Publications by authors named "Tze-Tze Liu"

55 Publications

Intestinal SIRT1 Deficiency-Related Intestinal Inflammation and Dysbiosis Aggravate TNFα-Mediated Renal Dysfunction in Cirrhotic Ascitic Mice.

Int J Mol Sci 2021 Jan 27;22(3). Epub 2021 Jan 27.

Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11267, Taiwan.

In advanced cirrhosis, the TNFα-mediated intestinal inflammation and bacteria dysbiosis are involved in the development of inflammation and vasoconstriction-related renal dysfunction. In colitis and acute kidney injury models, activation of SIRT1 attenuates the TNFα-mediated intestinal and renal abnormalities. This study explores the impacts of intestinal SIRT1 deficiency and TNFα-mediated intestinal abnormalities on the development of cirrhosis-related renal dysfunction. Systemic and renal hemodynamics, intestinal dysbiosis [cirrhosis dysbiosis ratio (CDR) as marker of dysbiosis], and direct renal vasoconstrictive response (renal vascular resistance (RVR) and glomerular filtration rate (GFR)) to cumulative doses of TNFα were measured in bile duct ligated (BDL)-cirrhotic ascitic mice. In SIRT1-BDL-ascitic mice, the worsening of intestinal dysbiosis exacerbates intestinal inflammation/barrier dysfunction, the upregulation of the expressions of intestinal/renal TNFα-related pathogenic signals, higher TNFα-induced increase in RVR, and decrease in GFR in perfused kidney. In intestinal SIRT1 knockout groups, the positive correlations were identified between intestinal SIRT1 activity and CDR. Particularly, the negative correlations were identified between CDR and RVR, with the positive correlation between CDR and GFR. In mice with advanced cirrhosis, the expression of intestinal SIRT1 is involved in the linkage between intestinal dysbiosis and vasoconstriction/hypoperfusion-related renal dysfunction through the crosstalk between intestinal/renal TNFα-related pathogenic inflammatory signals.
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http://dx.doi.org/10.3390/ijms22031233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865325PMC
January 2021

Prediction of functional consequences of the five newly discovered variations in Taiwan.

Data Brief 2019 Aug 11;25:104129. Epub 2019 Jun 11.

Department of Education and Research, Taipei City Hospital, Taipei, Taiwan.

Glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency; OMIM #300908) is the most common inborn error disorders worldwide. While the G6PD is the key enzyme of removing oxidative stress in erythrocytes, the early diagnosis is utmost vital to prevent chronic and drug-, food- or infection-induced hemolytic anemia. The characterization of the mutations is also important for the subsequent genetic counseling, especially for female carrier with ambiguous enzyme activities and males with mild mutations. While multiplex SNaPshot assay and Sanger sequencing were performed on 500 G6PD deficient males, five newly discovered variations, namely c.187G > A (p.E63K), c.585G > C (p.Q195H), c.586A > T (p.I196F), c.743G > A (p.G248D), and c.1330G > A (p.V444I) were detected in the other six patients. These variants were previously named as the Pingtung, Tainan, Changhua, Chiayi, and Tainan-2 variants, respectively. The analysis, as well as the prediction of the structure of the resultant mutant G6PD protein indicated that these five newly discovered variants might be disease causing mutations.
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http://dx.doi.org/10.1016/j.dib.2019.104129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595892PMC
August 2019

[Clinical, biochemical and molecular findings of propionic acidemia].

Arch Argent Pediatr 2019 06;117(3):e288-e291

Unidad de Genética Médica, Departamento de Puericultura y Pediatría, Universidad de Los Andes, Mérida, Venezuela.

Propionic acidemia is an infrequent disorder with an autosomal recessive inheritance pattern caused by the deficiency of the mitochondrial enzyme propionyl-CoA carboxylase that converts propionyl-CoA to D-methylmalonyl-CoA. We present the case of a male newborn who showed signs of respiratory distress, vomiting and tiredness during feeding. He presented metabolic acidosis, positive serum and urine ketone bodies, hyperammonemia, anemia, thrombocytopenia and hypoproteinemia. The biochemical study by gas chromatography coupled to mass spectrometry in a urine sample was suggestive of propionic acidemia. The molecular study in the PCCA gene found the mutations c.893A>G (p.K298R) in the father and c.937C> T (p.R313X) in the mother. There is a need to establish the diagnosis of this infrequent entity to implement the therapeutic measures available and provide the appropriate genetic counseling.
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http://dx.doi.org/10.5546/aap.2019.e288DOI Listing
June 2019

Applying a multiplexed primer extension method on dried blood spots increased the detection of carriers at risk of glucose-6-phosphate dehydrogenase deficiency in newborn screening program.

Clin Chim Acta 2019 Aug 22;495:271-277. Epub 2019 Apr 22.

Department of Education and Research, Taipei City Hospital, Taipei, Taiwan; Cancer Progression Research Center, National Yang-Ming University, Taipei, Taiwan. Electronic address:

Background: Patients with glucose-6-phosphate dehydrogenase deficiency might develop acute hemolytic anemia, chronic hemolytic anemia, and neonatal hyperbilirubinemia when exposed to high levels of oxidative stress. Severe hemolysis may occur in not only patients but also female carriers under certain conditions. However, 80%-85% of female carriers were undetected in an existing newborn screening program because of their wide-ranging levels of enzyme activity.

Methods: We developed a cost- and time-efficient multiplex SNaPshot assay using dried blood spots.

Results: By detecting 21 common mutations in Taiwan and Southeast Asia, the assay could determine 98.2% of the mutant alleles in our cohort of Taiwanese newborns. The 9 undetermined mutant alleles were consequently detected by Sanger sequencing, of which 5 unpublished variations-c.187G > A (Pingtung), c.585G > C (Tainan), c.586A > T (Changhua), c.743G > A (Chiayi), and c.1330G > A (Tainan-2)-were detected. Furthermore, 13% of mild mutations were missed in male infants whose enzyme levels at 6.1-7.0 U/gHb in the newborn screening program when set the cutoff value at 6.0 U/gHb. We therefore suggest increasing the cutoff value and applying the multiplex SNaPshot assay as the second tier for neonatal screening.

Conclusions: Our approach could significantly increase the detection rate of male patients and female carriers with a reasonable cost and a reasonable number of clinic referrals.
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http://dx.doi.org/10.1016/j.cca.2019.04.074DOI Listing
August 2019

Role of protein structure in variant annotation: structural insight of mutations causing 6-pyruvoyl-tetrahydropterin synthase deficiency.

Pathology 2019 Apr 8;51(3):274-280. Epub 2019 Mar 8.

Department of Chemical Pathology and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong. Electronic address:

Genetic defects on 6-pyruvoyl-tetrahydropterin synthase (PTPS) are the most prevalent cause of hyperphenylalaninaemia not due to phenylalanine hydrolyase deficiency (phenylketonuria). PTPS catalyses the second step of tetrahydrobiopterin (BH) cofactor biosynthesis, and its deficiency represents the most common form of BH deficiency. Untreated PTPS deficiency results in depletion of the neurotransmitters dopamine, catecholamine and serotonin causing neurological symptoms. We archived reported missense variants of the PTS gene. Common in silico algorithms were used to predict the effects of such variants, and substantial proportions (up to 19%) of the variants were falsely classified as benign or uncertain. We have determined the crystal structure of the human PTPS hexamer, allowing another level of interpretation to understand the potential deleterious consequences of the variants from a structural perspective. The in silico and structure approaches appear to be complimentary and may provide new insights that are not available from each alone. Information from the protein structure suggested that the variants affecting amino acid residues required for interaction between monomeric subunits of the PTPS hexamer were those misclassified as benign by in silico algorithms. Our findings illustrate the important utility of 3D protein structure in interpretation of variants and also current limitations of in silico prediction algorithms. However, software to analyse mutation in the perspective of 3D protein structure is far less readily available than other in silico prediction tools.
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http://dx.doi.org/10.1016/j.pathol.2018.11.011DOI Listing
April 2019

Somatic mutations of PREX2 gene in patients with hepatocellular carcinoma.

Sci Rep 2019 02 22;9(1):2552. Epub 2019 Feb 22.

Center for Infectious Disease and Cancer Research (CICAR), Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.

Characterized with a high recurrence rate and low detection rate, prevention is the best approach to reduce mortality in hepatocellular carcinoma (HCC). The overexpression of Phosphatidylinositol-3,4,5-Trisphosphate Dependent Rac Exchange Factor 2 (PREX2) is observed in various tumors, including HCC; and the frequent PREX2 mutations in melanoma are associated with invasiveness. We sought to identify somatic mutations and the functional changes in mutational signatures of PREX2. Genomic DNA sequencing was performed in 68 HCC samples with three types of hepatitis viral infection status: HBs Ag-positive, anti-HCV Ab-positive, and negative for any hepatitis B or C markers. Stabilities and interactions of proteins as well as cell proliferation and migration were evaluated. Fourteen non-silent point mutations in PREX2 were detected, with 16 of 68 HCC patients harboring at least one non-silent mutation. All mutant forms of PREX2, except for K400f, had an extended half-life compared with wild-type PREX2. Moreover, only the half-life of S1113R was twice that of the wild-type. PREX2 mutant-S1113R also promoted migration and activated the AKT pathway as well as impaired HectH9-mediated ubiquitination. Our study identified a gain-of-function mutation of PREX2 - S1113R in HCC. Such mutation enhanced PREX2 protein stability, promoted cell proliferation, and was associated with aggressiveness of HCC.
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http://dx.doi.org/10.1038/s41598-018-36810-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6385191PMC
February 2019

HOTAIR is a REST-regulated lncRNA that promotes neuroendocrine differentiation in castration resistant prostate cancer.

Cancer Lett 2018 10 23;433:43-52. Epub 2018 Jun 23.

Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan; Genome Research Center, National Yang-Ming University, Taipei, Taiwan; Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan; Cancer Progression Research Center, National Yang-Ming University, Taipei, Taiwan. Electronic address:

Long non-coding RNAs (lncRNAs) are emerging as novel diagnostic markers of prostate cancer (PCa) and new determinants of castration-resistant PCa (CRPC), an aggressive and metastatic form of PCa. In addition to androgen receptor (AR) signaling, neuroendocrine differentiation (NED) is associated with CRPC. Recent reports demonstrate that the downregulation of repressor element-1 silencing transcription factor (REST) protein is a key step in NED of PCa cells. Here, we report HOTAIR as a novel REST-repressed lncRNA that is upregulated in NED PCa cells and in CRPC. HOTAIR overexpression is sufficient to induce, whereas knockdown of HOTAIR suppressed NED of PCa cells. Gene ontology (GO) analysis of differentially expressed genes under HOTAIR overexpression and in CRPC versus benign prostatic hyperplasia (BPH) suggests that HOTAIR may participate in PCa progression. Taken together, our results provide the first evidence of lncRNA HOTAIR as a driver for NED of PCa cells.
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http://dx.doi.org/10.1016/j.canlet.2018.06.029DOI Listing
October 2018

Transcriptome analysis and prognosis of ALDH isoforms in human cancer.

Sci Rep 2018 02 9;8(1):2713. Epub 2018 Feb 9.

Institute of Biopharmaceutical Sciences, National Yang Ming University, Taipei, 112, Taiwan.

Overexpression of ALDH is associated with cancer stem-like features and poor cancer prognosis. High ALDH activity has been observed in cancer stem-like cells. There are a total of 19 human ALDH isoforms, all of which are associated with reducing oxidative stress and protecting cells from damage. However, it is unknown whether all ALDHs are associated with poor cancer prognosis and which ones play a significant role in cancer progression. In this study, we used RNA sequencing data from The Cancer Genome Atlas (TCGA) to evaluate the differential expression of 19 ALDH isoforms in 5 common human cancers. The 19 ALDH genes were analyzed with an integrating meta-analysis of cancer prognosis. Genotyping and next-generation RNA sequencing for 30 pairwise samples of head and neck squamous cell carcinoma were performed and compared with the TCGA cohort. The analysis showed that each ALDH isoform had a specific differential expression pattern, most of which were related to prognosis in human cancer. A lower expression of ALDH2 in the tumor was observed, which was independent from the ALDH2 rs671 SNP variant and the expression of other mitochondria-associated protein coding genes. This study provides new insight into the association between ALDH expression and cancer prognosis.
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http://dx.doi.org/10.1038/s41598-018-21123-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807355PMC
February 2018

The roles of alcohol dehydrogenase in patients with atrial fibrillation.

Pacing Clin Electrophysiol 2017 Dec 31;40(12):1446-1453. Epub 2017 Oct 31.

Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.

Background: Alcohol consumption is known to increase the risk of atrial fibrillation (AF). Whether the genotypes of alcohol-metabolizing genes (alcohol dehydrogenase [ADH1B]) are associated with the risk of AF recurrence after catheter ablation remains unclear.

Methods And Results: The ADH1B genotypes of 281 patients who received catheter ablation for AF were examined. We followed this group of patients to monitor their AF recurrence. Alcohol consumption levels of this cohort were evaluated before and after catheter ablation. There was no difference in the underlying diseases presented by the patients with different ADH1B genotypes. Regardless of the ADH1B genotypes, the amount of alcohol consumption was the only factor associated with left atrial dilatation. The ADH1B*2 alleles (hazard ratio: ADH1B*1/*2 vs *1/*1: 2.64; ADH1B*2/*2 vs *1/*1: 1.80, P = 0.02) and the levels of alcohol consumption were independently associated with AF recurrence in the patients with paroxysmal AF after catheter ablation. ADH1B polymorphisms were not associated with AF recurrence in the patients with nonparoxysmal AF. We also found that the association of increased AF recurrence with alcohol consumption and the ADH1B genotypes cannot be explained by mechanisms of systemic inflammation.

Conclusions: ADH1B*2/*2 genotype and amount of alcohol consumption increase the risk of AF recurrence after catheter ablation.
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http://dx.doi.org/10.1111/pace.13208DOI Listing
December 2017

Early measurement of IL-10 predicts the outcomes of patients with acute respiratory distress syndrome receiving extracorporeal membrane oxygenation.

Sci Rep 2017 04 21;7(1):1021. Epub 2017 Apr 21.

Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.

Patients diagnosed with acute respiratory distress syndrome are generally severely distressed and associated with high morbidity and mortality despite aggressive treatments such as extracorporeal membrane oxygenation (ECMO) support. To identify potential biomarker of predicting value for appropriate use of this intensive care resource, plasma interleukin-10 along with relevant inflammatory cytokines and immune cell populations were examined during the early and subsequent disease courses of 51 critically ill patients who received ECMO support. High interleukin-10 levels at the time of ECMO installation and during the first 6 hours after ECMO support of these patients stand as a promising biomarker associated with grave prognosis. The initial interleukin-10 level is correlated to other conventional risk evaluation scores as a predictive factor for survival, and furthermore, elevated interleukin-10 levels are also related to a delayed recovery of certain immune cell populations such as CD14CD16, CD14TLR4 monocytes, and T regulator cells. Genetically, high interleukin-10 is associated to two polymorphic nucleotides (-592 C and -819 C) at the interleukin-10 gene promoter area. Our finding provides prognostic and mechanistic information on the outcome of severely respiratory distressed patients, and potentially paves the strategy to develop new therapeutic modality based on the principles of precision medicine.
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http://dx.doi.org/10.1038/s41598-017-01225-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5430643PMC
April 2017

A recurrent WARS mutation is a novel cause of autosomal dominant distal hereditary motor neuropathy.

Brain 2017 May;140(5):1252-1266

Department of Neurology, Taipei Veterans General Hospital, Taipei 11217, Taiwan.

Distal hereditary motor neuropathy is a heterogeneous group of inherited neuropathies characterized by distal limb muscle weakness and atrophy. Although at least 15 genes have been implicated in distal hereditary motor neuropathy, the genetic causes remain elusive in many families. To identify an additional causal gene for distal hereditary motor neuropathy, we performed exome sequencing for two affected individuals and two unaffected members in a Taiwanese family with an autosomal dominant distal hereditary motor neuropathy in which mutations in common distal hereditary motor neuropathy-implicated genes had been excluded. The exome sequencing revealed a heterozygous mutation, c.770A > G (p.His257Arg), in the cytoplasmic tryptophanyl-tRNA synthetase (TrpRS) gene (WARS) that co-segregates with the neuropathy in the family. Further analyses of WARS in an additional 79 Taiwanese pedigrees with inherited neuropathies and 163 index cases from Australian, European, and Korean distal hereditary motor neuropathy families identified the same mutation in another Taiwanese distal hereditary motor neuropathy pedigree with different ancestries and one additional Belgian distal hereditary motor neuropathy family of Caucasian origin. Cell transfection studies demonstrated a dominant-negative effect of the p.His257Arg mutation on aminoacylation activity of TrpRS, which subsequently compromised protein synthesis and reduced cell viability. His257Arg TrpRS also inhibited neurite outgrowth and led to neurite degeneration in the neuronal cell lines and rat motor neurons. Further in vitro analyses showed that the WARS mutation could potentiate the angiostatic activities of TrpRS by enhancing its interaction with vascular endothelial-cadherin. Taken together, these findings establish WARS as a gene whose mutations may cause distal hereditary motor neuropathy and alter canonical and non-canonical functions of TrpRS.
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http://dx.doi.org/10.1093/brain/awx058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6248622PMC
May 2017

Haploinsufficiency of RCBTB1 is associated with Coats disease and familial exudative vitreoretinopathy.

Hum Mol Genet 2016 Apr 11;25(8):1637-47. Epub 2016 Feb 11.

Department of Life Sciences and Institute of Genome Sciences, Department of Medical Research, Taipei Veterans General Hospital, Taipei, 11217, Taiwan, ROC and

Familial exudative vitreoretinopathy (FEVR) belongs to a group of genetically and clinically heterogeneous disorders in retinal vascular development. To date, in approximately 50% of patients with FEVR, pathogenic mutations have been detected in FZD4, LRP5, TSPAN12, NDP and ZNF408. In this study, we identified two heterozygous frameshift mutations in RCBTB1 from three Taiwanese cases through exome sequencing. In patient-derived lymphoblastoid cell lines (LCLs), the protein level of RCBTB1 is approximately half that of unaffected control LCLs, which is indicative of a haploinsufficiency mechanism. By employing transient transfection and reporter assays for the transcriptional activity of β-catenin, we demonstrated that RCBTB1 participates in the Norrin/FZD4 signaling pathway and that knockdown of RCBTB1 by shRNA significantly reduced nuclear accumulation of β-catenin under Norrin and Wnt3a treatments. Furthermore, transgenic fli1:EGFP zebrafish with rcbtb1 knockdown exhibited anomalies in intersegmental and intraocular vessels. These results strongly support that reduced RCBTB1 expression may lead to defects in angiogenesis through the Norrin-dependent Wnt pathway, and that RCBTB1 is a putative genetic cause of vitreoretinopathies.
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http://dx.doi.org/10.1093/hmg/ddw041DOI Listing
April 2016

Draft Genome Sequence of Mycobacterium tuberculosis Clinical Strain W06, a Prevalent Beijing Genotype Isolated in Taiwan.

Genome Announc 2015 Dec 10;3(6). Epub 2015 Dec 10.

National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan, Miaoli, Taiwan

Mycobacterium tuberculosis strain W06, analyzed by molecular methods, was classified as a modern Beijing M. tuberculosis strain, the most predominant strain in Taiwan. To our knowledge, this is the first draft genome announcement of a Beijing M. tuberculosis strain in Taiwan.
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http://dx.doi.org/10.1128/genomeA.01460-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4675954PMC
December 2015

Measuring propionyl-CoA carboxylase activity in phytohemagglutinin stimulated lymphocytes using high performance liquid chromatography.

Clin Chim Acta 2016 Jan 24;453:13-20. Epub 2015 Nov 24.

Department of Education and Research, Taipei City Hospital, Taipei, Taiwan. Electronic address:

Background: Propionyl-CoA carboxylase (PCC) is a mitochondrial enzyme involved in the catabolism of several essential amino acids and odd chain fatty acids. Previous PCC assays have involved either a radiometric assay or have required mitochondria isolation and/or enzyme purification.

Methods: We developed an enzymatic method to analyze PCC activity in phytohemagglutinin (PHA) stimulated lymphocytes that involves high performance liquid chromatography.

Results: The method shows good linearity and sensitivity. PCC activity was unaffected even when lymphocytes were isolated and PHA stimulated after a whole blood sample had been stored at 4°C for 5days. This indicates that this method is suitable for analyzing samples from distant medical centers. The PCC activity of patients with propionic acidemia was found to be much lower than that of normal individuals and carriers. However, this PCC assay is significantly affected by the red blood cell contamination. In conclusion, this is a reliable method for performing PCC assays and only requires 0.5 to 1.0ml of whole blood from newborns.

Conclusions: The PCC assay established in this study is useful for the confirmation of PA in individuals, and prenatal diagnosis and genetic counseling for the affected families.
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http://dx.doi.org/10.1016/j.cca.2015.11.023DOI Listing
January 2016

MicroRNA-mediated regulation of gene expression in the response of rice plants to fungal elicitors.

RNA Biol 2015 ;12(8):847-63

a Centre for Research in Agricultural Genomics (CRAG) ; Edifici CRAG ; Barcelona , Spain.

MicroRNAs (miRNAs) are small non-coding RNAs that have important regulatory functions in plant growth, development, and response to abiotic stress. Increasing evidence also supports that plant miRNAs contribute to immune responses to pathogens. Here, we used deep sequencing of small RNA libraries for global identification of rice miRNAs that are regulated by fungal elicitors. We also describe 9 previously uncharacterized miRNAs in rice. Combined small RNA and degradome analyses revealed regulatory networks enriched in elicitor-regulated miRNAs supported by the identification of their corresponding target genes. Specifically, we identified an important number of miRNA/target gene pairs involved in small RNA pathways, including miRNA, heterochromatic and trans-acting siRNA pathways. We present evidence for miRNA/target gene pairs implicated in hormone signaling and cross-talk among hormone pathways having great potential in regulating rice immunity. Furthermore, we describe miRNA-mediated regulation of Conserved-Peptide upstream Open Reading Frame (CPuORF)-containing genes in rice, which suggests the existence of a novel regulatory network that integrates miRNA and CPuORF functions in plants. The knowledge gained in this study will help in understanding the underlying regulatory mechanisms of miRNAs in rice immunity and develop appropriate strategies for rice protection.
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http://dx.doi.org/10.1080/15476286.2015.1050577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4615225PMC
May 2016

Hierarchical clustering of breast cancer methylomes revealed differentially methylated and expressed breast cancer genes.

PLoS One 2015 23;10(2):e0118453. Epub 2015 Feb 23.

VGH-YM Genome Center, National Yang-Ming University, Taipei, Taiwan; Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.

Oncogenic transformation of normal cells often involves epigenetic alterations, including histone modification and DNA methylation. We conducted whole-genome bisulfite sequencing to determine the DNA methylomes of normal breast, fibroadenoma, invasive ductal carcinomas and MCF7. The emergence, disappearance, expansion and contraction of kilobase-sized hypomethylated regions (HMRs) and the hypomethylation of the megabase-sized partially methylated domains (PMDs) are the major forms of methylation changes observed in breast tumor samples. Hierarchical clustering of HMR revealed tumor-specific hypermethylated clusters and differential methylated enhancers specific to normal or breast cancer cell lines. Joint analysis of gene expression and DNA methylation data of normal breast and breast cancer cells identified differentially methylated and expressed genes associated with breast and/or ovarian cancers in cancer-specific HMR clusters. Furthermore, aberrant patterns of X-chromosome inactivation (XCI) was found in breast cancer cell lines as well as breast tumor samples in the TCGA BRCA (breast invasive carcinoma) dataset. They were characterized with differentially hypermethylated XIST promoter, reduced expression of XIST, and over-expression of hypomethylated X-linked genes. High expressions of these genes were significantly associated with lower survival rates in breast cancer patients. Comprehensive analysis of the normal and breast tumor methylomes suggests selective targeting of DNA methylation changes during breast cancer progression. The weak causal relationship between DNA methylation and gene expression observed in this study is evident of more complex role of DNA methylation in the regulation of gene expression in human epigenetics that deserves further investigation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0118453PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338251PMC
December 2015

A novel TFG mutation causes Charcot-Marie-Tooth disease type 2 and impairs TFG function.

Neurology 2014 Sep 6;83(10):903-12. Epub 2014 Aug 6.

From the Departments of Neurology (P.-C.T., K.-P.L., Y.-C. Liao, Y.-T.L., B.-W.S., Y.-C. Lee) and Radiology (H.-T.W.), Taipei Veterans General Hospital; Department of Neurology (K.-P.L., Y.-C. Liao, Y.-T.L., B.-W.S., Y.-C. Lee), Brain Research Center (P.-C.T., L.-S.K., M.-J.F., B.-W.S., Y.-C. Lee), Institute of Biomedical Informatics (Y.-H.H.), Center or Systems and Synthetic Biology (Y.-H.H., Y.-S.T.), Department of Life Sciences and Institute of Genome Sciences (L.-S.K., M.-J.F.), Genome Research Center (T.-T.L., L.-S.K.), and Institute of Neuroscience (B.-W.S.), National Yang-Ming University, Taipei; Neuroscience Laboratory (Y.-C.G.), Department of Neurology, China Medical University Hospital, Taichung; School of Medicine (Y.-C.G.), College of Medicine, China Medical University, Taichung; and Institute of Cellular and System Medicine (S.-F.Y.), National Health Research Institutes, Zhunan, Taiwan.

Objective: To describe a novel mutation in TRK-fused gene (TFG) as a new cause of dominant axonal Charcot-Marie-Tooth disease (CMT) identified by exome sequencing and further characterized by in vitro functional studies.

Methods: Exome sequencing and linkage analysis were utilized to investigate a large Taiwanese family with a dominantly inherited adult-onset motor and sensory axonal neuropathy in which mutations in common CMT2-implicated genes had been previously excluded. Functional effects of the mutant gene products were investigated in vitro.

Results: Exome sequencing of 2 affected individuals in this family revealed a novel heterozygous mutation, c.806G>T (p.Gly269Val), in TFG that perfectly cosegregates with the CMT2 phenotype in all 27 family members. This mutation occurs at an evolutionarily conserved residue and is absent in the 1,140 ethnically matched control chromosomes. Genome-wide linkage study also supported its disease-causative role. Cell transfection studies showed that the TFG p.Gly269Val mutation increased the propensity of TFG proteins to form aggregates, resulting in sequestration of both mutant and wild-type TFG proteins and might thus deplete functional TFG molecules. The secreted Gaussia luciferase reporter assay demonstrated that inhibition of endogenous TFG compromised the protein secretion pathways, which could only be rescued by expressing wild-type TFG but not the p.Gly269Val altered proteins. TFG mutation was not found in 55 additional unrelated patients with CMT2, suggesting its rarity.

Conclusion: This study identifies a new cause of dominant CMT2 and highlights the importance of TFG in the protein secretory pathways that are essential for proper functioning of the human peripheral nervous system.
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http://dx.doi.org/10.1212/WNL.0000000000000758DOI Listing
September 2014

Two frequent mutations associated with the classic form of propionic acidemia in Taiwan.

Biochem Genet 2014 Oct 27;52(9-10):415-29. Epub 2014 May 27.

Department of Education and Research, Taipei City Hospital, Taipei, Taiwan.

Propionyl-CoA carboxylase (PCC) is involved in the catabolism of branched chain amino acids, odd-numbered fatty acids, cholesterol, and other metabolites. PCC consists of two subunits, α and β, encoded by the PCCA and PCCB genes, respectively. Mutations in the PCCA or PCCB subunit gene may lead to propionic acidemia. In this study, we performed mutation analysis on ten propionic acidemia patients from eight unrelated and nonconsanguineous families in Taiwan. Two PCCA mutations, c.229C→T (p.R77W) and c.1262A→C (p.Q421P), were identified in a PCCA-deficient patient. Six mutations in the PCCB gene, including c.-4156_183+3713del, c.580T→C (p.S194P), c.838dup (p.L280Pfs 11), c.1301C→T (p.A434V), c.1316A→G (P.Y439C), and c.1534C→T (p.R512C), were identified in seven PCCB-deficient families. The c.-4156_183+3713del mutation is the first known large deletion that affects the PCCB gene functions. Furthermore, the c.1301C→T and c.-4156_183+3713del mutations in the PCCB gene have not been reported previously. Clinical features demonstrated that these two frequent mutations are associated with low enzyme activity and a classic propionic acidemia phenotype.
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http://dx.doi.org/10.1007/s10528-014-9657-6DOI Listing
October 2014

Generation and analysis of the expressed sequence tags from the mycelium of Ganoderma lucidum.

PLoS One 2013 2;8(5):e61127. Epub 2013 May 2.

Department of Biochemistry, Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei City, Taiwan, ROC.

Ganoderma lucidum (G. lucidum) is a medicinal mushroom renowned in East Asia for its potential biological effects. To enable a systematic exploration of the genes associated with the various phenotypes of the fungus, the genome consortium of G. lucidum has carried out an expressed sequence tag (EST) sequencing project. Using a Sanger sequencing based approach, 47,285 ESTs were obtained from in vitro cultures of G. lucidum mycelium of various durations. These ESTs were further clustered and merged into 7,774 non-redundant expressed loci. The features of these expressed contigs were explored in terms of over-representation, alternative splicing, and natural antisense transcripts. Our results provide an invaluable information resource for exploring the G. lucidum transcriptome and its regulation. Many cases of the genes over-represented in fast-growing dikaryotic mycelium are closely related to growth, such as cell wall and bioactive compound synthesis. In addition, the EST-genome alignments containing putative cassette exons and retained introns were manually curated and then used to make inferences about the predominating splice-site recognition mechanism of G. lucidum. Moreover, a number of putative antisense transcripts have been pinpointed, from which we noticed that two cases are likely to reveal hitherto undiscovered biological pathways. To allow users to access the data and the initial analysis of the results of this project, a dedicated web site has been created at http://csb2.ym.edu.tw/est/.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0061127PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3642047PMC
December 2013

ALPK1 genetic regulation and risk in relation to gout.

Int J Epidemiol 2013 Apr;42(2):466-74

Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig D-04103, Germany.

Background: The present study investigated whether single nucleotide polymorphisms (SNPs) in the alpha-protein kinase 1 (ALPK1) gene are associated with gout in aboriginal and Han Chinese Taiwanese.

Methods: A total of 1351 aborigines from the community (511 cases and 840 controls) and 511 Han people from hospital (104 cases and 407 controls) were recruited. SNPs in potentially functional regions of the 38 genes within 4q25 were identified and genotypes determined by direct sequencing. Quantitation of blood ALPK1 mRNA expression levels and luciferase assay of gout-associated rs231253 pGL3-SNP constructs cotransfected with hsa-miR-519e were examined.

Results: We found that ALPK1 gene was the most determinant of gout. Three SNPs of rs11726117 M861T [C], rs231247 [G] and rs231253 [G] were most associated with gout risk [odd ratios (OR) ≥1.44, P ≤ 3.78 × 10(-6)) in aborigines. A replication set using Han people had risk at rs11726117 and rs231247 (OR ≥1.72, P ≤ 4.08 × 10(-3)). From pooled analysis (Breslow-Day test, P > 0.33) assuming an additive model, each increasing copy of the risk allele of rs11726117 [C], rs231247 [G] and rs231253 [G] showed significantly elevated OR for gout ≥1.42 (P ≥ 1.53 × 10(-6)). Consistently, the composite homozygous of linked 3 SNPs (versus wild-type, OR = 1.83, P = 8.21 × 10(-4)) had strong associations with ALPK1 mRNA expression. Luciferase showed reduced hybridization between hsa-miR-519e and construct carrying gout-associated rs231253 [G] than the wild-type [C] (P = 6.19 × 10(-4)).

Conclusions: Our study found that a newly identified ALPK1 gene can effectively interfere with microRNA target recognition and modulates the mRNA expression; and the varying distribution of the implicated SNPs among cases and controls in the two studied populations suggests a significant role in gout susceptibility.
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http://dx.doi.org/10.1093/ije/dyt028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3695596PMC
April 2013

Draft Genome Sequence of the Oxytetracycline-Producing Bacterium Streptomyces rimosus ATCC 10970.

Genome Announc 2013 Mar 7;1(2):e0006313. Epub 2013 Mar 7.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom.

We report the draft genome of Streptomyces rimosus (ATCC 10970), a soil isolate that produces oxytetracycline, a commercially important and clinically useful antibiotic.
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http://dx.doi.org/10.1128/genomeA.00063-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3593331PMC
March 2013

Exome sequencing identifies GNB4 mutations as a cause of dominant intermediate Charcot-Marie-Tooth disease.

Am J Hum Genet 2013 Mar 21;92(3):422-30. Epub 2013 Feb 21.

Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan.

Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of inherited neuropathies. Mutations in approximately 45 genes have been identified as being associated with CMT. Nevertheless, the genetic etiologies of at least 30% of CMTs have yet to be elucidated. Using a genome-wide linkage study, we previously mapped a dominant intermediate CMT to chromosomal region 3q28-q29. Subsequent exome sequencing of two affected first cousins revealed heterozygous mutation c.158G>A (p.Gly53Asp) in GNB4, encoding guanine-nucleotide-binding protein subunit beta-4 (Gβ4), to cosegregate with the CMT phenotype in the family. Further analysis of GNB4 in an additional 88 unrelated CMT individuals uncovered another de novo mutation, c.265A>G (p.Lys89Glu), in this gene in one individual. Immunohistochemistry studies revealed that Gβ4 was abundant in the axons and Schwann cells of peripheral nerves and that expression of Gβ4 was significantly reduced in the sural nerve of the two individuals carrying the c.158G>A (p.Gly53Asp) mutation. In vitro studies demonstrated that both the p.Gly53Asp and p.Lys89Glu altered proteins impaired bradykinin-induced G-protein-coupled-receptor (GPCR) signaling, which was facilitated by the wild-type Gβ4. This study identifies GNB4 mutations as a cause of CMT and highlights the importance of Gβ4-related GPCR signaling in peripheral-nerve function in humans.
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http://dx.doi.org/10.1016/j.ajhg.2013.01.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3591844PMC
March 2013

Mutation Profile of the MUT Gene in Chinese Methylmalonic Aciduria Patients.

JIMD Rep 2012 31;6:55-64. Epub 2012 Jan 31.

Institute of Genetics, National Yang-Ming University, Taipei, Taiwan, Republic of China.

The mut-type methylmalonic aciduria (MMA, MIM 251000) is caused by a deficiency of mitochondrial methylmalonyl-CoA mutase (MCM, E.C. 5.4.99.2) activity, which results from defects in the MUT gene. To elucidate the mutation spectrum of the MUT gene in Chinese MMA patients, 13 exons of the MUT gene, including untranslated regions, were analyzed by PCR-based sequencing for 42 unrelated Chinese MMA patients. All the 42 patients were found to have at least one MUT mutation. A total of 41 mutations were identified. Of these mutations, 20 were novel ones, including one nonsense mutation (c.103C>T), 12 missense mutations (c.316A>C, c.424A>G, c.494A>G, c.554C>T, c.599T>C, c.919T>C, c.1009T>C, c.1061C>T, c.1141G>A, c.1208G>A, c.1267G>A, and c.1295A>C), one duplication (c.755dupA), three small deletions (c.398_399delGA, c.1046_1058del, and c.1835delG), two mutations that might affect mRNA splicing (c.754-1G>A and c.1084-10A>G), and one major deletion. Among the mutations identified, the c.1280G>A (15.5%), c.729_730insTT (10.7%), c.1106G>A (4.8%), c.1630_1631GG>TA (4.8%), and c.2080C>T (4.8%) accounted for 40% of the diseased alleles. The c.1280G>A and c.729_730insTT mutations were found to be the most frequent mutations in Southern and Northern Chinese, respectively. The results of microsatellite analysis suggest that the spread of c.729_730insTT among the Northern Chinese and of c.1280G>A and c.1630_1631GG>TA among the Southern Chinese may have undergone founder effects. This mutation analysis of the gene responsible for mut-type MMA will help to provide a molecular diagnostic aid for differential diagnosis of MMA and could be applied for carrier detection and prenatal diagnosis among Chinese family at risk of mut-type MMA.
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http://dx.doi.org/10.1007/8904_2011_117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565679PMC
February 2013

Mutations in KCND3 cause spinocerebellar ataxia type 22.

Ann Neurol 2012 Dec;72(6):859-69

Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan; Brain Research Center, National Yang-Ming University, Taipei, Taiwan.

Objective: To identify the causative gene in spinocerebellar ataxia (SCA) 22, an autosomal dominant cerebellar ataxia mapped to chromosome 1p21-q23.

Methods: We previously characterized a large Chinese family with progressive ataxia designated SCA22, which overlaps with the locus of SCA19. The disease locus in a French family and an Ashkenazi Jewish American family was also mapped to this region. Members from all 3 families were enrolled. Whole exome sequencing was performed to identify candidate mutations, which were narrowed by linkage analysis and confirmed by Sanger sequencing and cosegregation analyses. Mutational analyses were also performed in 105 Chinese and 55 Japanese families with cerebellar ataxia. Mutant gene products were examined in a heterologous expression system to address the changes in protein localization and electrophysiological functions.

Results: We identified heterozygous mutations in the voltage-gated potassium channel Kv4.3-encoding gene KCND3: an in-frame 3-nucleotide deletion c.679_681delTTC p.F227del in both the Chinese and French pedigrees, and a missense mutation c.1034G>T p.G345V in the Ashkenazi Jewish family. Direct sequencing of KCND3 further identified 3 mutations, c.1034G>T p.G345V, c.1013T>C p.V338E, and c.1130C>T p.T377M, in 3 Japanese kindreds. Immunofluorescence analyses revealed that the mutant p.F227del Kv4.3 subunits were retained in the cytoplasm, consistent with the lack of A-type K(+) channel conductance in whole cell patch-clamp recordings.

Interpretation: Our data identify the cause of SCA19/22 in patients of diverse ethnic origins as mutations in KCND3. These findings further emphasize the important role of ion channels as key regulators of neuronal excitability in the pathogenesis of cerebellar degeneration.
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http://dx.doi.org/10.1002/ana.23701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4085146PMC
December 2012

Complexity of the Mycoplasma fermentans M64 genome and metabolic essentiality and diversity among mycoplasmas.

PLoS One 2012 3;7(4):e32940. Epub 2012 Apr 3.

Laboratory Science in Medicine, Department of Biotechnology, Institute of Biotechnology in Medicine, National Yang Ming University, Taipei, Taiwan, Republic of China.

Recently, the genomes of two Mycoplasma fermentans strains, namely M64 and JER, have been completely sequenced. Gross comparison indicated that the genome of M64 is significantly bigger than the other strain and the difference is mainly contributed by the repetitive sequences including seven families of simple and complex transposable elements ranging from 973 to 23,778 bps. Analysis of these repeats resulted in the identification of a new distinct family of Integrative Conjugal Elements of M. fermentans, designated as ICEF-III. Using the concept of "reaction connectivity", the metabolic capabilities in M. fermentans manifested by the complete and partial connected biomodules were revealed. A comparison of the reported M. pulmonis, M. arthritidis, M. genitalium, B. subtilis, and E. coli essential genes and the genes predicted from the M64 genome indicated that more than 73% of the Mycoplasmas essential genes are preserved in M. fermentans. Further examination of the highly and partly connected reactions by a novel combinatorial phylogenetic tree, metabolic network, and essential gene analysis indicated that some of the pathways (e.g. purine and pyrimidine metabolisms) with partial connected reactions may be important for the conversions of intermediate metabolites. Taken together, in light of systems and network analyses, the diversity among the Mycoplasma species was manifested on the variations of their limited metabolic abilities during evolution.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0032940PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3317919PMC
August 2012

Identification and characterization of an indigo-producing oxygenase involved in indole 3-acetic acid utilization by Acinetobacter baumannii.

Antonie Van Leeuwenhoek 2012 May 5;101(4):881-90. Epub 2012 Feb 5.

Microbial Genetics Laboratory, Department of Microbiology, Tzu-Chi University, Hualien, Taiwan.

Acinetobacter baumannii harbours a gene cluster similar to the iac locus of Pseudomonas putida 1290, which can catabolize the plant hormone indole 3-acetic acid (IAA) as an energy source. However, there has been no evidence showing that IAA can be utilized by A. baumannii. This study showed that A. baumannii can grow in M9 minimal medium containing IAA as the sole carbon source. A mutagenesis study indicated that iacA, encoded in the iac locus of A. baumannii, is involved in the catabolism of IAA. As shown by western blotting analysis, the IacA protein was detected in A. baumannii grown in M9 minimal medium with IAA but not with pyruvate, suggesting that the expression of iacA is regulated by the presence of IAA. In vitro studies have shown that IacA can oxidize indole, an IAA-like molecule, converting it to indoxyl, which spontaneously dimerises to form indigo. In this study, we show that the crude extracts from either wild-type A. baumannii or Escherichia coli overexpressing IacA can oxidize IAA. These results imply that the iac gene cluster of A. baumannii is involved in IAA degradation and that the iacA gene is upregulated when cells encounter IAA in their native environments.
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http://dx.doi.org/10.1007/s10482-012-9704-4DOI Listing
May 2012

Mutation spectrum of and founder effects affecting the PTS gene in East Asian populations.

J Hum Genet 2012 Feb 12;57(2):145-52. Epub 2012 Jan 12.

Institute of Genetics, National Yang-Ming University, Taipei, Taiwan.

The enzyme 6-pyruvoyl-tetrahydropterin synthase (PTPS, gene symbol: PTS) is involved in the second step of the de novo biosynthesis of tetrahydrobiopterin (BH4), which is a vital cofactor of nitric oxide synthases and three types of aromatic amino acid hydroxylases; the latter are important enzymes in the production of neurotransmitters. We conducted a study of PTS mutations in East Asia, including Taiwan, Mainland China, Japan, South Korea, the Philippines, Thailand and Malaysia. A total of 43 mutations were identified, comprising 22 previously reported mutations and 21 new discovered mutations. Among these, the c.155A>G, c.259C>T, c. 272A>G, c.286G>A and c.84-291A>G mutations were the most common PTS mutations in East Asia, while the c.58T>C and c.243G>A mutations were, respectively, specific to Filipinos and Japanese originating from Okinawa. Further studies demonstrated that each of the mutations listed above was in linkage disequilibrium to a specific allele of polymorphic microsatellite marker, D11S1347. These results suggest the presence of founder effects that have affected these frequent mutations in East Asia populations. In this context, D11S1347 should become one of the most reliable polymorphic markers for use in prenatal diagnosis among PTPS deficient families, especially where mutations are yet to be identified.
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http://dx.doi.org/10.1038/jhg.2011.146DOI Listing
February 2012

Combined methylmalonic aciduria and homocystinuria cblC type of a Taiwanese infant with c.609G>A and C.567dupT mutations in the MMACHC gene.

Pediatr Neonatol 2011 Aug 16;52(4):223-6. Epub 2011 Jul 16.

Department of Pediatrics, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.

Combined methylmalonic aciduria and homocystinuria, cobalamin (cbl)C type (cblC disease), the most common inborn error of vitamin B(12), is a rare disorder of intracellular cbl metabolism because of mutations in the MMACHC gene located in chromosome region 1p34.1. It has become possible to establish phenotype-genotype correlations and to observe ethnicity-related trends. This article provides detailed clinical manifestations and outcomes of a Taiwanese infant boy with early-onset cblC disease, heterozygous for c.609G>A and c.567dupT mutations, although there is limited information about cases with c.609G>A or c.567dupT mutation in the literature. He had no significant clinical abnormality during his neonatal period, whereas elevated C3 level was noted at newborn screening. He presented later with life-threatening manifestations and failure to thrive, which resolved through our treatment, although delayed development was still noted at 6 months of age. To date, all reported cblC patients with the c.609G>A mutation have been East Asians. Therefore, we suggest that c.609G>A should be included in the initial mutation screening tests for a cblC patient in East Asian populations.
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http://dx.doi.org/10.1016/j.pedneo.2011.05.006DOI Listing
August 2011

Identification of diuretic non-responders with poor long-term clinical outcomes: a 1-year follow-up of 176 non-azotaemic cirrhotic patients with moderate ascites.

Clin Sci (Lond) 2011 Dec;121(11):509-21

Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, and Institute of Public Health, National Yang-Ming University, Taipei 11217, Taiwan.

In cirrhosis, the development of ascites and the response to diuretics are determined by the RAAS (renin-angiotensin-aldosterone system) and renal sodium handling system. We hypothesized that SNPs (single nucleotide polymorphisms) affecting candidate genes in the RAAS and renal sodium handling pathway may influence initial diuretic responsiveness and affect clinical outcome in non-azotaemic cirrhotic patients with moderate ascites. We prospectively recruited 176 patients and 245 controls and determined their genetic polymorphisms for 24 SNPs of ten genes involved in the RAAS and renal sodium handling pathway. In cirrhotic patients with moderate ascites, multivariate analysis showed that diuretic unresponsiveness was predicted by a high basal plasma aldosterone level, by a high aldosterone/renin ratio and by specific risk genotypes of ACE (gene encoding angiotensin-converting enzyme), CYP11B2 (gene encoding aldosterone synthase) and ADDA (gene encoding α-adducin). This association between genetic polymorphisms and diuretic unresponsiveness was confirmed by an independent validation cohort. Notably, additive effects in relation to diuretic unresponsiveness were observed in cases where there was the simultaneous presence of the three risk genotypes. Among patients carrying any of the risk genotypes, more episodes of paracentesis and ascites-related readmission after 3 months of treatment, as well as a reduced 1-year survival rate, were observed. In addition to traditional predictors, our present study provides additional genetic and neurohormonal predictors that will help to identify diuretic non-responders among cirrhotic patients with moderate ascites. Among those carrying unfavourable risk genotypes, additional therapies, including paracentesis and albumin infusion, should be started as early as possible.
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http://dx.doi.org/10.1042/CS20110018DOI Listing
December 2011

Genome sequence of the repetitive-sequence-rich Mycoplasma fermentans strain M64.

J Bacteriol 2011 Aug 3;193(16):4302-3. Epub 2011 Jun 3.

Institute of Biotechnology in Medicine, Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming University, 155 Linong Street, Section 2, Taipei, Taiwan 112, Republic of China.

Mycoplasma fermentans is a microorganism commonly found in the genitourinary and respiratory tracts of healthy individuals and AIDS patients. The complete genome of the repetitive-sequence-rich M. fermentans strain M64 is reported here. Comparative genomics analysis revealed dramatic differences in genome size between this strain and the recently completely sequenced JER strain.
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http://dx.doi.org/10.1128/JB.05228-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3147699PMC
August 2011