulin-like signaling, because Tequila mutant flies display several common phenotypes of insulin dysregulation, including reduced circulating Drosophila insulin-like peptide 2 (Dilp2), reduced Akt phosphorylation, reduced body size, and altered glucose homeostasis. These observations suggest that Tequila may confer life-span extension by acting as a modulator of Drosophila insulin-like signaling.
doi:10.1093/gerona/glv094
PMCID: PMC4675830  PMID: 26265729
Aging; Longevity; Neurotrypsin; Glucose homeostasis
6.  Alpha-mangostin from mangosteen (Garcinia mangostana Linn.) pericarp extract reduces high fat-diet induced hepatic steatosis in rats by regulating mitochondria function and apoptosis 
Background
Non-alcoholic fatty liver disease (NAFLD) is caused by multiple factors including hepatic oxidative stress, lipotoxicity, and mitochondrial dysfunction. Obesity is among the risk factors for NAFLD alongside type 2 diabetes mellitus and hyperlipidemia. α- mangostin (α-MG) extracts from the pericarps of mangosteen (Garcinia mangostana Linn.) may regulate high fat diet-induced hepatic steatosis; however the underlying mechanisms remain unknown. The aim of this study was to investigate the regulatory effect of α-MG on high fat diet-induced hepatic steatosis and the underlying mechanisms related to mitochondrial functionality and apoptosis in vivo and in vitro.
Methods
Sprague Dawley (SD) rats were fed on either AIM 93-M control diet, a high-fat diet (HFD), or high-fat diet supplemented with 25 mg/day mangosteen pericarp extract (MGE) for 11 weeks. Thereafter, the following were determined: body weight change, plasma free fatty acids, liver triglyceride content, antioxidant enzymes (superoxide dismutase, SOD; glutathione, GSH; glutathione peroxidase, GPx; glutathione reductase GRd; catalase, CAT) and mitochondrial complex enzyme activities. In the in vitro study, primary liver cells were treated with 1 mM free fatty acid (FFA) (palmitate: oleate acid = 2:0.25) to induce steatosis. Thereafter, the effects of α-MG (10 μM, 20 μM, 30 μM) on total and mitochondria ROS (tROS, mitoROS), mitochondria bioenergetic functions, and mitochondrial pathway of apoptosis were examined in the FFA-treated primary liver cells.
Results
The MGE group showed significantly decreased plasma free fatty acids and hepatic triglycerides (TG) and thiorbarbituric acid reactive substances (TBARS) levels; increased activities of antioxidant enzymes (SOD, GSH, GPx, GRd, CAT); and enhanced NADH-cytochrome c reductase (NCCR) and succinate-cytochrome c reductase (SCCR) activities in the liver tissue compared with HFD group. In the in vitro study, α-MG significantly increased mitochondrial membrane potential, enhanced cellular oxygen consumption rate (OCR), decreased tROS (total ROS) and mitoROS (mitochondrial ROS) levels ; reduced Ca2+ and cytochrome c (cyt c) release from mitochondria, and reduced caspases 9 and 3 activities compared with control group.
Conclusion
These findings demonstrate α-MG attenuated hepatic steatosis in high fat-diet fed rats potentially through enhanced cellular antioxidant capacity and improved mitochondrial functions as well as suppressed apoptosis of hepatocytes. The findings of study represent a novel nutritional approach on the use of α-MG in the prevention and management of NAFLD.
doi:10.1186/s12986-016-0148-0
PMCID: PMC5134003  PMID: 27980597
α-mangostin; Fat infiltration; Mitochondria dysfunction; Mitochondrial pathway apoptosis; Antioxidant enzymes
7.  Proteogenomics connects somatic mutations to signaling in breast cancer 
Nature  2016;534(7605):55-62.
Summary
Somatic mutations have been extensively characterized in breast cancer, but the effects of these genetic alterations on the proteomic landscape remain poorly understood. We describe quantitative mass spectrometry-based proteomic and phosphoproteomic analyses of 105 genomically annotated breast cancers of which 77 provided high-quality data. Integrated analyses allowed insights into the somatic cancer genome including the consequences of chromosomal loss, such as the 5q deletion characteristic of basal-like breast cancer. The 5q trans effects were interrogated against the Library of Integrated Network-based Cellular Signatures, thereby connecting CETN3 and SKP1 loss to elevated expression of EGFR, and SKP1 loss also to increased SRC. Global proteomic data confirmed a stromal-enriched group in addition to basal and luminal clusters and pathway analysis of the phosphoproteome identified a G Protein-coupled receptor cluster that was not readily identified at the mRNA level. Besides ERBB2, other amplicon-associated, highly phosphorylated kinases were identified, including CDK12, PAK1, PTK2, RIPK2 and TLK2. We demonstrate that proteogenomic analysis of breast cancer elucidates functional consequences of somatic mutations, narrows candidate nominations for driver genes within large deletions and amplified regions, and identifies therapeutic targets.
doi:10.1038/nature18003
PMCID: PMC5102256  PMID: 27251275
8.  Diabetes mellitus may affect the long-term survival of hepatitis B virus-related hepatocellular carcinoma patients after liver transplantation 
World Journal of Gastroenterology  2016;22(43):9571-9585.
AIM
To determine whether diabetes mellitus (DM) affects prognosis/recurrence after liver transplantation (LT) for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC).
METHODS
A retrospective study was conducted between January 2000 and August 2013 on 1631 patients with HBV-related HCC who underwent LT with antiviral prophylaxis. Patient data were obtained from the China Liver Transplant Registry (https://www.cltr.org/). To compare the outcomes and tumor recurrence in the HBV-related HCC patients with or without DM, statistical analyses were conducted using χ2 tests, Mann-Whitney tests, the Kaplan-Meier method, log-rank tests and multivariate step-wise Cox regression analysis.
RESULTS
Univariate analysis of 1631 patients who underwent LT found overall 1-, 3- and 5-year survival rates of 79%, 73% and 71% respectively in the DM patients, and 84%, 78% and 76% in the non-DM patients respectively. Overall survival rate differences after LT between the two groups were significant (P = 0.041), but recurrence-free survival rates were not (P = 0.096). By stratified analysis, the overall survival rates in DM patients for age > 50 years (P = 0.002), the presence of vascular invasion (P = 0.096), tumors ≤ 3 cm (P = 0.047), two to three tumor nodules (P = 0.007), Child-Pugh grade B (P = 0.018), and pre-LT alanine aminotransferase levels between 40 and 80 IU/L (P = 0.017) were significantly lower than in non-DM patients. Additionally, serum α-fetoprotein level > 2000 ng/mL (P = 0.052) was associated with a significant survival difference trend between DM and non-DM patients. Multivariate analysis showed that the presence of DM (P < 0.001, HR = 1.591; 95%CI: 1.239-2.041) was an independent predictor associated with poor survival after LT.
CONCLUSION
HBV-related HCC patients with DM have decreased long-term overall survival and poor LT outcomes. Prevention strategies for HCC patients with DM are recommended.
doi:10.3748/wjg.v22.i43.9571
PMCID: PMC5116601  PMID: 27920478
Diabetes mellitus; Hepatocellular carcinoma; Hepatitis B virus; Liver transplantation; Survival
9.  Descriptions of two new species of the genus Camaena from Guangxi, China (Gastropoda, Stylommatophora, Camaenidae) 
ZooKeys  2016;29-45.
The sinistral Camaena species are mainly distributed in southern China and northern Vietnam. There is a total of eight species or subspecies of sinistral Camaena recorded at present. By systematically collecting specimens in Guangdong, Guangxi and Yunnan in southern China and the northern areas in Vietnam, two new species, Camaena lingyunensis Zhou & Lin, sp. n. and Camaena detianensis Zhou & Lin, sp. n. have been discovered. These new species are here characterised based on the comparison of shells, their reproductive system, the molecular phylogenetic analyses of the mitochondrial genes COI and 16S, and the nuclear gene ITS2. Detailed descriptions of the morphological characters, the DNA sequences, and the habitat of the two new species are given. Differential comparisons with related species are provided as well as a key to the sinistral species of Camaena.
doi:10.3897/zookeys.634.10236
PMCID: PMC5126529  PMID: 27917048
Camaena detianensis sp. n.; Camaena lingyunensis sp. n.; camaenid species; molecular phylogeny; taxonomy
10.  Selective and Sensitive Detection of MiRNA-21 Based on Au-nanorod Functionalized Polydiacetylene Microtube Waveguide 
Biosensors & bioelectronics  2016;85:198-204.
doi:10.1016/j.bios.2016.05.019
PMCID: PMC4983514  PMID: 27179561
Polydiacetylene; MicroRNA; Optical waveguide; Biosensing
11.  Validation of Brunei’s Malay EQ-5D Questionnaire in Patients with Type 2 Diabetes 
PLoS ONE  2016;11(11):e0165555.
Background
The Malay spoken in Brunei a South East Asian country where Malay is the national language is distinctive and different from Malay spoken in Malaysia, Singapore and Indonesia. This study aimed to develop a Brunei Malay version of the 5-level EQ-5D questionnaire (EQ-5D-5L) and to assess its psychometric properties among patients with type 2 diabetes mellitus (T2DM).
Methods
The Brunei Malay EQ-5D-5L was developed by culturally adapting two existing Malay versions. A total of 154 Bruneians with T2DM completed the questionnaire in two different points of time with one week apart. Known-groups validity of the utility-based EQ-5D-5L index and visual analogue scale (EQ-VAS) was evaluated by comparing subgroups of patients known to differ in health status. Test-retest reliability was assessed using the intraclass correlation coefficient (ICC) or Cohen’s kappa.
Results
As hypothesized, patients known to have ‘better’ health had higher EQ-5D-5L index scores than those having ‘worse’ health in all 7 known-groups comparisons. The hypothesized difference in the EQ-VAS scores was observed in only 4 of the 7 known-groups comparisons. Kappa values ranged from 0.206 to 0.446 for the EQ-5D-5L items; the ICC value for the EQ-5D-5L index and EQ-VAS was 0.626 and 0.521, respectively.
Conclusions
The utility-based EQ-5D-5L index appears to be valid and reliable for measuring the health of Brunei patients with T2DM. The validity of the EQ-VAS in Brunei requires further investigation.
doi:10.1371/journal.pone.0165555
PMCID: PMC5105939  PMID: 27835652
12.  Molecular characterization and phylogenetic analysis of dengue virus type 1 in Guangdong in 2014 
SpringerPlus  2016;5(1):1942.
Background
Dengue is one of the most important emerging diseases of humans, with no preventive vaccines or antiviral cures available currently. In 2014, the Southeast Asian region experienced an unprecedented outbreak of dengue, especially in Guangdong, China.
Results
The nucleotide sequences of the E gene from 23 patients sera of dengue virus type 1 (DENV-1) from Guangzhou, China, were determined. One isolate that was recovered from a patient with serious liver damage was designated GZ02. The whole genome sequence of GZ02 was amplified, and confocal microscopy and plaque reduction neutralization test were performed to investigate the replication kinetics in liver L02 cells. In the study, assembly and genetic comparisons showed 11 of those E gene nucleotide sequences were absolutely accordant, and the nucleic acid sequence divergence among the other strains had no marked difference.
Conclusions
Phylogenetic analysis based on the E gene indicated that the 23 new strains were closely related to strains from Malaysia or Singapore. Two different genotypes (genotype I and III) of DENV-1 were co-circulating in Guangdong, Malaysia, and Singapore from 2013 to 2014. However, no recombination event was found after 2005 between DENV strains from Guangdong and Malaysia or Singapore. GZ02 had a significant replicative advantage over DG14 and the DV1 standard strain. Importation of DENV-1 from Southeast Asian countries may have been an important contributing factor to the 2014 outbreak in Guangdong.
doi:10.1186/s40064-016-3604-4
PMCID: PMC5102991  PMID: 27933232
Dengue virus type 1; E gene; Phylogenetic analysis; Virus isolation
13.  Family history and disease outcomes in patients with Crohn’s disease: A comparison between China and the United States 
AIM
To investigate the differences in family history of inflammatory bowel disease (IBD) and clinical outcomes among individuals with Crohn’s disease (CD) residing in China and the United States.
METHODS
We performed a survey-based cross-sectional study of participants with CD recruited from China and the United States. We compared the prevalence of IBD family history and history of ileal involvement, CD-related surgeries and IBD medications in China and the United States, adjusting for potential confounders.
RESULTS
We recruited 49 participants from China and 145 from the United States. The prevalence of family history of IBD was significantly lower in China compared with the United States (China: 4.1%, United States: 39.3%). The three most commonly affected types of relatives were cousin, sibling, and parent in the United States compared with child and sibling in China. Ileal involvement (China: 63.3%, United States: 63.5%) and surgery for CD (China: 51.0%, United States: 49.7%) were nearly equivalent in the two countries.
CONCLUSION
The lower prevalence of familial clustering of IBD in China may suggest that the etiology of CD is less attributed to genetic background or a family-shared environment compared with the United States. Despite the potential difference in etiology, surgery and ileal involvement were similar in the two countries. Examining the changes in family history during the continuing rise in IBD may provide further insight into the etiology of CD.
doi:10.4292/wjgpt.v7.i4.556
PMCID: PMC5095575  PMID: 27867689
Crohn’s disease; Family history; Disease outcome; Inflammatory bowel disease; Epidemiology; genetics; Environment; Medication; Surgery
14.  Urinary Biomarkers of Whole Grain Wheat Intake Identified by Non-targeted and Targeted Metabolomics Approaches 
Scientific Reports  2016;6:36278.
Mounting evidence suggests that whole grain (WG) intake plays an important role in chronic disease prevention. However, numerous human studies have failed to produce clear-cut conclusions on this topic. Here, a combination of non-targeted and targeted metabolomics approaches, together with kinetic studies, was used to investigate biomarkers of WG wheat intake and further explore the diet-disease associations. Via these integrated approaches, forty-one compounds were identified as the most discriminating endogenous metabolites after WG versus refined grain (RG) wheat bread consumption. The corresponding biological assessment of these endogenous changes suggests that, in contrast to RG consumption, WG wheat consumption may facilitate antioxidant defense systems and moderate the risk factors of cancer, cardiovascular diseases, and other chronic diseases. A panel of urinary markers consisting of seven alkylresorcinol metabolites and five benzoxazinoid derivatives as specific biomarkers, as well as five phenolic acid derivatives, was also established to cover multiple time points and longer time periods for correctly and objectively monitoring WG wheat intake. Through these findings, we have established a comprehensive biomarker pool to better assess WG wheat consumption, and to monitor the endogenous changes that are linked to health effects of WG wheat consumption.
doi:10.1038/srep36278
PMCID: PMC5090248  PMID: 27805021
15.  Improvement of Cell Survival During Human Pluripotent Stem Cell Definitive Endoderm Differentiation 
Stem Cells and Development  2015;24(21):2536-2546.
Definitive endoderm (DE) is a vital precursor for internal organs such as liver and pancreas. Efficient protocol to differentiate human embryonic stem cells (hESCs) or induced pluripotent stem cells (iPSCs) to DE is essential for regenerative medicine and for modeling diseases; yet, poor cell survival during DE differentiation remains unsolved. In this study, our use of B27 supplement in modified differentiation protocols has led to a substantial improvement. We used an SOX17-enhanced green fluorescent protein (eGFP) reporter hESC line to compare and modify established DE differentiation protocols. Both total live cell numbers and the percentages of eGFP-positive cells were used to assess differentiation efficiency. Among tested protocols, three modified protocols with serum-free B27 supplement were developed to generate a high number of DE cells. Massive cell death was avoided during DE differentiation and the percentage of DE cells remained high. When the resulting DE cells were further differentiated toward the pancreatic lineage, the expression of pancreatic-specific markers was significantly increased. Similar high DE differentiation efficiency was observed in H1 hESCs and iPSCs through the modified protocols. In B27 components, bovine serum albumin was found to facilitate DE differentiation and cell survival. Using our modified DE differentiation protocols, satisfactory quantities of quality DE can be produced as primary material for further endoderm lineage differentiation.
doi:10.1089/scd.2015.0018
PMCID: PMC4620527  PMID: 26132288
16.  SEPT12–NDC1 Complexes Are Required for Mammalian Spermiogenesis 
Male factor infertility accounts for approximately 50 percent of infertile couples. The male factor-related causes of intracytoplasmic sperm injection failure include the absence of sperm, immotile sperm, immature sperm, abnormally structured sperm, and sperm with nuclear damage. Our knockout and knock-in mice models demonstrated that SEPTIN12 (SEPT12) is vital for the formation of sperm morphological characteristics during spermiogenesis. In the clinical aspect, mutated SEPT12 in men results in oligozoospermia or teratozoospermia or both. Sperm with mutated SEPT12 revealed abnormal head and tail structures, decreased chromosomal condensation, and nuclear damage. Furthermore, several nuclear or nuclear membrane-related proteins have been identified as SEPT12 interactors through the yeast 2-hybrid system, including NDC1 transmembrane nucleoporin (NDC1). NDC1 is a major nuclear pore protein, and is critical for nuclear pore complex assembly and nuclear morphology maintenance in mammalian cells. Mutated NDC1 cause gametogenesis defects and skeletal malformations in mice, which were detected spontaneously in the A/J strain. In this study, we characterized the functional effects of SEPT12–NDC1 complexes during mammalian spermiogenesis. In mature human spermatozoa, SEPT12 and NDC1 are majorly colocalized in the centrosome regions; however, NDC1 is only slightly co-expressed with SEPT12 at the annulus of the sperm tail. In addition, SEPT12 interacts with NDC1 in the male germ cell line through coimmunoprecipitation. During murine spermiogenesis, we observed that NDC1 was located at the nuclear membrane of spermatids and at the necks of mature spermatozoa. In male germ cell lines, NDC1 overexpression restricted the localization of SEPT12 to the nucleus and repressed the filament formation of SEPT12. In mice sperm with mutated SEPT12, NDC1 dispersed around the manchette region of the sperm head and annulus, compared with concentrating at the sperm neck of wild-type sperm. These results indicate that SEPT12–NDC1 complexes are involved in mammalian spermiogenesis.
doi:10.3390/ijms17111911
PMCID: PMC5133908  PMID: 27854341
male infertility; SEPT12; NDC1
17.  Identifying regions of disease-related variants in admixed populations with the summation partition approach 
BMC Proceedings  2016;10(Suppl 7):131-134.
We propose a new method for identifying disease-related regions of single nucleotide variants in recently admixed populations. We use principal component analysis to derive both global and local ancestry information. We then use the summation partition approach to search for disease-related regions based on both rare variants and the local ancestral information of each region. We demonstrate this method using individuals with high systolic blood pressure from a sample of unrelated Mexican American subjects provided in the 19th Genetic Analysis Workshop.
doi:10.1186/s12919-016-0018-9
PMCID: PMC5133488  PMID: 27980624
18.  Network-guided interaction mining for the blood pressure phenotype of unrelated individuals in genetic analysis workshop 19 
BMC Proceedings  2016;10(Suppl 7):333-336.
Interactions between genes are an important part of the genetic architecture of complex diseases. In this paper, we use literature-guided individual genes known to be associated with type 2 diabetes (referred to as “seed genes”) to create a larger list of genes that share implied or direct networks with these seed genes. This larger list of genes are known to interact with each other, but whether they interact in ways to influence hypertension in individuals presents an interesting question. Using Genetic Analysis Workshop data on individuals with diabetes, for which only case-control labels of hypertension are known, we offer a foray into identification of diabetes-related gene interactions that are associated with hypertension. We use the approach of Lo et al. (Proc Natl Acad Sci U S A 105: 12387-12392, 2008), which creates a score to identify pairwise significant gene associations. We find that the genes GCK and PAX4, formerly known to be found within similar coexpression and pathway networks but without specific direct interactions, do, in fact, show significant joint interaction effects for hypertension.
doi:10.1186/s12919-016-0052-7
PMCID: PMC5133535  PMID: 27980658
19.  CaMKII induces permeability transition through Drp1 phosphorylation during chronic β-AR stimulation 
Nature Communications  2016;7:13189.
Mitochondrial permeability transition pore (mPTP) is involved in cardiac dysfunction during chronic β-adrenergic receptor (β-AR) stimulation. The mechanism by which chronic β-AR stimulation leads to mPTP openings is elusive. Here, we show that chronic administration of isoproterenol (ISO) persistently increases the frequency of mPTP openings followed by mitochondrial damage and cardiac dysfunction. Mechanistically, this effect is mediated by phosphorylation of mitochondrial fission protein, dynamin-related protein 1 (Drp1), by Ca2+/calmodulin-dependent kinase II (CaMKII) at a serine 616 (S616) site. Mutating this phosphorylation site or inhibiting Drp1 activity blocks CaMKII- or ISO-induced mPTP opening and myocyte death in vitro and rescues heart hypertrophy in vivo. In human failing hearts, Drp1 phosphorylation at S616 is increased. These results uncover a pathway downstream of chronic β-AR stimulation that links CaMKII, Drp1 and mPTP to bridge cytosolic stress signal with mitochondrial dysfunction in the heart.
β-adrenergic receptor signaling induces mitochondrial permeability transition pore (mPTP) opening. Here, Xu et al. show that this effect is mediated by phosphorylation of mitochondrial fission protein Drp1 by CamKII, which increases the frequency of transient mPTP opening.
doi:10.1038/ncomms13189
PMCID: PMC5067512  PMID: 27739424
20.  Oxidation mechanism of T91 steel in liquid lead-bismuth eutectic: with consideration of internal oxidation 
Scientific Reports  2016;6:35268.
Clarification of the microscopic events that occur during oxidation is of great importance for understanding and consequently controlling the oxidation process. In this study the oxidation product formed on T91 ferritic/martensitic steel in oxygen saturated liquid lead-bismuth eutectic (LBE) at 823 K was characterized at the nanoscale using focused-ion beam and transmission electron microscope. An internal oxidation zone (IOZ) under the duplex oxide scale has been confirmed and characterized systematically. Through the microscopic characterization of the IOZ and the inner oxide layer, the micron-scale and nano-scale diffusion of Cr during the oxidation in LBE has been determined for the first time. The micron-scale diffusion of Cr ensures the continuous advancement of IOZ and inner oxide layer, and nano-scale diffusion of Cr gives rise to the typical appearance of the IOZ. Finally, a refined oxidation mechanism including the internal oxidation and the transformation of IOZ to inner oxide layer is proposed based on the discussion. The proposed oxidation mechanism succeeds in bridging the gap between the existing models and experimental observations.
doi:10.1038/srep35268
PMCID: PMC5062345  PMID: 27734928
21.  Conditional Knockout of Breast Carcinoma Amplified Sequence 2 (BCAS2) in Mouse Forebrain Causes Dendritic Malformation via β-catenin 
Scientific Reports  2016;6:34927.
Breast carcinoma amplified sequence 2 (BCAS2) is a core component of the hPrP19 complex that controls RNA splicing. Here, we performed an exon array assay and showed that β-catenin is a target of BCAS2 splicing regulation. The regulation of dendrite growth and morphology by β-catenin is well documented. Therefore, we generated conditional knockout (cKO) mice to eliminate the BCAS2 expression in the forebrain to investigate the role of BCAS2 in dendrite growth. BCAS2 cKO mice showed a microcephaly-like phenotype with a reduced volume in the dentate gyrus (DG) and low levels of learning and memory, as evaluated using Morris water maze analysis and passive avoidance, respectively. Golgi staining revealed shorter dendrites, less dendritic complexity and decreased spine density in the DG of BCAS2 cKO mice. Moreover, the cKO mice displayed a short dendrite length in newborn neurons labeled by DCX, a marker of immature neurons, and BrdU incorporation. To further examine the mechanism underlying BCAS2-mediated dendritic malformation, we overexpressed β-catenin in BCAS2-depleted primary neurons and found that the dendritic growth was restored. In summary, BCAS2 is an upstream regulator of β-catenin gene expression and plays a role in dendrite growth at least partly through β-catenin.
doi:10.1038/srep34927
PMCID: PMC5054673  PMID: 27713508
22.  Complicated norovirus infection and assessment of severity by a modified Vesikari disease score system in hospitalized children 
BMC Pediatrics  2016;16:162.
Background
Norovirus (NoV) GII.4 is the most common genotype for norovirus gastroenteritis worldwide. New variants or subgenotypes are continuously emerging, thus posing a serious threat to child health.
Methods
We compared retrospectively the clinical manifestations and complications of norovirus gastroenteritis in children from April, 2004 through December, 2012. NoV variants were analyzed to investigate the association of circulating viral strains with the complications. A modified disease severity score system based on Vesikari score system was devised and to evaluate disease severity.
Results
Compared to the outbreak in 2004/2005 winter, significant higher incidence of complications in the later periods are: convulsive disorder (p < 0.001) in 2006/2007 winter gastrointestinal hemorrhage (p = 0.047) and severe abdominal pain or irritability (p = 0.033) in 2008/09/10 winter; gastrointestinal hemorrhage (p = 0.030), severe abdominal pain or irritability (p = 0.014), and prominent hyperthermia (fever >39 °C, p = 0.001) in 2011/2012 winter. GII.4 Den_Haag_2006b, GII.4 2010, GII.4 Sydney 2012, and GII.4 2012b were the predominant strains in the outbreaks after 2006. By the modified severity score system, severe norovirus disease occurred in 28.5 %, 32 %, 33.3 %, and 30.2 % of the patients in the four periods. A longer duration of hospitalization (p = 0.02) were found in those with high score irrespective of the year of admission.
Conclusions
Our study demonstrated NoV outbreaks in northern Taiwan caused by different GII.4 variants that were associated with specific complications and uncommon clinical presentations. A modified severity score system first proposed in this study was able to identify severe cases with a longer hospital stay in NoV-infected children.
doi:10.1186/s12887-016-0699-2
PMCID: PMC5053206  PMID: 27716222
Gastroenteritis; Norovirus; Complications; Disease severity score
23.  Identification, Molecular Cloning of IL-1β and Its Expression Profile during Nocardia seriolae Infection in Largemouth Bass, Micropterus salmoides 
In the present study, IL-1β cDNA was identified and analyzed from largemouth bass (Micropterus salmoides). Full length IL-1β mRNA was obtained using Rapid Amplification of cDNA Ends (RACE), which contains 78 bp 3′-UTR, a 455 bp 5′-UTR, and an open reading frame (ORF) of 702 bp coding for 233 amino acid residues. The molecular weight and theoretical isoelectric point of largemouth bass IL-1β protein was predicted to be 26.7 kDa and 6.08 respectively. A largemouth bass IL-1β phylogenetic analysis showed a close relation to the IL-1βs of striped trumpeter (Latris lineata), Chinese perch (Siniperca chuatsi), and Japanese sea bass (Lateolabrax japonicus). Peptidoglycan upregulated IL-1β in the spleen and head kidney, while lipopolysaccharide upregulated detectable levels of IL-1β in the spleen only. Largemouth bass, challenged with Nocardia seriolae (1.0 × 106 cfu/mL), showed a significant increase in IL-1β at 3 and 5 days post infection (dpi) in the spleen, while in the head kidney significant expression was found at 2 and 3 dpi, peaking at 3 dpi. Furthermore, tumor necrosis factor α (TNF-α) showed significantly higher expression in the spleen at 3 and 5 dpi, and in the head kidney at 1 and 3 dpi, with expression decreasing at 5 dpi in both tissues.
doi:10.3390/ijms17101670
PMCID: PMC5085703  PMID: 27706080
IL-1β; largemouth bass (Micropterus salmoides); Nocardia seriolae; immunoadjuvant
24.  Phosphoproteome Analysis Reveals the Molecular Mechanisms Underlying Deoxynivalenol-Induced Intestinal Toxicity in IPEC-J2 Cells 
Toxins  2016;8(10):270.
Deoxynivalenol (DON) is a widespread trichothecene mycotoxin that commonly contaminates cereal crops and has various toxic effects in animals and humans. DON primarily targets the gastrointestinal tract, the first barrier against ingested food contaminants. In this study, an isobaric tag for relative and absolute quantitation (iTRAQ)-based phosphoproteomic approach was employed to elucidate the molecular mechanisms underlying DON-mediated intestinal toxicity in porcine epithelial cells (IPEC-J2) exposed to 20 μM DON for 60 min. There were 4153 unique phosphopeptides, representing 389 phosphorylation sites, detected in 1821 phosphoproteins. We found that 289 phosphopeptides corresponding to 255 phosphoproteins were differentially phosphorylated in response to DON. Comprehensive Gene Ontology (GO) analysis combined with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment revealed that, in addition to previously well-characterized mitogen-activated protein kinase (MAPK) signaling, DON exposure altered phosphatidylinositol 3-kinase/Akt (PI3K/Akt) and Janus kinase/signal transducer, and activator of transcription (JAK/STAT) pathways. These pathways are involved in a wide range of biological processes, including apoptosis, the intestinal barrier, intestinal inflammation, and the intestinal absorption of glucose. DON-induced changes are likely to contribute to the intestinal dysfunction. Overall, identification of relevant signaling pathways yielded new insights into the molecular mechanisms underlying DON-induced intestinal toxicity, and might help in the development of improved mechanism-based risk assessments in animals and humans.
doi:10.3390/toxins8100270
PMCID: PMC5086631  PMID: 27669298
deoxynivalenol; intestinal toxicity; phosphoproteomics; signaling pathways
25.  Suppression of Type I Interferon Production by Human T-Cell Leukemia Virus Type 1 Oncoprotein Tax through Inhibition of IRF3 Phosphorylation 
Journal of Virology  2016;90(8):3902-3912.
ABSTRACT
Infection with human T-cell leukemia virus type 1 (HTLV-1) is associated with adult T-cell leukemia (ATL) and tropical spastic paraparesis. Type I interferons (IFNs) are key effectors of the innate antiviral response, and IFN-α combined with the nucleoside reverse transcriptase inhibitor zidovudine is considered the standard first-line therapy for ATL. HTLV-1 oncoprotein Tax is known to suppress innate IFN production and response but the underlying mechanisms remain to be fully established. In this study, we report on the suppression of type I IFN production by HTLV-1 Tax through interaction with and inhibition of TBK1 kinase that phosphorylates IRF3. Induced transcription of IFN-β was severely impaired in HTLV-1-transformed ATL cells and freshly infected T lymphocytes. The ability to suppress IRF3 activation was ascribed to Tax. The expression of Tax alone sufficiently repressed the induction of IFN production by RIG-I plus PACT, cGAMP synthase plus STING, TBK1, IKKε, IRF3, and IRF7, but not by IRF3-5D, a dominant-active phosphomimetic mutant. This suggests that Tax perturbs IFN production at the step of IRF3 phosphorylation. Tax mutants deficient for CREB or NF-κB activation were fully competent in the suppression of IFN production. Coimmunoprecipitation experiments confirmed the association of Tax with TBK1, IKKε, STING, and IRF3. In vitro kinase assay indicated an inhibitory effect of Tax on TBK1-mediated phosphorylation of IRF3. Taken together, our findings suggested a new mechanism by which HTLV-1 oncoprotein Tax circumvents the production of type I IFNs in infected cells. Our findings have implications in therapeutic intervention of ATL.
IMPORTANCE Human T-cell leukemia virus type 1 (HTLV-1) is the cause of adult T-cell leukemia (ATL), an aggressive and fatal blood cancer, as well as another chronic disabling disease of the spinal cord. Treatments are unsatisfactory, and options are limited. A combination of antiviral cellular protein alpha interferon and zidovudine, which is an inhibitor of a viral enzyme called reverse transcriptase, has been recommended as the standard first-line therapy for ATL. Exactly how HTLV-1 interacts with the cellular machinery for interferon production and action is not well understood. Our work sheds light on the mechanism of action for the inhibition of interferon production by an HTLV-1 oncogenic protein called Tax. Our findings might help to improve interferon-based anti-HTLV-1 and anti-ATL therapy.
doi:10.1128/JVI.00129-16
PMCID: PMC4810532  PMID: 26819312

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