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1.  Studies on Inhibition of Respiratory Cytochrome bc1 Complex by the Fungicide Pyrimorph Suggest a Novel Inhibitory Mechanism 
PLoS ONE  2014;9(4):e93765.
The respiratory chain cytochrome bc1 complex (cyt bc1) is a major target of numerous antibiotics and fungicides. All cyt bc1 inhibitors act on either the ubiquinol oxidation (QP) or ubiquinone reduction (QN) site. The primary cause of resistance to bc1 inhibitors is target site mutations, creating a need for novel agents that act on alternative sites within the cyt bc1 to overcome resistance. Pyrimorph, a synthetic fungicide, inhibits the growth of a broad range of plant pathogenic fungi, though little is known concerning its mechanism of action. In this study, using isolated mitochondria from pathogenic fungus Phytophthora capsici, we show that pyrimorph blocks mitochondrial electron transport by affecting the function of cyt bc1. Indeed, pyrimorph inhibits the activities of both purified 11-subunit mitochondrial and 4-subunit bacterial bc1 with IC50 values of 85.0 μM and 69.2 μM, respectively, indicating that it targets the essential subunits of cyt bc1 complexes. Using an array of biochemical and spectral methods, we show that pyrimorph acts on an area near the QP site and falls into the category of a mixed-type, noncompetitive inhibitor with respect to the substrate ubiquinol. In silico molecular docking of pyrimorph to cyt b from mammalian and bacterial sources also suggests that pyrimorph binds in the vicinity of the quinol oxidation site.
doi:10.1371/journal.pone.0093765
PMCID: PMC3974799  PMID: 24699450
2.  Fenofibrate lowers blood pressure in salt-sensitive but not salt-resistant hypertension 
Journal of hypertension  2013;31(4):820-829.
Objective
Peroxisome proliferator-activated receptor α agonists reduce blood pressure in rodents, but clinical trials provide conflicting data regarding their effects in humans. We tested the hypothesis that the effect of fenofibrate on blood pressure depends on salt sensitivity.
Methods
Thirty-one hypertensive volunteers (17 salt-resistant, 14 salt-sensitive) completed a randomized, crossover, double-blind protocol with three dietary phases: low salt diet (10 mmol/day) followed by two consecutive high salt diets (200 mmol/day), each for 6 days. During high salt, volunteers were randomized to fenofibrate 160 mg/day or placebo. Hemodynamic and metabolic parameters were measured on the last morning of each treatment arm.
Results
Fenofibrate reduced triglycerides similarly in salt-sensitive and salt-resistant volunteers. Fenofibrate did not affect blood pressure in salt-resistant volunteers. In salt-sensitive volunteers, fenofibrate significantly decreased diastolic (P =0.02 versus placebo) and mean arterial (P = 0.04 versus placebo) blood pressure during high salt. In all volunteers, the decrease in systolic pressure during fenofibrate correlated inversely with the salt sensitivity of mean arterial pressure as a continuous variable. Fenofibrate significantly decreased heart rate, plasma renin activity, and renal vascular resistance during high salt in salt-sensitive volunteers, but not salt-resistant volunteers. Fenofibrate did not affect sodium excretion or weight gain during high salt. The effect of salt intake and fenofibrate on plasma and urine epoxyeicosatrienoic acid concentrations differed in salt-resistant and salt-sensitive volunteers.
Conclusion
Fenofibrate reduces blood pressure, heart rate and renal vasoconstriction in salt-sensitive volunteers, but not in salt-resistant volunteers. These findings have implications for the treatment of hyperlipidemia in hypertensive individuals.
doi:10.1097/HJH.0b013e32835e8227
PMCID: PMC3800119  PMID: 23385647
blood pressure; fenofibrate; hypertension; peroxisome proliferator-activated receptor α; salt
3.  Complete Resequencing of 40 Genomes Reveals Domestication Events and Genes in Silkworm (Bombyx) 
Science (New York, N.Y.)  2009;326(5951):433-436.
A single–base pair resolution silkworm genetic variation map was constructed from 40 domesticated and wild silkworms, each sequenced to approximately threefold coverage, representing 99.88% of the genome. We identified ∼16 million single-nucleotide polymorphisms, many indels, and structural variations. We find that the domesticated silkworms are clearly genetically differentiated from the wild ones, but they have maintained large levels of genetic variability, suggesting a short domestication event involving a large number of individuals. We also identified signals of selection at 354 candidate genes that may have been important during domestication, some of which have enriched expression in the silk gland, midgut, and testis. These data add to our understanding of the domestication processes and may have applications in devising pest control strategies and advancing the use of silkworms as efficient bioreactors.
doi:10.1126/science.1176620
PMCID: PMC3951477  PMID: 19713493
4.  The sequence and de novo assembly of the giant panda genome 
Li, Ruiqiang | Fan, Wei | Tian, Geng | Zhu, Hongmei | He, Lin | Cai, Jing | Huang, Quanfei | Cai, Qingle | Li, Bo | Bai, Yinqi | Zhang, Zhihe | Zhang, Yaping | Wang, Wen | Li, Jun | Wei, Fuwen | Li, Heng | Jian, Min | Li, Jianwen | Zhang, Zhaolei | Nielsen, Rasmus | Li, Dawei | Gu, Wanjun | Yang, Zhentao | Xuan, Zhaoling | Ryder, Oliver A. | Leung, Frederick Chi-Ching | Zhou, Yan | Cao, Jianjun | Sun, Xiao | Fu, Yonggui | Fang, Xiaodong | Guo, Xiaosen | Wang, Bo | Hou, Rong | Shen, Fujun | Mu, Bo | Ni, Peixiang | Lin, Runmao | Qian, Wubin | Wang, Guodong | Yu, Chang | Nie, Wenhui | Wang, Jinhuan | Wu, Zhigang | Liang, Huiqing | Min, Jiumeng | Wu, Qi | Cheng, Shifeng | Ruan, Jue | Wang, Mingwei | Shi, Zhongbin | Wen, Ming | Liu, Binghang | Ren, Xiaoli | Zheng, Huisong | Dong, Dong | Cook, Kathleen | Shan, Gao | Zhang, Hao | Kosiol, Carolin | Xie, Xueying | Lu, Zuhong | Zheng, Hancheng | Li, Yingrui | Steiner, Cynthia C. | Lam, Tommy Tsan-Yuk | Lin, Siyuan | Zhang, Qinghui | Li, Guoqing | Tian, Jing | Gong, Timing | Liu, Hongde | Zhang, Dejin | Fang, Lin | Ye, Chen | Zhang, Juanbin | Hu, Wenbo | Xu, Anlong | Ren, Yuanyuan | Zhang, Guojie | Bruford, Michael W. | Li, Qibin | Ma, Lijia | Guo, Yiran | An, Na | Hu, Yujie | Zheng, Yang | Shi, Yongyong | Li, Zhiqiang | Liu, Qing | Chen, Yanling | Zhao, Jing | Qu, Ning | Zhao, Shancen | Tian, Feng | Wang, Xiaoling | Wang, Haiyin | Xu, Lizhi | Liu, Xiao | Vinar, Tomas | Wang, Yajun | Lam, Tak-Wah | Yiu, Siu-Ming | Liu, Shiping | Zhang, Hemin | Li, Desheng | Huang, Yan | Wang, Xia | Yang, Guohua | Jiang, Zhi | Wang, Junyi | Qin, Nan | Li, Li | Li, Jingxiang | Bolund, Lars | Kristiansen, Karsten | Wong, Gane Ka-Shu | Olson, Maynard | Zhang, Xiuqing | Li, Songgang | Yang, Huanming | Wang, Jian | Wang, Jun
Nature  2009;463(7279):311-317.
Using next-generation sequencing technology alone, we have successfully generated and assembled a draft sequence of the giant panda genome. The assembled contigs (2.25 gigabases (Gb)) cover approximately 94% of the whole genome, and the remaining gaps (0.05 Gb) seem to contain carnivore-specific repeats and tandem repeats. Comparisons with the dog and human showed that the panda genome has a lower divergence rate. The assessment of panda genes potentially underlying some of its unique traits indicated that its bamboo diet might be more dependent on its gut microbiome than its own genetic composition. We also identified more than 2.7 million heterozygous single nucleotide polymorphisms in the diploid genome. Our data and analyses provide a foundation for promoting mammalian genetic research, and demonstrate the feasibility for using next-generation sequencing technologies for accurate, cost-effective and rapid de novo assembly of large eukaryotic genomes.
doi:10.1038/nature08696
PMCID: PMC3951497  PMID: 20010809
5.  Current issues in locally advanced colorectal cancer treated by preoperative chemoradiotherapy 
In patients with locally advanced rectal cancer, preoperative chemoradiotherapy has proven to significantly improve local control and cause lower treatment-related toxicity compared with postoperative adjuvant treatment. Preoperative chemoradiotherapy followed by total mesorectal excision or tumor specific mesorectal excision has evolved as the standard treatment for locally advanced rectal cancer. The paradigm shift from postoperative to preoperative therapy has raised a series of concerns however that have practical clinical implications. These include the method used to predict patients who will show good response, sphincter preservation, the application of conservative management such as local excision or “wait-and-watch” in patients obtaining a good response following preoperative chemoradiotherapy, and the role of adjuvant chemotherapy. This review addresses these current issues in patients with locally advanced rectal cancer treated by preoperative chemoradiotherapy.
doi:10.3748/wjg.v20.i8.2023
PMCID: PMC3934472  PMID: 24587677
Colorectal cancer; Rectal cancer; Preoperative chemoradiotherapy; Conservative; Response
6.  Oral Antimycobacterial Therapy in Chronic Cutaneous Sarcoidosis 
JAMA dermatology  2013;149(9):1040-1049.
IMPORTANCE
Sarcoidosis is a chronic granulomatous disease for which there are limited therapeutic options. This is the first randomized, placebo-controlled study to demonstrate that antimycobacterial therapy reduces lesion diameter and disease severity among patients with chronic cutaneous sarcoidosis.
OBJECTIVE
To evaluate the safety and efficacy of once-daily antimycobacterial therapy on the resolution of chronic cutaneous sarcoidosis lesions.
DESIGN AND PARTICIPANTS
A randomized, placebo-controlled, single-masked trial on 30 patients with symptomatic chronic cutaneous sarcoidosis lesions deemed to require therapeutic intervention.
SETTING
A tertiary referral dermatology center in Nashville, Tennessee.
INTERVENTIONS
Participants were randomized to receive either the oral concomitant levofloxacin, ethambutol, azithromycin, and rifampin (CLEAR) regimen or a comparative placebo regimen for 8 weeks with a 180-day follow-up.
MAIN OUTCOMES AND MEASURES
Participants were monitored for absolute change in lesion diameter and decrease in granuloma burden, if present, on completion of therapy.
OBSERVATIONS
In the intention-to-treat analysis, the CLEAR-treated group had a mean (SD) decrease in lesion diameter of −8.4 (14.0) mm compared with an increase of 0.07 (3.2) mm in the placebo-treated group (P = .05). The CLEAR group had a significant reduction in granuloma burden and experienced a mean (SD) decline of −2.9 (2.5) mm in lesion severity compared with a decline of −0.6 (2.1) mm in the placebo group (P = .02).
CONCLUSIONS AND RELEVANCE
Antimycobacterial therapy may result in significant reductions in chronic cutaneous sarcoidosis lesion diameter compared with placebo. These observed reductions, associated with a clinically significant improvement in symptoms, were present at the 180-day follow-up period. Transcriptome analysis of sarcoidosis CD4+ T cells revealed reversal of pathways associated with disease severity and enhanced T-cell function following T-cell receptor stimulation.
doi:10.1001/jamadermatol.2013.4646
PMCID: PMC3927541  PMID: 23863960
7.  Draft Genome Sequence of Pseudomonas nitroreducens Strain TX1, Which Degrades Nonionic Surfactants and Estrogen-Like Alkylphenols 
Genome Announcements  2014;2(1):e01262-13.
Pseudomonas nitroreducens TX1 ATCC PTA-6168 was isolated from rice field drainage in Taiwan. The bacterium is of special interest because of its capability to use nonionic surfactants (alkylphenol polyethoxylates) and estrogen-like compounds (4-t-octylphenol and 4-nonylphenol) as a sole carbon source. This is the first report on the genome sequence of P. nitroreducens.
doi:10.1128/genomeA.01262-13
PMCID: PMC3907738  PMID: 24482523
8.  PSCC: Sensitive and Reliable Population-Scale Copy Number Variation Detection Method Based on Low Coverage Sequencing 
PLoS ONE  2014;9(1):e85096.
Background
Copy number variations (CNVs) represent an important type of genetic variation that deeply impact phenotypic polymorphisms and human diseases. The advent of high-throughput sequencing technologies provides an opportunity to revolutionize the discovery of CNVs and to explore their relationship with diseases. However, most of the existing methods depend on sequencing depth and show instability with low sequence coverage. In this study, using low coverage whole-genome sequencing (LCS) we have developed an effective population-scale CNV calling (PSCC) method.
Methodology/Principal Findings
In our novel method, two-step correction was used to remove biases caused by local GC content and complex genomic characteristics. We chose a binary segmentation method to locate CNV segments and designed combined statistics tests to ensure the stable performance of the false positive control. The simulation data showed that our PSCC method could achieve 99.7%/100% and 98.6%/100% sensitivity and specificity for over 300 kb CNV calling in the condition of LCS (∼2×) and ultra LCS (∼0.2×), respectively. Finally, we applied this novel method to analyze 34 clinical samples with an average of 2× LCS. In the final results, all the 31 pathogenic CNVs identified by aCGH were successfully detected. In addition, the performance comparison revealed that our method had significant advantages over existing methods using ultra LCS.
Conclusions/Significance
Our study showed that PSCC can sensitively and reliably detect CNVs using low coverage or even ultra-low coverage data through population-scale sequencing.
doi:10.1371/journal.pone.0085096
PMCID: PMC3897425  PMID: 24465483
9.  The Asia Oceania Human Proteome Organisation Membrane Proteomics Initiative. Preparation and characterization of the carbonate-washed membrane standard 
Proteomics  2010;10(22):4142-4148.
The Asia Oceania Human Proteome Organisation has embarked on a Membrane Proteomics Initiative with goals of systematic comparison of strategies for analysis of membrane proteomes and discovery of membrane proteins. This multi-laboratory project is based on analysis of a subcellular fraction from mouse liver that contains endoplasmic reticulum and other organelles. Here we present the strategy used for preparation and initial characterisation of the membrane sample, including validation that the carbonate-washing step enriches for integral and lipid-anchored membrane proteins. Analysis of seventeen independent datasets from five types of proteomic workflows is in progress.
doi:10.1002/pmic.201000126
PMCID: PMC3891941  PMID: 20486120
AOHUPO; Integral membrane proteins; Liver; Membrane proteomics
10.  Two-Step Source Tracing Strategy of Yersinia pestis and Its Historical Epidemiology in a Specific Region 
PLoS ONE  2014;9(1):e85374.
Source tracing of pathogens is critical for the control and prevention of infectious diseases. Genome sequencing by high throughput technologies is currently feasible and popular, leading to the burst of deciphered bacterial genome sequences. Utilizing the flooding genomic data for source tracing of pathogens in outbreaks is promising, and challenging as well. Here, we employed Yersinia pestis genomes from a plague outbreak at Xinghai county of China in 2009 as an example, to develop a simple two-step strategy for rapid source tracing of the outbreak. The first step was to define the phylogenetic position of the outbreak strains in a whole species tree, and the next step was to provide a detailed relationship across the outbreak strains and their suspected relatives. Through this strategy, we observed that the Xinghai plague outbreak was caused by Y. pestis that circulated in the local plague focus, where the majority of historical plague epidemics in the Qinghai-Tibet Plateau may originate from. The analytical strategy developed here will be of great help in fighting against the outbreaks of emerging infectious diseases, by pinpointing the source of pathogens rapidly with genomic epidemiological data and microbial forensics information.
doi:10.1371/journal.pone.0085374
PMCID: PMC3887043  PMID: 24416399
11.  Comparative Effects of Angiotensin Receptor BlockadeandACE Inhibition on the Fibrinolytic and Inflammatory Responses to Cardiopulmonary Bypass 
Clinical pharmacology and therapeutics  2012;91(6):10.1038/clpt.2011.356.
The effects of angiotensin-converting enzyme (ACE) inhibition and angiotensin II type 1 receptor blockade (ARB) on fibrinolysis and inflammation following cardiopulmonary bypass (CPB) are uncertain. This study tested the hypothesis that ACE inhibition enhances fibrinolysis and inflammation to greater extent than ARB in patients undergoing CPB.One week to five days prior to surgery, patients were randomized to ramipril 5mg/day,candesartan 16mg/day or placebo.ACE inhibition increased intraoperative bradykinin and tissue-type plasminogen activator (t-PA) concentrations compared to ARB. Both ACE inhibition and ARB decreased plasma transfusion compared to placebo, but only ACE inhibition decreased length of stay. Neither ACE inhibition nor ARB significantly affectedplasminogen activator inhibitor-1 (PAI-1), interleukin (IL)-6, IL-8, or IL-10 concentrations. ACE inhibition enhanced intraoperative fibrinolysis without increasing red cell transfusion risk. In contrast, neither ACE inhibition nor ARB affected the inflammatory response. ACE inhibitors and ARB may be safely continued until the day of surgery.
doi:10.1038/clpt.2011.356
PMCID: PMC3822756  PMID: 22549281
Angiotensin-converting enzyme inhibition; angiotensin receptor blocker; renin-angiotensin system; cardiac surgery; cardiopulmonary bypass; plasminogen activator; interleukin; bradykinin
12.  Angiotensin –Converting Enzyme Inhibition or Mineralocorticoid Receptor Blockade Do Not Affect Incidence of Atrial Fibrillation in Patients Undergoing Cardiac Surgery 
Critical care medicine  2012;40(10):2805-2812.
Objective
This study tested the hypothesis that interruption of the renin-angiotensin system with either an angiotensin-converting enzyme inhibitor or a mineralocorticoid receptor antagonist will decrease the incidence of atrial fibrillation after cardiac surgery.
Design
Randomized double-blind placebo-controlled study.
Setting
University affiliated hospitals.
Patients
Four-hundred and forty-five adult patients in normal sinus rhythm undergoing elective cardiac surgery.
Interventions
One week to four days prior to surgery, patients were randomized to treatment with placebo, ramipril (2.5 mg the first three days followed by 5mg/day, with the dose reduced to 2.5mg/d on the first postoperative day only), or spironolactone (25 mg/day).
Measurements
The primary endpoint was the occurrence of electrocardiographically confirmed postoperative atrial fibrillation. Secondary endpoints included acute renal failure, hyperkalemia, the incidence of hypotension, length of hospital stay, stroke, and death.
Main Results
The incidence of atrial fibrillation was 27.2% in the placebo group, 27.8% in the ramipril group, and 25.9% in the spironolactone group (P=0.95). Patients in the ramipril (0.7%) or spironolactone (0.7%) group were less likely to develop acute renal failure than those randomized to placebo (5.4%, P=0.006). Patients in the placebo group tended to be hospitalized longer than those in the ramipril or spironolactone group (6.8±8.2 days versus 5.7±3.2 and 5.8±3.4 days, respectively, P=0.08 for the comparison of placebo versus the active treatment groups using log-rank test). Compared to patients in the placebo group, patients in the spironolactone group were extubated sooner after surgery (576.4±761.5 minutes versus 1091.3±3067.3 minutes, P=0.04).
Conclusions
Neither angiotensin-converting enzyme inhibition nor mineralocorticoid receptor blockade decreased the primary outcome of postoperative atrial fibrillation. Treatment with an angiotensin-converting enzyme inhibitor or mineralocorticoid receptor antagonist was associated with decreased acute renal failure. Spironolactone use was also associated with a shorter duration of mechanical ventilation after surgery.
doi:10.1097/CCM.0b013e31825b8be2
PMCID: PMC3588582  PMID: 22824930
angiotensin-converting enzyme inhibitors; aldosterone; atrial fibrillation; renal insufficiency; cardiac surgery
13.  Characteristics and Survival of Korean Anal Cancer From the Korea Central Cancer Registry Data 
Annals of Coloproctology  2013;29(5):182-185.
Purpose
In Korea, anal cancer is rare disease entity with specific clinical characteristics. Therefore, no survival analysis with a sufficient patient population has been performed. The aim of this study was to evaluate the characteristics of Korean anal cancer, focusing on the survival according to tumor histologies, sex, and a specific age group, using the nationwide cancer registry.
Methods
Using the Korea Central Cancer Registry, we analyzed a total of 2,552 cases from 1993 to 2010. We assessed the 5-year relative survival by using tumor histology. In addition, survival differences of Surveillance Epidemiology and End Results (SEER) stage were analyzed for both sexes and for young-age cancer (younger than 40 years) and advanced-age cancer (older than 70 years).
Results
The 5-year relative survival among anal cancer patients increased from 38.9% for the period 1993-1995 to 65.6% for the period 2006-2010. The anal squamous cell carcinoma was the most common histology and showed better survival than other types of cancer. Females demonstrated better survival than males in all SEER stages. The 5-year survivals for patients in whom anal cancer developed before the age of 40 and at or after the age of 40 were 62.4% and 51.6%, respectively. The 5-year survival for patients in whom cancer developed at or after the age of 70 was much worse than that for patients in whom the cancer had developed prior to that age.
Conclusion
Korean anal cancer has certain distinctive characteristics of survival according to tumor histology, sex, and age. Despite limitations on available data, this study used the nationwide database to provide important information on the survival of Korean patients with anal cancer.
doi:10.3393/ac.2013.29.5.182
PMCID: PMC3837082  PMID: 24278855
Anal neoplasms; Korean; Survival
14.  Unique Mechanisms of Sheng Yu Decoction (聖愈湯 Shèng Yù Tang) on Ischemic Stroke Mice Revealed by an Integrated Neurofunctional and Transcriptome Analysis 
Sheng Yu Decoction (聖愈湯 Shèng Yù Tang; SYD) is a popular traditional Chinese medicine (TCM) remedy used in treating cardiovascular and brain-related dysfunction clinically; yet, its neuroprotective mechanisms are still unclear. Here, mice were subjected to an acute ischemic stroke to examine the efficacy and mechanisms of action of SYD by an integrated neurofunctional and transcriptome analysis. More than 80% of the mice died within 2 days after ischemic stroke with vehicle treatment. Treatments with SYD (1.0 g/kg, twice daily, orally or p.o.) and recombinant thrombolytic tissue plasminogen activator (rt-PA; 10 mg/kg, once daily, intravenously or i.v.) both significantly extended the lifespan as compared to that of the vehicle-treated stroke group. SYD successfully restored brain function, ameliorated cerebral infarction and oxidative stress, and significantly improved neurological deficits in mice with stroke. Molecular impact of SYD by a genome-wide transcriptome analysis using brains from stroke mice showed a total of 162 out of 2081 ischemia-induced probe sets were significantly influenced by SYD. Mining the functional modules and genetic networks of these 162 genes revealed a significant upregulation of neuroprotective genes in Wnt receptor signaling pathway (3 genes) and regulation of cell communication (7 genes) and downregulation of destructive genes in response to stress (13 genes) and in the induction of inflammation (5 genes), cytokine production (4 genes), angiogenesis (3 genes), vasculature (6 genes) and blood vessel (5 genes) development, wound healing (7 genes), defense response (7 genes), chemotaxis (4 genes), immune response (7 genes), antigen processing and presenting (3 genes), and leukocyte-mediated cytotoxicity (2 genes) by SYD. Our results suggest that SYD could protect mice against ischemic stroke primarily through significantly downregulating the damaging genes involved in stress, inflammation, angiogenesis, blood vessel formation, immune responses, and wound healing, as well as upregulating the genes mediating neurogenesis and cell communication, which make SYD beneficial for treating ischemic stroke.
doi:10.4103/2225-4110.119703
PMCID: PMC3925003  PMID: 24716184
Genome-wide transcriptome analysis; Ischemic stroke; Microarray; Positron emission tomography; Sheng Yu Decoction
15.  A human gut microbial gene catalog established by metagenomic sequencing 
Nature  2010;464(7285):59-65.
To understand the impact of gut microbes on human health and well-being it is crucial to assess their genetic potential. Here we describe the Illumina-based metagenomic sequencing, assembly and characterization of 3.3 million nonredundant microbial genes, derived from 576.7 Gb sequence, from faecal samples of 124 European individuals. The gene set, ~150 times larger than the human gene complement, contains an overwhelming majority of the prevalent microbial genes of the cohort and likely includes a large proportion of the prevalent human intestinal microbial genes. The genes are largely shared among individuals of the cohort. Over 99% of the genes are bacterial, suggesting that the entire cohort harbours between 1000 and 1150 prevalent bacterial species and each individual at least 160 such species, which are also largely shared. We define and describe the minimal gut metagenome and the minimal gut bacterial genome in terms of functions encoded by the gene set.
doi:10.1038/nature08821
PMCID: PMC3779803  PMID: 20203603
16.  p53 negatively regulates Aurora A via both transcriptional and posttranslational regulation 
Cell Cycle  2012;11(18):3433-3442.
p53 plays an important role in mitotic checkpoint, but what its role is remains enigmatic. Aurora A is a Ser/Thr kinase involved in correcting progression of mitosis. Here, we show that p53 is a negative regulator for Aurora A. We found that p53 deficiency leads to Aurora A elevation. Ectopic expression of p53 or DNA damage-induced expression of p53 can suppress the expression of Aurora A. Mechanistic studies show that p53 is a negative regulator for Aurora A expression through both transcriptional and posttranslational regulation. p53 knockdown in cancer cells reduces the level of p21, which, in turn, increases the activity of CDK2 followed by induction of Rb1 hyperphosphorylation and its dissociation with transcriptional factor E2F3. E2F3 can bind to Aurora A gene promoter, potentiating Aurora A gene expression and p53 deficiency, enhancing the binding of E2F3 on Aurora A promoter. Also, p53 deficiency leads to decelerating Aurora A’s turnover rate, due to the fact that p53 deficiency causes the downregulation of Fbw7α, a component of E3 ligase of Aurora A. Consistently, p53 knockdown-mediated Aurora A elevation is mitigated when Fbw7α is ectopically expressed. Thus, p53-mediated Aurora A degradation requires Fbw7α expression. Significantly, inverse correlation between p53 and Aurora A elevation is translated into the deregulation of centrosome amplification. p53 knockdown leads to high percentages of cells with abnormal amplification of centrosome. These data suggest that p53 is an important negative regulator of Aurora A, and that loss of p53 in many types of cancer could lead to abnormal elevation of Aurora A and dysregulated mitosis, which provides a growth advantage for cancer cells.
doi:10.4161/cc.21732
PMCID: PMC3466554  PMID: 22894933
cell cycle; gammaH2AX; human non-small cell lung carcinoma; mTOR; metronomic chemotherapy; oncogenes; personalized cancer treatment
17.  Correction: SOAP3-dp: Fast, Accurate and Sensitive GPU-Based Short Read Aligner 
PLoS ONE  2013;8(8):10.1371/annotation/823f3670-ed17-41ec-ba51-b50281651915.
doi:10.1371/annotation/823f3670-ed17-41ec-ba51-b50281651915
PMCID: PMC3750100  PMID: 23990856
18.  TRPP2 and TRPV4 Form an EGF-Activated Calcium Permeable Channel at the Apical Membrane of Renal Collecting Duct Cells 
PLoS ONE  2013;8(8):e73424.
Objective
Regulation of apical calcium entry is important for the function of principal cells of the collecting duct. However, the molecular identity and the regulators of the transporter/channel, which is responsible for apical calcium entry and what factors regulate the calcium conduction remain unclear.
Methods and Results
We report that endogenous TRPP2 and TRPV4 assemble to form a 23-pS divalent cation-permeable non-selective ion channel at the apical membrane of renal principal cells of the collecting duct. TRPP2\TRPV4 channel complex was identified by patch-clamp, immunofluorescence and co-immunprecipitation studies in both principal cells that either possess normal cilia (cilia (+)) or in which cilia are absent (cilia (-)). This channel has distinct biophysical and pharmacological and regulatory profiles compared to either TRPP2 or TRPV4 channels. The rate of occurrence detected by patch clamp was higher in cilia (-) compared to cilia (+) cells. In addition, shRNA knockdown of TRPP2 increased the prevalence of TRPV4 channel activity while knockdown of TRPV4 resulted in TRPP2 activity and knockdown of both proteins vastly decreased the 23-pS channel activity. Epidermal growth factor (EGF) stimulated TRPP2\TRPV4 channel through the EGF receptor (EGFR) tyrosine kinase-dependent signaling. With loss of cilia, apical EGF treatment resulted in 64-fold increase in channel activity in cilia (-) but not cilia (+) cells. In addition EGF increased cell proliferation in cilia (-) cell that was dependent upon TRPP2\TRPV4 channel mediated increase in intracellular calcium.
Conclusion
We conclude that in the absence of cilia, an EGF activated TRPP2\TRPV4 channel may play an important role in increased cell proliferation and cystogenesis.
doi:10.1371/journal.pone.0073424
PMCID: PMC3745395  PMID: 23977387
19.  Prognostic factors affecting the clinical outcome of carcinoma ex pleomorphic adenoma in the major salivary gland 
Background
Carcinoma ex pleomorphic adenoma (CXPA) is an uncommon malignant tumor with highly aggressive biological behavior. Our goal was to investigate the prognosis of CXPA in the major salivary glands and factors influencing it.
Methods
We retrospectively reviewed 51 patients diagnosed with CXPA of the major salivary glands between 1999 and 2006, comprising 36 males and 15 females, aged from 23 to 86 years. All patients underwent surgery with curative intention, and 21 received postoperative radiation therapy.
Results
Of the 51 patients, 39.2% developed locoregional recurrence and 27.5% developed distant metastases. Median follow-up was 54 months. At the time of analysis, 29 (56.9%) patients were deceased. Overall survival was 62.7% at 3 years and 50.3% at 5 years. Tumor-specific survival was 64.4% at 3 years and 53.5% at 5 years. Using chi-squared tests, invasiveness, T stage, lymph node involvement and clinical stage were found to be significantly associated with locoregional recurrence. Histological grade, invasiveness, lymph node involvement and perineural invasion were associated with distant metastases (P < 0.05). Cox analysis showed that T stage, lymph node involvement, histological grade and perineural invasion were independent prognostic factors for overall survival.
Conclusion
T stage, lymph node involvement, histological grade, perineural invasion and extent of invasion are important prognostic factors of CXPA in the major salivary glands. Surgery is the primary treatment modality for CXPA and postoperative radiation therapy may be used in patients with factors for poor prognosis.
doi:10.1186/1477-7819-11-180
PMCID: PMC3750873  PMID: 23924064
Carcinoma ex pleomorphic adenoma; Prognosis; Salivary gland; Pleomorphic carcinoma; Survival
20.  Draft Genome Sequence of the Bisphenol A-Degrading Bacterium Sphingobium sp. Strain YL23 
Genome Announcements  2013;1(4):e00549-13.
Sphingobium sp. strain YL23, a novel bacterium isolated from sewage sludge of a domestic wastewater treatment plant, has been shown to completely degrade bisphenol A under aerobic conditions. Here, we describe a 3.8-Mb assembly of its genome sequence and major findings from its annotation.
doi:10.1128/genomeA.00549-13
PMCID: PMC3731844  PMID: 23908290
21.  Data on the Characteristics and the Survival of Korean Patients With Colorectal Cancer From the Korea Central Cancer Registry 
Annals of Coloproctology  2013;29(4):144-149.
Purpose
The incidence rates of colorectal cancer (CRC) in Korea have been increasing during the past decade. Therefore, it is important to understand the characteristics, including survival, of Korean CRC patients. The aim of this study was to use the nationwide cancer registry to evaluate the characteristics of Korean CRC, focusing on the survival, according to tumor location, sex, and specific age groups.
Methods
Using the Korea Central Cancer Registry (KCCR), we analyzed a total of 226,352 CRC cases diagnosed from 1993 to 2010. The five-year relative survivals were compared for the proximal colon, the distal colon, and the rectum. Survival rates were compared between men and women and between patients of young age (less than 40 years old) and patients of advanced age (70 years old or older).
Results
The 5-year survival rates were improved in all subsites between 1993 and 2010. Distal colon cancer showed favorable survival compared to proximal colon or rectal cancer. Females demonstrated worse survival for local or regional cancers, and this difference was significant in for patients in their seventies. Young patients (<40 years old) showed better survival rates for overall and proximal colon cancer comparable to those for older patients (≥40 years old), but advanced age patients (≥70 years old) had worse survivals for all tumor subsites compared to their younger counterparts (<70 years old). These trends were similar in distant CRC.
Conclusion
Korean CRC has certain distinct characteristics of survival according to tumor location, sex, and age. Despite the limitations of available data, this study contributes to a better understanding of survival differences in Korean CRC.
doi:10.3393/ac.2013.29.4.144
PMCID: PMC3767863  PMID: 24032114
Colorectal neoplasms; Korean, Survival
22.  Inheritance Model Introduces Differential Bias in CNV Calls between Parents and Offspring 
Genetic epidemiology  2012;36(5):488-498.
Copy Number Variation (CNV) is increasingly implicated in disease pathogenesis. CNVs are often identified by statistical models applied to data from single nucleotide polymorphism (SNP) panels. Family information for samples provides additional information for CNV inference. Two modes of PennCNV (the Joint-call and Posterior-call), which are some of the most well-developed family-based CNV calling methods, use a “Joint-model” as a main component. This models all family members’ CNV states together with Mendelian inheritance. Methods based on the Joint-model are used to infer CNV calls of cases and controls in a pedigree, which may be compared to each other to test an association. Although benefits from the Joint-model have been shown elsewhere, equality of call rates in parents and offspring has not been evaluated previously. This can affect downstream analyses in studies that compare CNV rates in cases versus controls in pedigrees. In this paper, we show that the Joint-model can introduce different CNV call rates among family members in the absence of a true difference. First, we show that the Joint-model may analytically introduce differential CNV calls because of asymmetry of the model. We demonstrate these differential call rates using single-marker simulations. We show that call rates using the two modes of PennCNV also differ between parents-offspring in one multi-marker simulated dataset and two real datasets. Our results advise need for caution in use of the Joint-model calls in CNV association studies with family-based datasets.
doi:10.1002/gepi.21643
PMCID: PMC3678551  PMID: 22628073
Schizophrenia; Calling Algorithm; Family-Based Study; CNV burden
23.  An unusual case of silent acute ST-elevation myocardial infarction following amphetamine use 
Pakistan Journal of Medical Sciences  2013;29(4):1059-1061.
We report a case of silent acute ST-elevation myocardial infarction associated with amphetamine use in a 62 years old diabetic man. The patient was devoid of chest pain and had a normal cardiac enzyme analysis at the initial presentation. A routine electrocardiogram demonstrated acute inferior wall ST-elevation myocardial infarction. Coronary angiography confirmed a total occlusion of the posterior lateral branch of right coronary artery. The patient underwent successful percutaneous transluminal coronary angioplasty with stent placement. Amphetamine abuse may play a role in acute myocardial infarction. Adverse cardiovascular manifestations of amphetamine can occur with sudden overt chest pain or present insidiously. In view of the potential association of amphetamine and myocardial infarction, physicians should not rely only upon clinical symptoms. This report highlights the diabetic patients with amphetamine abuse should undergo a routine electrocardiogram in such circumstances.
PMCID: PMC3817761  PMID: 24353688
Amphetamine; Chest pain; Silent myocardial infarction
24.  Anti-Inflammatory Components from the Root of Solanum erianthum 
Two new norsesquiterpenoids, solanerianones A and B (1–2), together with nine known compounds, including four sesquiterpenoids, (−)-solavetivone (3), (+)-anhydro-β-rotunol (4), solafuranone (5), lycifuranone A (6); one alkaloid, N-trans-feruloyltyramine (7); one fatty acid, palmitic acid (8); one phenylalkanoid, acetovanillone (9), and two steroids, β-sitosterol (10) and stigmasterol (11) were isolated from the n-hexane-soluble part of the roots of Solanum erianthum. Their structures were elucidated on the basis of physical and spectroscopic data analyses. The anti-inflammatory activity of these isolates was monitored by nitric oxide (NO) production in lipopolysaccharide (LPS)-activated murine macrophage RAW264.7 cells. The cytotoxicity towards human lung squamous carcinoma (CH27), human hepatocellular carcinoma (Hep 3B), human oral squamous carcinoma (HSC-3) and human melanoma (M21) cell lines was also screened by using an MTT assay. Of the compounds tested, 3 exhibited the strongest NO inhibition with the average maximum inhibition (Emax) at 100 μM and median inhibitory concentration (IC50) values of 98.23% ± 0.08% and 65.54 ± 0.18 μM, respectively. None of compounds (1–9) was found to possess cytotoxic activity against human cancer cell lines at concentrations up to 30 μM.
doi:10.3390/ijms140612581
PMCID: PMC3709801  PMID: 23771024
Solanum erianthum; Solanaceae; root; solanerianone; norsesquiterpenoid; sesquiterpenoid; spirovetivene; anti-inflammatory; cytotoxicity
25.  SOAP3-dp: Fast, Accurate and Sensitive GPU-Based Short Read Aligner 
PLoS ONE  2013;8(5):e65632.
To tackle the exponentially increasing throughput of Next-Generation Sequencing (NGS), most of the existing short-read aligners can be configured to favor speed in trade of accuracy and sensitivity. SOAP3-dp, through leveraging the computational power of both CPU and GPU with optimized algorithms, delivers high speed and sensitivity simultaneously. Compared with widely adopted aligners including BWA, Bowtie2, SeqAlto, CUSHAW2, GEM and GPU-based aligners BarraCUDA and CUSHAW, SOAP3-dp was found to be two to tens of times faster, while maintaining the highest sensitivity and lowest false discovery rate (FDR) on Illumina reads with different lengths. Transcending its predecessor SOAP3, which does not allow gapped alignment, SOAP3-dp by default tolerates alignment similarity as low as 60%. Real data evaluation using human genome demonstrates SOAP3-dp's power to enable more authentic variants and longer Indels to be discovered. Fosmid sequencing shows a 9.1% FDR on newly discovered deletions. SOAP3-dp natively supports BAM file format and provides the same scoring scheme as BWA, which enables it to be integrated into existing analysis pipelines. SOAP3-dp has been deployed on Amazon-EC2, NIH-Biowulf and Tianhe-1A.
doi:10.1371/journal.pone.0065632
PMCID: PMC3669295  PMID: 23741504

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