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Sample records for hydratase fh fumarase

  1. The FH mutation database: an online database of fumarate hydratase mutations involved in the MCUL (HLRCC tumor syndrome and congenital fumarase deficiency

    Directory of Open Access Journals (Sweden)

    Tomlinson Ian PM

    2008-03-01

    Full Text Available Abstract Background Fumarate hydratase (HGNC approved gene symbol – FH, also known as fumarase, is an enzyme of the tricarboxylic acid (TCA cycle, involved in fundamental cellular energy production. First described by Zinn et al in 1986, deficiency of FH results in early onset, severe encephalopathy. In 2002, the Multiple Leiomyoma Consortium identified heterozygous germline mutations of FH in patients with multiple cutaneous and uterine leiomyomas, (MCUL: OMIM 150800. In some families renal cell cancer also forms a component of the complex and as such has been described as hereditary leiomyomatosis and renal cell cancer (HLRCC: OMIM 605839. The identification of FH as a tumor suppressor was an unexpected finding and following the identification of subunits of succinate dehydrogenase in 2000 and 2001, was only the second description of the involvement of an enzyme of intermediary metabolism in tumorigenesis. Description The FH mutation database is a part of the TCA cycle gene mutation database (formerly the succinate dehydrogenase gene mutation database and is based on the Leiden Open (source Variation Database (LOVD system. The variants included in the database were derived from the published literature and annotated to conform to current mutation nomenclature. The FH database applies HGVS nomenclature guidelines, and will assist researchers in applying these guidelines when directly submitting new sequence variants online. Since the first molecular characterization of an FH mutation by Bourgeron et al in 1994, a series of reports of both FH deficiency patients and patients with MCUL/HLRRC have described 107 variants, of which 93 are thought to be pathogenic. The most common type of mutation is missense (57%, followed by frameshifts & nonsense (27%, and diverse deletions, insertions and duplications. Here we introduce an online database detailing all reported FH sequence variants. Conclusion The FH mutation database strives to systematically

  2. Modeling tumor predisposing FH mutations in yeast: effects on fumarase activity, growth phenotype and gene expression profile.

    Science.gov (United States)

    Kokko, Antti; Ylisaukko-Oja, Sanna S K; Kiuru, Maija; Takatalo, Maarit S; Salmikangas, Paula; Tuimala, Jarno; Arango, Diego; Karhu, Auli; Aaltonen, Lauri A; Jäntti, Jussi

    2006-03-15

    Heterozygous mutations in the fumarase (FH) gene cause the tumor predisposition syndrome hereditary leiomyomatosis and renal cell cancer (MIM 605839). While most families segregate a benign phenotype of multiple leiomyomas, others display a phenotype with early-onset renal cancer and leiomyosarcoma. Modifier genes may play a role in this, but an alternative explanation is simple genotype-phenotype association. FH mutations predisposing to cancer appear to be truncating or in fully conserved amino acids, suggesting that mutations severely affecting FH activity might predispose to malignancy. In the present study, we analyzed 2 conserved fumarase mutations in yeast. H153R has been described in 3 cancer predisposition families; whereas all 3 reported K187R families have displayed the benign phenotype. Examining H153R and K187R should clarify whether cancer-related FH mutations differ from their benign phenotype-associated counterparts. Yeast strains containing the 2 mutations, and knockout and wild type (WT) references, were created and the growth phenotypes studied on selected carbon sources to assess mitochondrial function. Additionally, Fum1 protein production and activity were measured, and the strains were subjected to transcriptional profiling. On nonfermentable lactate medium, the fumarase knockout strains did not grow, whereas the mutants showed no differences, as compared to WT yeast. Although both mutant strains produced fumarase, a considerable decrease in enzyme activity was seen in mutants with respect to WT. Transcription of the majority of Krebs cycle enzymes was downregulated in response to mutations in fumarase. In conclusion, both mutants displayed some, albeit greatly reduced, fumarase activity. This activity was sufficient to support normal growth on nonfermentable carbon source, unlike the deletion phenotype, demonstrating the significance of the residual activity. The findings support the hypothesis that modifier gene(s), rather than phenotype

  3. A cancer-predisposing "hot spot" mutation of the fumarase gene creates a dominant negative protein.

    Science.gov (United States)

    Lorenzato, Annalisa; Olivero, Martina; Perro, Mario; Brière, Jean Jacques; Rustin, Pierre; Di Renzo, Maria Flavia

    2008-02-15

    The Fumarase (Fumarate Hydratase, FH) is a tumor suppressor gene whose germline heterozygous mutations predispose to hereditary leiomyomatosis and renal cell cancer (HLRCC). The FH gene encodes an enzyme of the Krebs cycle, functioning as a homotetramer and catalyzing the hydration of fumarate to malate. Among the numerous FH mutations reported so far, the R190H missense mutation is the most frequent in HLRCC patients. Here we show the functional analyses of the R190H, in comparison to the better characterized E319Q mutation. We first expressed wild-type and mutated proteins in FH deficient human skin fibroblasts, using lentiviral vectors. The wild-type transgene was able to restore the FH enzymatic activity in cells, while the R190H- and E319Q-FH were not. More interestingly, when the same transgenes were expressed in normal, FH-proficient cells, only the R190H-FH reduced the endogenous FH enzymatic activity. By enforcing the expression of equal amount of wild-type and R190H-FH in the same cell, we showed that the mutated FH protein directly inhibited enzymatic activity by nearly abrogating the FH homotetramer formation. These data demonstrate the dominant negative effect of the R190H missense mutation in the FH gene and suggest that the FH tumor-suppressing activity might be impaired in cells carrying a heterozygous mutation. (c) 2007 Wiley-Liss, Inc.

  4. Fumarase activity

    DEFF Research Database (Denmark)

    Nielsen, Per Mose; Eldirdiri, Abubakr; Bertelsen, Lotte Bonde

    2017-01-01

    ]fumarate conversion to [1,4-(13)C2]malate by fumarase has been proposed as a measure of necrosis in rat tumor models and in chemically induced AKI rats. Here we show that the degradation of cell membranes in connection with necrosis leads to elevated fumarase activity in plasma and urine and secondly...... that hyperpolarized [1,4-(13)C2]malate production 24 h after reperfusion correlates with renal necrosis in a 40-min unilateral ischemic rat model. Fumarase activity screening on bio-fluids can detect injury severity, in bilateral as well as unilateral AKI models, differentiating moderate and severe AKI as well...... as short- and long-term AKI. Furthermore after verification of renal injury by bio-fluid analysis the precise injury location can be monitored by in vivo measurements of the fumarase activity non-invasively by hyperpolarized [1,4-(13)C]fumarate MR imaging. The combined in vitro and in vivo biomarker of AKI...

  5. Isolation and Kinetic Characterization of Fumarase from Baker's Yeast

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    Vasić-Rački, D.

    2012-05-01

    Full Text Available Isolation and purification of fumarase (fumarate hydratase EC 4.2.1.2 from baker’s yeast was carried out. Yeast cells were disrupted by three methods: glass beads, ultrasound, and the combination of these two methods. Cell disruption methods were compared in their efficiency in Fig. 1. Protein fractionation was carried out by precipitation with ammonium sulphate. The concentrations of ammonium sulphate necessary for fumarase precipitation were found ex- perimentally and are presented in Fig. 2. After precipitation, fumarase samples were purified by gel filtration chromatography on columns filled with Sephadex G50 and Sephadex G100. Examples of the elution curve of one protein suspension sample on both columns are presented in Fig. 3 and Fig. 4. Only the samples having high fumarase activity were used in the next purifying step. Table 1 presents the collective results of the fumarase purification procedure. The tech- niques used enabled purification of fumarase with a yield of 25 %. The purified enzyme was employed in the hydration of fumaric acid to L-malic acid. Kinetic constants of fumarase were estimated and are presented in Table 2. They were determined from the experimental data measured by the initial reaction rate method. The hydration of fumaric acid to L-malic acid was carried out in a batch reactor and the results are presented in Fig. 5. The kinetic model was developed on the basis of kinetic data and reaction scheme, as presented by equations 1 and 2. It was combined with the mass balances in the batch reactor presented by equations 3 and 4. Considering that fumarase deactivation occurs, it was proposed that the activity loss could be described by a first-order kinetic model (equation 5. Fumarase activity was followed during the batch experiment by the enzyme assay and it was found that activity decay occurs. Deactivation constant was estimated from the independent experimental results and found to be 0.0031 min–1.

  6. Fumarase: a mitochondrial metabolic enzyme and a cytosolic/nuclear component of the DNA damage response.

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    Ohad Yogev

    2010-03-01

    Full Text Available In eukaryotes, fumarase (FH in human is a well-known tricarboxylic-acid-cycle enzyme in the mitochondrial matrix. However, conserved from yeast to humans is a cytosolic isoenzyme of fumarase whose function in this compartment remains obscure. A few years ago, FH was surprisingly shown to underlie a tumor susceptibility syndrome, Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC. A biallelic inactivation of FH has been detected in almost all HLRCC tumors, and therefore FH was suggested to function as a tumor suppressor. Recently it was suggested that FH inhibition leads to elevated intracellular fumarate, which in turn acts as a competitive inhibitor of HPH (HIF prolyl hydroxylase, thereby causing stabilization of HIF (Hypoxia-inducible factor by preventing proteasomal degradation. The transcription factor HIF increases the expression of angiogenesis regulated genes, such as VEGF, which can lead to high microvessel density and tumorigenesis. Yet this mechanism does not fully explain the large cytosolic population of fumarase molecules. We constructed a yeast strain in which fumarase is localized exclusively to mitochondria. This led to the discovery that the yeast cytosolic fumarase plays a key role in the protection of cells from DNA damage, particularly from DNA double-strand breaks. We show that the cytosolic fumarase is a member of the DNA damage response that is recruited from the cytosol to the nucleus upon DNA damage induction. This function of fumarase depends on its enzymatic activity, and its absence in cells can be complemented by high concentrations of fumaric acid. Our findings suggest that fumarase and fumaric acid are critical elements of the DNA damage response, which underlies the tumor suppressor role of fumarase in human cells and which is most probably HIF independent. This study shows an exciting crosstalk between primary metabolism and the DNA damage response, thereby providing a scenario for metabolic control of tumor

  7. Distinct expression profile in fumarate-hydratase-deficient uterine fibroids

    DEFF Research Database (Denmark)

    Vanharanta, S; Pollard, PJ; Lehtonen, HJ

    2006-01-01

    Defects in mitochondrial enzymes predispose to severe developmental defects as well as tumorigenesis. Heterozygous germline mutations in the nuclear gene encoding fumarate hydratase (FH), an enzyme catalyzing the hydration of fumarate in the Krebs tricarboxylic acid cycle, cause hereditary...

  8. Distinct expression profile in fumarate-hydratase-deficient uterine fibroids

    DEFF Research Database (Denmark)

    Vanharanta, S; Pollard, PJ; Lehtonen, HJ

    2006-01-01

    Defects in mitochondrial enzymes predispose to severe developmental defects as well as tumorigenesis. Heterozygous germline mutations in the nuclear gene encoding fumarate hydratase (FH), an enzyme catalyzing the hydration of fumarate in the Krebs tricarboxylic acid cycle, cause hereditary...... leiomyomatosis and renal cell cancer; yet the connection between disruption of mitochondrial metabolic pathways and neoplasia remains to be discovered. We have used an expression microarray approach for studying differences in global gene expression pattern caused by mutations in FH. Seven uterine fibroids...... carrying FH mutations were compared with 15 fibroids with wild-type FH. The two groups showed markedly different expression profiles, and multiple differentially expressed genes were detected. The most significant increase in FH mutants was seen in the expression of carbohydrate metabolism- and glycolysis...

  9. Identification and characterization of a novel fumarase gene by metagenome expression cloning from marine microorganisms

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    Tang Xian-Lai

    2010-11-01

    Full Text Available Abstract Background Fumarase catalyzes the reversible hydration of fumarate to L-malate and is a key enzyme in the tricarboxylic acid (TCA cycle and in amino acid metabolism. Fumarase is also used for the industrial production of L-malate from the substrate fumarate. Thermostable and high-activity fumarases from organisms that inhabit extreme environments may have great potential in industry, biotechnology, and basic research. The marine environment is highly complex and considered one of the main reservoirs of microbial diversity on the planet. However, most of the microorganisms are inaccessible in nature and are not easily cultivated in the laboratory. Metagenomic approaches provide a powerful tool to isolate and identify enzymes with novel biocatalytic activities for various biotechnological applications. Results A plasmid metagenomic library was constructed from uncultivated marine microorganisms within marine water samples. Through sequence-based screening of the DNA library, a gene encoding a novel fumarase (named FumF was isolated. Amino acid sequence analysis revealed that the FumF protein shared the greatest homology with Class II fumarate hydratases from Bacteroides sp. 2_1_33B and Parabacteroides distasonis ATCC 8503 (26% identical and 43% similar. The putative fumarase gene was subcloned into pETBlue-2 vector and expressed in E. coli BL21(DE3pLysS. The recombinant protein was purified to homogeneity. Functional characterization by high performance liquid chromatography confirmed that the recombinant FumF protein catalyzed the hydration of fumarate to form L-malate. The maximum activity for FumF protein occurred at pH 8.5 and 55°C in 5 mM Mg2+. The enzyme showed higher affinity and catalytic efficiency under optimal reaction conditions: Km= 0.48 mM, Vmax = 827 μM/min/mg, and kcat/Km = 1900 mM/s. Conclusions We isolated a novel fumarase gene, fumF, from a sequence-based screen of a plasmid metagenomic library from uncultivated

  10. A role for cytosolic fumarate hydratase in urea cycle metabolism and renal neoplasia.

    Science.gov (United States)

    Adam, Julie; Yang, Ming; Bauerschmidt, Christina; Kitagawa, Mitsuhiro; O'Flaherty, Linda; Maheswaran, Pratheesh; Özkan, Gizem; Sahgal, Natasha; Baban, Dilair; Kato, Keiko; Saito, Kaori; Iino, Keiko; Igarashi, Kaori; Stratford, Michael; Pugh, Christopher; Tennant, Daniel A; Ludwig, Christian; Davies, Benjamin; Ratcliffe, Peter J; El-Bahrawy, Mona; Ashrafian, Houman; Soga, Tomoyoshi; Pollard, Patrick J

    2013-05-30

    The identification of mutated metabolic enzymes in hereditary cancer syndromes has established a direct link between metabolic dysregulation and cancer. Mutations in the Krebs cycle enzyme, fumarate hydratase (FH), predispose affected individuals to leiomyomas, renal cysts, and cancers, though the respective pathogenic roles of mitochondrial and cytosolic FH isoforms remain undefined. On the basis of comprehensive metabolomic analyses, we demonstrate that FH1-deficient cells and tissues exhibit defects in the urea cycle/arginine metabolism. Remarkably, transgenic re-expression of cytosolic FH ameliorated both renal cyst development and urea cycle defects associated with renal-specific FH1 deletion in mice. Furthermore, acute arginine depletion significantly reduced the viability of FH1-deficient cells in comparison to controls. Our findings highlight the importance of extramitochondrial metabolic pathways in FH-associated oncogenesis and the urea cycle/arginine metabolism as a potential therapeutic target.

  11. A Role for Cytosolic Fumarate Hydratase in Urea Cycle Metabolism and Renal Neoplasia

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    Julie Adam

    2013-05-01

    Full Text Available The identification of mutated metabolic enzymes in hereditary cancer syndromes has established a direct link between metabolic dysregulation and cancer. Mutations in the Krebs cycle enzyme, fumarate hydratase (FH, predispose affected individuals to leiomyomas, renal cysts, and cancers, though the respective pathogenic roles of mitochondrial and cytosolic FH isoforms remain undefined. On the basis of comprehensive metabolomic analyses, we demonstrate that FH1-deficient cells and tissues exhibit defects in the urea cycle/arginine metabolism. Remarkably, transgenic re-expression of cytosolic FH ameliorated both renal cyst development and urea cycle defects associated with renal-specific FH1 deletion in mice. Furthermore, acute arginine depletion significantly reduced the viability of FH1-deficient cells in comparison to controls. Our findings highlight the importance of extramitochondrial metabolic pathways in FH-associated oncogenesis and the urea cycle/arginine metabolism as a potential therapeutic target.

  12. F/H Lab

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    Federal Laboratory Consortium — The F/H Laboratory is the largest of the eight laboratories within the SRS Analytical Area Project with over 100,000 square feet of floor space, 20,000 square foot...

  13. Fumarase activity: an in vivo and in vitro biomarker for acute kidney injury

    DEFF Research Database (Denmark)

    Nielsen, Per Mose; Eldirdiri, Abubakr; Bertelsen, Lotte Bonde

    2017-01-01

    (2)] fumarate conversion to [1,4-C-13(2)] malate by fumarase has been proposed as a measure of necrosis in rat tumor models and in chemically induced AKI rats. Here we show that the degradation of cell membranes in connection with necrosis leads to elevated fumarase activity in plasma and urine and secondly...

  14. Fatal mitochondrial encephalopathy caused by fumarase deficiency: A molecular-genetic study

    Energy Technology Data Exchange (ETDEWEB)

    Gellera, C.; Cavadini, P.; Baratta, S. [Istituto Nazionale Neurologic Carlo Besta, Milano (Italy)] [and others

    1994-09-01

    Fumarase deficiency is a rare autosomal recessive disorder of the citric acid cycle resulting in severe organic aciduria and encephalopathy. Mammalian cells contain two fumarase isoenzymes, one mitochondrial and one cytosolic. In rat, the two proteins are encoded by the same gene and are synthesized by alternative initiation of translation at two in-phase AUG codons. One single fumarase gene locus has been identified on human chromosome 1. In most of the patients so far described, the activities of both isozymes are severely affected, suggesting that mutations within a single gene may underlie the disease. Here, we report the molecular study of fumarase deficiency in a patient exhibiting compound heterozygosity for two different allelic mutations affecting the amino acid composition of both isoforms. The proband, an Italian boy of nonconsanguineous parents, died at 7 months of age of a progressive encephalopathy. Immunoblot demonstrated absence of cross-reacting material in both cytosolic and mitochondrial fraction of all tissues examined. Molecular analysis of the patient`s fumarase cDNA amplified by RT-PCR showed the presence of two mutations affecting the amino acid composition of both isoforms, a missense mutation resulting in the nonconservative amino acid substitution at codon 190 (Arg190Cys) and an amino acid in-frame insertion at codon 434 (Lys434ins). SSCP analysis of genomic PCR fragments encompassing the mutations demonstrated that the patient was heterozygous for both mutations, having inherited the Arg-to-Cys substitution from the father and the in-frame insertion from the mother. Finally, the effects of the mutations on enzyme function were investigated by expressing both normal and mutated fumarase cDNAs in a fumarase-deficient ({delta}FUM1) S. cerevisiae strain.

  15. The glycolytic shift in fumarate-hydratase-deficient kidney cancer lowers AMPK levels, increases anabolic propensities and lowers cellular iron levels

    KAUST Repository

    Tong, Winghang

    2011-09-01

    Inactivation of the TCA cycle enzyme, fumarate hydratase (FH), drives a metabolic shift to aerobic glycolysis in FH-deficient kidney tumors and cell lines from patients with hereditary leiomyomatosis renal cell cancer (HLRCC), resulting in decreased levels of AMP-activated kinase (AMPK) and p53 tumor suppressor, and activation of the anabolic factors, acetyl-CoA carboxylase and ribosomal protein S6. Reduced AMPK levels lead to diminished expression of the DMT1 iron transporter, and the resulting cytosolic iron deficiency activates the iron regulatory proteins, IRP1 and IRP2, and increases expression of the hypoxia inducible factor HIF-1α, but not HIF-2α. Silencing of HIF-1α or activation of AMPK diminishes invasive activities, indicating that alterations of HIF-1α and AMPK contribute to the oncogenic growth of FH-deficient cells. © 2011 Elsevier Inc.

  16. Cascade screening for familial hypercholesterolemia (FH)

    NARCIS (Netherlands)

    R.M. Ned (Renée); E.J.G. Sijbrands (Eric)

    2011-01-01

    textabstractFamilial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by abnormally high concentrations of low-density lipoprotein (LDL) cholesterol in the blood, which predisposes affected persons to premature coronary heart disease (CHD) and death. FH is one of the most co

  17. Nitrile Hydratase Genes Are Present in Multiple Eukaryotic Supergroups

    Science.gov (United States)

    Marron, Alan O.; Akam, Michael; Walker, Giselle

    2012-01-01

    Background Nitrile hydratases are enzymes involved in the conversion of nitrile-containing compounds into ammonia and organic acids. Although they are widespread in prokaryotes, nitrile hydratases have only been reported in two eukaryotes: the choanoflagellate Monosiga brevicollis and the stramenopile Aureococcus anophagefferens. The nitrile hydratase gene in M. brevicollis was believed to have arisen by lateral gene transfer from a prokaryote, and is a fusion of beta and alpha nitrile hydratase subunits. Only the alpha subunit has been reported in A. anophagefferens. Methodology/Principal Findings Here we report the detection of nitrile hydratase genes in five eukaryotic supergroups: opisthokonts, amoebozoa, archaeplastids, CCTH and SAR. Beta-alpha subunit fusion genes are found in the choanoflagellates, ichthyosporeans, apusozoans, haptophytes, rhizarians and stramenopiles, and potentially also in the amoebozoans. An individual alpha subunit is found in a dinoflagellate and an individual beta subunit is found in a haptophyte. Phylogenetic analyses recover a clade of eukaryotic-type nitrile hydratases in the Opisthokonta, Amoebozoa, SAR and CCTH; this is supported by analyses of introns and gene architecture. Two nitrile hydratase sequences from an animal and a plant resolve in the prokaryotic nitrile hydratase clade. Conclusions/Significance The evidence presented here demonstrates that nitrile hydratase genes are present in multiple eukaryotic supergroups, suggesting that a subunit fusion gene was present in the last common ancestor of all eukaryotes. The absence of nitrile hydratase from several sequenced species indicates that subunits were lost in multiple eukaryotic taxa. The presence of nitrile hydratases in many other eukaryotic groups is unresolved due to insufficient data and taxon sampling. The retention and expression of the gene in distantly related eukaryotic species suggests that it plays an important metabolic role. The novel family of eukaryotic

  18. Metabolic reprogramming for producing energy and reducing power in fumarate hydratase null cells from hereditary leiomyomatosis renal cell carcinoma.

    Directory of Open Access Journals (Sweden)

    Youfeng Yang

    Full Text Available Fumarate hydratase (FH-deficient kidney cancer undergoes metabolic remodeling, with changes in mitochondrial respiration, glucose, and glutamine metabolism. These changes represent multiple biochemical adaptations in glucose and fatty acid metabolism that supports malignant proliferation. However, the metabolic linkages between altered mitochondrial function, nucleotide biosynthesis and NADPH production required for proliferation and survival have not been elucidated. To characterize the alterations in glycolysis, the Krebs cycle and the pentose phosphate pathways (PPP that either generate NADPH (oxidative or do not (non-oxidative, we utilized [U-(13C]-glucose, [U-(13C,(15N]-glutamine, and [1,2- (13C2]-glucose tracers with mass spectrometry and NMR detection to track these pathways, and measured the oxygen consumption rate (OCR and extracellular acidification rate (ECAR of growing cell lines. This metabolic reprogramming in the FH null cells was compared to cells in which FH has been restored. The FH null cells showed a substantial metabolic reorganization of their intracellular metabolic fluxes to fulfill their high ATP demand, as observed by a high rate of glucose uptake, increased glucose turnover via glycolysis, high production of glucose-derived lactate, and low entry of glucose carbon into the Krebs cycle. Despite the truncation of the Krebs cycle associated with inactivation of fumarate hydratase, there was a small but persistent level of mitochondrial respiration, which was coupled to ATP production from oxidation of glutamine-derived α-ketoglutarate through to fumarate. [1,2- (13C2]-glucose tracer experiments demonstrated that the oxidative branch of PPP initiated by glucose-6-phosphate dehydrogenase activity is preferentially utilized for ribose production (56-66% that produces increased amounts of ribose necessary for growth and NADPH. Increased NADPH is required to drive reductive carboxylation of α-ketoglutarate and fatty acid

  19. Metabolic reprogramming for producing energy and reducing power in fumarate hydratase null cells from hereditary leiomyomatosis renal cell carcinoma.

    Science.gov (United States)

    Yang, Youfeng; Lane, Andrew N; Ricketts, Christopher J; Sourbier, Carole; Wei, Ming-Hui; Shuch, Brian; Pike, Lisa; Wu, Min; Rouault, Tracey A; Boros, Laszlo G; Fan, Teresa W-M; Linehan, W Marston

    2013-01-01

    Fumarate hydratase (FH)-deficient kidney cancer undergoes metabolic remodeling, with changes in mitochondrial respiration, glucose, and glutamine metabolism. These changes represent multiple biochemical adaptations in glucose and fatty acid metabolism that supports malignant proliferation. However, the metabolic linkages between altered mitochondrial function, nucleotide biosynthesis and NADPH production required for proliferation and survival have not been elucidated. To characterize the alterations in glycolysis, the Krebs cycle and the pentose phosphate pathways (PPP) that either generate NADPH (oxidative) or do not (non-oxidative), we utilized [U-(13)C]-glucose, [U-(13)C,(15)N]-glutamine, and [1,2- (13)C2]-glucose tracers with mass spectrometry and NMR detection to track these pathways, and measured the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) of growing cell lines. This metabolic reprogramming in the FH null cells was compared to cells in which FH has been restored. The FH null cells showed a substantial metabolic reorganization of their intracellular metabolic fluxes to fulfill their high ATP demand, as observed by a high rate of glucose uptake, increased glucose turnover via glycolysis, high production of glucose-derived lactate, and low entry of glucose carbon into the Krebs cycle. Despite the truncation of the Krebs cycle associated with inactivation of fumarate hydratase, there was a small but persistent level of mitochondrial respiration, which was coupled to ATP production from oxidation of glutamine-derived α-ketoglutarate through to fumarate. [1,2- (13)C2]-glucose tracer experiments demonstrated that the oxidative branch of PPP initiated by glucose-6-phosphate dehydrogenase activity is preferentially utilized for ribose production (56-66%) that produces increased amounts of ribose necessary for growth and NADPH. Increased NADPH is required to drive reductive carboxylation of α-ketoglutarate and fatty acid synthesis

  20. Fumarate hydratase inactivation in renal tumors: HIF1α, NRF2, and "cryptic targets" of transcription factors

    Institute of Scientific and Technical Information of China (English)

    Aikseng Ooi; Kyle A.Furge

    2012-01-01

    Biallelic inactivation of fumarate hydratase (FH) causes type 2 papillary renal cell carcinoma (PRCC2),uterine fibroids,and cutaneous leimyomas,a condition known as hereditary leiomyomatosis and renal cell cancer (HLRCC).The most direct effect of FH inactivation is intracellular fumarate accumulation.A majority of studies on FH inactivation over the past decade have focused on the theory that intracellular fumarate stabilizes hypoxia-inducible factor 1α (HIF1A) through competitive inhibition of HIF prolyl hydroxylases.Recently,a competing theory that intracellular fumarate activates nuclear factor (erythroidderived 2)-like 2 (NRF2) through post-translational modification of its negative regulator.Kelch-like ECH- associated protein 1 (KEAP1) has emerged from a computational modeling study and mouse model studies.This review dissects the origin of these two governing theories and highlights the presence of chromatin-structure-regulated targets of transcription factors,which we refer to as "cryptic targets" of transcription factors.One such cryptic target is heme oxygenase Ⅰ (HMOX1),the expression of which is known to be modulated by the gene product of SWI/SNF-related,matrix-associated,actin-dependent regulator of chromatin,subfamily a,member 4 (SMARCA4,also known as BRG1).

  1. A Robust Acquisition Scheme for FH Signal in Adverse Environments

    Institute of Scientific and Technical Information of China (English)

    Ya-Ding Chen; Shao-Qian Li; Yu-Fan Cheng; Gang Wu

    2009-01-01

    Both partial-band jamming and multi- tone jamming have severe effect on the acquisition of frequency-hopping (FH) signal in adverse environments. In this paper, an anti-jamming FH signal acquisition scheme based on cognitive correlation process is proposed to boost the robustness of acquisition. The main idea of this scheme is to utilize a priori knowledge of FH speed and FH pattern to distinguish jamming signal from received signal. Furthermore, theoretic analysis on detection probability and false probability is given to demonstrate the robust performance of the FH signal acquisition method compared with conventional acquisition scheme without any prior information on FH speed and pattern in adverse environments.

  2. Germline fumarate hydratase mutations in patients with ovarian mucinous cystadenoma

    DEFF Research Database (Denmark)

    Ylisaukko-oja, Sanna K.; Cybulski, Cezary; Lehtonen, Rainer;

    2006-01-01

    analyzed for somatic FH mutations. Two patients diagnosed with ovarian mucinous cystadenoma (two out of 33, 6%) were found to be FH germline mutation carriers. One of the changes was a novel mutation (Ala231Thr) and the other one (435insAAA) was previously described in FH deficiency families. These results...

  3. The aconitate hydratase family from Citrus

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    Cercos Manuel

    2010-10-01

    Full Text Available Abstract Background Research on citrus fruit ripening has received considerable attention because of the importance of citrus fruits for the human diet. Organic acids are among the main determinants of taste and organoleptic quality of fruits and hence the control of fruit acidity loss has a strong economical relevance. In citrus, organic acids accumulate in the juice sac cells of developing fruits and are catabolized thereafter during ripening. Aconitase, that transforms citrate to isocitrate, is the first step of citric acid catabolism and a major component of the citrate utilization machinery. In this work, the citrus aconitase gene family was first characterized and a phylogenetic analysis was then carried out in order to understand the evolutionary history of this family in plants. Gene expression analyses of the citrus aconitase family were subsequently performed in several acidic and acidless genotypes to elucidate their involvement in acid homeostasis. Results Analysis of 460,000 citrus ESTs, followed by sequencing of complete cDNA clones, identified in citrus 3 transcription units coding for putatively active aconitate hydratase proteins, named as CcAco1, CcAco2 and CcAco3. A phylogenetic study carried on the Aco family in 14 plant species, shows the presence of 5 Aco subfamilies, and that the ancestor of monocot and dicot species shared at least one Aco gene. Real-time RT-PCR expression analyses of the three aconitase citrus genes were performed in pulp tissues along fruit development in acidic and acidless citrus varieties such as mandarins, oranges and lemons. While CcAco3 expression was always low, CcAco1 and CcAco2 genes were generally induced during the rapid phase of fruit growth along with the maximum in acidity and the beginning of the acid reduction. Two exceptions to this general pattern were found: 1 Clemenules mandarin failed inducing CcAco2 although acid levels were rapidly reduced; and 2 the acidless "Sucreña" orange

  4. Adipose-Specific Deficiency of Fumarate Hydratase in Mice Protects Against Obesity, Hepatic Steatosis, and Insulin Resistance.

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    Yang, Hao; Wu, Jiang W; Wang, Shu P; Severi, Ilenia; Sartini, Loris; Frizzell, Norma; Cinti, Saverio; Yang, Gongshe; Mitchell, Grant A

    2016-11-01

    Obesity and type 2 diabetes are associated with impaired mitochondrial function in adipose tissue. To study the effects of primary deficiency of mitochondrial energy metabolism in fat, we generated mice with adipose-specific deficiency of fumarate hydratase (FH), an integral Krebs cycle enzyme (AFHKO mice). AFHKO mice have severe ultrastructural abnormalities of mitochondria, ATP depletion in white adipose tissue (WAT) and brown adipose tissue, low WAT mass with small adipocytes, and impaired thermogenesis with large unilocular brown adipocytes. AFHKO mice are strongly protected against obesity, insulin resistance, and fatty liver despite aging and high-fat feeding. AFHKO white adipocytes showed normal lipolysis but low triglyceride synthesis. ATP depletion in normal white adipocytes by mitochondrial toxins also decreased triglyceride synthesis, proportionally to ATP depletion, suggesting that reduced triglyceride synthesis may result nonspecifically from adipocyte energy deficiency. At thermoneutrality, protection from insulin resistance and hepatic steatosis was diminished. Taken together, the results show that under the cold stress of regular animal room conditions, adipocyte-specific FH deficiency in mice causes mitochondrial energy depletion in adipose tissues and protects from obesity, hepatic steatosis, and insulin resistance, suggesting that in cold-stressed animals, mitochondrial function in adipose tissue is a determinant of fat mass and insulin sensitivity. © 2016 by the American Diabetes Association.

  5. 子载波FH-OFDM系统仿真

    Institute of Scientific and Technical Information of China (English)

    郑志国; 张元铜; 梅顺良

    2010-01-01

    文章结合OFDM与FH两者的特点,分析了两种FH-OFDM通信系统模型,并给出了子载波FH-OFDM系统的公式.在此基础上,利用Matlab对子载波FH-OFDM进行了仿真,并对仿真结果进行了分析,结果表明子载波FH-OFDM具有更好的误码性能和更强的抗多径干扰能力.

  6. Michael hydratase alcohol dehydrogenase or just alcohol dehydrogenase?

    NARCIS (Netherlands)

    Resch, V.A.; Jin, J.; Chen, B.S.; Hanefeld, U.

    2014-01-01

    The Michael hydratase – alcohol dehydrogenase (MhyADH) from Alicycliphilus denitrificans was previously identified as a bi-functional enzyme performing a hydration of α,β-unsaturated ketones and subsequent oxidation of the formed alcohols. The investigations of the bi-functionality were based on a

  7. The Application of Nitrile Hydratases in Organic Synthesis

    NARCIS (Netherlands)

    Van Pelt, S.

    2010-01-01

    Nitrile hydratases (NHases, E.C. 4.2.1.84) catalyse the transformation of nitriles into the corresponding amides and were first discovered 30 years ago in studies on the microbial degradation of toxic cyano-group-containing compounds. The use of NHases in synthetic chemistry is especially

  8. Michael hydratase alcohol dehydrogenase or just alcohol dehydrogenase?

    NARCIS (Netherlands)

    Resch, V.A.; Jin, J.; Chen, B.S.; Hanefeld, U.

    2014-01-01

    The Michael hydratase – alcohol dehydrogenase (MhyADH) from Alicycliphilus denitrificans was previously identified as a bi-functional enzyme performing a hydration of α,β-unsaturated ketones and subsequent oxidation of the formed alcohols. The investigations of the bi-functionality were based on a s

  9. Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations.

    Science.gov (United States)

    Pollard, P J; Brière, J J; Alam, N A; Barwell, J; Barclay, E; Wortham, N C; Hunt, T; Mitchell, M; Olpin, S; Moat, S J; Hargreaves, I P; Heales, S J; Chung, Y L; Griffiths, J R; Dalgleish, A; McGrath, J A; Gleeson, M J; Hodgson, S V; Poulsom, R; Rustin, P; Tomlinson, I P M

    2005-08-01

    The nuclear-encoded Krebs cycle enzymes, fumarate hydratase (FH) and succinate dehydrogenase (SDHB, -C and -D), act as tumour suppressors. Germline mutations in FH predispose individuals to leiomyomas and renal cell cancer (HLRCC), whereas mutations in SDH cause paragangliomas and phaeochromocytomas (HPGL). In this study, we have shown that FH-deficient cells and tumours accumulate fumarate and, to a lesser extent, succinate. SDH-deficient tumours principally accumulate succinate. In situ analyses showed that these tumours also have over-expression of hypoxia-inducible factor 1alpha (HIF1alpha), activation of HIF1alphatargets (such as vascular endothelial growth factor) and high microvessel density. We found no evidence of increased reactive oxygen species in our cells. Our data provide in vivo evidence to support the hypothesis that increased succinate and/or fumarate causes stabilization of HIF1alpha a plausible mechanism, inhibition of HIF prolyl hydroxylases, has previously been suggested by in vitro studies. The basic mechanism of tumorigenesis in HPGL and HLRCC is likely to be pseudo-hypoxic drive, just as it is in von Hippel-Lindau syndrome.

  10. FUM2, a Cytosolic Fumarase, Is Essential for Acclimation to Low Temperature in Arabidopsis thaliana.

    Science.gov (United States)

    Dyson, Beth C; Miller, Matthew A E; Feil, Regina; Rattray, Nicholas; Bowsher, Caroline G; Goodacre, Royston; Lunn, John E; Johnson, Giles N

    2016-09-01

    Although cold acclimation is a key process in plants from temperate climates, the mechanisms sensing low temperature remain obscure. Here, we show that the accumulation of the organic acid fumaric acid, mediated by the cytosolic fumarase FUM2, is essential for cold acclimation of metabolism in the cold-tolerant model species Arabidopsis (Arabidopsis thaliana). A nontargeted metabolomic approach, using gas chromatography-mass spectrometry, identifies fumarate as a key component of the cold response in this species. Plants of T-DNA insertion mutants, lacking FUM2, show marked differences in their response to cold, with contrasting responses both in terms of metabolite concentrations and gene expression. The fum2 plants accumulated higher concentrations of phosphorylated sugar intermediates and of starch and malate. Transcripts for proteins involved in photosynthesis were markedly down-regulated in fum2.2 but not in wild-type Columbia-0. Plants of fum2 show a complete loss of the ability to acclimate photosynthesis to low temperature. We conclude that fumarate accumulation plays an essential role in low temperature sensing in Arabidopsis, either indirectly modulating metabolic or redox signals or possibly being itself directly involved in cold sensing.

  11. Substitution, cooperative, and solvent effects on π pnicogen bonds in the FH(2)P and FH(2)As complexes.

    Science.gov (United States)

    An, Xiu-Lin; Li, Ran; Li, Qing-Zhong; Liu, Xiao-Feng; Li, Wen-Zuo; Cheng, Jian-Bo

    2012-09-01

    Ab initio calculations have been carried out to study the substitution effect on the π pnicogen bond in ZH(2)P-C(2)HM (Z = H, H(3)C, NC, F; M = H, CH(3), Li) dimer, cooperative effect of the π pnicogen bond and hydrogen bond in XH-FH(2)Y-C(2)H(4) (X = HO, NC, F; Y = P and As) trimer, and solvent effect on the π pnicogen bond in FH(2)P-C(2)H(2), FH(2)P-C(2)H(4), FH(2)As-C(2)H(2), and FH(2)As-C(2)H(4) dimers. The interaction energy of π pnicogen bond increases in magnitude from -1.51 kcal mol(-1) in H(3)P-C(2)H(2) dimer to -7.53 kcal mol(-1) in FH(2)P-C(2)HLi dimer at the MP2/aug-cc-pVTZ level. The π pnicogen bond is enhanced by 12-30 % due to the presence of hydrogen bond in the trimer. The π pnicogen bond is also enhanced in solvents. The natural bond orbital analysis and symmetry adapted perturbation theory (SAPT) were used to unveil the source of substitution, cooperative, and solvent effects.

  12. Characterisation of nitrilase and nitrile hydratase biocatalytic systems

    CSIR Research Space (South Africa)

    Brady, D

    2004-03-01

    Full Text Available and Nagasawa 2000). Other compounds commercially produced using nitrilase bioca- talysts are (R)-mandelic acid and (R)-3-chloromandelic acid (Mitsubishi Rayon Co). Although few commercial processes that utilise nitrilase and nitrile hydratase exist... acid (HClO4) eluent at pH 2, 0.6 ml/min flow rate, Waters 625 LC pump, and a Waters 486 UV detector. The Chiracel OD column (Daicel, Japan) was used for determination of methyl ester derivatives of mandelic acid, and Chiracel OB-H was used...

  13. FH3, a domain found in formins, targets the fission yeast formin Fus1 to the projection tip during conjugation

    DEFF Research Database (Denmark)

    Petersen, J; Nielsen, O; Egel, R;

    1998-01-01

    of the late G2 cells in a vegetatively growing population. Expression of both FH3-GFP fusions also affected cytokinesis. Overexpression of the spindle pole body component Sad1 altered the distribution of both Sad1 and the FH3-GFP domain. Together these data suggest that proteins at multiple sites can interact...... is required for conjugation, and is localized to the projection tip in cells of mating pairs. We replaced genomic fus1+ with green fluorescent protein (GFP)- tagged versions that lacked either the FH1, FH2, or FH3 domain. Deletion of any FH domain essentially abolished mating. FH3, but neither FH1 nor FH2...

  14. FH535 inhibited migration and growth of breast cancer cells.

    Science.gov (United States)

    Iida, Joji; Dorchak, Jesse; Lehman, John R; Clancy, Rebecca; Luo, Chunqing; Chen, Yaqin; Somiari, Stella; Ellsworth, Rachel E; Hu, Hai; Mural, Richard J; Shriver, Craig D

    2012-01-01

    There is substantial evidence indicating that the WNT signaling pathway is activated in various cancer cell types including breast cancer. Previous studies reported that FH535, a small molecule inhibitor of the WNT signaling pathway, decreased growth of cancer cells but not normal fibroblasts, suggesting this pathway plays a role in tumor progression and metastasis. In this study, we tested FH535 as a potential inhibitor for malignant phenotypes of breast cancer cells including migration, invasion, and growth. FH535 significantly inhibited growth, migration, and invasion of triple negative (TN) breast cancer cell lines (MDA-MB231 and HCC38) in vitro. We demonstrate that FH535 was a potent growth inhibitor for TN breast cancer cell lines (HCC38 and MDA-MB-231) but not for other, non-TN breast cancer cell lines (MCF-7, T47D or SK-Br3) when cultured in three dimensional (3D) type I collagen gels. Western blotting analyses suggest that treatment of MDA-MB-231 cells with FH535 markedly inhibited the expression of NEDD9 but not activations of FAK, Src, or downstream targets such as p38 and Erk1/2. We demonstrated that NEDD9 was specifically associated with CSPG4 but not with β1 integrin or CD44 in MDA-MB-231 cells. Analyses of gene expression profiles in breast cancer tissues suggest that CSPG4 expression is higher in Basal-type breast cancers, many of which are TN, than any other subtypes. These results suggest not only a mechanism for migration and invasion involving the canonical WNT-signaling pathways but also novel strategies for treating patients who develop TN breast cancer.

  15. FH535 inhibited migration and growth of breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Joji Iida

    Full Text Available There is substantial evidence indicating that the WNT signaling pathway is activated in various cancer cell types including breast cancer. Previous studies reported that FH535, a small molecule inhibitor of the WNT signaling pathway, decreased growth of cancer cells but not normal fibroblasts, suggesting this pathway plays a role in tumor progression and metastasis. In this study, we tested FH535 as a potential inhibitor for malignant phenotypes of breast cancer cells including migration, invasion, and growth. FH535 significantly inhibited growth, migration, and invasion of triple negative (TN breast cancer cell lines (MDA-MB231 and HCC38 in vitro. We demonstrate that FH535 was a potent growth inhibitor for TN breast cancer cell lines (HCC38 and MDA-MB-231 but not for other, non-TN breast cancer cell lines (MCF-7, T47D or SK-Br3 when cultured in three dimensional (3D type I collagen gels. Western blotting analyses suggest that treatment of MDA-MB-231 cells with FH535 markedly inhibited the expression of NEDD9 but not activations of FAK, Src, or downstream targets such as p38 and Erk1/2. We demonstrated that NEDD9 was specifically associated with CSPG4 but not with β1 integrin or CD44 in MDA-MB-231 cells. Analyses of gene expression profiles in breast cancer tissues suggest that CSPG4 expression is higher in Basal-type breast cancers, many of which are TN, than any other subtypes. These results suggest not only a mechanism for migration and invasion involving the canonical WNT-signaling pathways but also novel strategies for treating patients who develop TN breast cancer.

  16. Stereochemical Consequences of Vinylpyruvate Hydratase-Catalyzed Reactions.

    Science.gov (United States)

    Johnson, William H; Stack, Tyler M M; Taylor, Stephanie M; Burks, Elizabeth A; Whitman, Christian P

    2016-07-26

    A stereochemical analysis has been carried out on two vinylpyruvate hydratases (VPH), which convert 2-hydroxy-2,4-pentadienoate to 2-keto-4S-hydroxypentanoate in meta-fission pathways. Bacterial strains with this pathway can use aromatic compounds as sole sources of energy and carbon. The analysis was carried out using the 5-methyl and 5-chloro derivatives of 2-hydroxy-2,4-pentadienoate with the enzymes from Pseudomonas putida mt-2 (Pp) and Leptothrix cholodnii SP-6 (Lc). In both organisms, VPH is in a complex with the preceding enzyme in the pathway, 4-oxalocrotonate decarboxylase (4-OD). In D2O, a deuteron is incorporated stereospecifically at the C-3 and C-5 positions of product by both Pp and Lc enzymes. Accordingly, the complexes generate (3S,5S)-3,5-[di-D]-2-keto-4S-hydroxyhexanoate and (3S,5R)-3,5-[di-D]-2-keto-4R-hydroxy-5-chloropentanoate (4R and 5R due to a priority numbering change). The substitution at C-5 (CH3 or Cl) or the source of the enzyme (Pp or Lc) does not change the stereochemical outcome. One mechanism that can account for the results is the ketonization of the 5-substituted dienol to the α,β-unsaturated ketone (placing a deuteron at C-5 in D2O), followed by the conjugate addition of water (placing a deuteron at C-3). The stereochemical outcome for VPH (from Pp and Lc) is the same as that reported for a related enzyme, 2-oxo-hept-4-ene-1,7-dioate hydratase, from Escherichia coli C. The combined observations suggest similar mechanisms for these three enzymes that could possibly be common to this group of enzymes.

  17. Effects of naturally occurring missense mutations and G525V in the hydratase domain of human d-bifunctional protein on hydratase activity

    Directory of Open Access Journals (Sweden)

    Shirou Tsuchida

    2015-03-01

    Full Text Available d-bifunctional protein (d-BP deficiency is thought to lead to severe lipid metabolism disorders. To investigate the effect of naturally occurring missense mutations in the hydratase domain in d-BP, we constructed several d-BP hydratase variants and measured their activities. Missense mutations at sites whose conservation rates among 30 eukaryotes were < 70% did not affect hydratase activity. We predicted that missense mutations of highly conserved amino acids would markedly reduce activity. However, R562H and R562L, naturally occurring missense mutations of highly conserved amino acids, did not reduce activity. This result suggests that a missense mutation in a highly conserved amino acid does not always lead to severe lipid metabolism disorders. We also investigated the effect of G525V, which had been found in a mildly symptomatic patient with d-BP deficiency who was heterozygous for G525 and G658X. G525V markedly reduced hydratase activity. We had predicted that heterozygous G525V and G658X would lead to severely disordered lipid metabolism. However, the symptoms were inconsistent with this prediction. Characterizing mutations in the d-BP gene and the symptoms of d-BP deficiency may require pleiotropy, not only in vitro, studies.

  18. H CANYON PROCESSING IN CORRELATION WITH FH ANALYTICAL LABS

    Energy Technology Data Exchange (ETDEWEB)

    Weinheimer, E.

    2012-08-06

    Management of radioactive chemical waste can be a complicated business. H Canyon and F/H Analytical Labs are two facilities present at the Savannah River Site in Aiken, SC that are at the forefront. In fact H Canyon is the only large-scale radiochemical processing facility in the United States and this processing is only enhanced by the aid given from F/H Analytical Labs. As H Canyon processes incoming materials, F/H Labs provide support through a variety of chemical analyses. Necessary checks of the chemical makeup, processing, and accountability of the samples taken from H Canyon process tanks are performed at the labs along with further checks on waste leaving the canyon after processing. Used nuclear material taken in by the canyon is actually not waste. Only a small portion of the radioactive material itself is actually consumed in nuclear reactors. As a result various radioactive elements such as Uranium, Plutonium and Neptunium are commonly found in waste and may be useful to recover. Specific processing is needed to allow for separation of these products from the waste. This is H Canyon's specialty. Furthermore, H Canyon has the capacity to initiate the process for weapons-grade nuclear material to be converted into nuclear fuel. This is one of the main campaigns being set up for the fall of 2012. Once usable material is separated and purified of impurities such as fission products, it can be converted to an oxide and ultimately turned into commercial fuel. The processing of weapons-grade material for commercial fuel is important in the necessary disposition of plutonium. Another processing campaign to start in the fall in H Canyon involves the reprocessing of used nuclear fuel for disposal in improved containment units. The importance of this campaign involves the proper disposal of nuclear waste in order to ensure the safety and well-being of future generations and the environment. As processing proceeds in the fall, H Canyon will have a substantial

  19. Identification of catalytically important residues of the carotenoid 1,2-hydratases from Rubrivivax gelatinosus and Thiocapsa roseopersicina

    NARCIS (Netherlands)

    Hiseni, A.; Otten, L.G.; Arends, I.W.C.E.

    2015-01-01

    Carotenoid 1,2-hydratases (CrtC) catalyze the selective addition of water to an isolated carbon–carbon double bond. Although their involvement in the carotenoid biosynthetic pathway is well understood, little is known about the mechanism by which these hydratases transform carotenoids such as lycope

  20. An adaptive rate algorithm for FH/BFSK signaling

    Science.gov (United States)

    Stuber, Gordon L.; Mark, Jon W.; Blake, Ian F.

    1988-12-01

    The authors present a feedback rate control technique for FH/BFSK (frequency-hop/binary phase-shift keying) signaling over a jammed flat-flat fading channel. An algorithm is developed for tracking the channel fade level, dynamically adjusting the transmitted data rate, and mitigating the effects of partial-band noise jamming. Simulation studies indicate that improvements of about 2 dB can be obtained in the coded performance with the proposed adaptive rate system, when compared to a nonadaptive system operating over the same communication medium with identical power and bandwidth resources.

  1. UBSS and blind parameters estimation algorithms for synchronous or thogonal FH signals

    Institute of Scientific and Technical Information of China (English)

    Weihong Fu; Yongqiang Hei; Xiaohui Li

    2014-01-01

    By using the sparsity of frequency hopping (FH) signals, an underdetermined blind source separation (UBSS) algorithm is presented. Firstly, the short time Fourier transform (STFT) is per-formed on the mixed signals. Then, the mixing matrix, hopping frequencies, hopping instants and the hooping rate can be esti-mated by the K-means clustering algorithm. With the estimated mixing matrix, the directions of arrival (DOA) of source signals can be obtained. Then, the FH signals are sorted and the FH pattern is obtained. Final y, the shortest path algorithm is adopted to recover the time domain signals. Simulation results show that the correla-tion coefficient between the estimated FH signal and the source signal is above 0.9 when the signal-to-noise ratio (SNR) is higher than 0 dB and hopping parameters of multiple FH signals in the synchronous orthogonal FH network can be accurately estimated and sorted under the underdetermined conditions.

  2. Purification, characterization, and cloning of a bifunctional molybdoenzyme with hydratase and alcohol dehydrogenase activity

    NARCIS (Netherlands)

    Jin, J.; Straathof, A.J.J.; Pinkse, M.W.H.; Hanefeld, U.

    2010-01-01

    A bifunctional hydratase/alcohol dehydrogenase was isolated from the cyclohexanol degrading bacterium Alicycliphilus denitrificans DSMZ 14773. The enzyme catalyzes the addition of water to α,β-unsaturated carbonyl compounds and the subsequent alcohol oxidation. The purified enzyme showed three

  3. Purification, characterization, and cloning of a bifunctional molybdoenzyme with hydratase and alcohol dehydrogenase activity

    NARCIS (Netherlands)

    Jin, J.; Straathof, A.J.J.; Pinkse, M.W.H.; Hanefeld, U.

    2010-01-01

    A bifunctional hydratase/alcohol dehydrogenase was isolated from the cyclohexanol degrading bacterium Alicycliphilus denitrificans DSMZ 14773. The enzyme catalyzes the addition of water to α,β-unsaturated carbonyl compounds and the subsequent alcohol oxidation. The purified enzyme showed three subun

  4. FUM2, a Cytosolic Fumarase, Is Essential for Acclimation to Low Temperature in Arabidopsis thaliana1[OPEN

    Science.gov (United States)

    Dyson, Beth C.; Miller, Matthew A.E.; Feil, Regina; Rattray, Nicholas; Bowsher, Caroline G.

    2016-01-01

    Although cold acclimation is a key process in plants from temperate climates, the mechanisms sensing low temperature remain obscure. Here, we show that the accumulation of the organic acid fumaric acid, mediated by the cytosolic fumarase FUM2, is essential for cold acclimation of metabolism in the cold-tolerant model species Arabidopsis (Arabidopsis thaliana). A nontargeted metabolomic approach, using gas chromatography-mass spectrometry, identifies fumarate as a key component of the cold response in this species. Plants of T-DNA insertion mutants, lacking FUM2, show marked differences in their response to cold, with contrasting responses both in terms of metabolite concentrations and gene expression. The fum2 plants accumulated higher concentrations of phosphorylated sugar intermediates and of starch and malate. Transcripts for proteins involved in photosynthesis were markedly down-regulated in fum2.2 but not in wild-type Columbia-0. Plants of fum2 show a complete loss of the ability to acclimate photosynthesis to low temperature. We conclude that fumarate accumulation plays an essential role in low temperature sensing in Arabidopsis, either indirectly modulating metabolic or redox signals or possibly being itself directly involved in cold sensing. PMID:27440755

  5. Decreased mitochondrial activities of malate dehydrogenase and fumarase in tomato lead to altered root growth and architecture via diverse mechanisms.

    Science.gov (United States)

    van der Merwe, Margaretha J; Osorio, Sonia; Moritz, Thomas; Nunes-Nesi, Adriano; Fernie, Alisdair R

    2009-02-01

    Transgenic tomato (Solanum lycopersicum) plants in which either mitochondrial malate dehydrogenase or fumarase was antisense inhibited have previously been characterized to exhibit altered photosynthetic metabolism. Here, we demonstrate that these manipulations also resulted in differences in root growth, with both transgenics being characterized by a dramatic reduction of root dry matter deposition and respiratory activity but opposite changes with respect to root area. A range of physiological, molecular, and biochemical experiments were carried out in order to determine whether changes in root morphology were due to altered metabolism within the root itself, alterations in the nature of the transformants' root exudation, consequences of alteration in the efficiency of photoassimilate delivery to the root, or a combination of these factors. Grafting experiments in which the transformants were reciprocally grafted to wild-type controls suggested that root length and area were determined by the aerial part of the plant but that biomass was not. Despite the transgenic roots displaying alteration in the expression of phytohormone-associated genes, evaluation of the levels of the hormones themselves revealed that, with the exception of gibberellins, they were largely unaltered. When taken together, these combined experiments suggest that root biomass and growth are retarded by root-specific alterations in metabolism and gibberellin contents. These data are discussed in the context of current models of root growth and biomass partitioning.

  6. Biochemical characterization and FAD-binding analysis of oleate hydratase from Macrococcus caseolyticus.

    Science.gov (United States)

    Joo, Young-Chul; Jeong, Ki-Woong; Yeom, Soo-Jin; Kim, Yeong-Su; Kim, Yangmee; Oh, Deok-Kun

    2012-03-01

    A putative fatty acid hydratase gene from Macrococcus caseolyticus was cloned and expressed in Escherichia coli. The recombinant enzyme was a 68 kDa dimer with a molecular mass of 136 kDa. The enzymatic products formed from fatty acid substrates by the putative enzyme were isolated with high purity (>99%) by solvent fractional crystallization at low temperature. After the identification by GC-MS, the purified hydroxy fatty acids were used as standards to quantitatively determine specific activities and kinetic parameters for fatty acids as substrates. Among the fatty acids evaluated, specific activity and catalytic efficiency (k(cat)/K(m)) were highest for oleic acid, indicating that the putative fatty acid hydratase was an oleate hydratase. Hydration occurred only for cis-9-double and cis-12-double bonds of unsaturated fatty acids without any trans-configurations. The maximum activity for oleate hydration was observed at pH 6.5 and 25 °C with 2% (v/v) ethanol and 0.2 mM FAD. Without FAD, all catalytic activity was abolished. Thus, the oleate hydratase is an FAD-dependent enzyme. The residues G29, G31, S34, E50, and E56, which are conserved in the FAD-binding motif of fatty acid hydratases (GXGXXG((A/S))X((15-21))E((D))), were selected by alignment, and the spectral properties and kinetic parameters of their alanine-substituted variants were analyzed. Among the five variants, G29A, G31A, and E56A showed no interaction with FAD and exhibited no activity. These results indicate that G29, G31, and E56 are essential for FAD-binding.

  7. An Arabidopsis Class Ⅱ Formin, AtFH19, Nucleates Actin Assembly, Binds to the Barbed End of Actin Filaments, and Antagonizes the Effect of AtFH1 on Actin Dynamics

    Institute of Scientific and Technical Information of China (English)

    Yiyan Zheng; Haibo Xin; Jinxing Lin; Chun-Ming Liu; Shanjin Huang

    2012-01-01

    Formin is a major protein responsible for regulating the nucleation of actin filaments,and as such,it permits the cell to control where and when to assemble actin arrays.It is encoded by a multigene family comprising 21 members in Arabidopsis thaliana.The Arabidopsis formins can be separated into two phylogenetically-distinct classes:there are 11 class Ⅰ formins and 10 class Ⅱ formins.Significant questions remain unanswered regarding the molecular mechanism of actin nucleation and elongation stimulated by each formin isovariant,and how the different isovariants coordinate to regulate actin dynamics in cells.Here,we characterize a class Ⅱ formin,AtFH19,biochemically.We found that AtFH19 retains all general properties of the formin family,including nucleation and barbed end capping activity.It can also generate actin filaments from a pool of actin monomers bound to profilin.However,both the nucleation and barbed end capping activities of AtFH19 are less efficient compared to those of another well-characterized formin,AtFH1.Interestingly,AtFH19 FH1FH2 competes with AtFH1 FH1FH2 in binding actin filament barbed ends,and inhibits the effect of AtFH1 FH1FH2 on actin.We thus propose a mechanism in which two quantitatively different formins coordinate to regulate actin dynamics by competing for actin filament barbed ends.

  8. [Effects of nitriles and amides on the growth and the nitrile hydratase activity of the Rhodococcus sp. strain gt1].

    Science.gov (United States)

    Maksimov, A Iu; Kuznetsova, M V; Ovechkina, G V; Kozlov, S V; Maksimova, Iu G; Demakov, V A

    2003-01-01

    Effects of some nitriles and amides, as well as glucose and ammonium, on the growth and the nitrile hydratase (EC 4.2.1.84) activity of the Rhodococcus sp. strain gt1 isolated from soil were studied. The activity of nitrile hydratase mainly depended on carbon and nitrogen supply to cells. The activity of nitrile hydratase was high in the presence of glucose and ammonium at medium concentrations and decreased at concentrations of glucose more than 0.3%. Saturated unsubstituted aliphatic nitriles and amides were found to be a good source of nitrogen and carbon. However, the presence of nitriles and amides in the medium was not absolutely necessary for the expression of the activity of nitrile hydratase isolated from the Rhodococcus sp. strain gt1.

  9. Expression control of nitrile hydratase and amidase genes in Rhodococcus erythropolis and substrate specificities of the enzymes.

    Science.gov (United States)

    Rucká, Lenka; Volkova, Olga; Pavlík, Adam; Kaplan, Ondřej; Kracík, Martin; Nešvera, Jan; Martínková, Ludmila; Pátek, Miroslav

    2014-06-01

    Bacterial amidases and nitrile hydratases can be used for the synthesis of various intermediates and products in the chemical and pharmaceutical industries and for the bioremediation of toxic pollutants. The aim of this study was to analyze the expression of the amidase and nitrile hydratase genes of Rhodococcus erythropolis and test the stereospecific nitrile hydratase and amidase activities on chiral cyanohydrins. The nucleotide sequences of the gene clusters containing the oxd (aldoxime dehydratase), ami (amidase), nha1, nha2 (subunits of the nitrile hydratase), nhr1, nhr2, nhr3 and nhr4 (putative regulatory proteins) genes of two R. erythropolis strains, A4 and CCM2595, were determined. All genes of both of the clusters are transcribed in the same direction. RT-PCR analysis, primer extension and promoter fusions with the gfp reporter gene showed that the ami, nha1 and nha2 genes of R. erythropolis A4 form an operon transcribed from the Pami promoter and an internal Pnha promoter. The activity of Pami was found to be weakly induced when the cells grew in the presence of acetonitrile, whereas the Pnha promoter was moderately induced by both the acetonitrile or acetamide used instead of the inorganic nitrogen source. However, R. erythropolis A4 cells showed no increase in amidase and nitrile hydratase activities in the presence of acetamide or acetonitrile in the medium. R. erythropolis A4 nitrile hydratase and amidase were found to be effective at hydrolysing cyanohydrins and 2-hydroxyamides, respectively.

  10. Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation.

    Science.gov (United States)

    Watts, Gerald F; Gidding, Samuel; Wierzbicki, Anthony S; Toth, Peter P; Alonso, Rodrigo; Brown, W Virgil; Bruckert, Eric; Defesche, Joep; Lin, Khoo Kah; Livingston, Michael; Mata, Pedro; Parhofer, Klaus G; Raal, Frederick J; Santos, Raul D; Sijbrands, Eric J G; Simpson, William G; Sullivan, David R; Susekov, Andrey V; Tomlinson, Brian; Wiegman, Albert; Yamashita, Shizuya; Kastelein, John J P

    2015-07-01

    Familial hypercholesterolaemia (FH) is a dominantly inherited disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL) cholesterol and causes premature coronary heart disease. There are at least 20 million people with FH worldwide, but the majority remains undetected and current treatment is often suboptimal.To address this major gap in coronary prevention we present, from an international perspective, consensus-based guidance on the care of FH. The guidance was generated from seminars and workshops held at an international symposium. The recommendations focus on the detection, diagnosis, assessment and management of FH in adults and children, and set guidelines for clinical purposes. They also refer to best practice for cascade screening and risk notifying and testing families for FH, including use of genetic testing. Guidance on treatment is based on risk stratification, management of non-cholesterol risk factors and safe and effective use of LDL lowering therapies. Recommendations are given on lipoprotein apheresis. The use of emerging therapies for FH is also foreshadowed.This international guidance acknowledges evidence gaps, but aims to make the best use of contemporary practice and technology to achieve the best outcomes for the care of FH. It should accordingly be employed to inform clinical judgment and be adjusted for country-specific and local healthcare needs and resources.

  11. Integrated guidance on the care of familial hypercholesterolemia from the International FH Foundation.

    Science.gov (United States)

    Watts, Gerald F; Gidding, Samuel; Wierzbicki, Anthony S; Toth, Peter P; Alonso, Rodrigo; Brown, W Virgil; Bruckert, Eric; Defesche, Joep; Lin, Khoo Kah; Livingston, Michael; Mata, Pedro; Parhofer, Klaus G; Raal, Frederick J; Santos, Raul D; Sijbrands, Eric J G; Simpson, William G; Sullivan, David R; Susekov, Andrey V; Tomlinson, Brian; Wiegman, Albert; Yamashita, Shizuya; Kastelein, John J P

    2014-01-01

    Familial hypercholesterolemia (FH) is a dominantly inherited disorder present from birth that markedly elevates plasma low-density lipoprotein cholesterol and causes premature coronary heart disease. There are at least 20 million people with FH worldwide, but the majority remains undetected, and current treatment is often suboptimal. To address this major gap in coronary prevention we present, from an international perspective, consensus-based guidance on the care of FH. The guidance was generated from seminars and workshops held at an international symposium. The recommendations focus on the detection, diagnosis, assessment, and management of FH in adults and children and set guidelines for clinical purposes. They also refer to best practice for cascade screening and risk notifying and testing families for FH, including use of genetic testing. Guidance on treatment is based on risk stratification, management of noncholesterol risk factors, and the safe and effective use of low-density lipoprotein-lowering therapies. Recommendations are given on lipoprotein apheresis. The use of emerging therapies for FH is also foreshadowed. This international guidance acknowledges evidence gaps but aims to make the best use of contemporary practice and technology to achieve the best outcomes for the care of FH. It should accordingly be used to inform clinical judgment and be adjusted for country-specific and local healthcare needs and resources.

  12. [Atypical leiomyoma in a patient with cutaneous leiomyomatosis and mutation of the enzyme fumarate hydratase].

    Science.gov (United States)

    Calderón-Komáromy, Angélica; Arias-Palomo, Dolores; Tardío, Juan C; Freites-Martínez, Azael; Borbujo, Jesús

    2016-03-01

    We report the case of a 56 year-old male with an atypical leiomyoma in the context of a cutaneous leiomyomatosis and a family history of uterine leiomyomatosis. The genetic study revealed a mutation in the gene for the enzyme fumarate hydratase, but he has not had any renal malignancy so far. Atypical leiomyoma is a rare tumor that usually presents as a single lesion and is exceptional in patients with cutaneous leiomyomatosis. The relation between fumarate hydratase enzyme mutations with multiple leiomyomas, uterine leiomyomatosis and an increased risk of developing kidney cancer is widely known. However, the role of these mutations in the development of atypical leiomyomas is still impossible to clarify given the few cases reported in the literature.

  13. The bacterial catabolism of polycyclic aromatic hydrocarbons: Characterization of three hydratase-aldolase-catalyzed reactions

    Directory of Open Access Journals (Sweden)

    Jake A. LeVieux

    2016-12-01

    Full Text Available Polycyclic aromatic hydrocarbons (PAHs are highly toxic, pervasive environmental pollutants with mutagenic, teratogenic, and carcinogenic properties. There is interest in exploiting the nutritional capabilities of microbes to remove PAHs from various environments including those impacted by improper disposal or spills. Although there is a considerable body of literature on PAH degradation, the substrates and products for many of the enzymes have never been identified and many proposed activities have never been confirmed. This is particularly true for high molecular weight PAHs (e.g., phenanthrene, fluoranthene, and pyrene. As a result, pathways for the degradation of these compounds are proposed to follow one elucidated for naphthalene with limited experimental verification. In this pathway, ring fission produces a species that can undergo a non-enzymatic cyclization reaction. An isomerase opens the ring and catalyzes a cis to trans double bond isomerization. The resulting product is the substrate for a hydratase-aldolase, which catalyzes the addition of water to the double bond of an α,β-unsaturated ketone, followed by a retro-aldol cleavage. Initial kinetic and mechanistic studies of the hydratase-aldolase in the naphthalene pathway (designated NahE and two hydratase-aldolases in the phenanthrene pathway (PhdG and PhdJ have been completed. Crystallographic work on two of the enzymes (NahE and PhdJ provides a rudimentary picture of the mechanism and a platform for future work to identify the structural basis for catalysis and the individual specificities of these hydratase-aldolases.

  14. An Aeroplysinin-1 Specific Nitrile Hydratase Isolated from the Marine Sponge Aplysina cavernicola

    Directory of Open Access Journals (Sweden)

    Peter Proksch

    2013-08-01

    Full Text Available A nitrile hydratase (NHase that specifically accepts the nitrile aeroplysinin-1 (1 as a substrate and converts it into the dienone amide verongiaquinol (7 was isolated, partially purified and characterized from the Mediterranean sponge Aplysina cavernicola; although it is currently not known whether the enzyme is of sponge origin or produced by its symbiotic microorganisms. The formation of aeroplysinin-1 and of the corresponding dienone amide is part of the chemical defence system of A. cavernicola. The latter two compounds that show strong antibiotic activity originate from brominated isoxazoline alkaloids that are thought to protect the sponges from invasion of bacterial pathogens. The sponge was shown to contain at least two NHases as two excised protein bands from a non denaturating Blue Native gel showed nitrile hydratase activity, which was not observed for control samples. The enzymes were shown to be manganese dependent, although cobalt and nickel ions were also able to recover the activity of the nitrile hydratases. The temperature and pH optimum of the studied enzymes were found at 41 °C and pH 7.8. The enzymes showed high substrate specificity towards the physiological substrate aeroplysinin-1 (1 since none of the substrate analogues that were prepared either by partial or by total synthesis were converted in an in vitro assay. Moreover de-novo sequencing by mass spectrometry was employed to obtain information about the primary structure of the studied NHases, which did not reveal any homology to known NHases.

  15. An Aeroplysinin-1 Specific Nitrile Hydratase Isolated from the Marine Sponge Aplysina cavernicola

    Science.gov (United States)

    Lipowicz, Bartosz; Hanekop, Nils; Schmitt, Lutz; Proksch, Peter

    2013-01-01

    A nitrile hydratase (NHase) that specifically accepts the nitrile aeroplysinin-1 (1) as a substrate and converts it into the dienone amide verongiaquinol (7) was isolated, partially purified and characterized from the Mediterranean sponge Aplysina cavernicola; although it is currently not known whether the enzyme is of sponge origin or produced by its symbiotic microorganisms. The formation of aeroplysinin-1 and of the corresponding dienone amide is part of the chemical defence system of A. cavernicola. The latter two compounds that show strong antibiotic activity originate from brominated isoxazoline alkaloids that are thought to protect the sponges from invasion of bacterial pathogens. The sponge was shown to contain at least two NHases as two excised protein bands from a non denaturating Blue Native gel showed nitrile hydratase activity, which was not observed for control samples. The enzymes were shown to be manganese dependent, although cobalt and nickel ions were also able to recover the activity of the nitrile hydratases. The temperature and pH optimum of the studied enzymes were found at 41 °C and pH 7.8. The enzymes showed high substrate specificity towards the physiological substrate aeroplysinin-1 (1) since none of the substrate analogues that were prepared either by partial or by total synthesis were converted in an in vitro assay. Moreover de-novo sequencing by mass spectrometry was employed to obtain information about the primary structure of the studied NHases, which did not reveal any homology to known NHases. PMID:23966036

  16. Ferrous and ferric ions-based high-throughput screening strategy for nitrile hydratase and amidase.

    Science.gov (United States)

    Lin, Zhi-Jian; Zheng, Ren-Chao; Lei, Li-Hua; Zheng, Yu-Guo; Shen, Yin-Chu

    2011-06-01

    Rapid and direct screening of nitrile-converting enzymes is of great importance in the development of industrial biocatalytic process for pharmaceuticals and fine chemicals. In this paper, a combination of ferrous and ferric ions was used to establish a novel colorimetric screening method for nitrile hydratase and amidase with α-amino nitriles and α-amino amides as substrates, respectively. Ferrous and ferric ions reacted sequentially with the cyanide dissociated spontaneously from α-amino nitrile solution, forming a characteristic deep blue precipitate. They were also sensitive to weak basicity due to the presence of amino amide, resulting in a yellow precipitate. When amino amide was further hydrolyzed to amino acid, it gave a light yellow solution. Mechanisms of color changes were further proposed. Using this method, two isolates with nitrile hydratase activity towards 2-amino-2,3-dimethyl butyronitrile, one strain capable of hydrating 2-amino-4-(hydroxymethyl phosphiny) butyronitrile and another microbe exhibiting amidase activity against 2-amino-4-methylsulfanyl butyrlamide were obtained from soil samples and culture collections of our laboratory. Versatility of this method enabled it the first direct and inexpensive high-throughput screening system for both nitrile hydratase and amidase. Copyright © 2011 Elsevier B.V. All rights reserved.

  17. Characterization of Linoleate 10-Hydratase of Lactobacillus plantarum and Novel Antifungal Metabolites

    Science.gov (United States)

    Chen, Yuan Y.; Liang, Nuan Y.; Curtis, Jonathan M.; Gänzle, Michael G.

    2016-01-01

    Lactobacilli convert linoleic acid to the antifungal compound 10-hydroxy-12-octadecenoic acid (10-HOE) by linoleate 10-hydratase (10-LAH). However, the effect of this conversion on cellular membrane physiology and properties of the cell surface have not been demonstrated. Moreover, Lactobacillus plantarum produces 13-hydroxy-9-octadecenoic acid (13-HOE) in addition to 10-HOE, but the antifungal activity of 13-HOE was unknown. Phylogenetic analyses conducted in this study did not differentiate between 10-LAH and linoleate 13-hydratase (13-LAH). Thus, linoleate hydratases (LAHs) must be characterized through their differences in their activities of linoleate conversion. Four genes encoding putative LAHs from lactobacilli were cloned, heterologous expressed, purified and identified as FAD-dependent 10-LAH. The unsaturated fatty acid substrates stimulated the growth of lactobacilli. We also investigated the role of 10-LAH in ethanol tolerance, membrane fluidity and hydrophobicity of cell surfaces in lactobacilli by disruption of lah. Compared with the L. plantarum lah deficient strain, 10-LAH in wild-type strain did not exert effect on cell survival and membrane fluidity under ethanol stress, but influenced the cell surface hydrophobicity. Moreover, deletion of 10-LAH in L. plantarum facilitated purification of 13-HOE and demonstration of its antifungal activity against Penicillium roqueforti and Aspergillus niger. PMID:27757104

  18. Autosomal recessive hypercholesterolemia (ARH) and homozygous familial hypercholesterolemia (FH): a phenotypic comparison.

    Science.gov (United States)

    Pisciotta, Livia; Priore Oliva, Claudio; Pes, Giovanni Mario; Di Scala, Lilla; Bellocchio, Antonella; Fresa, Raffaele; Cantafora, Alfredo; Arca, Marcello; Calandra, Sebastiano; Bertolini, Stefano

    2006-10-01

    Autosomal recessive hypercholesterolemia (ARH) is a rare disorder, due to complete loss of function of an adaptor protein (ARH protein) required for receptor-mediated hepatic uptake of LDL. ARH is a phenocopy of homozygous familial hypercholesterolemia (HoFH) due to mutations in LDL receptor (LDLR) gene; however, previous studies suggested that ARH phenotype is less severe than that of HoFH. To test this hypothesis we compared 42 HoFH and 42 ARH patients. LDLR and ARH genes were analysed by Southern blotting and sequencing. LDLR activity was measured in cultured fibroblasts. In ARH plasma LDL cholestrol (LDL-C) level (14.25+/-2.29 mmol/L) was lower than in receptor-negative HoFH (21.38+/-3.56 mmol/L) but similar to that found in receptor-defective HoFH (15.52+/-2.39 mmol/L). The risk of coronary artery disease (CAD) was 9-fold lower in ARH patients. No ARH patients FH. The CAD prevalence was or tended to be lower in ARH also in the 21-40 (45% versus 86%) and 41-60 (78% versus 100%) age groups. Heterozygous ARH carriers showed higher level of LDL-C (+17%) than non-carrier family members. In conclusion the clinical phenotype of ARH is milder than that of receptor-negative HoFH and resembles that observed in receptor-defective HoFH.

  19. Identification and characterization of an oleate hydratase-encoding gene from Bifidobacterium breve

    Science.gov (United States)

    O'Connell, Kerry Joan; Motherway, Mary O'Connell; Hennessey, Alan A; Brodhun, Florian; Ross, R Paul; Feussner, Ivo; Stanton, Catherine; Fitzgerald, Gerald F; van Sinderen, Douwe

    2013-01-01

    Bifidobacteria are common commensals of the mammalian gastrointestinal tract. Previous studies have suggested that a bifidobacterial myosin cross reactive antigen (MCRA) protein plays a role in bacterial stress tolerance, while this protein has also been linked to the biosynthesis of conjugated linoleic acid (CLA) in bifidobacteria. In order to increase our understanding on the role of MCRA in bifidobacteria we created and analyzed an insertion mutant of the MCRA-encoding gene of B. breve NCFB 2258. Our results demonstrate that the MCRA protein of B. breve NCFB 2258 does not appear to play a role in CLA production, yet is an oleate hydratase, which contributes to bifidobacterial solvent stress protection. PMID:23851389

  20. Interaction of formin FH2 with skeletal muscle actin. EPR and DSC studies.

    Science.gov (United States)

    Kupi, Tünde; Gróf, Pál; Nyitrai, Miklós; Belágyi, József

    2013-10-01

    Formins are highly conserved proteins that are essential in the formation and regulation of the actin cytoskeleton. The formin homology 2 (FH2) domain is responsible for actin binding and acts as an important nucleating factor in eukaryotic cells. In this work EPR and DSC were used to investigate the properties of the mDia1-FH2 formin fragment and its interaction with actin. MDia1-FH2 was labeled with a maleimide spin probe (MSL). EPR results suggested that the MSL was attached to a single SH group in the FH2. In DSC and temperature-dependent EPR experiments we observed that mDia1-FH2 has a flexible structure and observed a major temperature-induced conformational change at 41 °C. The results also confirmed the previous observation obtained by fluorescence methods that formin binding can destabilize the structure of actin filaments. In the EPR experiments the intermolecular connection between the monomers of formin dimers proved to be flexible. Considering the complex molecular mechanisms underlying the cellular roles of formins this internal flexibility of the dimers is probably important for manifestation of their biological functions.

  1. Effect of ezetimibe coadministered with statins in genotype-confirmed heterozygous FH patients.

    Science.gov (United States)

    Pisciotta, Livia; Fasano, Tommaso; Bellocchio, Antonella; Bocchi, Letizia; Sallo, Raffaella; Fresa, Raffaele; Colangeli, Isabella; Cantafora, Alfredo; Calandra, Sebastiano; Bertolini, Stefano

    2007-10-01

    We investigated the effect of statins and statins plus ezetimibe in 65 FH heterozygotes carrying LDLR-defective or LDLR-negative mutations as well as the effect of ezetimibe monotherapy in 50 hypercholesterolemic (HCH) patients intolerant to statins. PCSK9 and NPC1L1 genes were analysed to assess the role of genetic variants in response to therapy. In FH patients combined therapy reduced LDL-C by 57%, irrespective of the type of LDLR mutation. The additional decrease of plasma LDL-C induced by ezetimibe showed wide inter-individual variability (from -39% to -4.7%) and was negatively correlated with percent LDL-C decrease due to statin alone (r=-0.713, PG polymorphism (L272L) in hyper-responders, an observation confirmed also in FH patients hyper-responders to ezetimibe. In both FH and HCH patients, the G allele carriers tended to have a higher LDL-C reduction in response to ezetimibe. These observations suggest that in FH heterozygotes LDL-C reduction following combined therapy reflects a complex interplay between hepatic synthesis and intestinal absorption of cholesterol.

  2. Dynamical resonance in F+H2 chemical reaction and rotational excitation effect

    Institute of Scientific and Technical Information of China (English)

    YANG XueMing; XIE DaiQian; ZHANG DongHui

    2007-01-01

    Reaction resonance is a frontier topic in chemical dynamics research, and it is also essential to the understanding of mechanisms of elementary chemical reactions. This short article describes an important development in the frontier of research. Experimental evidence of reaction resonance has been detected in a full quantum state resolved reactive scattering study of the F+H2 reaction. Highly accurate full quantum scattering theoretical modeling shows that the reaction resonance is caused by two Feshbach resonance states. Further studies show that quantum interference is present between the two resonance states for the forward scattering product. This study is a significant step forward in our understanding of chemical reaction resonance in the benchmark F+H2 system. Further experimental studies on the effect of H2 rotational excitation on dynamical resonance have been carried out. Dynamical resonance in the F+H2 (j = 1) reaction has also been observed.

  3. 3-Methylglutaconyl-Coenzyme-A Hydratase Deficiency and the Development of Dilated Cardiomyopathy

    Science.gov (United States)

    Spergel, Craig D.; Milko, Mariya; Edwards, Christopher; Steinhoff, Jeff P.

    2014-01-01

    A 25-year-old Canadian male with a history of 3-methylglutaconyl-coenzyme-A hydratase deficiency, also known as 3-methylglutaconic aciduria type I, a very rare inborn error of metabolism, presented with respiratory distress, nausea, vomiting and signs of multisystem organ failure due to a suspected underlying infectious process. An electrocardiogram revealed bilateral atrial enlargement and an elevated brain natriuretic peptide on the initial laboratory studies, which prompted a more thorough cardiac workup. The transthoracic echocardiogram revealed a dilated cardiomyopathy with severe systolic dysfunction. The deficient enzyme present in this patient is involved in the pathway of leucine catabolism and is particularly important in various tissues for energy production and sterol synthesis. The dilated cardiomyopathy in this patient possibly had a variety of potential mechanisms including: a mitochondrial myopathy due to the deficiency of this enzyme leading to a defect in energy production inside cardiac myocytes; or a direct toxicity from 3-methylglutaconic acid (3-MGA) and its toxic metabolites; or a cardiac dysfunction due to a variety of other potential mechanisms. In conclusion, this patient’s clinical presentation suggested that 3-methylglutaconyl-CoA hydratase deficiency could cause a severe dilated cardiomyopathy and heart failure.

  4. 4-Oxalocrotonate tautomerase, its homologue YwhB, and active vinylpyruvate hydratase : Synthesis and evaluation of 2-fluoro substrate analogues

    NARCIS (Netherlands)

    Johnson, William H; Wang, Susan C; Stanley, Thanuja M; Czerwinski, Robert M; Almrud, Jeffrey J; Poelarends, Gerrit J; Murzin, Alexey G; Whitman, Christian P

    2004-01-01

    A series of 2-fluoro-4-alkene and 2-fluoro-4-alkyne substrate analogues were synthesized and examined as potential inhibitors of three enzymes: 4-oxalocrotonate tautomerase (4-OT) and vinylpyruvate hydratase (VPH) from the catechol meta-fission pathway and a closely related 4-OT homologue found in B

  5. Biochemical characterization of the carotenoid 1,2-hydratases (CrtC) from Rubrivivax gelatinosus and Thiocapsa roseopersicina

    NARCIS (Netherlands)

    Hiseni, A.; Arends, I.W.C.E.; Otten, L.G.

    2011-01-01

    Two carotenoid 1,2-hydratase (CrtC) genes from the photosynthetic bacteria Rubrivivax gelatinosus and Thiocapsa roseopersicina were cloned and expressed in Escherichia coli in an active form and purified by affinity chromatography. The biochemical properties of the recombinant enzymes and their subs

  6. 4-Oxalocrotonate tautomerase, its homologue YwhB, and active vinylpyruvate hydratase : Synthesis and evaluation of 2-fluoro substrate analogues

    NARCIS (Netherlands)

    Johnson, William H; Wang, Susan C; Stanley, Thanuja M; Czerwinski, Robert M; Almrud, Jeffrey J; Poelarends, Gerrit J; Murzin, Alexey G; Whitman, Christian P

    2004-01-01

    A series of 2-fluoro-4-alkene and 2-fluoro-4-alkyne substrate analogues were synthesized and examined as potential inhibitors of three enzymes: 4-oxalocrotonate tautomerase (4-OT) and vinylpyruvate hydratase (VPH) from the catechol meta-fission pathway and a closely related 4-OT homologue found in B

  7. Structure reveals regulatory mechanisms of a MaoC-like hydratase from Phytophthora capsici involved in biosynthesis of polyhydroxyalkanoates (PHAs.

    Directory of Open Access Journals (Sweden)

    Huizheng Wang

    Full Text Available BACKGROUND: Polyhydroxyalkanoates (PHAs have attracted increasing attention as "green plastic" due to their biodegradable, biocompatible, thermoplastic, and mechanical properties, and considerable research has been undertaken to develop low cost/high efficiency processes for the production of PHAs. MaoC-like hydratase (MaoC, which belongs to (R-hydratase involved in linking the β-oxidation and the PHA biosynthetic pathways, has been identified recently. Understanding the regulatory mechanisms of (R-hydratase catalysis is critical for efficient production of PHAs that promise synthesis an environment-friendly plastic. METHODOLOGY/PRINCIPAL FINDINGS: We have determined the crystal structure of a new MaoC recognized from Phytophthora capsici. The crystal structure of the enzyme was solved at 2.00 Å resolution. The structure shows that MaoC has a canonical (R-hydratase fold with an N-domain and a C-domain. Supporting its dimerization observed in structure, MaoC forms a stable homodimer in solution. Mutations that disrupt the dimeric MaoC result in a complete loss of activity toward crotonyl-CoA, indicating that dimerization is required for the enzymatic activity of MaoC. Importantly, structure comparison reveals that a loop unique to MaoC interacts with an α-helix that harbors the catalytic residues of MaoC. Deletion of the loop enhances the enzymatic activity of MaoC, suggesting its inhibitory role in regulating the activity of MaoC. CONCLUSIONS/SIGNIFICANCE: The data in our study reveal the regulatory mechanism of an (R-hydratase, providing information on enzyme engineering to produce low cost PHAs.

  8. LR11/SorLA links triglyceride-rich lipoproteins to risk of developing cardiovascular disease in FH patients

    NARCIS (Netherlands)

    Vongpromek, Ranitha; Bujo, Hideaki; Hoekstra, Menno; Schneider, Wolfgang J.; van der Zee, Leonie; Schinkel, Arend F.L.; Korporaal, Suzanne J; Dik, Willem A.; Ebinuma, Hiroyuki; Jiang, Meizi; Verhoeven, Adrie J.M.; Sijbrands, Eric J. G.; Mulder, Monique T.

    2015-01-01

    Objective: Familial Hypercholesterolemia (FH) is associated with an increased risk of cardiovascular disease (CVD). However, whether an individual heterozygous FH patient will develop CVD depends on other genetic- and environmental risk factors as well. LDL receptor-related protein with 11 ligand

  9. Class FH sunflower seeds (Helianthus annuus) as an energy/protein ...

    African Journals Online (AJOL)

    The digestible energy (DE) content of milled and whole class FH sunflower seed (SS) was determined in a digestion trial and ... that SS can be used effectively as a protein/energy source in diets for early weaned piglets. ..... Supplement 4.

  10. A qualitative study of patients' perceptions of the value of molecular diagnosis for familial hypercholesterolemia (FH).

    Science.gov (United States)

    Hallowell, Nina; Jenkins, Nicholas; Douglas, Margaret; Walker, Simon; Finnie, Robert; Porteous, Mary; Lawton, Julia

    2017-01-01

    For many years, familial hypercholesterolemia (FH), an inherited disorder, has been diagnosed using phenotypic features plus family history of early onset cardiovascular disease (CVD), and has been successfully treated using statin therapy. DNA testing is now available and this has been incorporated into familial cascade screening programmes in many parts of Europe. Little is known about patients' perceptions of the value of undergoing molecular diagnosis for FH. In-depth interviews were carried out with patients (n = 38) being treated for FH who were the first in their family to undergo DNA testing for FH. Data were analysed thematically. While interviewees regarded DNA testing as an unexceptional event, it was seen as a positive innovation because it confirmed that their family carried a particular disorder, offered an aetiological explanation for their hypercholesterolemia and provided information about their own and family members' future risks. From the patient perspective, the main benefit of molecular diagnosis lies in its ability to provide information which allows (younger) family members to access genetic screening and, thus, timely treatment. The implications for future developments in genetic services and the need to investigate further the provision of molecular testing in mainstream specialties are briefly discussed.

  11. Formin homology 1 (OsFH1) regulates submergence-dependent root hair development in rice plants.

    Science.gov (United States)

    Huang, Jin; Liu, Jingmiao; Han, Chang-Deok

    2013-08-01

    By using a forward genetic approach, a formin homology 1 gene (OsFH1) was identified as a critical regulator of rice root hair development. The phenotypic effect of OsFH1 on root hair development was verified by using three independent mutants, one point mutation and two T-DNA insertions. The study showed that OsFH1 is required for the elongation of root-hairs. However, Osfh1 exhibited growth defect of root hairs only when roots were grown submerged in solution. To understand how OsFH1 impinges on plant responses to root submergence, the growth responses of Osfh1 root hairs to anoxia, carbohydrate supplementation and exogenous hormones (auxin and ethylene) and nutrients (Fe and Pi) were examined. However, none of these treatments rescued the growth defects of Osfhl1 root hairs. This study demonstrates that OsFH1 could be involved in preventing submergence-induced inhibition of root hair growth.

  12. Expansion of ribosomally produced natural products: a nitrile hydratase- and Nif11-related precursor family

    Directory of Open Access Journals (Sweden)

    Mitchell Douglas A

    2010-05-01

    Full Text Available Abstract Background A new family of natural products has been described in which cysteine, serine and threonine from ribosomally-produced peptides are converted to thiazoles, oxazoles and methyloxazoles, respectively. These metabolites and their biosynthetic gene clusters are now referred to as thiazole/oxazole-modified microcins (TOMM. As exemplified by microcin B17 and streptolysin S, TOMM precursors contain an N-terminal leader sequence and C-terminal core peptide. The leader sequence contains binding sites for the posttranslational modifying enzymes which subsequently act upon the core peptide. TOMM peptides are small and highly variable, frequently missed by gene-finders and occasionally situated far from the thiazole/oxazole forming genes. Thus, locating a substrate for a particular TOMM pathway can be a challenging endeavor. Results Examination of candidate TOMM precursors has revealed a subclass with an uncharacteristically long leader sequence closely related to the enzyme nitrile hydratase. Members of this nitrile hydratase leader peptide (NHLP family lack the metal-binding residues required for catalysis. Instead, NHLP sequences display the classic Gly-Gly cleavage motif and have C-terminal regions rich in heterocyclizable residues. The NHLP family exhibits a correlated species distribution and local clustering with an ABC transport system. This study also provides evidence that a separate family, annotated as Nif11 nitrogen-fixing proteins, can serve as natural product precursors (N11P, but not always of the TOMM variety. Indeed, a number of cyanobacterial genomes show extensive N11P paralogous expansion, such as Nostoc, Prochlorococcus and Cyanothece, which replace the TOMM cluster with lanthionine biosynthetic machinery. Conclusions This study has united numerous TOMM gene clusters with their cognate substrates. These results suggest that two large protein families, the nitrile hydratases and Nif11, have been retailored for

  13. Nitrile Hydratase and Amidase from Rhodococcus rhodochrous Hydrolyze Acrylic Fibers and Granular Polyacrylonitriles

    Science.gov (United States)

    Tauber, M. M.; Cavaco-Paulo, A.; Robra, K.-H.; Gübitz, G. M.

    2000-01-01

    Rhodococcus rhodochrous NCIMB 11216 produced nitrile hydratase (320 nkat mg of protein−1) and amidase activity (38.4 nkat mg of protein−1) when grown on a medium containing propionitrile. These enzymes were able to hydrolyze nitrile groups of both granular polyacrylonitriles (PAN) and acrylic fibers. Nitrile groups of PAN40 (molecular mass, 40 kDa) and PAN190 (molecular mass, 190 kDa) were converted into the corresponding carbonic acids to 1.8 and 1.0%, respectively. In contrast, surfacial nitrile groups of acrylic fibers were only converted to the corresponding amides. X-ray photoelectron spectroscopy analysis showed that 16% of the surfacial nitrile groups were hydrolyzed by the R. rhodochrous enzymes. Due to the enzymatic modification, the acrylic fibers became more hydrophilic and thus, adsorption of dyes was enhanced. This was indicated by a 15% increase in the staining level (K/S value) for C.I. Basic Blue 9. PMID:10742253

  14. Real-time PCR detection of Fe-type nitrile hydratase genes from environmental isolates suggests horizontal gene transfer between multiple genera.

    Science.gov (United States)

    Coffey, Lee; Owens, Erica; Tambling, Karen; O'Neill, David; O'Connor, Laura; O'Reilly, Catherine

    2010-11-01

    Nitriles are widespread in the environment as a result of biological and industrial activity. Nitrile hydratases catalyse the hydration of nitriles to the corresponding amide and are often associated with amidases, which catalyze the conversion of amides to the corresponding acids. Nitrile hydratases have potential as biocatalysts in bioremediation and biotransformation applications, and several successful examples demonstrate the advantages. In this work a real-time PCR assay was designed for the detection of Fe-type nitrile hydratase genes from environmental isolates purified from nitrile-enriched soils and seaweeds. Specific PCR primers were also designed for amplification and sequencing of the genes. Identical or highly homologous nitrile hydratase genes were detected from isolates of numerous genera from geographically diverse sites, as were numerous novel genes. The genes were also detected from isolates of genera not previously reported to harbour nitrile hydratases. The results provide further evidence that many bacteria have acquired the genes via horizontal gene transfer. The real-time PCR assay should prove useful in searching for nitrile hydratases that could have novel substrate specificities and therefore potential in industrial applications.

  15. Unveiling of novel regio-selective fatty acid double bond hydratases from Lactobacillus acidophilus involved in the selective oxyfunctionalization of mono- and di-hydroxy fatty acids.

    Science.gov (United States)

    Kim, Kyoung-Rok; Oh, Hye-Jin; Park, Chul-Soon; Hong, Seung-Hye; Park, Ji-Young; Oh, Deok-Kun

    2015-11-01

    The aim of this study is the first time demonstration of cis-12 regio-selective linoleate double-bond hydratase. Hydroxylation of fatty acids, abundant feedstock in nature, is an emerging alternative route for many petroleum replaceable products thorough hydroxy fatty acids, carboxylic acids, and lactones. However, chemical route for selective hydroxylation is still quite challenging owing to low selectivity and many environmental concerns. Hydroxylation of fatty acids by hydroxy fatty acid forming enzymes is an important route for selective biocatalytic oxyfunctionalization of fatty acids. Therefore, novel fatty acid hydroxylation enzymes should be discovered. The two hydratase genes of Lactobacillus acidophilus were identified by genomic analysis, and the expressed two recombinant hydratases were identified as cis-9 and cis-12 double-bond selective linoleate hydratases by in vitro functional validation, including the identification of products and the determination of regio-selectivity, substrate specificity, and kinetic parameters. The two different linoleate hydratases were the involved enzymes in the 10,13-dihydroxyoctadecanoic acid biosynthesis. Linoleate 13-hydratase (LHT-13) selectively converted 10 mM linoleic acid to 13S-hydroxy-9(Z)-octadecenoic acid with high titer (8.1 mM) and yield (81%). Our study will expand knowledge for microbial fatty acid-hydroxylation enzymes and facilitate the designed production of the regio-selective hydroxy fatty acids for useful chemicals from polyunsaturated fatty acid feedstocks.

  16. Biological characteristics and the application in pharmacology study of FH/ Wjd rats%FH/Wjd大鼠的生物学特性及其在药理学研究中的应用

    Institute of Scientific and Technical Information of China (English)

    李语玲; 梁建辉

    2012-01-01

    The Fawn-Hooded (FH/Wjd) rat is one of the FH inbred strain. Considered as an ideal animal model for the study of heavy drinking, the FH/Wjd rats exhibit several characteristics , including excessive voluntary intake of alcohol (>5g· kg-1 · d ) , high preference to ethanol ( >65% ) , significant alcohol deprivation reaction, as well as easily established operational self-αdministration drinking behavior. Furthermore, the hypo-function of 5-HT in the central nervous system makes the FH/Wjd rats behave quite specially in animal behavioral tests . For example, the FH/Wjd rats show noticeable immobility in the forced swimming test, similar to features in the depression ani -mal model. Thus, the FH/Wjd rats can serve as an animal model for studies on depression.%Fawn-Hooded(FH/Wjd)大鼠是一种近交系大鼠,属于 FH大鼠中的一个亚系,具备饮酒量大(>5g·kg-1·d-1)和酒精偏爱度高(>65%)的特点,存在明显的酒精剥夺效 应,并可在短期内建立操作性自身饮酒行为,是一种理想的先天性嗜酒动物模型.此外,FH/Wjd大鼠中枢神经系统5-羟色胺(5-hydroxytryptamine,5-HT)功能低下,在强迫游泳实验中,FH/Wjd大鼠的行为绝望表现明显.因此,可以作为研究抑郁症的动物模型.

  17. Rapid isolation of pure Complement Factor H from serum for functional studies by the use of a monoclonal antibody that discriminates FH from all the other isoforms.

    Science.gov (United States)

    Berra, Silvia; Clivio, Alberto

    2016-04-01

    Several mutations have been identified in the gene coding for Complement Factor H (FH) from patients with atypical Hemolytic Uraemic Syndrome (aHUS), Age-related Macular Degeneration (AMD) and Membranoproliferative Glomerulonephritis (MPGN). These data allow for a precise description of the structural changes affecting FH, but a simple test for specifically assessing FH function routinely is not yet of common use. We have produced and characterised a monoclonal antibody (5H5) which discriminates between FH and the smaller FH-like 1 and FH-related proteins and show here that it specifically binds to FH without detecting the smaller isoforms. We therefore used this mAb for a quick, one-step micro-purification of FH directly from control sera and showed that this affinity chromatography procedure is not disruptive of its cofactor function. We also developed a modified sheep erythrocytes haemolysis test using our antibody and affinity-purified FH. These tests can be used in conjunction for assessing the function of FH purified from patients affected by FH-related diseases. Moreover we used this mAb to develop a FH-specific ELISA test.

  18. AtFH8 Is Involved in Root Development under Effect of Low-Dose Latrunculin B in Dividing Cells

    Institute of Scientific and Technical Information of China (English)

    Xiu-Hua Xue; Chun-Qing Guo; Fei Du; Quan-Long Lu; Chuan-Mao Zhang; Hai-Yun Ren

    2011-01-01

    Formins have been paid much attention for their potent nucleating activity. However,the connection between the in vivo functions of AtFHs (Arabidopsis thaliana formin homologs) and their effects on actin organization is poorly understood. In this study,we characterized the bundling activity of AtFH8 in vitro and in vivo. Biochemical analysis showed that AtFH8(FH1FH2) could form dimers and bundle preformed actin filaments or induce stellar structures during actin polymerization. Expression of truncated forms of AtFH8 and immunolocalization analysis showed that AtFH8 localized primarily to nuclear envelope in interphase and to the new cell wall after cytokinesis,depending primarily on its N-terminal transmembrane domain. GUS histochemical staining showed AtFH8 was predominantly expressed in Arabidopsis root meristem,vasculature,and outgrowth points of lateral roots. The primary root growth and lateral root initiation of atfh8 could be decreased by latrunculin B (LatB). Analysis of the number of dividing cells in Arabidopsis root tips showed that much fewer dividing cells in Lat B-treated atfh8 plants than wild-type plants,which indicates that AtFH8 was involved in cell division. Actin cytoskeleton in root meristem of atfh8-1 was more sensitive to LatB treatment than that of wild-type. Altogether,our results indicate that AtFH8 is an actin filament nucleator and bundler that functions in cell division and root development.

  19. Heterologous expression, purification, and enzymatic characterization of the acyclic carotenoid 1,2-hydratase from Rubrivivax gelatinosus.

    Science.gov (United States)

    Steiger, Sabine; Mazet, Andreas; Sandmann, Gerhard

    2003-06-01

    The carotenoid 1,2-hydratase CrtC from Rubrivivax gelatinosus has been expressed in Escherichia coli in an active form and purified by affinity chromatography. The enzyme catalyzes the conversion of various acyclic carotenes including 1-hydroxy derivatives. This broad substrate specificity reflects the participation of CrtC in 1'-HO-spheroidene and in spirilloxanthin biosynthesis. Enzyme kinetic studies including the determination of substrate specificity constants indicate that among the alternative biosynthetic routes to 1'-HO-spheroidene the one via spheroidene is the dominating pathway. In contrast to CrtC from Rvi. gelatinosus, the equivalent enzyme from Rhodobacter capsulatus, a closely related bacterium which lacks the biosynthetic branch to spirilloxanthin and accumulates spheroidene instead of substantial amounts of 1'-HO-spheroidene, is extremely poor in converting 1-HO-carotenoids. The individual catalytic properties of both carotenoid 1,2-hydratases reflect the in situ carotenogenic pathways in both purple photosynthetic bacteria.

  20. Ab initio potential energy and dipole moment surfaces of the F(-)(H2O) complex.

    Science.gov (United States)

    Kamarchik, Eugene; Toffoli, Daniele; Christiansen, Ove; Bowman, Joel M

    2014-02-05

    We present full-dimensional, ab initio potential energy and dipole moment surfaces for the F(-)(H2O) complex. The potential surface is a permutationally invariant fit to 16,114 coupled-cluster single double (triple)/aVTZ energies, while the dipole surface is a covariant fit to 11,395 CCSD(T)/aVTZ dipole moments. Vibrational self-consistent field/vibrational configuration interaction (VSCF/VCI) calculations of energies and the IR-spectrum are presented both for F(-)(H2O) and for the deuterated analog, F(-)(D2O). A one-dimensional calculation of the splitting of the ground state, due to equivalent double-well global minima, is also reported.

  1. Homozygous familial hypercholesterolemia (HoFH in Germany: an epidemiological survey

    Directory of Open Access Journals (Sweden)

    Walzer S

    2013-05-01

    Full Text Available S Walzer,1 K Travers,2 S Rieder,3 E Erazo-Fischer,3 D Matusiewicz41MArS Market Access and Pricing Strategy UG (hb, Weil am Rhein, Germany; 2United Biosource Corporation, Lexington, USA; 3Alcimed GmbH, Cologne, Germany; 4Institute for Health Care Management and Research, Faculty of Economics and Business Administration, University of Duisburg-Essen, Essen, GermanyIntroduction: In Europe a disease is recognized as rare if less than 1 in 2000 people suffer from the specific disease. In patients with familial homozygous hypercholesterolemia (HoFH the accumulation of low-density lipoprotein cholesterol (LDL-C leads to generalized atherosclerosis due to an insufficient functioning of the LDL-C receptors. Patients die early sometimes even in the mid-30s, from myocardial infarction or stroke. For the German population, insufficient epidemiological evidence exists.Methods: A systematic literature search in EMBASE and Medline was performed in conjunction with a targeted manual search for epidemiological HoFH studies. Additionally a nationwide survey was conducted in Germany in all identified apheresis- and lipid centers. The purpose of the survey was the validation of the systematic literature search results based on empirical (practice data.Results: In total 961 publications were found, 874 were excluded based on pre-defined exclusion criteria leaving only 87 for further review. After review of the identified abstracts (n = 87 23 publications were identified as epidemiological studies. Only one publication was found which reported a prevalence of 1:1,000,000. The qualitative survey among 187 physicians in Germany also revealed a low prevalence: 95 HoFH patients were identified in 35 centers.Conclusion: The estimated frequency of homozygous familial hypercholesterolemia patients in Germany is around 95 (1:860,000 and the disease should be recognized as rare according to the definition of the European Medical Agency.Keywords: epidemiology, homozygous

  2. Performance Analysis of Wireless Mobile Radio Hybrid(DS/FH) Spread Spectrum Network

    Institute of Scientific and Technical Information of China (English)

    余晓刚; 王华; 匡镜明

    2004-01-01

    By the flexible redefinition of frequency-occupation and frequency-collision event, the frequency-collision probability of hybrid(DS/FH) spread spectrum network is analyzed. This probability is based on the simultaneous transmission number threshold and is discussed in synchronous and asynchronous circumstances respectively. And then, the network throughput based on the packet correct reception probability is analyzed. Two models which have finite and infinite population respectively is discussed. At last, the numerical results are given.

  3. Functional characterization of a fatty acid double-bond hydratase from Lactobacillus plantarum and its interaction with biosynthetic membranes.

    Science.gov (United States)

    Ortega-Anaya, Joana; Hernández-Santoyo, Alejandra

    2015-12-01

    Hydrogenation of linoleic acid and other polyunsaturated fatty acids is a detoxification mechanism that is present in the Lactobacillus genus of lactic bacteria. The first stage in this multi-step process is hydration of the substrate with formation of 10-hydroxy-9-cis-octadecenoic acid due to fatty-acid hydratase activity that has been detected only in the membrane-associated cell fraction; however, its interaction with the cell membrane is unknown. To provide information in this respect we characterized the homotrimeric 64.7 kDa-native protein from Lactobacillus plantarum; afterwards, it was reconstituted in proteoliposomes and analyzed by confocal fluorescence microscopy. The results showed that hydratase is an extrinsic-membrane protein and hence, the enzymatic reaction occurs at the periphery of the cell. This location may be advantageous in the detoxifying process since the toxic linoleic acid molecule can be bound to hydratase and converted to non-toxic 10-hydroxy-9-cis-octadecenoic acid before it reaches cell membrane. Additionally, we propose that the interaction with membrane periphery occurs through electrostatic contacts. Finally, the structural model of L. plantarum hydratase was constructed based on the amino acid sequence and hence, the putative binding sites with linoleic acid were identified: site 1, located in an external hydrophobic pocket at the C-terminus of the protein and site 2, located at the core and in contact with a FAD molecule. Interestingly, it was found that the linoleic acid molecule arranges around a methionine residue in both sites (Met154 and Met81, respectively) that acts as a rigid pole, thus playing a key role in binding unsaturated fatty acids.

  4. Biochemical characterization of the carotenoid 1,2-hydratases (CrtC) from Rubrivivax gelatinosus and Thiocapsa roseopersicina.

    Science.gov (United States)

    Hiseni, Aida; Arends, Isabel W C E; Otten, Linda G

    2011-08-01

    Two carotenoid 1,2-hydratase (CrtC) genes from the photosynthetic bacteria Rubrivivax gelatinosus and Thiocapsa roseopersicina were cloned and expressed in Escherichia coli in an active form and purified by affinity chromatography. The biochemical properties of the recombinant enzymes and their substrate specificities were studied. The purified CrtCs catalyze cofactor independently the conversion of lycopene to 1-HO- and 1,1'-(HO)(2)-lycopene. The optimal pH and temperature for hydratase activity was 8.0 and 30°C, respectively. The apparent K (m) and V (max) values obtained for the hydration of lycopene were 24 μM and 0.31 nmol h(-1) mg(-1) for RgCrtC and 9.5 μM and 0.15 nmol h(-1) mg(-1) for TrCrtC, respectively. Sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis revealed two protein bands of 44 and 38 kDa for TrCrtC, which indicate protein processing. Both hydratases are also able to convert the unnatural substrate geranylgeraniol (C20 substrate), which functionally resembles the natural substrate lycopene.

  5. Fire Hydrants, FH valve, Published in 2008, 1:24000 (1in=2000ft) scale, Box Elder County.

    Data.gov (United States)

    NSGIC GIS Inventory (aka Ramona) — This Fire Hydrants dataset, published at 1:24000 (1in=2000ft) scale, was produced all or in part from Other information as of 2008. It is described as 'FH valve'....

  6. Cyanide hydratases and cyanide dihydratases: emerging tools in the biodegradation and biodetection of cyanide.

    Science.gov (United States)

    Martínková, Ludmila; Veselá, Alicja Barbara; Rinágelová, Anna; Chmátal, Martin

    2015-11-01

    The purpose of this study is to summarize the current knowledge of the enzymes which are involved in the hydrolysis of cyanide, i.e., cyanide hydratases (CHTs; EC 4.2.1.66) and cyanide dihydratases (CynD; EC 3.5.5.1). CHTs are probably exclusively produced by filamentous fungi and widely occur in these organisms; in contrast, CynDs were only found in a few bacterial genera. CHTs differ from CynDs in their reaction products (formamide vs. formic acid and ammonia, respectively). Several CHTs were also found to transform nitriles but with lower relative activities compared to HCN. Mutants of CynDs and CHTs were constructed to study the structure-activity relationships in these enzymes or to improve their catalytic properties. The effect of the C-terminal part of the protein on the enzyme activity was determined by constructing the corresponding deletion mutants. CynDs are less active at alkaline pH than CHTs. To improve its bioremediation potential, CynD from Bacillus pumilus was engineered by directed evolution combined with site-directed mutagenesis, and its operation at pH 10 was thus enabled. Some of the enzymes have been tested for their potential to eliminate cyanide from cyanide-containing wastewaters. CynDs were also used to construct cyanide biosensors.

  7. Mechanism of tungsten-dependent acetylene hydratase from quantum chemical calculations

    Science.gov (United States)

    Liao, Rong-Zhen; Yu, Jian-Guo; Himo, Fahmi

    2010-01-01

    Acetylene hydratase is a tungsten-dependent enzyme that catalyzes the nonredox hydration of acetylene to acetaldehyde. Density functional theory calculations are used to elucidate the reaction mechanism of this enzyme with a large model of the active site devised on the basis of the native X-ray crystal structure. Based on the calculations, we propose a new mechanism in which the acetylene substrate first displaces the W-coordinated water molecule, and then undergoes a nucleophilic attack by the water molecule assisted by an ionized Asp13 residue at the active site. This is followed by proton transfer from Asp13 to the newly formed vinyl anion intermediate. In the subsequent isomerization, Asp13 shuttles a proton from the hydroxyl group of the vinyl alcohol to the α-carbon. Asp13 is thus a key player in the mechanism, but also W is directly involved in the reaction by binding and activating acetylene and providing electrostatic stabilization to the transition states and intermediates. Several other mechanisms are also considered but the energetic barriers are found to be very high, ruling out these possibilities. PMID:21149684

  8. Self-subunit swapping occurs in another gene type of cobalt nitrile hydratase.

    Directory of Open Access Journals (Sweden)

    Yi Liu

    Full Text Available Self-subunit swapping is one of the post-translational maturation of the cobalt-containing nitrile hydratase (Co-NHase family of enzymes. All of these NHases possess a gene organization of , which allows the activator protein to easily form a mediatory complex with the α-subunit of the NHase after translation. Here, we discovered that the incorporation of cobalt into another type of Co-NHase, with a gene organization of , was also dependent on self-subunit swapping. We successfully isolated a recombinant NHase activator protein (P14K of Pseudomonas putida NRRL-18668 by adding a Strep-tag N-terminal to the P14K gene. P14K was found to form a complex [α(StrepP14K(2] with the α-subunit of the NHase. The incorporation of cobalt into the NHase of P. putida was confirmed to be dependent on the α-subunit substitution between the cobalt-containing α(StrepP14K(2 and the cobalt-free NHase. Cobalt was inserted into cobalt-free α(StrepP14K(2 but not into cobalt-free NHase, suggesting that P14K functions not only as a self-subunit swapping chaperone but also as a metallochaperone. In addition, NHase from P. putida was also expressed by a mutant gene that was designed with a order. Our findings expand the general features of self-subunit swapping maturation.

  9. High-level expression in Corynebacterium glutamicum of nitrile hydratase from Rhodococcus rhodochrous for acrylamide production.

    Science.gov (United States)

    Kang, Mi-Suk; Han, Sang-Soo; Kim, Mi-Young; Kim, Bu-Youn; Huh, Jong-Pil; Kim, Hak-Sung; Lee, Jin-Ho

    2014-05-01

    The nhhBAG gene of Rhodococcus rhodochrous M33 that encodes nitrile hydratase (NHase), converting acrylonitrile into acrylamide, was cloned and expressed in Corynebacterium glutamicum under the control of an ilvC promoter. The specific enzyme activity in recombinant C. glutamicum cells was about 13.6 μmol/min/mg dry cell weight (DCW). To overexpress the NHase, five types of plasmid variants were constructed by introducing mutations into 80 nucleotides near the translational initiation region (TIR) of nhhB. Of them, pNBM4 with seven mutations showed the highest NHase activity, exhibiting higher expression levels of NhhB and NhhA than wild-type pNBW33, mainly owing to decreased secondary-structure stability and an introduction of a conserved Shine-Dalgarno sequence in the translational initiation region. In a fed-batch culture of recombinant Corynebacterium cells harboring pNBM4, the cell density reached 53.4 g DCW/L within 18 h, and the specific and total enzyme activities were estimated to be 37.3 μmol/min/mg DCW and 1,992 μmol/min/mL, respectively. The use of recombinant Corynebacterium cells for the production of acrylamide from acrylonitrile resulted in a conversion yield of 93 % and a final acrylamide concentration of 42.5 % within 6 h when the total amount of fed acrylonitrile was 456 g.

  10. Discovery of acetylene hydratase activity of the iron-sulphur protein IspH.

    Science.gov (United States)

    Span, Ingrid; Wang, Ke; Wang, Weixue; Zhang, Yonghui; Bacher, Adelbert; Eisenreich, Wolfgang; Li, Kai; Schulz, Charles; Oldfield, Eric; Groll, Michael

    2012-01-01

    The final step of the methylerythritol phosphate isoprenoid biosynthesis pathway is catalysed by the iron-sulphur enzyme IspH, producing the universal precursors of terpenes: isopentenyl diphosphate and dimethylallyl diphosphate. Here we report an unforeseen reaction discovered during the investigation of the interaction of IspH with acetylene inhibitors by X-ray crystallography, Mößbauer, and nuclear magnetic resonance spectroscopy. In addition to its role as a 2H(+)/2e(-) reductase, IspH can hydrate acetylenes to aldehydes and ketones via anti-Markovnikov/Markovnikov addition. The reactions only occur with the oxidised protein and proceed via η(1)-O-enolate intermediates. One of these is characterized crystallographically and contains a C4 ligand oxygen bound to the unique, fourth iron in the 4Fe-4S cluster: this intermediate subsequently hydrolyzes to produce an aldehyde product. This unexpected side to IspH reactivity is of interest in the context of the mechanism of action of other acetylene hydratases, as well as in the design of antiinfectives targeting IspH.

  11. Self-Subunit Swapping Occurs in Another Gene Type of Cobalt Nitrile Hydratase

    Science.gov (United States)

    Xia, Yuanyuan; Cui, Youtian; Kobayashi, Michihiko; Zhou, Zhemin

    2012-01-01

    Self-subunit swapping is one of the post-translational maturation of the cobalt-containing nitrile hydratase (Co-NHase) family of enzymes. All of these NHases possess a gene organization of , which allows the activator protein to easily form a mediatory complex with the α-subunit of the NHase after translation. Here, we discovered that the incorporation of cobalt into another type of Co-NHase, with a gene organization of , was also dependent on self-subunit swapping. We successfully isolated a recombinant NHase activator protein (P14K) of Pseudomonas putida NRRL-18668 by adding a Strep-tag N-terminal to the P14K gene. P14K was found to form a complex [α(StrepP14K)2] with the α-subunit of the NHase. The incorporation of cobalt into the NHase of P. putida was confirmed to be dependent on the α-subunit substitution between the cobalt-containing α(StrepP14K)2 and the cobalt-free NHase. Cobalt was inserted into cobalt-free α(StrepP14K)2 but not into cobalt-free NHase, suggesting that P14K functions not only as a self-subunit swapping chaperone but also as a metallochaperone. In addition, NHase from P. putida was also expressed by a mutant gene that was designed with a order. Our findings expand the general features of self-subunit swapping maturation. PMID:23226397

  12. Roots of angiosperm formins: The evolutionary history of plant FH2 domain-containing proteins

    Directory of Open Access Journals (Sweden)

    Žárský Viktor

    2008-04-01

    Full Text Available Abstract Background Shuffling of modular protein domains is an important source of evolutionary innovation. Formins are a family of actin-organizing proteins that share a conserved FH2 domain but their overall domain architecture differs dramatically between opisthokonts (metazoans and fungi and plants. We performed a phylogenomic analysis of formins in most eukaryotic kingdoms, aiming to reconstruct an evolutionary scenario that may have produced the current diversity of domain combinations with focus on the origin of the angiosperm formin architectures. Results The Rho GTPase-binding domain (GBD/FH3 reported from opisthokont and Dictyostelium formins was found in all lineages except plants, suggesting its ancestral character. Instead, mosses and vascular plants possess the two formin classes known from angiosperms: membrane-anchored Class I formins and Class II formins carrying a PTEN-like domain. PTEN-related domains were found also in stramenopile formins, where they have been probably acquired independently rather than by horizontal transfer, following a burst of domain rearrangements in the chromalveolate lineage. A novel RhoGAP-related domain was identified in some algal, moss and lycophyte (but not angiosperm formins that define a specific branch (Class III of the formin family. Conclusion We propose a scenario where formins underwent multiple domain rearrangements in several eukaryotic lineages, especially plants and chromalveolates. In plants this replaced GBD/FH3 by a probably inactive RhoGAP-like domain, preserving a formin-mediated association between (membrane-anchored Rho GTPases and the actin cytoskeleton. Subsequent amplification of formin genes, possibly coincident with the expansion of plants to dry land, was followed by acquisition of alternative membrane attachment mechanisms present in extant Class I and Class II formins, allowing later loss of the RhoGAP-like domain-containing formins in angiosperms.

  13. Fault tree analysis of the F&H Canyon Exhaust Systems at the Savannah River Site

    Energy Technology Data Exchange (ETDEWEB)

    Low, J.M.; Marshall, K.M.

    1993-10-01

    The Canyon Exhaust System (CES) for the F&H Canyon chemical Separations Facilities are considered safety class items (SCIs). SCIs are defined in DOE Order 6430.1A as systems, components, and structures, including portions of process systems, whose failure could adversely affect the environment or safety and health of the public. As such, any modification to SCIs must be carefully reviewed for impact to safety. During the last year, the Savannah River Technology Center of WSRC has been requested to perform two major evolutions on the Canyon Exhaust Systems. These evaluations include an Upgrade to Canyon Exhaust System (UCES) Project for both F&H Areas and a Backfit analysis for a standby diesel generator in F-Area. The purpose of the first evaluation was to evaluate the impact of cost reduction options on the UCES reliability. The purpose of the second analysis was to provide justification for not upgrading an existing standby diesel generator to meet current safety class standards.

  14. A novel carotenoid 1,2-hydratase (CruF) from two species of the non-photosynthetic bacterium Deinococcus.

    Science.gov (United States)

    Sun, Zongtao; Shen, Shaochuan; Wang, Chao; Wang, Hu; Hu, Yaping; Jiao, Jiandong; Ma, Tingting; Tian, Bing; Hua, Yuejin

    2009-08-01

    A novel carotenoid 1,2-hydratase (CruF) responsible for the C-1',2' hydration of gamma-carotene was identified in the non-photosynthetic bacteria Deinococcus radiodurans R1 and Deinococcus geothermalis DSM 11300. Gene expression and disruption experiments demonstrated that dr0091 and dgeo2309 encode CruF in D. radiodurans and D. geothermalis, respectively. Their homologues were also found in the genomes of cyanobacteria, and exhibited little homology to the hydroxyneurosporene synthase (CrtC) proteins found mainly in photosynthetic bacteria. Phylogenetic analysis showed that CruF homologues form a separate family, which is evolutionarily distant from the known CrtC family.

  15. Enoyl-CoA hydratase mediates polyhydroxyalkanoate mobilization in Haloferax mediterranei.

    Science.gov (United States)

    Liu, Guiming; Cai, Shuangfeng; Hou, Jing; Zhao, Dahe; Han, Jing; Zhou, Jian; Xiang, Hua

    2016-04-07

    Although polyhydroxyalkanoate (PHA) accumulation and mobilization are one of the most general mechanisms for haloarchaea to adapt to the hypersaline environments with changeable carbon sources, the PHA mobilization pathways are still not clear for any haloarchaea. In this study, the functions of five putative (R)-specific enoyl-CoA hydratases (R-ECHs) in Haloferax mediterranei, named PhaJ1 to PhaJ5, respectively, were thoroughly investigated. Through gene deletion and complementation, we demonstrated that only certain of these ECHs had a slight contribution to poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) biosynthesis. But significantly, PhaJ1, the only R-ECH that is associated with PHA granules, was shown to be involved in PHA mobilization in this haloarchaeon. PhaJ1 catalyzes the dehydration of (R)-3-hydroxyacyl-CoA, the common product of PHA degradation, to enoyl-CoA, the intermediate of the β-oxidation cycle, thus could link PHA mobilization to β-oxidation pathway in H. mediterranei. This linkage was further indicated from the up-regulation of the key genes of β-oxidation under the PHA mobilization condition, as well as the obvious inhibition of PHA degradation upon inhibition of the β-oxidation pathway. Interestingly, 96% of phaJ-containing haloarchaeal species possess both phaC (encoding PHA synthase) and the full set genes of β-oxidation, implying that the mobilization of carbon storage in PHA through the β-oxidation cycle would be general in haloarchaea.

  16. The integration of cyanide hydratase and tyrosinase catalysts enables effective degradation of cyanide and phenol in coking wastewaters.

    Science.gov (United States)

    Martínková, Ludmila; Chmátal, Martin

    2016-10-01

    The aim of this study was to design an effective method for the bioremediation of coking wastewaters, specifically for the concurrent elimination of their highly toxic components - cyanide and phenols. Almost full degradation of free cyanide (0.32-20 mM; 8.3-520 mg L(-1)) in the model and the real coking wastewaters was achieved by using a recombinant cyanide hydratase in the first step. The removal of cyanide, a strong inhibitor of tyrosinase, enabled an effective degradation of phenols by this enzyme in the second step. Phenol (16.5 mM, 1,552 mg L(-1)) was completely removed from a real coking wastewater within 20 h and cresols (5.0 mM, 540 mg L(-1)) were removed by 66% under the same conditions. The integration of cyanide hydratase and tyrosinase open up new possibilities for the bioremediation of wastewaters with complex pollution. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Enzyme-substrate binding landscapes in the process of nitrile biodegradation mediated by nitrile hydratase and amidase.

    Science.gov (United States)

    Zhang, Yu; Zeng, Zhuotong; Zeng, Guangming; Liu, Xuanming; Chen, Ming; Liu, Lifeng; Liu, Zhifeng; Xie, Gengxin

    2013-08-01

    The continuing discharge of nitriles in various industrial processes has caused serious environmental consequences of nitrile pollution. Microorganisms possess several nitrile-degrading pathways by direct interactions of nitriles with nitrile-degrading enzymes. However, these interactions are largely unknown and difficult to experimentally determine but important for interpretation of nitrile metabolisms and design of nitrile-degrading enzymes with better nitrile-converting activity. Here, we undertook a molecular modeling study of enzyme-substrate binding modes in the bi-enzyme pathway for degradation of nitrile to acid. Docking results showed that the top substrates having favorable interactions with nitrile hydratase from Rhodococcus erythropolis AJ270 (ReNHase), nitrile hydratase from Pseudonocardia thermophila JCM 3095 (PtNHase), and amidase from Rhodococcus sp. N-771 (RhAmidase) were benzonitrile, 3-cyanopyridine, and L-methioninamide, respectively. We further analyzed the interactional profiles of these top poses with corresponding enzymes, showing that specific residues within the enzyme's binding pockets formed diverse contacts with substrates. This information on binding landscapes and interactional profiles is of great importance for the design of nitrile-degrading enzyme mutants with better oxidation activity toward nitriles or amides in the process of pollutant treatments.

  18. Fusion tags for protein solubility, purification and immunogenicity in Escherichia coli: The novel Fh8 system

    Directory of Open Access Journals (Sweden)

    Sofia eCosta

    2014-02-01

    Full Text Available Proteins are now widely produced in diverse microbial cell factories. The Escherichia coli is still the dominant host for recombinant protein production but, as a bacterial cell, it also has its issues: the aggregation of foreign proteins into insoluble inclusion bodies is perhaps the main limiting factor of the E. coli expression system. Conversely, E. coli benefits of cost, ease of use and scale make it essential to design new approaches directed for improved recombinant protein production in this host cell.With the aid of genetic and protein engineering novel tailored-made strategies can be designed to suit user or process requirements. Gene fusion technology has been widely used for the improvement of soluble protein production and/or purification in E. coli, and for increasing peptide’s immunogenicity as well. New fusion partners are constantly emerging and complementing the traditional solutions, as for instance, the Fh8 fusion tag that has been recently studied and ranked among the best solubility enhancer partners. In this review, we provide an overview of current strategies to improve recombinant protein production in E. coli, including the key factors for successful protein production, highlighting soluble protein production, and a comprehensive summary of the latest available and traditionally-used gene fusion technologies. A special emphasis is given to the recently discovered Fh8 fusion system that can be used for soluble protein production, purification and immunogenicity in E. coli. The number of existing fusion tags will probably increase in the next few years, and efforts should be taken to better understand how fusion tags act in E. coli. This knowledge will undoubtedly drive the development of new tailored-made tools for protein production in this bacterial system.

  19. Characterization of Diverse Subvariants of the Meningococcal Factor H (fH) Binding Protein for Their Ability To Bind fH, To Mediate Serum Resistance, and To Induce Bactericidal Antibodies

    NARCIS (Netherlands)

    K.L. Seib; B. Brunelli; B. Brogioni; E. Palumbo; S. Bambini; A. Muzzi; F. Dimarcello; S. Marchi; A. van den Ende; B. Aricó; S. Savino; M. Scarselli; M. Comanducci; R. Rappuoli; M.M. Giuliani; M. Pizza

    2011-01-01

    Neisseria meningitidis is a commensal of the human nasopharynx but is also a major cause of septicemia and meningitis. The meningococcal factor H binding protein (fHbp) binds human factor H (fH), enabling down-regulation of complement activation on the bacterial surface. fHbp is a component of two s

  20. Gene cloning of an efficiency oleate hydratase from Stenotrophomonas nitritireducens for polyunsaturated fatty acids and its application in the conversion of plant oils to 10-hydroxy fatty acids.

    Science.gov (United States)

    Kang, Woo-Ri; Seo, Min-Ju; Shin, Kyung-Chul; Park, Jin-Byung; Oh, Deok-Kun

    2017-01-01

    Hydroxy fatty acids are used as precursors of lactones and dicarboxylic acids, as starting materials of polymers, and as additives in coatings and paintings. Stenotrophomonas nitritireducens efficiently converts cis-9 polyunsaturated fatty acids (PUFAs) to 10-hydroxy fatty acids. However, gene encoding enzyme involved in this conversion has not been identified to date. We purified a putative fatty acid double-bond hydratase from S. nitritireducens by ultrafiltration and HiPrep DEAE FF and Resource Q ion exchange chromatographies. Peptide sequences of the purified enzyme were obtained by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) analysis. Sequence of the partial gene encoding this putative fatty acid double-bond hydratase was determined by degenerate polymerase chain reaction (PCR) based on the peptide sequences. The remaining gene sequence was identified by rapid amplification of cDNA ends using cDNA of S. nitritireducens as a template, and the full-length gene was cloned subsequently. The expressed enzyme was identified as an oleate hydratase by determining its kinetic parameters toward unsaturated fatty acids. S. nitritireducens oleate hydratase showed higher activity toward PUFAs compared with other available oleate hydratases. This suggested that the enzyme could be used effectively to convert plant oils to 10-hydroxy fatty acids because these oils contained unsaturated fatty acids such as oleic acid (OA) and linoleic acid (LA) and PUFAs such as α-linolenic acid and/or γ-linolenic acid. The enzyme converted soybean oil and perilla seed oil hydrolyzates containing 10 mM total unsaturated fatty acids, including OA, LA, and ALA, to 8.87 and 8.70 mM total 10-hydroxy fatty acids, respectively, in 240 min. To our knowledge, this is the first study on the biotechnological conversion of PUFA-containing oils to hydroxy fatty acids. Biotechnol. Bioeng. 2017;114: 74-82. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  1. LR11/SorLA links triglyceride-rich lipoproteins to risk of developing cardiovascular disease in FH patients.

    Science.gov (United States)

    Vongpromek, Ranitha; Bujo, Hideaki; Hoekstra, Menno; Schneider, Wolfgang J; van der Zee, Leonie; Schinkel, Arend F L; Korporaal, Suzanne J A; Dik, Willem A; Ebinuma, Hiroyuki; Jiang, Meizi; Verhoeven, Adrie J M; Sijbrands, Eric J G; Mulder, Monique T

    2015-12-01

    Familial Hypercholesterolemia (FH) is associated with an increased risk of cardiovascular disease (CVD). However, whether an individual heterozygous FH patient will develop CVD depends on other genetic- and environmental risk factors as well. LDL receptor-related protein with 11 ligand binding repeat (LR11) and its soluble form (sLR11) play a role in the progression of atherosclerosis. We investigated the involvement of LR11 and sLR11 in CVD development in FH patients and in LDLR deficient (Ldlr(-/-)) mice. In statin-treated asymptomatic male heterozygous FH subjects, plasma sLR11 levels correlated with carotid intima-media thickness. Increased plasma sLR11 levels were found in Ldlr(-/-) and also in wild-type mice exclusively after high-fat feeding. Hepatic LR11 mRNA levels, however, were higher in chow-fed Ldlr(-/-) in comparison with wild-type mice and were further increased after a high fat diet. Similar results were obtained with Apoe(-/-) mice, but not with wild-type mice. LR11 mRNA and protein levels and release of sLR11 from cultured HepG2 and aortic smooth muscle cells were upregulated by postprandial triglyceride-rich lipoproteins (TGRL). Overexpression of human LR11 in CHO cells resulted in increased binding and association of 12I-labeled TGRL, but not of 12I-labeled LDL. Our data strongly suggest an involvement of LR11 in mediating the harmful effects of a high-fat diet on CVD progression. Elevated sLR11 levels may increase the CVD risk especially in subjects with delayed clearance of triglyceride-rich remnants, such as in FH patients. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  2. Genetics Home Reference: fumarase deficiency

    Science.gov (United States)

    ... an important series of reactions known as the citric acid cycle or Krebs cycle, which allows cells to use ... with the function of this reaction in the citric acid cycle. Impairment of the process that generates energy for ...

  3. FH-OWA Operator and Its Application in Fuzzy Multiple Attribute Decision Making%FH-OWA算子及其在模糊多属性决策中的应用

    Institute of Scientific and Technical Information of China (English)

    梁鑫; 裴道武

    2015-01-01

    现实中,绝大多数的决策是模糊决策,而决策结果很大程度上取决于聚合算子的选取。为了使信息聚合更加科学合理,研究了H-OWA算子(Heronian ordered weighted averaging operator)。鉴于H-OWA算子的优点和局限性,提出了基于三角模糊数的FH-OWA算子(fuzzy Heronian ordered weighted averaging operator),并研究了其幂等性、单调性、有界性及交替性。最后,将FH-OWA算子应用于模糊多属性决策中,并与原文献进行了比较和分析,结果表明FH-OWA算子在信息聚合时侧重所有决策者意见的“一致性”,而不是个别专家的权威性。%In reality, most of the decision making is fuzzy decision making, and the result depends largely on the selection of aggregation operators. In order to be more scientific and reasonable in the decision making process, this paper studies the Heronian ordered weighted averaging operator (H-OWA). In view of the advantages and limitations of H-OWA operator, this paper proposes a new fuzzy Heronian ordered weighted averaging operator (FH-OWA) based on triangle fuzzy numbers and proves its properties, such as commutativity, idempotency, boundedness and alternating. Finally, by applying the FH-OWA operator to a fuzzy multiple attribute decision making problem and compared with the original literature, the results show that the FH-OWA operator places strong emphasis on the“consistency”of all decision-makers’opinions rather than some individual experts’authority.

  4. 家族性高胆固醇血症(FH)致病基因的研究进展%Research progress of genetic causes of familial hypercholesterolemia (FH)

    Institute of Scientific and Technical Information of China (English)

    陈晨

    2012-01-01

    家族性高胆固醇血症( familial hypercholesterolemia,FH)的临床特征为血总胆固醇升高,尤其是低密度脂蛋白胆固醇(low density lipoprotein cholesterol,LDL-c)升高,沉积于组织,形成皮肤或肌腱黄色瘤,导致动脉粥样硬化甚至早发冠心病.FH的发病机制为LDL受体(LDL receptor,LDLR)或apoB基因突变引起LDL受体途径功能缺陷,主要为常染色体显性遗传疾患,具有基因剂量效应;部分患者为常染色体隐性遗传,机制为LDL受体衔接蛋白1(LDL receptor adaptor protein 1,LDLRAP1)失功能型突变,导致LDL内化活性降低.罕见的人类枯草溶菌素转化酶9 (proprotein convertase subtilisin/kexin type 9,PCSK9)发生功能型突变也可引起严重的FH表型.PCSK9通过降解LDLR蛋白间接下调LDL受体途径,其失功能突变可致血浆LDL水平下降.因此PCSK9是目前降脂药物的研究热点.%Familial hypercholesterolemia (FH) is characterized by raised serum low density lipoprotein cholesterol (LDL-c) levels, which result in excess deposition of cholesterol in tissues, and then lead to atherosclerosis and premature coronary heart disease. The mutations of LDL receptor or apoB play main roles in this disease. FH results from defects in the uptake and degradation of LDL via the LDL receptor pathway. FH is primarily an autosomal dominant disorder with a gene-dosage effect. An autosomal recessive form of FH caused by loss-of-function mutations in LDL receptor adaptor protein 1 (LDLRAP1), which encodes a protein required for internalization of the LDL receptor ( LDLR). Rare gain-of-function mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9) cosegregate with hypercholesterolemia, and one mutation is associated with a particularly severe FH phenotype. Expression of PCSK9 normally down-regulates the LDLR pathway by indirectly causing degradation of LDLR protein, and loss-of-function mutations in PCSK9 result in low plasma LDL levels. Thus,PCSK9 is an

  5. Aldol reactions of the trans-o-hydroxybenzylidenepyruvate hydratase-aldolase (tHBP-HA) from Pseudomonas fluorescens N3.

    Science.gov (United States)

    Sello, Guido; Di Gennaro, Patrizia

    2013-08-01

    In this paper, a recombinant trans-o-hydroxybenzylidenepyruvate hydratase-aldolase (tHBP-HA) of Pseudomonas fluorescens N3 was used as a new catalyst for aldol condensation reactions. The reaction of some aldehydes with a different electronic activation catalyzed by tHBP-HA is presented and discussed together with some hints on the product structure. The enzyme is strictly pyruvate-dependent but uses different aldehydes as acceptors. The structure of the products is highly dependent on the electronic characteristics of the aldehyde. The results are interesting for both their synthetic importance and the mechanism of the formation of the products. Not only the products obtained and the recognition power are reported, but also some characteristics of its mechanism are analyzed. The results clearly show that the enzyme is efficiently prepared, purified, and stored, that it recognizes many different substrates, and that the products depend on the substrate electronic nature.

  6. Enzymatic hydrolysis of nitriles by an engineered nitrile hydratase (papain Gln19Glu) in aqueous-organic media.

    Science.gov (United States)

    Versari, Andrea; Ménard, Robert; Lortie, Robert

    2002-07-05

    A mutant of the cysteine protease papain, displaying nitrile hydratase and amidase activities, was expressed in Pichia pastoris and used for the hydrolysis of peptide nitriles in aqueous-organic media. The rate of hydrolysis of these nitriles is lowered by increasing acetone concentration. This is caused by an increase of the Michaelis constant, and a variation of Vmax proportional to the amount of water in the mixture. The hydrolysis of the amide is less affected by the increase in co-solvent, which results in lower accumulation of this intermediate product. With the peptide nitrile tested, high nitrile concentrations could be used to promote the production of the amide and prevent its hydrolysis to the acid by diminishing the relative rate of amide hydrolysis. A number of non-peptidyl nitriles were also tested as potential substrates but activity was detected for only one compound with structural resemblance to peptide nitriles.

  7. The first example of a nitrile hydratase model complex that reversibly binds nitriles.

    Science.gov (United States)

    Shearer, Jason; Jackson, Henry L; Schweitzer, Dirk; Rittenberg, Durrell K; Leavy, Tanya M; Kaminsky, Werner; Scarrow, Robert C; Kovacs, Julie A

    2002-09-25

    Nitrile hydratase (NHase) is an iron-containing metalloenzyme that converts nitriles to amides. The mechanism by which this biochemical reaction occurs is unknown. One mechanism that has been proposed involves nucleophilic attack of an Fe-bound nitrile by water (or hydroxide). Reported herein is a five-coordinate model compound ([Fe(III)(S(2)(Me2)N(3)(Et,Pr))](+)) containing Fe(III) in an environment resembling that of NHase, which reversibly binds a variety of nitriles, alcohols, amines, and thiocyanate. XAS shows that five-coordinate [Fe(III)(S(2)(Me2)N(3)(Et,Pr))](+) reacts with both methanol and acetonitrile to afford a six-coordinate solvent-bound complex. Competitive binding studies demonstrate that MeCN preferentially binds over ROH, suggesting that nitriles would be capable of displacing the H(2)O coordinated to the iron site of NHase. Thermodynamic parameters were determined for acetonitrile (DeltaH = -6.2(+/-0.2) kcal/mol, DeltaS = -29.4(+/-0.8) eu), benzonitrile (-4.2(+/-0.6) kcal/mol, DeltaS = -18(+/-3) eu), and pyridine (DeltaH = -8(+/-1) kcal/mol, DeltaS = -41(+/-6) eu) binding to [Fe(III)(S(2)(Me2)N(3)(Et,Pr))](+) using variable-temperature electronic absorption spectroscopy. Ligand exchange kinetics were examined for acetonitrile, iso-propylnitrile, benzonitrile, and 4-tert-butylpyridine using (13)C NMR line-broadening analysis, at a variety of temperatures. Activation parameters for ligand exchange were determined to be DeltaH(+ +) = 7.1(+/-0.8) kcal/mol, DeltaS(+ +) = -10(+/-1) eu (acetonitrile), DeltaH(+ +) = 5.4(+/-0.6) kcal/mol, DeltaS(+ +) = -17(+/-2) eu (iso-propionitrile), DeltaH(+ +) = 4.9(+/-0.8) kcal/mol, DeltaS(+ +) = -20(+/-3) eu (benzonitrile), and DeltaH(+ +) = 4.7(+/-1.4) kcal/mol DeltaS(+ +) = -18(+/-2) eu (4-tert-butylpyridine). The thermodynamic parameters for pyridine binding to a related complex, [Fe(III)(S(2)(Me2)N(3)(Pr,Pr))](+) (DeltaH = -5.9(+/-0.8) kcal/mol, DeltaS = -24(+/-3) eu), are also reported, as well as kinetic

  8. The First Example of a Nitrile Hydratase Model Complex that Reversibly Binds Nitriles

    Science.gov (United States)

    Shearer, Jason; Jackson, Henry L.; Schweitzer, Dirk; Rittenberg, Durrell K.; Leavy, Tanya M.; Kaminsky, Werner; Scarrow, Robert C.; Kovacs, Julie A.

    2015-01-01

    Nitrile hydratase (NHase) is an iron-containing metalloenzyme that converts nitriles to amides. The mechanism by which this biochemical reaction occurs is unknown. One mechanism that has been proposed involves nucleophilic attack of an Fe-bound nitrile by water (or hydroxide). Reported herein is a five-coordinate model compound ([FeIII(S2Me2N3(Et,Pr))]+) containing Fe(III) in an environment resembling that of NHase, which reversibly binds a variety of nitriles, alcohols, amines, and thiocyanate. XAS shows that five-coordinate [FeIII(S2Me2N3(Et,Pr))]+ reacts with both methanol and acetonitrile to afford a six-coordinate solvent-bound complex. Competitive binding studies demonstrate that MeCN preferentially binds over ROH, suggesting that nitriles would be capable of displacing the H2O coordinated to the iron site of NHase. Thermodynamic parameters were determined for acetonitrile (ΔH = −6.2(±0.2) kcal/mol, ΔS = −29.4(±0.8) eu), benzonitrile (−4.2(±0.6) kcal/mol, ΔS = −18(±3) eu), and pyridine (ΔH = −8(±1) kcal/mol, ΔS = −41(±6) eu) binding to [FeIII(S2Me2N3(Et,Pr))]+ using variable-temperature electronic absorption spectroscopy. Ligand exchange kinetics were examined for acetonitrile, iso-propylnitrile, benzonitrile, and 4-tert-butylpyridine using 13C NMR line-broadening analysis, at a variety of temperatures. Activation parameters for ligand exchange were determined to be ΔH‡ = 7.1(±0.8) kcal/mol, ΔS‡ = −10(±1) eu (acetonitrile), ΔH‡ = 5.4(±0.6) kcal/mol, ΔS‡ = −17(±2) eu (iso-propionitrile), ΔH‡ = 4.9(±0.8) kcal/mol, ΔS‡ = −20(±3) eu (benzonitrile), and ΔH‡ = 4.7(±1.4) kcal/mol ΔS‡ = −18(±2) eu (4-tert-butylpyridine). The thermodynamic parameters for pyridine binding to a related complex, [FeIII(S2Me2N3(Pr,Pr))]+ (ΔH = −5.9(±0.8) kcal/mol, ΔS = −24(±3) eu), are also reported, as well as kinetic parameters for 4-tert-butylpyridine exchange (ΔH‡ = 3.1(±0.8) kcal/mol, ΔS‡)−25(±3) eu

  9. ESS-FH: Enhanced Security Scheme for Fast Handover in Hierarchical Mobile IPv6

    Science.gov (United States)

    You, Ilsun; Lee, Jong-Hyouk; Sakurai, Kouichi; Hori, Yoshiaki

    Fast Handover for Hierarchical Mobile IPv6 (F-HMIPv6) that combines advantages of Fast Handover for Mobile IPv6 (FMIPv6) and Hierarchical Mobile IPv6 (HMIPv6) achieves the superior performance in terms of handover latency and signaling overhead compared with previously developed mobility protocols. However, without being secured, F-HMIPv6 is vulnerable to various security threats. In 2007, Kang and Park proposed a security scheme, which is seamlessly integrated into F-HMIPv6. In this paper, we reveal that Kang-Park's scheme cannot defend against the Denial of Service (DoS) and redirect attacks while largely relying on the group key. Then, we propose an Enhanced Security Scheme for F-HMIPv6 (ESS-FH) that achieves the strong key exchange and the key independence as well as addresses the weaknesses of Kang-Park's scheme. More importantly, it enables fast handover between different MAP domains. The proposed scheme is formally verified based on BAN-logic, and its handover latency is analyzed and compared with that of Kang-Park's scheme.

  10. Waste characterization for the F/H Effluent Treatment Facility in support of waste certification

    Energy Technology Data Exchange (ETDEWEB)

    Brown, D.F.

    1994-10-17

    The Waste Acceptance Criteria (WAC) procedures define the rules concerning packages of solid Low Level Waste (LLW) that are sent to the E-area vaults (EAV). The WACs tabulate the quantities of 22 radionuclides that require manifesting in waste packages destined for each type of vault. These quantities are called the Package Administrative Criteria (PAC). If a waste package exceeds the PAC for any radionuclide in a given vault, then specific permission is needed to send to that vault. To avoid reporting insignificant quantities of the 22 listed radionuclides, the WAC defines the Minimum Reportable Quantity (MRQ) of each radionuclide as 1/1000th of the PAC. If a waste package contains less than the MRQ of a particular radionuclide, then the package`s manifest will list that radionuclide as zero. At least one radionuclide has to be reported, even if all are below the MRQ. The WAC requires that the waste no be ``hazardous`` as defined by SCDHEC/EPA regulations and also lists several miscellaneous physical/chemical requirements for the packages. This report evaluates the solid wastes generated within the F/H Effluent Treatment Facility (ETF) for potential impacts on waste certification.

  11. Adjuvant-enhanced antibody and cellular responses to inclusion bodies expressing FhSAP2 correlates with protection of mice to Fasciola hepatica.

    Science.gov (United States)

    Rivera, Francheska; Espino, Ana M

    2016-01-01

    Fasciola hepatica saposin-like protein-2 (FhSAP2) is a protein differentially expressed in various developmental stages of F. hepatica. Recombinant FhSAP2 has demonstrated the induction of partial protection in mice and rabbits when it is administered subcutaneously (SC) in Freund's adjuvant. Because FhSAP2 is overexpressed in bacteria in the form of inclusion bodies (IBs), we isolated IBs expressing FhSAP2 and tested their immunogenicity when administered SC in mice emulsified in two different adjuvants: QS-21 and Montanide TM ISA720. Animals received three injections containing 20 μg of protein two weeks apart and 4 weeks after the third injection, mice were infected with 10 F. hepatica metacercariae by oral route. The percentages of protection induced by FhSAP2-IBs were estimated to be between 60.0 and 62.5% when compared with adjuvant-vaccinated, infected controls. By determining the levels of IgG1 and IgG2a antibodies and IL-4 and IFNγ cytokines in the serum of experimental animals, it was found that both Th1 and Th2 immune responses were significantly increased in the FhSAP2-IBs vaccinated groups compared with the adjuvant-vaccinated, infected control groups. The adjuvant-vaccinated groups had significantly lower IgG1 to IgG2a ratios and lower IL-4 to IFNγ ratios than the FhSAP2-IBs vaccinated animals, which is indicative of higher levels of Th2 immune responses. Irrespective to the adjuvant used, animals vaccinated with FhSAP2-IBs exhibited significantly higher survival percentage and less liver damage than the adjuvant-control groups. This study suggests that FhSAP2 has potential as vaccine against F. hepatica and that the protection elicited by this molecule could be linked to a mechanism driven by the CD4-Th1 cells.

  12. [Effect of melaxen and valdoxan on free radical processes intensity, aconitate hydratase activity and citrate content in rats tissues under hyperthyroidism].

    Science.gov (United States)

    Gorbenko, M V; Popova, T N; Shul'gin, K K; Popov, S S; Agarkov, A A

    2014-01-01

    The influence of melaxen and valdoxan on the biochemiluminescence parameters, aconitate hydratase activity and citrate level in rats heart and liver during development of experimental hyperthyroidism has been investigated. Administration of these substances promoted a decrease of biochemiluminescence parameters, which had been increased in tissues of rats in response to the development of oxidative stress under hyperthyroidism. Aconitate hydratase activity and citrate concentration in rats liver and heart, growing at pathological conditions, changed towards control value after administration of the drugs correcting melatonin level. The results indicate the positive effect of valdoxan and melaxen on oxidative status of the organism under the development of experimental hyperthyroidism that is associated with antioxidant action of melatonin.

  13. Production of 13S-hydroxy-9(Z)-octadecenoic acid from linoleic acid by whole recombinant cells expressing linoleate 13-hydratase from Lactobacillus acidophilus.

    Science.gov (United States)

    Park, Ji-Young; Lee, Seon-Hwa; Kim, Kyoung-Rok; Park, Jin-Byung; Oh, Deok-Kun

    2015-08-20

    Linoleate 13-hydratase from Lactobacillus acidophilus LMG 11470 converted linoleic acid to hydroxyl fatty acid, which was identified as 13S-hydroxy-9(Z)-octadecenoic acid (13-HOD) by GC-MS and NMR. The expression of linoleate 13-hydratase gene in Escherichia coli was maximized by using pACYC plasmid and super optimal broth with catabolite repression (SOC) medium containing 40mM Mg(2+). To optimize induction conditions, recombinant cells were cultivated at 37°C, 1mM isopropyl-β-d-thiogalactopyranoside was added at 2h, and the culture was further incubated at 16°C for 18h. Recombinant cells expressing linoleate 13-hydratase from L. acidophilus were obtained under the optimized expression conditions and used for 13-HOD production from linoleic acid. The optimal reaction conditions were pH 6.0, 40°C, 0.25% (v/v) Tween 40, 25gl(-1) cells, and 100gl(-1) linoleic acid, and under these conditions, whole recombinant cells produced 79gl(-1) 13-HOD for 3h with a conversion yield of 79% (w/w), a volumetric productivity of 26.3gl(-1)h(-1), and a specific productivity of 1.05g g-cells(-1)h(-1). To the best of our knowledge, the recombinant cells produced hydroxy fatty acid with the highest concentration and productivity reported so far.

  14. Stanol ester margarine alone and with simvastatin lowers serum cholesterol in families with familial hypercholesterolemia caused by the FH-North Karelia mutation.

    Science.gov (United States)

    Vuorio, A F; Gylling, H; Turtola, H; Kontula, K; Ketonen, P; Miettinen, T A

    2000-02-01

    In heterozygous familial hypercholesterolemia (FH), serum low density lipoprotein (LDL) cholesterol levels are already elevated at birth. Premature coronary heart disease occurs in approximately 30% of heterozygous untreated adult patients. Accordingly, to retard development of atherosclerosis, preventive measures for lowering cholesterol should be started even in childhood. To this end, 19 FH families consumed dietary stanol ester for 3 months. Stanol ester margarine lowers the serum cholesterol level by inhibiting cholesterol absorption. Each individual in the study replaced part of his or her daily dietary fat with 25 g of 80% rapeseed oil margarine containing stanol esters (2.24 g/d stanols, mainly sitostanol). The families who consumed this margarine for 12 weeks included 24 children, aged 3 to 13 years, with the North Karelia variant of FH (FH-NK), 4 FH-NK parents, and 16 healthy family members, and a separate group of 12 FH-NK adults who consumed the margarine for 6 weeks and who were on simvastatin therapy (20 or 40 mg/d). Fat-soluble vitamins were measured by high-pressure liquid chromatography, and cholesterol precursor sterols (indexes of cholesterol synthesis) and cholestanol and plant sterols (indexes of cholesterol absorption efficiency) were assayed by gas-liquid chromatography. No side effects occurred. Serum LDL cholesterol levels were reduced by 18% (P<0.001), 11%, 12% (P<0.001), and 20% (P<0.001) in the 4 groups, respectively. The serum campesterol-to-cholesterol ratios fell by 31% (P<0.001), 29%, 23% (P<0.001), and 36% (P<0.001), respectively, suggesting that cholesterol absorption efficiency was inhibited. Serum lathosterol ratios were elevated by 38% (P<0.001), 11%, 15% (P<0.001), and 19% (P<0.001), respectively, suggesting that cholesterol synthesis was compensatorily upregulated. The FH-NK children increased their serum lathosterol ratio more than did the FH-NK adults treated with stanol ester margarine and simvastatin (P<0.01). In the FH

  15. Effects of Follower Jamming to FH Communication%跟踪干扰对跳频通信性能影响

    Institute of Scientific and Technical Information of China (English)

    全厚德; 闫云斌; 崔佩璋

    2012-01-01

    In this paper, the follower jamming and the jamming ellipse are analyzed. After studying the jamming ellipse and combining the mathematical model of FH signal, the mathematical model of follower jamming is built. The MFSK modulation was be adopted to the FH system,and then the performance of FH-MFSK system under the follower jamming is analyzed. The simulation results show that, when the FH-MFSK system is jammed by the follower jamming, the bit error rate (BER) of FH-MFSK communication system is bigger, and the anti-jamming performance of FH-MFSK system is degradation, and the anti-jamming performance of follower jamming in the FH-MFSK system is increased obviously, when the MFSK modulation is adopted. Finally, the anti-jamming measures of follower jamming are proposed.%针对跳频通信中跟踪干扰的问题,分析了跟踪干扰及其对应的干扰椭圆,结合跳频信号的数学模型建立了跟踪干扰的数学模型;在调制方式为MFSK的情况下,给出了跟踪干扰对FH-MFSK通信系统的误码率性能.仿真结果表明,当跳频通信系统遭受跟踪干扰时,系统的误码率升高,抗干扰性能下降明显,而采用多进制频移键控调制可以提高系统的抗跟踪干扰能力;最后给出了抗跟踪干扰的一些措施.

  16. Antibacterial efficacy of Nisin, Pediocin 34 and Enterocin FH99 against Listeria monocytogenes and cross resistance of its bacteriocin resistant variants to common food preservatives

    Directory of Open Access Journals (Sweden)

    G. Kaur

    2013-01-01

    Full Text Available Antilisterial efficiency of three bacteriocins, viz, Nisin, Pediocin 34 and Enterocin FH99 was tested individually and in combination against Listeria mononcytogenes ATCC 53135. A greater antibacterial effect was observed when the bacteriocins were combined in pairs, indicating that the use of more than one LAB bacteriocin in combination have a higher antibacterial action than when used individually. Variants of Listeria monocytogenes ATCC 53135 resistant to Nisin, Pediocin 34 and Enterocin FH99 were developed. Bacteriocin cross-resistance of wild type and their corresponding resistant variants were assessed and results showed that resistance to a bacteriocin may extend to other bacteriocins within the same class. Resistance to Pediocin 34 conferred cross resistance to Enterocin FH 99 but not to Nisin. Similarly resistance to Enterocin FH99 conferred cross resistance to Pediocin 34 but not to Nisin. Also, the sensitivity of Nisin, Pediocin 34 and Enterocin FH99 resistant variants of Listeria monocytogenes to low pH, salt, sodium nitrite, and potassium sorbate was assayed in broth and compared to the parental wild-type strain. The Nisin, Pediocin 34 and Enterocin FH99 resistant variants did not have intrinsic resistance to low pH, sodium chloride, potassium sorbate, or sodium nitrite. In no case were the bacteriocin resistant Listeria monocytogenes variants examined were more resistant to inhibitors than the parental strains.

  17. Enhancement of thermo-stability and product tolerance of Pseudomonas putida nitrile hydratase by fusing with self-assembling peptide.

    Science.gov (United States)

    Liu, Yi; Cui, Wenjing; Liu, Zhongmei; Cui, Youtian; Xia, Yuanyuan; Kobayashi, Michihiko; Zhou, Zhemin

    2014-09-01

    Self-assembling amphipathic peptides (SAPs) are the peptides that can spontaneously assemble into ordered nanostructures. It has been reported that the attachment of SAPs to the N- or C-terminus of an enzyme can benefit the thermo-stability of the enzyme. Here, we discovered that the thermo-stability and product tolerance of nitrile hydratase (NHase) were enhanced by fusing with two of the SAPs (EAK16 and ELK16). When the ELK16 was fused to the N-terminus of β-subunit, the resultant NHase (SAP-NHase-2) became an active inclusion body; EAK16 fused NHase in the N-terminus of β-subunit (SAP-NHase-1) and ELK16 fused NHase in the C-terminus of β-subunit (SAP-NHase-10) did not affect NHase solubility. Compared with the deactivation of the wild-type NHase after 30 min incubation at 50°C, SAP-NHase-1, SAP-NHase-2 and SAP-NHase-10 retained 45%, 30% and 50% activity; after treatment in the buffer containing 10% acrylamide, the wild-type retained 30% activity, while SAP-NHase-1, SAP-NHase-2 and SAP-NHase-10 retained 52%, 42% and 55% activity. These SAP-NHases with enhanced thermo-stability and product tolerance would be helpful for further industrial applications of the NHase.

  18. Nitrile hydratase of Rhodococcus erythropolis: characterization of the enzyme and the use of whole cells for biotransformation of nitriles.

    Science.gov (United States)

    Kamble, Ashwini L; Banoth, Linga; Meena, Vachan Singh; Singh, Amit; Chisti, Yusuf; Banerjee, U C

    2013-08-01

    The intracellular cobalt-type nitrile hydratase was purified from the bacterium Rhodococcuserythropolis. The pure enzyme consisted of two subunits of 29 and 30 kDa. The molecular weight of the native enzyme was estimated to be 65 kDa. At 25 °C the enzyme had a half-life of 25 h. The Michaelis-Menten constants Km and vmax for the enzyme were 0.624 mM and 5.12 μmol/min/mg, respectively, using 3-cyanopyridine as the substrate. The enzyme-containing freely-suspended bacterial cells and the cells immobilized within alginate beads were evaluated for converting the various nitriles to amides. In a packed bed reactor, alginate beads (2 % alginate; 3 mm bead diameter) containing 200 mg/mL of cells, achieved a conversion of >90 % for benzonitrile and 4-cyanopyridine in 38 h (25 °C, pH 7.0) at a feed substrate concentration of 100 mM. The beads could be reused for up to six reaction cycles.

  19. Towards Structural-Functional Mimics of Acetylene Hydratase: Reversible Activation of Acetylene using a Biomimetic Tungsten Complex.

    Science.gov (United States)

    Peschel, Lydia M; Belaj, Ferdinand; Mösch-Zanetti, Nadia C

    2015-10-26

    The synthesis and characterization of a biomimetic system that can reversibly bind acetylene (ethyne) is reported. The system has been designed to mimic catalytic intermediates of the tungstoenzyme acetylene hydratase. The thiophenyloxazoline ligand S-Phoz (2-(4',4'-dimethyloxazolin-2'-yl)thiophenolate) is used to generate a bioinspired donor environment around the W center, facilitating the stabilization of W-acetylene adducts. The featured complexes [W(C2 H2 )(CO)(S-Phoz)2 ] (2) and [WO(C2 H2 )(S-Phoz)2 ] (3) are extremely rare from a synthetic and structural point of view as very little is known about W-C2 H2 adducts. Upon exposure to visible light, 3 can release C2 H2 from its coordination sphere to yield the 14-electron species [WO(S-Phoz)2 ] (4). Under light-exclusion 4 re-activates C2 H2 making this the first fully characterized system for the reversible activation of acetylene.

  20. Traditional uses, botany, phytochemistry, pharmacology and toxicology of Panax notoginseng (Burk.) F.H. Chen: A review.

    Science.gov (United States)

    Wang, Ting; Guo, Rixin; Zhou, Guohong; Zhou, Xidan; Kou, Zhenzhen; Sui, Feng; Li, Chun; Tang, Liying; Wang, Zhuju

    2016-07-21

    Panax notoginseng (Burk.) F.H. Chen is a widely used traditional Chinese medicine known as Sanqi or Tianqi in China. This plant, which is distributed primarily in the southwest of China, has wide-ranging pharmacological effects and can be used to treat cardiovascular diseases, pain, inflammation and trauma as well as internal and external bleeding due to injury. This paper provides up-to-date information on investigations of this plant, including its botany, ethnopharmacology, phytochemistry, pharmacology and toxicology. The possible uses and perspectives for future investigation of this plant are also discussed. The relevant information on Panax notoginseng (Burk.) F.H. Chen was collected from numerous resources, including classic books about Chinese herbal medicine, and scientific databases, including Pubmed, SciFinder, ACS, Ebsco, Elsevier, Taylor, Wiley and CNKI. More than 200 chemical compounds have been isolated from Panax notoginseng (Burk.) F.H. Chen, including saponins, flavonoids and cyclopeptides. The plant has pharmacological effects on the cardiovascular system, immune system as well as anti-inflammatory, anti-atherosclerotic, haemostatic and anti-tumour activities, etc. Panax notoginseng is a valuable traditional Chinese medical herb with multiple pharmacological effects. This review summarizes the botany, ethnopharmacology, phytochemistry, pharmacology and toxicology of P. notoginseng, and presents the constituents and their corresponding chemical structures found in P. notoginseng comprehensively for the first time. Future research into its phytochemistry of bio-active components should be performed by using bioactivity-guided isolation strategies. Further work on elucidation of the structure-function relationship among saponins, understanding of multi-target network pharmacology of P. notoginseng, as well as developing its new clinical usage and comprehensive utilize will enhance the therapeutic potentials of P. notoginseng. Copyright © 2016

  1. Generation of iPSC line iPSC-FH2.1 in hypoxic conditions from human foreskin fibroblasts

    Directory of Open Access Journals (Sweden)

    María Questa

    2016-03-01

    Full Text Available Human foreskin fibroblasts were used to generate the iPSC line iPSC-FH2.1 using the EF1a-hSTEMCCA-loxP vector expressing OCT4, SOX2, c-MYC and KLF4, in 5% O2 culture conditions. Stemness was confirmed, as was pluripotency both in vivo and in vitro, in normoxia and hypoxia. Human Embryonic Stem Cell (hESC line WA-09 and reprogrammed fibroblast primary culture HFF-FM were used as controls.

  2. Electronic Structure Theory Study of the Microsolvated F(-)(H2O) + CH3I SN2 Reaction.

    Science.gov (United States)

    Zhang, Jiaxu; Yang, Li; Sheng, Li

    2016-05-26

    The potential energy profile of microhydrated fluorine ion reaction with methyl iodine has been characterized by extensive electronic structure calculations. Both hydrogen-bonded F(-)(H2O)---HCH2I and ion-dipole F(-)(H2O)---CH3I complexes are formed for the reaction entrance and the PES in vicinity of these complexes is very flat, which may have important implications for the reaction dynamics. The water molecule remains on the fluorine side until the reactive system goes to the SN2 saddle point. It can easily move to the iodine side with little barrier, but in a nonsynchronous reaction path after the dynamical bottleneck to the reaction, which supports the previous prediction for microsolvated SN2 systems. The influence of solvating water molecule on the reaction mechanism is probed by comparing with the influence of the nonsolvated analogue and other microsolvated SN2 systems. Taking the CCSD(T) single-point calculations based on MP2-optimized geometries as benchmark, the DFT functionals B97-1 and B3LYP are found to better characterize the potential energy profile for the title reaction and are recommended as the preferred methods for the direct dynamics simulations to uncover the dynamic behaviors.

  3. Studies on Fermentation Conditions of Antagonistic Actinomyle Fh-chib against Botrytis cinerea%番茄灰霉病菌拮抗基因工程菌株Fh-chib培养条件的研究

    Institute of Scientific and Technical Information of China (English)

    韩文霞; 李伟泽; 陈立; 陈五岭

    2012-01-01

    [Objective]The aim was to identify the pathogen to cause citrus tristeza disease in Anyue County of Sichuan Province.[Method]The complete nucleotide sequence of citrus tristeza virus (CTV) coat protein (CP) was determined by using RT-PCR, cloning and sequencing techniques.[Result]Eighteen CTV isolates (22.2%) were collected in a total of 81 field citrus samples in Anyue, Sichuan province. Se quence comparison and phylogenetic tree of 18 CTV isolates and other CTV isolates indicated that citrus tristeza disease in Anyue was caused by CTV. These diseases belonged to five groups, and the genetic relationship between CTV was complicated.[Conclusion]The research pro vides theoretical basis for the prevention and control of CTV in Anyue area.%[目的]筛选番茄灰霉病菌拮抗基因工程菌株Fh-chib的最佳培养条件.[方法]在单因素试验的基础上,采用正交试验设计对番茄灰霉病菌拮抗菌株Fh-chib的最佳培养条件(碳源、氮源和无机盐)进行了研究.[结果]工程菌株Fh-chib的最佳培养基配方为0.50%葡萄糖、1.00%蔗糖、1.00%酵母膏、1.50%麸皮、1.00%黄豆饼粉、0.03% MgSO4和0.40% CaCI2.各个因素对发酵液抑菌活性影响的主次顺序为:葡萄糖>蔗糖> CaCI2>黄豆饼粉>酵母膏>麸皮>MgSO4.[结论]为该菌株的工业化生产奠定了基础.

  4. Kinetic effects of sulfur oxidation on catalytic nitrile hydration: nitrile hydratase insights from bioinspired ruthenium(II) complexes.

    Science.gov (United States)

    Kumar, Davinder; Nguyen, Tho N; Grapperhaus, Craig A

    2014-12-01

    Kinetic investigations inspired by the metalloenzyme nitrile hydratase were performed on a series of ruthenium(II) complexes to determine the effect of sulfur oxidation on catalytic nitrile hydration. The rate of benzonitrile hydration was quantified as a function of catalyst, nitrile, and water concentrations. Precatalysts L(n)RuPPh3 (n = 1-3; L(1) = 4,7-bis(2'-methyl-2'-mercapto-propyl)-1-thia-4,7-diazacyclononane; L(2) = 4-(2'-methyl-2'-sulfinatopropyl)-7-(2'-methyl-2'-mercapto-propyl)-1-thia-4,7-diazacyclononane; L(3) = 4-(2'-methyl-2'-sulfinatopropyl)-7-(2'-methyl-2'-sulfenato-propyl)-1-thia-4,7-diazacyclononane) were activated by substitution of triphenylphosphine with substrate in hot dimethylformamide solution. Rate measurements are consistent with a dynamic equilibrium between inactive aqua (L(n)Ru-OH2) and active nitrile (L(n)Ru-NCR) derivatives with K = 21 ± 1, 9 ± 0.9, and 23 ± 3 for L(1) to L(3), respectively. Subsequent hydration of the L(n)Ru-NCR intermediate yields the amide product with measured hydration rate constants (k's) of 0.37 ± 0.01, 0.82 ± 0.07, and 1.59 ± 0.12 M(-1) h(-1) for L(1) to L(3), respectively. Temperature dependent studies reveal that sulfur oxidation lowers the enthalpic barrier by 27 kJ/mol, but increases the entropic barrier by 65 J/(mol K). Density functional theory (DFT) calculations (B3LYP/LanL2DZ (Ru); 6-31G(d) (all other atoms)) support a nitrile bound catalytic cycle with lowering of the reaction barrier as a consequence of sulfur oxidation through enhanced nitrile binding and attack of the water nucleophile through a highly organized transition state.

  5. 2-haloacrylate hydratase, a new class of flavoenzyme that catalyzes the addition of water to the substrate for dehalogenation.

    Science.gov (United States)

    Mowafy, Amr M; Kurihara, Tatsuo; Kurata, Atsushi; Uemura, Tadashi; Esaki, Nobuyoshi

    2010-09-01

    Enzymes catalyzing the conversion of organohalogen compounds are useful in the chemical industry and environmental technology. Here we report the occurrence of a new reduced flavin adenine dinucleotide (FAD) (FADH(2))-dependent enzyme that catalyzes the removal of a halogen atom from an unsaturated aliphatic organohalogen compound by the addition of a water molecule to the substrate. A soil bacterium, Pseudomonas sp. strain YL, inducibly produced a protein named Caa67(YL) when the cells were grown on 2-chloroacrylate (2-CAA). The caa67(YL) gene encoded a protein of 547 amino acid residues (M(r) of 59,301), which shared weak but significant sequence similarity with various flavoenzymes and contained a nucleotide-binding motif. We found that 2-CAA is converted into pyruvate when the reaction was carried out with purified Caa67(YL) in the presence of FAD and a reducing agent [NAD(P)H or sodium dithionite] under anaerobic conditions. The reducing agent was not stoichiometrically consumed during this reaction, suggesting that FADH(2) is conserved by regeneration in the catalytic cycle. When the reaction was carried out in the presence of H(2)(18)O, [(18)O]pyruvate was produced. These results indicate that Caa67(YL) catalyzes the hydration of 2-CAA to form 2-chloro-2-hydroxypropionate, which is chemically unstable and probably spontaneously dechlorinated to form pyruvate. 2-Bromoacrylate, but not other 2-CAA analogs such as acrylate and methacrylate, served as the substrate of Caa67(YL). Thus, we named this new enzyme 2-haloacrylate hydratase. The enzyme is very unusual in that it requires the reduced form of FAD for hydration, which involves no net change in the redox state of the coenzyme or substrate.

  6. The immune modulatory peptide FhHDM-1 secreted by the helminth Fasciola hepatica prevents NLRP3 inflammasome activation by inhibiting endolysosomal acidification in macrophages.

    Science.gov (United States)

    Alvarado, Raquel; To, Joyce; Lund, Maria E; Pinar, Anita; Mansell, Ashley; Robinson, Mark W; O'Brien, Bronwyn A; Dalton, John P; Donnelly, Sheila

    2017-01-01

    The NLRP3 inflammasome is a multimeric protein complex that controls the production of IL-1β, a cytokine that influences the development of both innate and adaptive immune responses. Helminth parasites secrete molecules that interact with innate immune cells, modulating their activity to ultimately determine the phenotype of differentiated T cells, thus creating an immune environment that is conducive to sustaining chronic infection. We show that one of these molecules, FhHDM-1, a cathelicidin-like peptide secreted by the helminth parasite, Fasciola hepatica, inhibits the activation of the NLRP3 inflammasome resulting in reduced secretion of IL-1β by macrophages. FhHDM-1 had no effect on the synthesis of pro-IL-1β. Rather, the inhibitory effect was associated with the capacity of the peptide to prevent acidification of the endolysosome. The activation of cathepsin B protease by lysosomal destabilization was prevented in FhHDM-1-treated macrophages. By contrast, peptide derivatives of FhHDM-1 that did not alter the lysosomal pH did not inhibit secretion of IL-1β. We propose a novel immune modulatory strategy used by F. hepatica, whereby secretion of the FhHDM-1 peptide impairs the activation of NLRP3 by lysosomal cathepsin B protease, which prevents the downstream production of IL-1β and the development of protective T helper 1 type immune responses that are detrimental to parasite survival.-Alvarado, R., To, J., Lund, M. E., Pinar, A., Mansell, A., Robinson, M. W., O'Brien, B. A., Dalton, J. P., Donnelly, S. The immune modulatory peptide FhHDM-1 secreted by the helminth Fasciola hepatica prevents NLRP3 inflammasome activation by inhibiting endolysosomal acidification in macrophages. © FASEB.

  7. Enzymatic hydration activity assessed by selective spectrophotometric detection of alcohols: a novel screening assay using oleate hydratase as a model enzyme.

    Science.gov (United States)

    Hiseni, Aida; Medici, Rosario; Arends, Isabel W C E; Otten, Linda G

    2014-06-01

    Hydroxy fatty acids (HFAs) are high-added-value compounds, which are incorporated in polymers, lubricants, emulsifiers and stabilizers and have potential medicinal use. In nature, HFAs are regio-specifically synthesized by several enzymes, including P450 monooxygenases, lipoxygenases, hydratases, 12-hydroxylases, and diol synthases. The growing demand for HFAs warrants the development of simple and efficient analytical methods that enable high-throughput detection of the hydroxylated product in the presence of its unsaturated precursor. Herein a novel high-throughput assay for the detection of alcohols is described using oleate hydratase (OHase, EC 4.2.1.53) from Elizabethkingia meningoseptica as the model enzyme. The developed assay is based on the selective spectrophotometric detection of alkyl nitrites formed upon the reaction between the hydroxyl group and nitrous acid. The assay proved to discriminate between unsaturated fatty acids as well as small cyclic and acyclic unsaturated alkenes and their corresponding alcohols. Lower detection limits were 1.5-3 mM with excellent Z'-factors. Enzymatic reactions using OHase with oleic acid resulted in somewhat lower Z-factors for various enzyme preparations. This small scale assay can enable fast discovery of new microorganisms or improved enzymes from mutant libraries and will be useful for biocatalytic strategies involving fatty acid (de)hydrating enzymes.

  8. Myosin-cross-reactive antigen (MCRA) protein from Bifidobacterium breve is a FAD-dependent fatty acid hydratase which has a function in stress protection

    LENUS (Irish Health Repository)

    Rosberg-Cody, Eva

    2011-02-17

    Abstract Background The aim of this study was to determine the catalytic activity and physiological role of myosin-cross-reactive antigen (MCRA) from Bifidobacterium breve NCIMB 702258. MCRA from B. breve NCIMB 702258 was cloned, sequenced and expressed in heterologous hosts (Lactococcus and Corynebacterium) and the recombinant proteins assessed for enzymatic activity against fatty acid substrates. Results MCRA catalysed the conversion of palmitoleic, oleic and linoleic acids to the corresponding 10-hydroxy fatty acids, but shorter chain fatty acids were not used as substrates, while the presence of trans-double bonds and double bonds beyond the position C12 abolished hydratase activity. The hydroxy fatty acids produced were not metabolised further. We also found that heterologous Lactococcus and Corynebacterium expressing MCRA accumulated increasing amounts of 10-HOA and 10-HOE in the culture medium. Furthermore, the heterologous cultures exhibited less sensitivity to heat and solvent stresses compared to corresponding controls. Conclusions MCRA protein in B. breve can be classified as a FAD-containing double bond hydratase, within the carbon-oxygen lyase family, which may be catalysing the first step in conjugated linoleic acid (CLA) production, and this protein has an additional function in bacterial stress protection.

  9. Interacting resonances in the F+H2 reaction revisited: complex terms, Riemann surfaces, and angular distributions.

    Science.gov (United States)

    Sokolovski, D; Sen, S K; Aquilanti, V; Cavalli, S; De Fazio, D

    2007-02-28

    We study the effect of overlapping resonances on the angular distributions of the reaction F+H2(v=0,j=0)-->HF(v=2,j=0)+H in the collision energy range from 5 to 65 meV, i.e., under the reaction barrier. Reactive scattering calculations were performed using the hyperquantization algorithm on the potential energy surface of Stark and Werner [J. Chem. Phys. 104, 6515 (1996)]. The positions of the Regge and complex energy poles are obtained by Pade reconstruction of the scattering matrix element. The Sturmian theory is invoked to relate the Regge and complex energy terms. For two interacting resonances, a two-sheet Riemann surface is contracted and inverted. The semiclassical complex angular momentum analysis is used to decompose the scattering amplitude into the direct and resonance contributions.

  10. Disease: H01022 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available H01022 Diseases of the tricarboxylic acid cycle, including: Fumarase (FH) deficienc...y; Succinate dehydrogenase (SDH) deficiency; Alpha-ketoglutarate dehydrogenase (AKGDH) deficiency Diseases o

  11. Effect of growth media on cell envelope composition and nitrile hydratase stability in Rhodococcus rhodochrous strain DAP 96253.

    Science.gov (United States)

    Tucker, Trudy-Ann; Crow, Sidney A; Pierce, George E

    2012-11-01

    Rhodococcus is an important industrial microorganism that possesses diverse metabolic capabilities; it also has a cell envelope, composed of an outer layer of mycolic acids and glycolipids. Selected Rhodococcus species when induced are capable of transforming nitriles to the corresponding amide by the enzyme nitrile hydratase (NHase), and subsequently to the corresponding acid via an amidase. This nitrile biochemistry has generated interest in using the rhodococci as biocatalysts. It was hypothesized that altering sugars in the growth medium might impact cell envelope components and have effects on NHase. When the primary carbon source in growth media was changed from glucose to fructose, maltose, or maltodextrin, the NHase activity increased. Cells grown in the presence of maltose and maltodextrin showed the highest activities against propionitrile, 197 and 202 units/mg cdw, respectively. Stability of NHase was also affected as cells grown in the presence of maltose and maltodextrin retained more NHase activity at 55 °C (45 and 23 %, respectively) than cells grown in the presence of glucose or fructose (19 and 10 %, respectively). Supplementation of trehalose in the growth media resulted in increased NHase stability at 55 °C, as cells grown in the presence of glucose retained 40 % NHase activity as opposed to 19 % without the presence of trehalose. Changes in cell envelope components, such mycolic acids and glycolipids, were evaluated by high-performance liquid chromatography (HPLC) and thin-layer chromatography (TLC), respectively. Changing sugars and the addition of inducing components for NHase, such as cobalt and urea in growth media, resulted in changes in mycolic acid profiles. Mycolic acid content increased 5 times when cobalt and urea were added to media with glucose. Glycolipids levels were also affected by the changes in sugars and addition of inducing components. This research demonstrates that carbohydrate selection impacts NHase activity and

  12. Use of Metallopeptide Based Mimics Demonstrates That the Metalloprotein Nitrile Hydratase Requires Two Oxidized Cysteinates for Catalytic Activity

    Energy Technology Data Exchange (ETDEWEB)

    Shearer, J.; Callan, P; Amie, J

    2010-01-01

    Nitrile hydratases (NHases) are non-heme Fe{sup III} or non-corrin Co{sup III} containing metalloenzymes that possess an N{sub 2}S{sub 3} ligand environment with nitrogen donors derived from amidates and sulfur donors derived from cysteinates. A closely related enzyme is thiocyanate hydrolase (SCNase), which possesses a nearly identical active-site coordination environment as CoNHase. These enzymes are redox inactive and perform hydrolytic reactions; SCNase hydrolyzes thiocyanate anions while NHase converts nitriles into amides. Herein an active CoNHase metallopeptide mimic, [Co{sup III}NHase-m1] (NHase-m1 = AcNH-CCDLP-CGVYD-PA-COOH), that contains Co{sup III} in a similar N{sub 2}S{sub 3} coordination environment as CoNHase is reported. [Co{sup III}NHase-m1] was characterized by electrospray ionization-mass spectrometry (ESI-MS), gel-permeation chromatography (GPC), Co K-edge X-ray absorption spectroscopy (Co-S: 2.21 {angstrom}; Co-N: 1.93 {angstrom}), vibrational, and optical spectroscopies. We find that [Co{sup III}NHase-m1] will perform the catalytic conversion of acrylonitrile into acrylamide with up to 58 turnovers observed after 18 h at 25 C (pH 8.0). FTIR data used in concert with calculated vibrational data (mPWPW91/aug-cc-TZVPP) demonstrates that the active form of [Co{sup III}NHase-m1] has a ligated SO{sub 2} (? = 1091 cm{sup -1}) moiety and a ligated protonated SO(H) (? = 928 cm{sup -1}) moiety; when only one oxygenated cysteinate ligand (i.e., a mono-SO{sub 2} coordination motif) or the bis-SO{sub 2} coordination motif are found within [Co{sup III}NHase-m1] no catalytic activity is observed. Calculations of the thermodynamics of ligand exchange (B3LYP/aug-cc-TZVPP) suggest that the reason for this is that the SO{sub 2}/SO(H) equatorial ligand motif promotes both water dissociation from the Co{sup III}-center and nitrile coordination to the Co{sup III}-center. In contrast, the under- or overoxidized motifs will either strongly favor a five coordinate Co

  13. FhCaBP2: a Fasciola hepatica calcium-binding protein with EF-hand and dynein light chain domains.

    Science.gov (United States)

    Thomas, Charlotte M; Timson, David J

    2015-09-01

    FhCaBP2 is a Fasciola hepatica protein which belongs to a family of helminth calcium-binding proteins which combine an N-terminal domain containing two EF-hand motifs and a C-terminal dynein light chain-like (DLC-like) domain. Its predicted structure showed two globular domains joined by a flexible linker. Recombinant FhCaBP2 interacted reversibly with calcium and manganese ions, but not with magnesium, barium, strontium, copper (II), colbalt (II), iron (II), nickel, lead or potassium ions. Cadmium (II) ions appeared to bind non-site-specifically and destabilize the protein. Interaction with either calcium or magnesium ions results in a conformational change in which the protein's surface becomes more hydrophobic. The EF-hand domain alone was able to interact with calcium and manganese ions; the DLC-like domain was not. Alteration of a residue (Asp-58 to Ala) in the second EF-hand motif in this domain abolished ion-binding activity. This suggests that the second EF-hand is the one responsible for ion-binding. FhCaBP2 homodimerizes and the extent of dimerization was not affected by calcium ions or by the aspartate to alanine substitution in the second EF-hand. The isolated EF-hand and DLC-like domains are both capable of homodimerization. FhCaBP2 interacted with the calmodulin antagonists trifluoperazine, chlorpromazine, thiamylal and W7. Interestingly, while chlorpromazine and thiamylal interacted with the EF-hand domain (as expected), trifluoperazine and W7 bound to the DLC-like domain. Overall, FhCaBP2 has distinct biochemical properties compared with other members of this protein family from Fasciola hepatica, a fact which supports the hypothesis that these proteins have different physiological roles.

  14. Characteristics of alcohol-preferring behavior in FH/Wjd rats%先天性嗜酒大鼠的饮酒行为特性

    Institute of Scientific and Technical Information of China (English)

    景丽; 张振华; 王卫平; 张敏; 罗娟; 陈锋; Andrew J LAWRENCE; 梁建辉

    2009-01-01

    目的 系统考察先天性嗜酒(FH/Wjd)大鼠嗜酒的行为特性.方法 采用双瓶(5%或10%乙醇和自来水)自由选择的方法 ,观察FH/Wjd大鼠的饮酒量、饮水量和乙醇偏爱率,并进一步探讨FH/Wjd大鼠饮酒的昼夜差异性;在乙醇剥夺实验中,研究乙醇剥夺24 h对FH/Wjd大鼠饮酒量和乙醇偏爱率的影响;选用固定比率(FR1)实验程序,探讨FH/Wjd大鼠操作性自身饮酒的行为特点.结果 在双瓶自由选择饮酒实验中,给予5%乙醇,大鼠的饮酒量为(4.3±0.2)g·kg-1·d-1,饮水量为(20.1±2.3)g·kg-1·d-1,乙醇偏爱率为(82.9±2.0)%;给予10%乙醇,大鼠的饮酒量为(6.4± 0.2)g·kg-1·d-1,饮水量为(37.2±2.7)g·kg-1·d-1,乙醇偏爱率为(69.2±2.0)%,与5%乙醇相比较,饮酒量和饮水量显著增大,但乙醇偏爱率明显降低.FH/Wjd大鼠的饮酒行为呈明显的昼夜节律,夜间饮酒量和乙醇偏爱率均显著高于白天,夜间饮水量虽呈增加趋势,但差异无显著性.FH/Wjd大鼠乙醇剥夺24 h,再次给酒后1 h的饮酒量增加37.7%,乙醇偏爱率增加22.1%;再次给酒后24 h的饮酒量增加15.6%,乙醇偏爱率存在增高趋势,但差异无显著性.FH/Wjd大鼠操作性自身饮酒行为训练13 d后, 连续测试3 d, 操作性饮酒行为的偏爱率为49%~64%.结论 FH/Wjd大鼠具有饮酒量大和乙醇偏爱率高的特点,存在明显的乙醇剥夺效应,并可在短期内建立操作性自身饮酒行为,是一种理想的先天嗜酒动物模型.

  15. 一种提高跳频系统密钥量的新方法%Novel method of enhancing the key amount for FH systems

    Institute of Scientific and Technical Information of China (English)

    沈斐; 宋铁成; 叶芝慧; 刘彤; 夏玮玮

    2004-01-01

    基于信息论原理, 提出了一种非等间隔跳频系统的方案, 针对不允许频谱重叠系统和允许频谱重叠系统, 分别给出了实现方法并对其安全性能进行了理论分析. 首先给出了跳频系统的绝对密钥量和相对密钥量、等间隔和非等间隔跳频系统等定义; 然后分析了等间隔和非等间隔跳频系统的绝对密钥量和相对密钥量, 从而看出在计算机技术和集成电路设计技术得到飞速发展的情况下, 跳频系统的绝对密钥量已变成制约其保密性和安全性的关键; 理论分析和实例计算可以看出, 采用非等间隔跳频后其绝对密钥量有大幅度提高, 特别是允许频谱重叠的系统, 比等间隔跳频系统提高了2个数量级以上.%Based on the principle of information theory, a novel scheme of unequal-interval frequency-hopping (FH) systems is proposed. For cases of spectrum overlapping systems and non-overlapping systems, the implementation methods are presented and the security performances are discussed theoretically. Firstly, the definitions of absolute and relative key amounts of FH systems, equal-interval and unequal-interval FH systems are given. Then, the absolute key amount and relative key amount are analyzed for equal-interval and unequal-interval FH systems. The results indicate that the absolute key amount has become the key point in improving the security and secrecy of FH systems, especially in today's epoch of highly developed computer science and IC design technology. Theoretical analysis and practical examples show that the absolute key amount of unequal-interval FH systems is generally over two orders larger than that of equal-interval ones when spectrum overlapping is allowable. Therefore, there is great superiority in enhancing the security and secrecy for the scheme mentioned.

  16. Novel TRAIL sensitizer Taraxacum officinale F.H. Wigg enhances TRAIL-induced apoptosis in Huh7 cells.

    Science.gov (United States)

    Yoon, Ji-Yong; Cho, Hyun-Soo; Lee, Jeong-Ju; Lee, Hyo-Jung; Jun, Soo Young; Lee, Jae-Hye; Song, Hyuk-Hwan; Choi, SangHo; Saloura, Vassiliki; Park, Choon Gil; Kim, Cheol-Hee; Kim, Nam-Soon

    2016-04-01

    TRAIL (TNF-related apoptosis inducing ligand) is a promising anti-cancer drug target that selectively induces apoptosis in cancer cells. However, many cancer cells are resistant to TRAIL-induced apoptosis. Therefore, reversing TRAIL resistance is an important step for the development of effective TRAIL-based anti-cancer therapies. We previously reported that knockdown of the TOR signaling pathway regulator-like (TIPRL) protein caused TRAIL-induced apoptosis by activation of the MKK7-c-Jun N-terminal Kinase (JNK) pathway through disruption of the MKK7-TIPRL interaction. Here, we identified Taraxacum officinale F.H. Wigg (TO) as a novel TRAIL sensitizer from a set of 500 natural products using an ELISA system and validated its activity by GST pull-down analysis. Furthermore, combination treatment of Huh7 cells with TRAIL and TO resulted in TRAIL-induced apoptosis mediated through inhibition of the MKK7-TIPRL interaction and subsequent activation of MKK7-JNK phosphorylation. Interestingly, HPLC analysis identified chicoric acid as a major component of the TO extract, and combination treatment with chicoric acid and TRAIL induced TRAIL-induced cell apoptosis via JNK activation due to inhibition of the MKK7-TIPRL interaction. Our results suggest that TO plays an important role in TRAIL-induced apoptosis, and further functional studies are warranted to confirm the importance of TO as a novel TRAIL sensitizer for cancer therapy. © 2015 Wiley Periodicals, Inc.

  17. A Self-assembled Fluoride-Water Cyclic Cluster of $[F(H_2O)]_4^{4-}$ in a Molecular Box

    CERN Document Server

    Hossain, Md Alamgir; Pramanik, Avijit; Wong, Bryan M; Haque, Syed A; Powell, Douglas R

    2013-01-01

    We present an unprecedented fluoride-water cyclic cluster of $[F(H_2O)]_4^{4-}$ assembled in a cuboid-shaped molecular box formed by two large macrocycles. Structural characterization reveals that the $[F(H_2O)]_4^{4-}$ is assembled by strong H-bonding interactions (OH...F = 2.684(3) to 2.724(3) {\\AA}), where a fluoride anion plays the topological role of a water molecule in the classical cyclic water octamer. The interaction of fluoride was further confirmed by $^{19}$F NMR and $^1$H NMR spectroscopies, indicating the encapsulation of the anionic species within the cavity in solution. High level DFT calculations and Bader topological analyses fully support the crystallographic results, demonstrating that the bonding arrangement in the fluoride-water cluster arises from the unique geometry of the host.

  18. 基于Baker变换的混沌跳频序列的实现%The implement of chaotic FH sequences based on Baker transform

    Institute of Scientific and Technical Information of China (English)

    甘良才; 俞柏峰; 易丹

    2001-01-01

    本文基于Baker变换的分段线性混沌映射,利用DSP实现了一种混沌跳频序列。并对该混沌跳频序列的平衡性,跳频间隔和最大汉明相关性,从数值模拟与硬件实现上进行了比较分析。实验结果与数值模拟结果相一致,具有良好的性能,适合于跳频通信。最后,还与其他混沌序列进行了比较,证明该方法是可行的,也适合于直扩系统。%Based on piecewise-linear chaotic map of Baker transform,thispaper p r oposes a method to implement chaotic frequency-hopping(FH)sequences by using DS P processor.This paper also analyzes the balance,the FH distance and the maxim um Hamming correlation of this FH sequences in both numerical analysis and experim ent.The results show that the experiment's results are accordance with the nume r ical analysis's results.The sequences have excellent properties and are suitabl e for FH system.Finally,this paper proves that the method is feasible by compar in g with some other chaotic sequences.The sequences also are suitable for DS/SS system.

  19. Proteomic analysis of Fasciola hepatica excretory and secretory products (FhESPs) involved in interacting with host PBMCs and cytokines by shotgun LC-MS/MS.

    Science.gov (United States)

    Liu, Qing; Huang, Si-Yang; Yue, Dong-Mei; Wang, Jin-Lei; Wang, Yujian; Li, Xiangrui; Zhu, Xing-Quan

    2017-02-01

    Fasciola hepatica is a helminth parasite with a worldwide distribution, which can cause chronic liver disease, fasciolosis, leading to economic losses in the livestock and public health in many countries. Control is mostly reliant on the use of drugs, and as a result, drug resistance has now emerged. The identification of F. hepatica genes involved in interaction between the parasite and host immune system is utmost important to elucidate the evasion mechanisms of the parasite and develop more effective strategies against fasciolosis. In this study, we aimed to identify molecules in F. hepatica excretory and secretory products (FhESPs) interacting with the host peripheral blood mononuclear cells (PBMCs), Th1-like cytokines (IL2 and IFN-γ), and Th17-like cytokines (IL17) by Co-IP combined with tandem mass spectrometry. The results showed that 14, 16, and 9 proteins in FhESPs could bind with IL2, IL17, and IFN-γ, respectively, which indicated that adult F. hepatica may evade the host immune responses through directly interplaying with cytokines. In addition, nine proteins in FhESPs could adhere to PBMCs. Our findings provided potential targets as immuno-regulators, and will be helpful to elucidate the molecular basis of host-parasite interactions and search for new potential proteins as vaccine and drug target candidates.

  20. Study on the mutation breeding of β-glucanase from Asp. Niger FH1%黑曲酶β-葡聚糖酶菌株诱变选育研究

    Institute of Scientific and Technical Information of China (English)

    贺小贤; 陈合; 齐香君; 赵敏

    2005-01-01

    以黑曲霉(Aspergillus niger)FH1为出发菌株,采用物理与化学相结合的方法,诱变选育出一株β-葡聚糖酶活性较高的菌株FH12.对该菌株进行摇瓶发酵条件的实验,酶活比出发菌株提高2.23倍.

  1. Catalytic Mechanism of Nitrile Hydratase Proposed by Time-resolved X-ray Crystallography Using a Novel Substrate, tert-Butylisonitrile*S⃞

    Science.gov (United States)

    Hashimoto, Koichi; Suzuki, Hiroyuki; Taniguchi, Kayoko; Noguchi, Takumi; Yohda, Masafumi; Odaka, Masafumi

    2008-01-01

    Nitrile hydratases (NHases) have an unusual iron or cobalt catalytic center with two oxidized cysteine ligands, cysteine-sulfinic acid and cysteine-sulfenic acid, catalyzing the hydration of nitriles to amides. Recently, we found that the NHase of Rhodococcus erythropolis N771 exhibited an additional catalytic activity, converting tert-butylisonitrile (tBuNC) to tert-butylamine. Taking advantage of the slow reactivity of tBuNC and the photoreactivity of nitrosylated NHase, we present the first structural evidence for the catalytic mechanism of NHase with time-resolved x-ray crystallography. By monitoring the reaction with attenuated total reflectance-Fourier transform infrared spectroscopy, the product from the isonitrile carbon was identified as a CO molecule. Crystals of nitrosylated inactive NHase were soaked with tBuNC. The catalytic reaction was initiated by photo-induced denitrosylation and stopped by flash cooling. tBuNC was first trapped at the hydrophobic pocket above the iron center and then coordinated to the iron ion at 120 min. At 440 min, the electron density of tBuNC was significantly altered, and a new electron density was observed near the isonitrile carbon as well as the sulfenate oxygen of αCys114. These results demonstrate that the substrate was coordinated to the iron and then attacked by a solvent molecule activated by αCys114-SOH. PMID:18948265

  2. The Fe-type nitrile hydratase from Comamonas testosteroni Ni1 does not require an activator accessory protein for expression in Escherichia coli.

    Science.gov (United States)

    Kuhn, Misty L; Martinez, Salette; Gumataotao, Natalie; Bornscheuer, Uwe; Liu, Dali; Holz, Richard C

    2012-08-03

    We report herein the functional expression of an Fe-type nitrile hydratase (NHase) without the co-expression of an activator protein or the Escherichia coli chaperone proteins GroES/EL. Soluble protein was obtained when the α- and β-subunit genes of the Fe-type NHase Comamonas testosteroni Ni1 (CtNHase) were synthesized with optimized E. coli codon usage and co-expressed. As a control, the Fe-type NHase from Rhodococcus equi TG328-2 (ReNHase) was expressed with (ReNHase(+Act)) and without (ReNHase(-Act)) its activator protein, establishing that expression of a fully functional, metallated ReNHase enzyme requires the co-expression of its activator protein, similar to all other Fe-type NHase enzymes reported to date, whereas the CtNHase does not. The X-ray crystal structure of CtNHase was determined to 2.4Å resolution revealing an αβ heterodimer, similar to other Fe-type NHase enzymes, except for two important differences. First, two His residues reside in the CtNHase active site that are not observed in other Fe-type NHase enzymes and second, the active site Fe(III) ion resides at the bottom of a wide solvent exposed channel. The solvent exposed active site, along with the two active site histidine residues, are hypothesized to play a role in iron incorporation in the absence of an activator protein.

  3. The Fe-type nitrile hydratase from Comamonas testosteroni Ni1 does not require an activator accessory protein for expression in Escherichia coli

    Energy Technology Data Exchange (ETDEWEB)

    Kuhn, Misty L.; Martinez, Salette; Gumataotao, Natalie; Bornscheuer, Uwe; Liu, Dali; Holz, Richard C. (Loyola); (Greifswald)

    2012-10-10

    We report herein the functional expression of an Fe-type nitrile hydratase (NHase) without the co-expression of an activator protein or the Escherichia coli chaperone proteins GroES/EL. Soluble protein was obtained when the {alpha}- and {beta}-subunit genes of the Fe-type NHase Comamonas testosteroni Ni1 (CtNHase) were synthesized with optimized E. coli codon usage and co-expressed. As a control, the Fe-type NHase from Rhodococcus equi TG328-2 (ReNHase) was expressed with (ReNHase{sup +Act}) and without (ReNHase{sup -Act}) its activator protein, establishing that expression of a fully functional, metallated ReNHase enzyme requires the co-expression of its activator protein, similar to all other Fe-type NHase enzymes reported to date, whereas the CtNHase does not. The X-ray crystal structure of CtNHase was determined to 2.4 {angstrom} resolution revealing an {alpha}{beta} heterodimer, similar to other Fe-type NHase enzymes, except for two important differences. First, two His residues reside in the CtNHase active site that are not observed in other Fe-type NHase enzymes and second, the active site Fe(III) ion resides at the bottom of a wide solvent exposed channel. The solvent exposed active site, along with the two active site histidine residues, are hypothesized to play a role in iron incorporation in the absence of an activator protein.

  4. [Intensity of apoptotic processes, aconitate hydratase activity and citrate level in patients with type 2 diabetes mellitus complicated steatohepatitis under application of epifamin at basic therapy].

    Science.gov (United States)

    Popov, S S; Pashkov, A N; Agarkov, A A; Shulgin, K K

    2015-01-01

    DNA fragmentation, caspase-1 and caspase-3, aconitate hydratase (AH) activities, and citrate content have been investigated in the blood of patients with type 2 diabetes mellitus complicated by steatohepatitis. These indicators of apoptotic processes intensity and oxidative stress development were estimated after basic treatment and a combined therapy including epifamin. Before treatment DNA fragmentation blood leukocytes, decrease of AH activity and increase of caspases activities in the serum of patients were detected. Treatment with epifamin provided more pronounced changes in the investigated parameters towards control values as compared to basis therapy. Epifamin caused a positive effect on the citrate content in the serum of patients. Epifamin inclusion to the basic therapy was accompanied by a more pronounced changes towards the normal values of such biochemical parameters as ALT, AST, b-lipoproteins, cholesterol, fasting glucose and postprandial glucose levels. All these changes may be obviously attributed to epifamin-induced correction of the melatonin level and manifestation of adaptogenic properties and antioxidant effects of the hormone.

  5. Prestaciones de una modulación FH-MFSK como técnica de múltiple acceso en comunicaciones móviles

    OpenAIRE

    Agustí Comes, Ramon; Junyent Giralt, Gabriel; Casadevall Palacio, Fernando José

    1983-01-01

    En esta comunicación presentamos una modulación en banda ensanchada FH-MFSK (Frequency Hopping - Multiple Frequency Shift Keying) apta para utilizarse en comunicaciones militares móviles como técnica de múltiple acceso. Establecemos también cual es el número de usuarios que pueden compartir la banda de frecuencias disponible según un modo de acceso aleatorio y suponiendo una estadística de Rayleigh para los desvanecimientos rápidos de la señal recibida. Finalmente, mostramos resultados para e...

  6. 转发干扰下DS/FH混合扩频测控信号检测性能%Detection Performance of DS/FH Hybrid Signals for TT & C under Repeater Jamming*

    Institute of Scientific and Technical Information of China (English)

    杨文革; 路伟涛; 卞燕山; 洪家财

    2013-01-01

    Studying the performance deterioration of DS/FH signals for TT&C(Telemetry Tracking&Command) in interfered environment is of great importance to this novel system. Expressions for probability of detection and false alarming of DS/FH(Direct Spread/Frequency Hopping)signals for TT&C under repeater jamming are de-duced. The probability of false alarming,PSLR(Peak Side lobe Level Ratio)and Correlation Coefficient are simulated and analyzed with different configuration of DS(Direct Spread)and FH(Frequency Hopping)spread-ing gain based on Matlab/Simulink. It is concluded that victim′s receiver is suffered“deception jamming”as long as relative delay time is less than frequency hop duration,which denotes correctness of deduce and offers references for following work.

  7. Biological monitoring of Upper Three Runs Creek, Savannah River Plant, Aiken County, South Carolina. Final report on macroinvertebrate stream assessments for F/H area ETF effluent discharge, July 1987--February 1990

    Energy Technology Data Exchange (ETDEWEB)

    Specht, W.L.

    1991-10-01

    In anticipation of the fall 1988 start up of effluent discharges into Upper Three Creek by the F/H Area Effluent Treatment Facility of the Savannah River Site, Aiken, SC, a two and one half year biological study was initiated in June 1987. Upper Three Runs Creek is an intensively studied fourth order stream known for its high species richness. Designed to assess the potential impact of F?H area effluent on the creek, the study includes qualitative and quantitative macroinvertebrate stream surveys at five sites, chronic toxicity testing of the effluent, water chemistry and bioaccumulation analysis. This final report presents the results of both pre-operational and post-operational qualitative and quantitative (artificial substrate) macroinvertebrate studies. Six quantitative and three qualitative studies were conducted prior to the initial release of the F/H ETF effluent and five quantitative and two qualitative studies were conducted post-operationally.

  8. Lethal neonatal case and review of primary short-chain enoyl-CoA hydratase (SCEH) deficiency associated with secondary lymphocyte pyruvate dehydrogenase complex (PDC) deficiency.

    Science.gov (United States)

    Bedoyan, Jirair K; Yang, Samuel P; Ferdinandusse, Sacha; Jack, Rhona M; Miron, Alexander; Grahame, George; DeBrosse, Suzanne D; Hoppel, Charles L; Kerr, Douglas S; Wanders, Ronald J A

    2017-04-01

    Mutations in ECHS1 result in short-chain enoyl-CoA hydratase (SCEH) deficiency which mainly affects the catabolism of various amino acids, particularly valine. We describe a case compound heterozygous for ECHS1 mutations c.836T>C (novel) and c.8C>A identified by whole exome sequencing of proband and parents. SCEH deficiency was confirmed with very low SCEH activity in fibroblasts and nearly absent immunoreactivity of SCEH. The patient had a severe neonatal course with elevated blood and cerebrospinal fluid lactate and pyruvate concentrations, high plasma alanine and slightly low plasma cystine. 2-Methyl-2,3-dihydroxybutyric acid was markedly elevated as were metabolites of the three branched-chain α-ketoacids on urine organic acids analysis. These urine metabolites notably decreased when lactic acidosis decreased in blood. Lymphocyte pyruvate dehydrogenase complex (PDC) activity was deficient, but PDC and α-ketoglutarate dehydrogenase complex activities in cultured fibroblasts were normal. Oxidative phosphorylation analysis on intact digitonin-permeabilized fibroblasts was suggestive of slightly reduced PDC activity relative to control range in mitochondria. We reviewed 16 other cases with mutations in ECHS1 where PDC activity was also assayed in order to determine how common and generalized secondary PDC deficiency is associated with primary SCEH deficiency. For reasons that remain unexplained, we find that about half of cases with primary SCEH deficiency also exhibit secondary PDC deficiency. The patient died on day-of-life 39, prior to establishing his diagnosis, highlighting the importance of early and rapid neonatal diagnosis because of possible adverse effects of certain therapeutic interventions, such as administration of ketogenic diet, in this disorder. There is a need for better understanding of the pathogenic mechanisms and phenotypic variability in this relatively recently discovered disorder. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Concerted interaction between pnicogen and halogen bonds in XCl-FH2P-NH3 (X=F, OH, CN, NC, and FCC).

    Science.gov (United States)

    Li, Qing-Zhong; Li, Ran; Liu, Xiao-Feng; Li, Wen-Zuo; Cheng, Jian-Bo

    2012-04-10

    We analyze the interplay between pnicogen-bonding and halogen-bonding interactions in the XCl-FH(2)P-NH(3) (X=F, OH, CN, NC, and FCC) complex at the MP2/aug-cc-pVTZ level. Synergetic effects are observed when pnicogen and halogen bonds coexist in the same complex. These effects are studied in terms of geometric and energetic features of the complexes. Natural bond orbital theory and Bader's theory of "atoms in molecules" are used to characterize the interactions and analyze their enhancement with varying electron density at critical points and orbital interactions. The physical nature of the interactions and the mechanism of the synergetic effects are studied using symmetry-adapted perturbation theory. By taking advantage of all the aforementioned computational methods, the present study examines how both interactions mutually influence each other.

  10. Use of scaled external correlation, a double many-body expansion, and variational transition state theory to calibrate a potential energy surface for FH2

    Science.gov (United States)

    Lynch, Gillian C.; Steckler, Rozeanne; Varandas, Antonio J. C.; Truhlar, Donald G.; Schwenke, David W.

    1991-01-01

    New ab initio results and a double many-body expansion formalism have been used to parameterize a new FH2 potential energy surface with improved properties near the saddle point and in the region of long-range attraction. The functional form of the new surface includes dispersion forces by a double many-body expansion. Stationary point properties for the new surface are calculated along with the product-valley barrier maxima of vibrationally adiabatic potential curves for F + H2 - HF(nu-prime = 3) + H, F + HD - HF(nu-prime = 3) + D, and F + D2 - DF(nu-prime = 4) + D. The new surface should prove useful for studying the effect on dynamics of a low, early barrier with a wide, flat bend potential.

  11. Evaluation of the immune response of male and female rats vaccinated with cDNA encoding a cysteine proteinase of Fasciola hepatica (FhPcW1).

    Science.gov (United States)

    Wesołowska, Agnieszka; Norbury, Luke J; Januszkiewicz, Kamil; Jedlina, Luiza; Jaros, Sławomir; Zawistowska-Deniziak, Anna; Zygner, Wojciech; Wędrychowicz, Halina

    2013-06-01

    Not only do males and females of many species vary in their responses to certain parasitic infections, but also to treatments such as vaccines. However, there are very few studies investigating differences among sexes following vaccination and infection. Here we demonstrate that female Sprague-Dawley rats vaccinated with cDNA encoding a recently discovered cysteine proteinase of Fasciola hepatica (FhPcW1) develop considerably lower liver fluke burdens after F. hepatica infection than their male counterparts. This is accompanied by differences in the course of their immune responses which involve different eosinophil and monocyte responses throughout the study as well as humoral responses. It is evident that host gender influences the outcome of parasitic infections after vaccination and research on both sexes should be considered when developing new treatments against parasites.

  12. FH Tulsa-1 and -2: Two unique alleles for familial hypercholesterolemia presenting in an affected two-year-old African-American male

    Energy Technology Data Exchange (ETDEWEB)

    Blackett, P.R.; Altmiller, D.H. [Univ. of Oklahoma Health Services Center, Oklahoma City, OK (United States); Jelley, D. [Childrens Medical Center, Tulsa, OK (United States); Wilson, D.P. [Driscoll Children`s Hospital, Corpus Christi, TX (United States)

    1995-11-20

    A two-year-old African American boy presented with cutaneous xanthomata and extreme hypercholesterolemia. Subsequent studies revealed that the LDL-cholesterol was 1,001 mg/dl and apoB 507 mg/dl. LDL-receptor activity was almost undetectable, which is compatible with the finding of two newly described defective alleles on exon 4 of the LDL-receptor gene coding for part of the ligand-binding domain. One allele contained a 21 base-pair insertion from codon 200 to 207 whereas the other had a point mutation at codon 207. The rarity of genes for FH reported in individuals of African ancestry is discussed. 16 refs., 2 figs., 2 tabs.

  13. Production of δ-decalactone from linoleic acid via 13-hydroxy-9(Z)-octadecenoic acid intermediate by one-pot reaction using linoleate 13-hydratase and whole Yarrowia lipolytica cells.

    Science.gov (United States)

    Kang, Woo-Ri; Seo, Min-Ju; An, Jung-Ung; Shin, Kyung-Chul; Oh, Deok-Kun

    2016-05-01

    To produce δ-decalactone from linoleic acid by one-pot reaction using linoleate 13-hydratase with supplementation with whole Yarrowia lipolytica cells. Whole Y. lipolytica cells at 25 g l(-1) produced1.9 g l(-1) δ-decalactone from 7.5 g 13-hydroxy-9(Z)-octadecenoic acid l(-1) at pH 7.5 and 30 °C for 21 h. Linoleate 13-hydratase from Lactobacillus acidophilus at 3.5 g l(-1) with supplementation with 25 g Y. lipolytica cells l(-1) in one pot at 3 h produced 1.9 g l(-1) δ-decalactone from 10 g linoleic acid l(-1) via 13-hydroxy-9(Z)-octadecenoic acid intermediate at pH 7.5 and 30°C after 18 h, with a molar conversion yield of 31 % and productivity of 106 mg l(-1) h(-1). To the best of our knowledge, this is the first production of δ-decalactone using unsaturated fatty acid.

  14. Dating the origin of hepatitis B virus reveals higher substitution rate and adaptation on the branch leading to F/H genotypes.

    Science.gov (United States)

    Paraskevis, Dimitrios; Angelis, Konstantinos; Magiorkinis, Gkikas; Kostaki, Evangelia; Ho, Simon Y W; Hatzakis, Angelos

    2015-12-01

    The evolution of hepatitis B virus (HBV), particularly its origins and evolutionary timescale, has been the subject of debate. Three major scenarios have been proposed, variously placing the origin of HBV in humans and great apes from some million years to only a few thousand years ago (ka). To compare these scenarios, we analyzed 105 full-length HBV genome sequences from all major genotypes sampled globally. We found a high correlation between the demographic histories of HBV and humans, as well as coincidence in the times of origin of specific subgenotypes with human migrations giving rise to their host indigenous populations. Together with phylogenetic evidence, this suggests that HBV has co-expanded with modern humans. Based on the co-expansion, we conducted a Bayesian dating analysis to estimate a precise evolutionary timescale for HBV. Five calibrations were used at the origins of F/H genotypes, D4, C3 and B6 from respective indigenous populations in the Pacific and Arctic and A5 from Haiti. The estimated time for the origin of HBV was 34.1ka (95% highest posterior density interval 27.6-41.3ka), coinciding with the dispersal of modern non-African humans. Our study, the first to use full-length HBV sequences, places a precise timescale on the HBV epidemic and also shows that the "branching paradox" of the more divergent genotypes F/H from Amerindians is due to an accelerated substitution rate, probably driven by positive selection. This may explain previously observed differences in the natural history of HBV between genotypes F1 and A2, B1, and D. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Suppressor screen and phenotype analyses revealed an emerging role of the Monofunctional peroxisomal enoyl-CoA hydratase 2 in compensated cell enlargement

    Directory of Open Access Journals (Sweden)

    Mana eKatano

    2016-02-01

    Full Text Available Efficient use of seed nutrient reserves is crucial for germination and establishment of plant seedlings. Mobilizing seed oil reserves in Arabidopsis involves β-oxidation, the glyoxylate cycle, and gluconeogenesis, which provide essential energy and the carbon skeletons needed to sustain seedling growth until photoautotrophy is acquired. We demonstrated that H+-PPase activity is required for gluconeogenesis. Lack of H+-PPase in fugu5 mutants increases cytosolic pyrophosphate (PPi levels, which partially reduces sucrose synthesis de novo and inhibits cell division. In contrast, post-mitotic cell expansion in cotyledons was unusually enhanced, a phenotype called compensation. Therefore, it appears that PPi inhibits several cellular functions, including cell cycling, to trigger compensated cell enlargement (CCE. Here, we mutagenized fugu5-1 seeds with 12C6+ heavy-ion irradiation and screened mutations that restrain CCE to gain insight into the genetic pathway(s involved in CCE. We isolated A#3-1, in which cell size was severely reduced, but cell number remained similar to that of original fugu5-1. Moreover, cell number decreased in A#3-1 single mutant (A#3-1sm, similar to that of fugu5-1, but cell size was almost equal to that of the wild type. Surprisingly, A#3-1 mutation did not affect CCE in other compensation exhibiting mutant backgrounds, such as an3-4 and fugu2-1/fas1-6. Subsequent map-based cloning combined with genome sequencing and HRM curve analysis identified enoyl-CoA hydratase 2 (ECH2 as the causal gene of A#3-1. The above phenotypes were consistently observed in the ech2-1 allele and supplying sucrose restored the morphological and cellular phenotypes in fugu5-1, ech2-1, A#3-1sm, fugu5-1 ech2-1 and A#3-1;fugu5-1. Taken together, these results suggest that defects in either H+-PPase or ECH2 compromise cell proliferation due to defects in mobilizing stored lipids. In contrast, ECH2 alone likely promotes CCE during the post-mitotic cell

  16. Part I. Cobalt thiolate complexes modeling the active site of cobalt nitrile hydratase. Part II. Formation of inorganic nanoparticles on protein scaffolding in Escherichia coli glutamine synthetase

    Science.gov (United States)

    Kung, Irene Yuk Man

    Part I. A series of novel cobalt dithiolate complexes with mixed imine/amine ligand systems is presented here as electronic and structural models for the active site in the bacterial enzyme class, nitrile hydratase (NHase). Pentadentate cobalt(II) complexes with S2N 3 ligand environments are first studied as precursors to the more relevant cobalt(III) complexes. Adjustment of the backbone length by removal of a methylene group increases the reactivity of the system; whereas reduction of the two backbone imine bonds to allow free rotation about those bonds may decrease reactivity. Reactivity change due to the replacement of the backbone amine proton with a more sterically challenging methyl group is not yet clear. Upon oxidation, the monocationic pentadentate cobalt(III) complex, 1b, shows promising reactivity similar to that of NHase. The metal's open coordination site allows reversible binding of the endogenous, monoanionic ligands, N 3- and NCS-. Oxygenation of the thiolate sulfur atoms by exposure to O2 and H2O 2 produces sulfenate and sulfinate ligands in complex 8, which resembles the crystal structure of "deactivated" Fe NHase. However, its lack of reactivity argues against the oxygenated enzyme structure as the active form. Six-coordinate cobalt(III) complexes with S2N4 amine/amine ligand systems are also presented as analogues of previously reported iron(III) compounds, which mimic the spectroscopic properties of Fe NHase. The cobalt complexes do not seem to similarly model Co NHase. However, the S = 0 cobalt(III) center can be spectroscopically silent and difficult to detect, making comparison with synthetic models using common techniques hard. Part II. Dodecameric Escherichia coli glutamine synthetase mutant, E165C, stacks along its six-fold axis to produce tubular nanostructures in the presence of some divalent metal ions, as does the wild type enzyme. The centrally located, engineered Cys-165 residues appear to bind to various species and may serve as

  17. [EFFECTS OF MELATONIN ON THE ACONITATE HYDRATASE ACTIVITY, CONTENT OF LIPID PEROXIDATION PRODUCTS AND SOME NON-ENZYMATIC ANTIOXIDANTS IN THE BLOOD OF PATIENTS WITH TYPE 2 DIABETES MELLITUS COMPLICATED BY STEATOHEPATITIS].

    Science.gov (United States)

    Popov, S S; Pashkov, A N; Shul'gin, K K

    2015-01-01

    Type 2 diabetes mellitus complicated by steatohepatitis is accompanied by a decrease in aconitate hydratase activity, increase in the content of diene conjugates, decrease in the concentration of α-tocopherol, and change in the citrate level in the blood serum of patients, which is evidence of the development of oxidative stress as a result of the intensification of free radical oxidation of biosubstrates and decreasing degree of antioxidant defense of the organism. Combined therapy with melaxen provided a more significant change of the investigated parameters toward the norm (on the average by 36%, p 0.05) in comparison with basic treatment. This result was evidently associated with implementation of the antioxidant effect of melatonin, the level of which is corrected under the action of the drug employed.

  18. The Drosophila hnRNP F/H Homolog Glorund Uses Two Distinct RNA-Binding Modes to Diversify Target Recognition

    Energy Technology Data Exchange (ETDEWEB)

    Tamayo, Joel V.; Teramoto, Takamasa; Chatterjee, Seema; Hall, Traci M. Tanaka; Gavis, Elizabeth R.

    2017-04-01

    The Drosophila hnRNP F/H homolog, Glorund (Glo), regulates nanos mRNA translation by interacting with a structured UA-rich motif in the nanos 3' untranslated region. Glo regulates additional RNAs, however, and mammalian homologs bind G-tract sequences to regulate alternative splicing, suggesting that Glo also recognizes G-tract RNA. To gain insight into how Glo recognizes both structured UA-rich and G-tract RNAs, we used mutational analysis guided by crystal structures of Glo’s RNA-binding domains and identified two discrete RNA-binding surfaces that allow Glo to recognize both RNA motifs. By engineering Glo variants that favor a single RNA-binding mode, we show that a subset of Glo’s functions in vivo is mediated solely by the G-tract binding mode, whereas regulation of nanos requires both recognition modes. Our findings suggest a molecular mechanism for the evolution of dual RNA motif recognition in Glo that may be applied to understanding the functional diversity of other RNA-binding proteins.

  19. Stereochemical conversion of C3-vinyl group to 1-hydroxyethyl group in bacteriochlorophyll c by the hydratases BchF and BchV: adaptation of green sulfur bacteria to limited-light environments.

    Science.gov (United States)

    Harada, Jiro; Teramura, Misato; Mizoguchi, Tadashi; Tsukatani, Yusuke; Yamamoto, Ken; Tamiaki, Hitoshi

    2015-12-01

    Photosynthetic green sulfur bacteria inhabit anaerobic environments with very low-light conditions. To adapt to such environments, these bacteria have evolved efficient light-harvesting antenna complexes called as chlorosomes, which comprise self-aggregated bacteriochlorophyll c in the model green sulfur, bacterium Chlorobaculum tepidum. The pigment possess a hydroxy group at the C3(1) position that produces a chiral center with R- or S-stereochemistry and the C3(1) -hydroxy group serves as a connecting moiety for the self-aggregation. Chlorobaculum tepidum carries the two possible homologous genes for C3-vinyl hydratase, bchF and bchV. In the present study, we constructed deletion mutants of each of these genes. Pigment analyses of the bchF-inactivated mutant, which still has BchV as a sole hydratase, showed higher ratios of S-epimeric bacteriochlorophyll c than the wild-type strain. The heightened prevalence of S-stereoisomers in the mutant was more remarkable at lower light intensities and caused a red shift of the chlorosomal Qy absorption band leading to advantages for light-energy transfer. In contrast, the bchV-mutant possessing only BchF showed a significant decrease of the S-epimers and accumulations of C3-vinyl BChl c species. As trans- criptional level of bchV was upregulated at lower light intensity, the Chlorobaculum tepidum adapted to low-light environments by control of the bchV transcription. © 2015 The Authors. Molecular Microbiology published by John Wiley & Sons Ltd.

  20. NH4F/H3PO4体系中阳极氧化法制备TiO2纳米管阵列%Fabrication of TiO2 Nanotube Arrays via Electrochemical Anodization in NH4F/H3PO4 Electrolyte Solution System

    Institute of Scientific and Technical Information of China (English)

    李纲; 刘中清; 王磊; 卢静; 张昭

    2009-01-01

    以价廉的Ni板代替常用的Pt片为阴极,纯钛为阳极,采用电化学阳极氧化法在NH4F-H3PO4体系中制备出TiO2纳米管阵列.详细研究了制备参数(溶液酸度、氟离子浓度、外加电压和氧化时间)对所获纳米管阵列形貌的影响.采用场发射扫描电镜(FE-SEM)和X射线衍射(XRD)对样品的形貌和晶相结构进行了表征.在最优化的条件下,可以获得形貌规整、表面干净、有序的TiO2纳米管阵列.纳米管阵列的平均管径为60 nm.管长约530 nm.采用阳极氧化法制备的纳米管阵列是非晶态的.经400℃热处理2 h后,可以转变为锐钛矿相.实验结果还发现,经过热处理后,纳米管阵列变得更为有序,管径扩大至约95 nm.%TiO2 nanotube arrays were fabricated by anodization of titanium in aqueous electrolyte solution of NH4F+H3PO4 using a Nickel sheet of low cost as cathode instead of conventionally used noble Platinum. The effects of preparation parameters, i.e., concentration of H3PO4 and F-, applied voltage and anodization time, on the morphology of as-prepared nanotube arrays were systematically studied. Field emission scanning electron microscope(FE-SEM) and X-ray dittraction(XRD) analysis were carried out to characterize the morphology and structure of the samples. The results showed that the self-ordered TiO2 nanotube arrays with an average pore size of 60 nm and a length of 530 nm could be obtained under optimum conditions. The as-prepared nanotube arrays were amorphous and transformed to an anatase crystal structure after being annealed at 400 ℃ for 2 h. It was also found that the freshly-prepared nanotube arrays got more ordered after calcination, with a pore size of ca. 95 nm.

  1. Research of Applying DS/FH Hybrid Spread-spectrum Communication in Mine Mobile Communication System%DS/FH混合扩频通信应用于矿井移动通信系统的研究

    Institute of Scientific and Technical Information of China (English)

    谢艳辉; 孙福文

    2009-01-01

    矿井移动通信系统是矿井安全生产、抢险救灾的重要保障.为了提高矿井移动通信系统的可靠性和稳定性,文章提出将DS/FH混合扩频技术应用于矿井移动通信系统的方案,从理论上对DS/FH混合扩频技术进行了详细分析,在此基础上,基于Systemview建立了通信系统的仿真模型.仿真结果和系统的误码率特性分析证明了DS/FH混合扩频技术应用的可行性,为矿井移动通信的发展提供了重要的理论依据.%Mine mobile communication system is the important guarantee of mine safety production and emergency rescue and disaster relief. In order to improve the reliability and stability of mine mobile communication system, the paper put forward a scheme of applying DS/FH hybrid spread-spectrum communication in mine mobile communication system and theoretically made detailed analysis on DS/FH hybrid spread-spectrum communication technology. On the basis of the theory analysis, simulation model of the communication system was established based on Systemview. The simulation result and BER characteristics analysis proved the application feasibility of DS/FH hybrid spread-spectrum communication technology, which provides important theory basis for development of mine mobile communication.

  2. Degradation of the neonicotinoid insecticide acetamiprid via the N-carbamoylimine derivate (IM-1-2) mediated by the nitrile hydratase of the nitrogen-fixing bacterium Ensifer meliloti CGMCC 7333.

    Science.gov (United States)

    Zhou, Ling-Yan; Zhang, Long-Jiang; Sun, Shi-Lei; Ge, Feng; Mao, Shi-Yun; Ma, Yuan; Liu, Zhong-Hua; Dai, Yi-Jun; Yuan, Sheng

    2014-10-15

    The metabolism of the widely used neonicotinoid insecticide acetamiprid (ACE) has been extensively studied in plants, animals, soils, and microbes. However, hydration of the N-cyanoimine group in ACE to the N-carbamoylimine derivate (IM-1-2) by purified microbes, the enzyme responsible for this biotransformation, and further degradation of IM-1-2 have not been studied. The present study used liquid chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy to determine that the nitrogen-fixing bacterium Ensifer meliloti CGMCC 7333 transforms ACE to IM-1-2. CGMCC 7333 cells degraded 65.1% of ACE in 96 h, with a half-life of 2.6 days. Escherichia coli Rosetta (DE3) overexpressing the nitrile hydratase (NHase) from CGMCC 7333 and purified NHase converted ACE to IM-1-2 with degradation ratios of 97.1% in 100 min and 93.9% in 120 min, respectively. Interestingly, IM-1-2 was not further degraded by CGMCC 7333, whereas it was spontaneously hydrolyzed at the N-carbamoylimine group to the derivate ACE-NH, which was further converted to the derivative ACE-NH2. Then, ACE-NH2 was cleaved to the major metabolite IM-1-4. IM-1-2 showed significantly lower insecticidal activity than ACE against the aphid Aphis craccivora Koch. The present findings will improve the understanding of the environmental fate of ACE and the corresponding enzymatic mechanisms of degradation.

  3. Inducing Expression and Reaction Characteristic of Nitrile Hydratase from Rhodococcus sp. SHZ-1%Rhodococcus sp.SHZ-1腈水合酶的诱导表达和稳定性研究

    Institute of Scientific and Technical Information of China (English)

    王超; 张根林; 徐小琳; 李春

    2007-01-01

    Inducing expression and the reaction characteristic of nitrile hydratase (NHase) from Rhodococcus sp.SHZ-1 were investigated. The results showed that the expression of NHase was greatly enhanced with the cooperation of acrylonitrile and ammonium chloride as inducer in the medium and the specific activity of NHase was increased of 44%. Then the temperature, pH, concentration of acrylonitrile and acrylamide were evaluated, which affected the activity and reaction characteristic of NHase. It was found that the temperature and concentration of acrylamide were the most important factors for the catalyzation of NHase. The optimal catalysis temperature of NHase from Rhodococcus sp. SHZ-1 was 30℃, and the activation energy of the hydration of NHase was 90.2kJ·mol-1 in the temperature range from 5℃ to 30℃. Km of NHase was 0.095mol.L-1 using acrylonitrile(AN)as substrate, and NHase activity was inhibited seriously when acrylonitrile concentration was up to 40g·L-1, the substrate inhibition constant Ki is 0.283mol·L-1. Moreover, the NHase from Rhodococcus sp. SHZ-1 had very strong tolerance to acrylamide, in which the final concentration of acrylamide reached to 642g·L-1 and the residual activity of NHase still maintained 8.6% of the initial enzyme activity.

  4. Hereditary leiomyomatosis and renal cell cancer presenting as metastatic kidney cancer at 18 years of age : implications for surveillance

    NARCIS (Netherlands)

    van Spaendonck-Zwarts, Karin Y.; Badeloe, Sadhanna; Oosting, Sjoukje F.; Hovenga, Sjoerd; Semmelink, Harry J. F.; van Moorselaar, R. Jeroen A.; van Waesberghe, Jan Hein; Mensenkamp, Arjen R.; Menko, Fred H.

    2012-01-01

    Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant syndrome characterized by skin piloleiomyomas, uterine leiomyomas and papillary type 2 renal cancer caused by germline mutations in the fumarate hydratase (FH) gene. Previously, we proposed renal imaging for FH mutation

  5. Hereditary leiomyomatosis and renal cell cancer presenting as metastatic kidney cancer at 18 years of age: implications for surveillance

    NARCIS (Netherlands)

    Spaendonck-Zwarts, K.Y. van; Badeloe, S.; Oosting, S.F.; Hovenga, S.; Semmelink, H.J.; Moorselaar, R.J. van; Waesberghe, J.H. van; Mensenkamp, A.R.; Menko, F.H.

    2012-01-01

    Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant syndrome characterized by skin piloleiomyomas, uterine leiomyomas and papillary type 2 renal cancer caused by germline mutations in the fumarate hydratase (FH) gene. Previously, we proposed renal imaging for FH mutation

  6. 丙烯酰胺转化菌的分离筛选及其产酶条件%Screening of acrylamide bioconversion bacterium and of its nitrile hydratase producing conditions

    Institute of Scientific and Technical Information of China (English)

    孙先锋; 沈旭丰; 吕小明; 周飞

    2009-01-01

    A strain T3, which has the better ability of acrylamide bioconversion, was isolated from activated sludge in wastewater treatment system at an acrylic fiber factory. T3 is primarily identified as Rhodococcus sp. according to its mor-phological observation. The process conditions producing nitrile hydratase for T3 were investigated. The results indicated that optimal conditions are initial medium pH 7. 5, culture temperature 35℃ and culture time 72h; And the study also showed that 0. 05g/L Co2+ is very important to improving enzyme activity. Under the optimum fermentation conditions, the enzyme activity of T3 cell culture fluid may reaches its maximum value 128.3U/mg, which increased by 55. 1% than before.%从腈纶厂污水处理系统的活性污泥中分离和筛选到一株丙烯酰胺转化菌.经初步鉴定,菌株T3属于红球菌属(Rlwdococcus sp.).对菌株T3产生腈水合酶的最适条件进行研究,结果表明,该菌株的最适产酶条件为培养基初始pH值7.5,培养温度35℃,培养时间72h,同时加入0.05g/L Co2+也会明显提高酶活性.在最适产酶条件下,菌株,13培养液的最高比酶活可达128.3U/mg,比优化前提高55.1%.

  7. Neonization method for stopping, mean excitation energy, straggling, and for total and differential ionization cross sections of CH4, NH3, H2O and FH by impact of heavy projectiles

    Science.gov (United States)

    Montanari, C. C.; Miraglia, J. E.

    2014-01-01

    We propose a neonization method to deal with molecules composed by hydrides of the second row of the periodic table of elements: CH4, NH3, OH2 and FH. This method describes these ten-electron molecules as dressed atoms in a pseudo-spherical potential. We test it by covering most of the inelastic collisional magnitudes of experimental interest: ionization cross sections (total, single and double differential), stopping power, energy-loss straggling and mean excitation energy. To this end, the neonization method has been treated with different collisional formalisms, such as the continuum-distorted-wave-eikonal-initial-state, the first order Born, and the shell-wise local plasma approximations. We show that the present model reproduces the different empirical values with high reliability in the intermediate to high-energy region. We also include the expansion of the spherical wave functions in terms of Slater-type orbitals and the analytic expression for the spherical potentials. This makes it possible in the future to tackle present neonization strategy with other collisional models.

  8. 肝片吸虫 Fh8明显增强 STEC 的 Stx1可溶性表达及 Stx1单克隆抗体制备%Fasciola hepatica 8 Significantly Enhances Soluble Expression of Stx1 from STEC and Stx1 Monoclonal Antibody Preparation

    Institute of Scientific and Technical Information of China (English)

    张雪寒; 张碧成; 张强; 汪伟; 何孔旺

    2016-01-01

    Shiga toxin 1 (Stx1 ),AB5 pentamers protein,is one of major virulent factors of Shiga Toxin-produ-cing Escherichia coli (STEC).The N-terminal fragment of Stx1 A subunit encodes a signal peptide,and its C-termi-nal amino acid sequences presents high hydrophobicity and low immunogenicity by bioinformatics software analysis, and these features lead to expression failure and inclusion of target protein.In this study,our aim is to clone stx1 gene and express soluble protein for development of monoclonal antibodies against Stx1 A.The 21 0 bp of Fh8 gene from Fasciola hepatica was cloned into pCold Ⅰ with Nde Ⅰ and Xho Ⅰ,and the middle fragment between 73 -759 ntof stx1A subunit was amplified,fused with Fh8 gene to construct recombinant strain of BL21 (DE3)/pColdⅠ-Fh8-stx1.His-Fh8-stx1A was immunized Balb /c mice to prepare positive hybridomas and monoclonal antibodies by Sp2 /0 cell fusion screening.We successfully constructed a recombinant plasmid pCold Ⅰ-Fh8-stx1a,expressed His-Fh8-Stx1 A in prokaryotic cells in soluble form.Three stably secreting anti-Stx1 A monoclonal antibodies (McAb)of hybridoma cell lines were developed,one of them was used to prepare high titer ascites.Western Blot assay showed ascites after purified are able to react with recombinant His-Fh8-Stx1 A and Shiga toxin 1 crude ex-tract.We successfully prepared soluble Stx1 A protein with good antigenicity,and three monoclonal antibodies with high titers,these will lay substantial foundation for future study,i.e.developing sandwich ELISA and colloidal gold test strip to detect STEC.%志贺毒素1(Shiga toxin 1,Stx1),系五聚体蛋白,是产志贺毒素性大肠杆菌(Shiga Toxin-producing Escherichia coli,STEC)主要的毒素因子,但 Stx1体外极不易可溶性表达,旨在克隆和表达志贺毒素1(Shiga toxin 1,Stx1)A 亚基,体外获得可溶性表达的 Stx1,以研制单克隆抗体。生物信息学软件分析 Stx1 A 亚基氨基酸序列,Stx1 A1

  9. SAJAA JA Marfan' (Converte.fh9

    African Journals Online (AJOL)

    Studio G5

    dominant condition, with variable expression. The pathology is related to ... maintenance with isoflurane, while breathing spontaneously via a face mask. The procedure .... syndrome: clinical report and review of the literature. Clin. Dysmorphol.

  10. Study of the Glutaminase Inhibitor CB-839 in Solid Tumors

    Science.gov (United States)

    2016-08-18

    Solid Tumors; Triple-Negative Breast Cancer; Non Small Cell Lung Cancer; Renal Cell Carcinoma; Mesothelioma; Fumarate Hydratase (FH)-Deficient Tumors; Succinate Dehydrogenase (SDH)-Deficient Gastrointestinal Stromal Tumors (GIST); Succinate Dehydrogenase (SDH)-Deficient Non-gastrointestinal Stromal Tumors; Tumors Harboring Isocitrate Dehydrogenase-1 (IDH1) and IDH2 Mutations; Tumors Harboring Amplifications in the cMyc Gene

  11. http://www.aulamedica.es/fh/pdf/1129.pdf

    Directory of Open Access Journals (Sweden)

    R. López-Sepúlveda

    2014-01-01

    Full Text Available Purpose: To compare the safety profile of telaprevir (TLV and boceprevir (BOC with each other and with those described in clinical trials (CT. Material and methods: Retrospective multicenter observational study. Variables collected: age, sex, type of patient (naive, nonresponder or recurrent, fibroscan, Hb nadir, neutrophil and platelet count, presence of rash, anorectal discomfort, number of patients treated with erythropoiesis stimulating factors (EPO and colony stimulating factors granulocyte (G-CSF. Results: BOC vs CT: anemia (56.5% vs. 49%., Thrombocytopenia (56.5% vs 32%, p = 0.023. neutropenia (17.4% vs. 29.5%. Use of EPO (13% vs 43%;. p = 0.008, pruritus (13% vs. 21.1%, rash (16.1% vs. 8.7%, anorectal discomfort (4.3% vs. 0%, p = 0.0001, dysgeusia (47.8% vs. 37%. TLV vs. CT: anemia (51.2% vs. 32%, p = 0.014, neutropenia (2.3 vs 3.6%, thrombocytopenia (41.9% vs. 27.4%, p = 0.05, pruritus (39.5% vs 47, rash (16.3% vs 55%, P <0.001, anorectal discomfort (39.5% vs 26%, dysgeusia (14% vs. 9.5%. BOC vs TLV: anemia (56.5% vs 51.2%, neutropenia (17.4% vs 2.3%, thrombocytopenia (56.5% vs 41.9%, rash (8.7% vs 16.3%, pruritus (39.5% vs 13% and anorectal discomfort (4.3% vs 39.5%, P = 0.006, dysgeusia (14% vs 47.8%, P = 0.007, EPO (13% vs. 25.6%. GCSF was used for a patient treated with TLV. Conclusions: 1. BOC and TLV have shown a worse safety profile for anemia, thrombocytopenia and anorectal discomfort than those described in CT. 2. As in CT, anemia, neutropenia and thrombocytopenia were more common with BOC. Patients treated with TLV experienced more pruritus, rash and anorectal discomfort.

  12. http://www.aulamedica.es/fh/pdf/7860.pdf

    Directory of Open Access Journals (Sweden)

    Carmen Haro Márquez

    2015-01-01

    Full Text Available Purpose: To assess adherence and beliefs about long-term medicines for other chronic conditions among HIV-infected patients as well as to evaluate their relationship. Method: A cross-sectional study was conducted from may to july 2014 in HIV-infected patients treated with antiretroviral treatment (ART and ≥1 long-term medicines for other chronic diseases. The variables analysed in the study were demographics: sex, age, education, employment status, living situation; clinical: mode of transmission, HIV plasma viral load ,T-CD4+, CDC classification; and pharmacotherapeutics: type of ART, adherence to long-term medicines for other chronic conditions using the 4-item Morisky Medication Adherence (MMAS Scale. MMAS scores were dichotomised into adherent/non-adherent. The Beliefs about Medicines Questionnaires (BMQ was used to assess patients’ beliefs about the long-term medicines. The BMQ-Specific has two scales (necessity and concern with five questions each that uses a 5-point Likert scale. Internal consistency within BMQ scales was measured with Cronbach’s and their association with adherence was assessed with t-Student tests, using SPSS 20.0. Results: We included 126 patients (80.4% male, mean age 49.0}8.3. The mean of long-term medicines was 2.9}2.0. The percentage of non-adherent patients was 54.0%. 63.5% of patients had AIDS, that showed statistically significant relationship with non-adherence. Concerns were negatively related to self-reported adherence (14.6}5.7 vs. 12.1}6.1; p=0.019. No relationship between adherence and necessity was found (17.3}5.6 vs. 18.8}4.4; p=0.188. Internal consistency for BMQ-Specific was high (Cronbach’s =0.724. Conclusion: Higher concerns are associated with higher self-reported adherence to long-term medicines in HIV infected-patients

  13. http://www.aulamedica.es/fh/pdf/8547.pdf

    Directory of Open Access Journals (Sweden)

    Rosa María Damas Fuentes

    2015-01-01

    Full Text Available Objetive: To analyze the latex content of drugs in hospital formulary and establish possible therapeutic alternatives. Methods: All drugs susceptible of having latex were selected and written information was obtained from manufacturers. A therapeutic alternative was found for each of them, if possible. Results: Written information from manufacturer was obtained for 605 (97.9% and from label information for 8 of 632 selected drugs. For 43.9% of not safe drugs (total 57 on patients with latex allergy, a therapeutic alternative was found in hospital formulary. Conclusions: Knowing drugs having latex improve the prescription security, while the therapeutic alternatives chart eases the validation. The published data updates the scarce and variable information for patients and healthcare professionals.

  14. http://www.aulamedica.es/fh/pdf/10518.pdf

    Directory of Open Access Journals (Sweden)

    Marta García-Queiruga

    2016-05-01

    Full Text Available Objective: To assess the level of adherence to treatment with imatinib in patients with chronic myeloid leukaemia and its association with therapeutic response. Materials and methods: Study conducted on October, 2013 – March, 2014, including patients diagnosed with Chronic Myeloid Leukaemia on treatment with imatinib in the hospital. Therapeutic adherence was assessed through the standard Morisky-Green Questionnaire and the medication dispensing record. Those patients who did not complete 6 months of treatment and/or did not complete the questionnaire were excluded. Therapeutic response was assessed following clinical guidelines. The descriptive analysis of variables and correlation was conducted through Pearsons’s Chi-Square Test. Results: The study included 31 patients. When assessing the level of association between response variables and therapeutic adherence: 1. The highest molecular response was reached by 68.4% of those patients with high adherence, and by 75% of those patients with intermediate adherence. 2. Complete molecular response was achieved by 57.9% of patients with high adherence, and by 58.3% of patients with intermediate adherence. No statistically significant differences were found in response variables between patients with high and intermediate therapeutic adherence. No association was observed between level of adherence and therapeutic response. Conclusions: We cannot confirm that a different level of therapeutic adherence might have an impact on response to imatinib, though this should be taken into account in cases of therapeutic failure or sub-optimal response

  15. http://www.aulamedica.es/fh/pdf/10689.pdf

    Directory of Open Access Journals (Sweden)

    Marta García-Queiruga

    2017-03-01

    Full Text Available p>Purpose: To present the requirements, development, structure and results of an electronic interconsultation platform (e-Interconsultation for communication between primary and hospital care. Method: A working group was created and set out its purposes, working schedule, software requirements, the structure of the electronic platform, validation procedure, and its implementation. Once the software had been developed and validated and training sessions were conducted, the electronicplatform was launched in June 2015. Results: After 1 year of operation, a total of 321 electronic interconsultations had been made, 110 of which were referrals from hospital care to primary care in addition to 211 from primary to hospital care. The validation of prescriptions and the need for drug monitoring in primary care are among main reasons for consultation. Conclusions: The e-Interconsultation platform is a valid, efficient and user-friendly mean of consultation or patient referrals between both healthcare levels.

  16. Value of serum phosphopyruvate hydratase protein for the diagnosis of cerebral injuries in patients with brain malignant tumor%血清磷酸丙酮酸水合酶检测在颅内恶性肿瘤患者放射性脑损伤诊断中的价值

    Institute of Scientific and Technical Information of China (English)

    杜丽莉; 韩存芝; 荆结线; 赵先文; 田保国

    2012-01-01

    Objective To study the value of serum phosphopyruvate hydratase PH protein for the diagnosis of cerebral injuries in patients with brain malignant tumor.Methods Serum PH protein levels were detected by enzyme-linked immunosorbent assay in 56 patients with brain malignant tumor. Compare the differences among the status of cerebral injuries.And compare the differences among the patients with general with different radiotherapy methods 32 cases,three dimensional conformal radiothrapy 24 cases,and different peritumoral brain edema levels (cmild 18 cases, moderate ao cases severe 30 cases). Results Before radiotherapy the levels of serum PH protein in patients and the health control were (4.12±0.56),(4.66±0.62)μg/L,no significant differece(P>0.05).And there was also no significant difference between the before and after radiotherapy for the cerebroma,the levels were(7.84±0.72) μg/L,(t=3.89,P=0.001 ).The PH levels of general radiation therapy and three dimensional comformal radiotherapy were (13.59±0.92),(6.14±0.52)μg/L.There was cignificant difference(P=0.002) After radiotherapy,The levels of serum PH protein of the different dropsical degree,mild,moderate and severe were(4.47:±0.55),(6.17±0.62),(15.21±0.86) μg/L, respectively,showing significant difference (F=15.61,P=0.0001). The therapies influenced the serum PH levels (P<0.05)Conclusion High levels of serum PH protein are associated with severe cerebral injuries in brain malignant tumor.So high serum PH level may serve as an progressive predictor of the injury.%目的 研究血清磷酸丙酮酸水合酶(PH)在颅内恶性肿瘤患者放射性脑损伤早期诊断中的作用.方法 采用酶联免疫吸附试验检测56例颅内恶性肿瘤患者(脑转移瘤26例,脑肿瘤30例)在接受放射性治疗前、后的血清PH水平,比较其差异.同时比较颅内恶性肿瘤患者不同放疗方案(普通放疗组32例,三维适形放疗组24例)、瘤周水肿程度(轻度18例,中度20例,重度18

  17. [Molecular biology of renal cancer: bases for genetic directed therapy in advanced disease].

    Science.gov (United States)

    Maroto Rey, José Pablo; Cillán Narvaez, Elena

    2013-06-01

    There has been expansion of therapeutic options in the management of metastatic renal cell carcinoma due to a better knowledge of the molecular biology of kidney cancers. There are different tumors grouped under the term renal cell carcinoma, being clear cell cancer the most frequent and accounting for 80% of kidney tumors. Mutations in the Von Hippel-Lindau gene can be identified in up to 80% of sporadic clear cell cancer, linking a genetically inheritable disease where vascular tumors are frequent, with renal cell cancer. Other histologic types present specific alterations in molecular pathways, like c-MET in papillary type I tumors, and Fumarase Hydratase in papillary type II tumors. Identification of the molecular alteration for a specific tumor may offer an opportunity for treatment selection based on biomarkers, and, in the future, for developing an engineering designed genetic treatment.

  18. Incidental diagnosis of HLRCC following investigation for Asperger Syndrome: actionable and actioned.

    Science.gov (United States)

    Duong, Bich-Thu; Savarirayan, Ravi; Winship, Ingrid

    2016-01-01

    Incidental findings are inevitable as clinical research and practice transitions from a single gene approach to a genomic approach. A novel deletion of the Fumarate Hydratase (FH) gene was identified in a 22 year old male who underwent a molecular karyotype as part of an autism spectrum disorder research project. This unexpected result implies a predisposition to Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC), a rare, autosomal dominant condition and has unforeseen implications for him and his family. We review the typical features and management of HLRCC and discuss the challenges that face health professionals, as genetic testing advances and becomes more accessible.

  19. Implementation and development of portal authentication technology base on FH-AC system%基于FH-AC系统Portal认证的实现与开发

    Institute of Scientific and Technical Information of China (English)

    吴迪

    2015-01-01

    随着当今移动互联网的快速发展,WiFi设备成为人们生活当中不可缺少的组成部分,而传统的无线网络在接入稳定性和安全性方面有待进一步提高。为了解决上述问题,设计了基于FH⁃AC系统的Portal认证系统。该系统通过对原有Portal协议进行改进并且采用Socket/HTTP通信和CHAP认证技术等一系列技术来提升系统性能,使整个系统在使用过程中能够更快更稳定地接入当前无线网络,其系统安全性也得到进一步的提升。%With the rapid development of mobile Internet,WiFi equipments have already been a necessary part of every⁃one’s life. However,the traditional wireless network needs to be improved in terms of stability and security access. In order to solving these problems,Portal authentication system based on FH⁃AC system was designed. The system performance was en⁃hanced by improving the original Portal protocol,and using Socket/Http communications and CHAP authentication technology. The whole system is made to be accessed to the current wireless network more fast and more stably. Moreover,the system securi⁃ty has also been further improved.

  20. Structure of FH Sequence in Satelite FH Communication%卫星跳频通信中一种跳频序列的构造

    Institute of Scientific and Technical Information of China (English)

    马世旺; 陆锐敏; 邹攀红

    2015-01-01

    跳频序列的设计是跳频通信的关键技术之一,采用直接式算法构造跳频序列,使用m序列对4分段Tent映射产生的序列进行重新排列.仿真结果表明,相对于直接采用4分段Tent映射产生的跳频序列,构造的跳频序列在保持均衡性和复杂度的条件下对独立性、汉明相关性、平均跳频间隔等方面的性能都有不同程度的提升,其中独立性的性能提升尤为突出.

  1. Analysis of a MULE-cyanide hydratase gene fusion in Verticillium dahliae

    Science.gov (United States)

    The genome of the phytopathogenic fungus Verticillium dahliae encodes numerous Class II “cut-and-paste” transposable elements, including those of a small group of MULE transposons. We have previously identified a fusion event between a MULE transposon sequence and sequence encoding a cyanide hydrata...

  2. Production of D-malate by maleate hydratase from Pseudomonas pseudoalcaligenes.

    NARCIS (Netherlands)

    Werf, van der M.J.

    1994-01-01

    The biological activity of a chiral compound with respect to its pharmaceutical and agrochemical activity, flavour and taste can vary dramatically for the different enantiomers. Especially when using chiral compounds for pharmaceutical or agrochemical applications, the presence of the "wrong" stereo

  3. Isolation and characterization of Aconitate hydratase 4 (Aco4) from soybean

    Science.gov (United States)

    Aconitase catalyzes the reversible isomerization of two tricarboxylic acids citrate and isocitrate during the Krebs cycle. Five aconitase genes namely Aco1, Aco2, Aco3, Aco4 and Aco5 have been identified in soybean. Previously, Aco4 was mapped on chromosome 11. The purpose of this investigation was ...

  4. Biotransformation of benzonitrile herbicides via the nitrile hydratase-amidase pathway in rhodococci.

    Science.gov (United States)

    Veselá, Alicja B; Pelantová, Helena; Sulc, Miroslav; Macková, Martina; Lovecká, Petra; Thimová, Markéta; Pasquarelli, Fabrizia; Pičmanová, Martina; Pátek, Miroslav; Bhalla, Tek Chand; Martínková, Ludmila

    2012-12-01

    The aim of this work was to determine the ability of rhodococci to transform 3,5-dichloro-4-hydroxybenzonitrile (chloroxynil), 3,5-dibromo-4-hydroxybenzonitrile (bromoxynil), 3,5-diiodo-4-hydroxybenzonitrile (ioxynil) and 2,6-dichlorobenzonitrile (dichlobenil); to identify the products and determine their acute toxicities. Rhodococcus erythropolis A4 and Rhodococcus rhodochrous PA-34 converted benzonitrile herbicides into amides, but only the former strain was able to hydrolyze 2,6-dichlorobenzamide into 2,6-dichlorobenzoic acid, and produced also more of the carboxylic acids from the other herbicides compared to strain PA-34. Transformation of nitriles into amides decreased acute toxicities for chloroxynil and dichlobenil, but increased them for bromoxynil and ioxynil. The amides inhibited root growth in Lactuca sativa less than the nitriles but more than the acids. The conversion of the nitrile group may be the first step in the mineralization of benzonitrile herbicides but cannot be itself considered to be a detoxification.

  5. SAJAA MarApr 19-24 Con.fh9

    African Journals Online (AJOL)

    Studio G5

    rocuronium for fast and safe tracheal intubation (similar to succinylcholine). ... The distance chin-thyroid was > 60 mm, the distance chin-hyoid. > 40 mm ..... 4 Baykara N, Solak M, Toker K. Predicting recovery from deep neuromuscular block by ...

  6. Treatability studies on F/H Area ``hot spot`` groundwater composite. Revision 1

    Energy Technology Data Exchange (ETDEWEB)

    Bibler, J.P.

    1993-08-30

    The data found in this report were collected from laboratory experiments that were conducted to characterize the ``hot spot`` groundwater before and after pH adjustment, to describe the settling behavior and particle size of the precipitates resulting from pH adjustment, and to compare several methods of pH adjustment. Although Decontamination Factors (DFs) for all precipitating agents are similar, the best settling characteristics and most manageable precipitate were produced when 25 ppM Al{sup 3+} was introduced as Al{sub 2}(SO{sub 4}){sub 3} and pH adjustment was made from 6--8 with NaOH. The resulting precipitate will not be a hazardous secondary waste.

  7. Performance of Adaptive Antennas in FH-GSM Using Conventional Beamforming

    DEFF Research Database (Denmark)

    Mogensen, Preben Elgaard; Leth-Espensen, P; Zetterberg, P.

    2000-01-01

    This paper presents the performance of adaptive antennas in a 1/3 reuse frequency hopping GSM network using conventional beamforming. It mainly focuses on C/I improvement for the purpose of capacity enhancement. The performance evaluation has been conducted by means of network computer simulations...... for low azimuth spread values. For large values of azimuth spread (relative to the antenna beamwidth), the performance gain is reduced significantly. For an azimuth spread of 10 degrees-12 degrees, which has been measured in urban macro-cellular environments, the C/I gain for M = 8 is reduced to approx. 5...

  8. Angewandte Forschung an Fachhochschulen im Verbund mit der Wirtschaft (FH3)

    DEFF Research Database (Denmark)

    Kulicke, Marianne; Zimmermann, Ann; Kroll, Henning;

    2008-01-01

    Toothed whales use echolocation to locate and track prey. Most knowledge of toothed whale echolocation stems from studies on trained animals, and little is known about how toothed whales regulate and use their biosonar systems in the wild. Recent research suggests that an automatic gain control m...

  9. A steady tracking technology adopted to fast FH/BPSK signal under satellite channel

    Science.gov (United States)

    Guo, SuLi; Lou, Zhigang; Wang, XiDuo; Xia, ShuangZhi

    2015-07-01

    In order to survive under the conditions with great jamming and interference, fast frequency hopped signal are employed in satellite communication system. This paper discusses the nonlinear phases induced by the equipment and atmosphere, and their influence on the FFH/BPSK tracking loop. Two methods are developed including compensating phase which is based on channel estimation and compensating Doppler frequency based on velocity normalization. Simulation results for a real circuit with proper parameters shows that the degradation due to the demodulation of frequency-hopped is only a fraction of one dB in an AWGN environment under satellite channel.

  10. Data of evolutionary structure change: 1FH5H-1F8TH [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available sequence>YCARD----AMDYW ure>EEEEE---- > H 1F8TH YCASYDDYTWFTYW ...>EEEEE EEE > ATOM 2442 CA TYR H 91 35.896 -66.234 42....H 1F8TH ITYSG-STGYN ...>EE -EEEEE> ATOM 2104 CA ILE H 51 40.678 -5

  11. Growth performance of FH male calves fed milk replacer made of local ingredients for veal production

    Directory of Open Access Journals (Sweden)

    Elizabeth Wina

    1996-06-01

    Full Text Available The research was designed to evaluate the local feedstuff to be used in milk replacer (MP and its utilization for veal production . Fifteen male calves of the Friesian Holstein breed, 5-6 weeks old were used in the experiment lasting for 8 weeks. The treatments were (i commercial milk replacer (SPK, (ii local (SPL-1 and (iii mixture ofSPK and SPL-1 (SPKL. The amount of dry matter offerred is 3 % of live weight each and was given twice daily (in the morning and late afternoon . Elephant grass (0 .5 kg was offerred at noon . The observed parameters were average daily gain (ADG, dry matter (DM and crude protein (CP intake, carcass percentage, weight of carcass components, physical and chemical characteristics of meat. The results show that feed consumptions were 1,981, 1,613 and 1,050 g1day and ADGs were 897,496 and 73 g for treatments SPK, SPKL and SPL, respectively . Carcass percentage was 56.84 and 58 .76% with protein content was 87 .47 and 84 .78% for treatments SPK and SPKL, respectively . The benefit per head of calf was higher when fed mixture of local and commercial MP than fed only commercial MP but the benefit per day was higher when fed commercial MP than mixture of local and commercial. In conclusion, a cheaper milk replacer with less milk protein content resulting in a lower gain but higher benefit per head of calf than a commercial milk replacer containing high milk protein content

  12. FLUOR HANFORD (FH) MAKES CLEANUP A REALITY IN NEARLY 11 YEARS AT HANFORD

    Energy Technology Data Exchange (ETDEWEB)

    GERBER, M.S.

    2007-05-24

    For nearly 11 years, Fluor Hanford has been busy cleaning up the legacy of nuclear weapons production at one of the Department of Energy's (DOE'S) major sites in the United States. As prime nuclear waste cleanup contractor at the vast Hanford Site in southeastern Washington state, Fluor Hanford has changed the face of cleanup. Fluor beginning on October 1, 1996, Hanford Site cleanup was primarily a ''paper exercise.'' The Tri-Party Agreement, officially called the Hanford Federal Facility Agreement and Consent Order - the edict governing cleanup among the DOE, U.S. Environmental Protection Agency (EPA) and Washington state - was just seven years old. Milestones mandated in the agreement up until then had required mainly waste characterization, reporting, and planning, with actual waste remediation activities off in the future. Real work, accessing waste ''in the field'' - or more literally in huge underground tanks, decaying spent fuel POO{approx}{approx}S, groundwater, hundreds of contaminated facilities, solid waste burial grounds, and liquid waste disposal sites -began in earnest under Fluor Hanford. The fruits of labors initiated, completed and/or underway by Fluor Hanford can today be seen across the site. Spent nuclear fuel is buttoned up in secure, dry containers stored away from regional water resources, reactive plutonium scraps are packaged in approved containers, transuranic (TRU) solid waste is being retrieved from burial trenches and shipped offsite for permanent disposal, contaminated facilities are being demolished, contaminated groundwater is being pumped out of aquifers at record rates, and many other inventive solutions are being applied to Hanford's most intransigent nuclear wastes. (TRU) waste contains more than 100 nanocuries per gram, and contains isotopes higher than uranium on the Periodic Table of the Elements. (A nanocurie is one-billionth of a curie.) At the same time, Fluor Hanford has dramatically improved safety records, and cost effectively maintained and streamlined infrastructure and equipment that is impossibly old and in many cases ''extinct'' in terms of spare parts and vendor support. The story of Fluor's achievements at the Hanford Site - the oldest and most productive plutonium site in the world - is both inspiring and instructive.

  13. TCA Cycle Defects and Cancer: When Metabolism Tunes Redox State

    Directory of Open Access Journals (Sweden)

    Simone Cardaci

    2012-01-01

    Full Text Available Inborn defects of the tricarboxylic acid (TCA cycle enzymes have been known for more than twenty years. Until recently, only recessive mutations were described which, although resulted in severe multisystem syndromes, did not predispose to cancer onset. In the last ten years, a causal role in carcinogenesis has been documented for inherited and acquired alterations in three TCA cycle enzymes, succinate dehydrogenase (SDH, fumarate hydratase (FH, and isocitrate dehydrogenase (IDH, pointing towards metabolic alterations as the underlying hallmark of cancer. This paper summarizes the neoplastic alterations of the TCA cycle enzymes focusing on the generation of pseudohypoxic phenotype and the alteration of epigenetic homeostasis as the main tumor-promoting effects of the TCA cycle affecting defects. Moreover, we debate on the ability of these mutations to affect cellular redox state and to promote carcinogenesis by impacting on redox biology.

  14. A systems approach to predict oncometabolites via context-specific genome-scale metabolic networks.

    Directory of Open Access Journals (Sweden)

    Hojung Nam

    2014-09-01

    Full Text Available Altered metabolism in cancer cells has been viewed as a passive response required for a malignant transformation. However, this view has changed through the recently described metabolic oncogenic factors: mutated isocitrate dehydrogenases (IDH, succinate dehydrogenase (SDH, and fumarate hydratase (FH that produce oncometabolites that competitively inhibit epigenetic regulation. In this study, we demonstrate in silico predictions of oncometabolites that have the potential to dysregulate epigenetic controls in nine types of cancer by incorporating massive scale genetic mutation information (collected from more than 1,700 cancer genomes, expression profiling data, and deploying Recon 2 to reconstruct context-specific genome-scale metabolic models. Our analysis predicted 15 compounds and 24 substructures of potential oncometabolites that could result from the loss-of-function and gain-of-function mutations of metabolic enzymes, respectively. These results suggest a substantial potential for discovering unidentified oncometabolites in various forms of cancers.

  15. ДОСЛІДЖЕННЯ ХІМІЧНИХ ПЕРЕТВОРЕНЬ У ВУГЛЕВОДНЕВОМУ СКЛАДІ РОБОЧОЇ РІДИНИ «ГІДРОНІКОЙЛ» FH-51

    Directory of Open Access Journals (Sweden)

    А.М. Соловйов

    2007-02-01

    Full Text Available  Подано результати дослідження структурно-групового складу зразків товарної і після нальоту 3600 год авіаційної гідравлічної рідини «Гідронікойл» FH-51 методами дистиляції та рідинної хроматографії. Отримані результати досліджень показали наявність перебігу процесів термоокиснювальної деструкції вуглеводнів, що спричиняє суттєве зниження якості робочої рідини і погіршення її експлуатаційних властивостей. Підтверджено, що наявну систему контролю якості гідравлічних рідин науково не обґрунтовано і вона не забезпечує сучасних високих вимог до збереження експлуатаційної якості робочої рідини для гідравлічної системи літака. Актуальним постає завдання удосконалення існуючої системи  контролю якості гідравлічних рідин під час експлуатації.

  16. Diseño y realización de un emisor-receptor FH-MFSK (II)

    OpenAIRE

    Agustí Comes, Ramon

    1988-01-01

    En este artículo se describen las principales características de un emisor-receptor que utiliza una técnica de saltos de frecuencia a gran velocidad con SAW dispersivos. Se introduce un recuperador de sincronismo de salto que utiliza un control automático de probabilidad de falsa alarma para combatir la incertidumbre en el valor de la potencia de las señales interferentes recibidas. Peer Reviewed

  17. Diseño y realización de un emisor-receptor FH-MFSK (I)

    OpenAIRE

    Agustí Comes, Ramon

    1988-01-01

    En este artículo se describen las principales características de un emisor-receptor que utiliza una técnica de saltos de frecuencia a gran velocidad: con SAW dispersivos. Se introduce un recuperador de sincronismo de salto que utiliza un control automático de probabilidad de falsa alarma para combatir la incertidumbre en el valor de la potencia de las señales interferentes recibidas. Peer Reviewed

  18. 短波CHESS跳频系统的性能分析%The Performance Analysis of HF CHESS FH System

    Institute of Scientific and Technical Information of China (English)

    刘忠英; 姚富强

    2000-01-01

    以提高短波数据传输速率为主要目的的CHESS系统及技术目前受到普遍关注.先介绍了CHESS系统,对其核心技术--差分跳频的原理、相应G函数跳频图案的性能进行了研究,并对其性能进行了检验,得出了一些有益的结论.

  19. Chaotic FH sequences based on baker transform%基于Baker变换的混沌跳频序列

    Institute of Scientific and Technical Information of China (English)

    甘良才; 易丹

    2000-01-01

    基于Baker变换,采用一类分段线性混沌映射,提出了一种混沌跳频序列的产生方法.从理论上分析了该混沌跳频序列的平衡性,跳频间隔和最大汉明相关性,并进行了数值模拟.结果表明:理论分析与数值模拟结果一致,该序列具有良好的性能.

  20. Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF.

    Science.gov (United States)

    Koivunen, Peppi; Hirsilä, Maija; Remes, Anne M; Hassinen, Ilmo E; Kivirikko, Kari I; Myllyharju, Johanna

    2007-02-16

    The stability and transcriptional activity of the hypoxia-inducible factors (HIFs) are regulated by two oxygen-dependent events that are catalyzed by three HIF prolyl 4-hydroxylases (HIF-P4Hs) and one HIF asparaginyl hydroxylase (FIH). We have studied possible links between metabolic pathways and HIF hydroxylases by analyzing the abilities of citric acid cycle intermediates to inhibit purified human HIF-P4Hs and FIH. Fumarate and succinate were identified as in vitro inhibitors of all three HIF-P4Hs, fumarate having K(i) values of 50-80 microM and succinate 350-460 microM, whereas neither inhibited FIH. Oxaloacetate was an additional inhibitor of all three HIF-P4Hs with K(i) values of 400-1000 microM and citrate of HIF-P4H-3, citrate being the most effective inhibitor of FIH with a K(i) of 110 microM. Culturing of cells with fumarate diethyl or dimethyl ester, or a high concentration of monoethyl ester, stabilized HIF-1alpha and increased production of vascular endothelial growth factor and erythropoietin. Similar, although much smaller, changes were found in cultured fibroblasts from a patient with fumarate hydratase (FH) deficiency and upon silencing FH using small interfering RNA. No such effects were seen upon culturing of cells with succinate diethyl or dimethyl ester. As FIH was not inhibited by fumarate, our data indicate that the transcriptional activity of HIF is quite high even when binding of the coactivator p300 is prevented. Our data also support recent suggestions that the increased fumarate and succinate levels present in the FH and succinate dehydrogenase-deficient tumors, respectively, can inhibit the HIF-P4Hs with consequent stabilization of HIF-alphas and effects on tumor pathology.

  1. Structure and mechanism of a nonhaem-iron SAM-dependent C-methyltransferase and its engineering to a hydratase and an O-methyltransferase.

    Science.gov (United States)

    Zou, Xiao-Wei; Liu, Yu-Chen; Hsu, Ning-Shian; Huang, Chuen-Jiuan; Lyu, Syue-Yi; Chan, Hsiu-Chien; Chang, Chin-Yuan; Yeh, Hsien-Wei; Lin, Kuan-Hung; Wu, Chang-Jer; Tsai, Ming-Daw; Li, Tsung-Lin

    2014-06-01

    In biological systems, methylation is most commonly performed by methyltransferases (MTs) using the electrophilic methyl source S-adenosyl-L-methionine (SAM) via the S(N)2 mechanism. (2S,3S)-β-Methylphenylalanine, a nonproteinogenic amino acid, is a building unit of the glycopeptide antibiotic mannopeptimycin. The gene product of mppJ from the mannopeptimycin-biosynthetic gene cluster is the MT that methylates the benzylic C atom of phenylpyruvate (Ppy) to give βMePpy. Although the benzylic C atom of Ppy is acidic, how its nucleophilicity is further enhanced to become an acceptor for C-methylation has not conclusively been determined. Here, a structural approach is used to address the mechanism of MppJ and to engineer it for new functions. The purified MppJ displays a turquoise colour, implying the presence of a metal ion. The crystal structures reveal MppJ to be the first ferric ion SAM-dependent MT. An additional four structures of binary and ternary complexes illustrate the molecular mechanism for the metal ion-dependent methyltransfer reaction. Overall, MppJ has a nonhaem iron centre that bind, orients and activates the α-ketoacid substrate and has developed a sandwiched bi-water device to avoid the formation of the unwanted reactive oxo-iron(IV) species during the C-methylation reaction. This discovery further prompted the conversion of the MT into a structurally/functionally unrelated new enzyme. Through stepwise mutagenesis and manipulation of coordination chemistry, MppJ was engineered to perform both Lewis acid-assisted hydration and/or O-methyltransfer reactions to give stereospecific new compounds. This process was validated by six crystal structures. The results reported in this study will facilitate the development and design of new biocatalysts for difficult-to-synthesize biochemicals.

  2. Peroxisomal multifunctional enzyme type 2 from the fruitfly: dehydrogenase and hydratase act as separate entities, as revealed by structure and kinetics.

    Science.gov (United States)

    Haataja, Tatu J K; Koski, M Kristian; Hiltunen, J Kalervo; Glumoff, Tuomo

    2011-05-01

    All of the peroxisomal β-oxidation pathways characterized thus far house at least one MFE (multifunctional enzyme) catalysing two out of four reactions of the spiral. MFE type 2 proteins from various species display great variation in domain composition and predicted substrate preference. The gene CG3415 encodes for Drosophila melanogaster MFE-2 (DmMFE-2), complements the Saccharomyces cerevisiae MFE-2 deletion strain, and the recombinant protein displays both MFE-2 enzymatic activities in vitro. The resolved crystal structure is the first one for a full-length MFE-2 revealing the assembly of domains, and the data can also be transferred to structure-function studies for other MFE-2 proteins. The structure explains the necessity of dimerization. The lack of substrate channelling is proposed based on both the structural features, as well as by the fact that hydration and dehydrogenation activities of MFE-2, if produced as separate enzymes, are equally efficient in catalysis as the full-length MFE-2.

  3. Nitrile, amide and temperature effects on amidase-kinetics during acrylonitrile bioconversion by nitrile-hydratase/amidase in situ cascade system.

    Science.gov (United States)

    Cantarella, Laura; Gallifuoco, Alberto; Spera, Agata; Cantarella, Maria

    2013-08-01

    In this study the amidase kinetics of an in situ NHase/AMase cascade system was explored as a function of operational parameters such as temperature, substrate concentration and product formation. The results indicated that controlling amidase inactivation, during acrylonitrile bioconversion, makes it possible to recover the intermediate product of the two-step reaction in almost a pure form, without using purified enzyme. It has been demonstrated, in long-term experiments performed in continuous stirred UF-membrane bioreactors, that amidase is kinetically controlled by its proper substrate, depending on the structure, and by acrylonitrile. Using acrylamide, AMase-stability is temperature dependent (5°C, kd=0.008 h(-1); 30°C kd=0.023 h(-1)). Using benzamide, amidase is thermally stable up to 50°C and no substrate inhibition/inactivation occurs. With acrylonitrile, AMase-activity and -stability remain unchanged at concentrations <200 mM but at 200 mM, 35°C, after 70 h process, 90% irreversible inactivation occurs as no AMase-activity on benzamide revives. Copyright © 2013 Elsevier Ltd. All rights reserved.

  4. Cloning, sequencing, and expression of nitrile hydratase gene of mutant 4D strain of Rhodococcus rhodochrous PA 34 in E. coli.

    Science.gov (United States)

    Pratush, Amit; Seth, Amit; Bhalla, T C

    2012-10-01

    The NHase encoding gene of mutant 4D was isolated by PCR amplification. The NHase gene of mutant 4D was successfully cloned and expressed in Escherichia coli by using Ek/LIC Duet cloning kits (Novagen). For the active expression of the NHase gene, the co-expression of small cobalt transporter gene (P-protein gene) has also been co-expressed with NHase gene E. coli. The nucleotide sequence of this NHase gene revealed high homology with the H-NHase of Rhodococcus rhodochrous J1. The recombinant E. coli cells showed higher NHase activity (5.9 U/mg dcw) as compared to the wild (4.1 U/mg dcw) whereas it is less than the mutant strain (8.4 U/mg dcw). Addition of cobalt ion in Luria-Bertani medium is needed up to a very small concentration (0.4 mM) for NHase activity. The recombinant E. coli exhibited maximum NHase activity at 6 h of incubation and was purified with a yield of 56 % with specific activity of 37.1 U/mg protein.

  5. Properties of Square-Pyramidal Alkyl-Thiolate FeIII-Complexes, Including an Analogue of the Unmodified Form of Nitrile Hydratase

    Science.gov (United States)

    Lugo-Mas, Priscilla; Taylor, Wendy; Schweitzer, Dirk; Theisen, Roslyn M.; Xu, Liang; Shearer, Jason; Swartz, Rodney D.; Gleaves, Morgan C.; DiPasquale, Antonio; Kaminsky, Werner; Kovacs, Julie A.

    2009-01-01

    The syntheses and structures of three new coordinatively unsaturated, monomeric, square pyramidal thiolate-ligated Fe(III) complexes are described, [FeIII((tame—N3)S2Me2)]+ (1), [FeIII(Et—N2S2Me2)(py)]1- (3), and [FeIII((tame—N2S)S2Me2)]2- (15). The anionic bis-carboxamide, tris-thiolate N2S3 coordination sphere of 15 is potentially similar to that of the yet-to-be characterized unmodified form of NHase. Comparison of the magnetic and reactivity properties of these reveals how anionic charge build-up (from cationic 1 to anionic 3 and dianionic 15) and spin-state influence apical ligand affinity. For all of the ligand-field combinations examined, an intermediate S= 3/2 spin-state was shown to be favored by a strong N2S2 basal plane ligand-field, and this was found to reduce the affinity for apical ligands, even when they are built-in. This is in contrast to the post-translationaly modified NHase active site, which is low-spin, and displays a higher affinity for apical ligands. Cationic 1 and its reduced FeII precursor are shown to bind NO and CO, respectively, to afford [FeIII((tame-N3)S2Me(NO)]+ (18, νNO= 1865 cm-1), an analogue of NO-inactivated NHase, and [FeII((tame-N3)S2Me)(CO)] (16; νCO stretch (1895 cm-1). Anions (N3-, CN-) are shown to be unreactive towards 1, 3 and 15, and neutral ligands unreactive towards 3 and 15, even when present in 100-fold excess, and at low—temperatures. The curtailed reactivity of 15, an analogue of the unmodified form of NHase, and its apical-oxygenated S= 3/2 derivative [FeIII((tame—N2SO2)S2Me2)]2- (20) suggests that regioselective post—translational oxygenation of the basal plane NHase cysteinate sulfurs plays an important role in promoting substrate binding. This is supported by previously reported theoretical (DFT) calculations.1 PMID:18989922

  6. 通用超短波跳频电台的研究与实现%Research and Implementation of General VHF FH Radio

    Institute of Scientific and Technical Information of China (English)

    李胜峰

    2012-01-01

    VHF frequency-hopping communications in the international most advanced technology was undoubtedly the U.S.defense and military communications technology,VHF frequency hopping radio is widely used in countries in military fields.Class radio is also widely used for commercial,especially in the consortium or multinational corporations,in order to guarantee the security of the information.This paper describes the basic principles of frequency hopping communication around the VHF frequency hopping radio system requirements,program design and the analysis and gives radio engineering program.%在国际上超短波跳频通信最先进的技术当属美国国防军事通信技术,超短波跳频电台在各国军用领域使用广泛,该类电台目前也开始广泛用于商业、特别是在用于各财团或跨国公司,以保证信息的安全。该文阐述了跳频通信基本原理,围绕超短波跳频电台系统的需求、方案设计等问题做了相应的分析,并给出电台的工程实现方案。

  7. Estrogen as Jekyll and Hyde: regulation of cell death [v2; ref status: indexed, http://f1000r.es/4fh

    Directory of Open Access Journals (Sweden)

    Wen Zhou

    2014-09-01

    Full Text Available Sustained estrogenic exposure increases the risk and/or the progression of various cancers, including those of the breast, endometrium and ovary. Unexpectedly, physiological level of estrogen together with a novel IKKα inhibitor BAY11-7082 could effectively induce cell apoptosis in ER-positive breast cancer cells, suggesting combining estrogen with IKKα inhibition may be beneficial for breast cancer patients. This opinion article touches upon the dual role estrogen played in inducing cancer cell death and asks whether use of estrogen in combination with IKKα-targeted therapy would be possible reconsider the newly identified crosstalk between ER and NFκB pathway which can be utilized to switch the effects of estrogen on cell death.

  8. The nuclear physics input to astrophysics modelling, and the r- and p-processes: Where do we stand 50 years after B^2FH and Cameron?

    Science.gov (United States)

    Arnould, M.

    2008-11-01

    This is a brief review of the progress made since the seminal contributions to the foundations of the theory of nucleosynthesis by M. Burbidge, G. Burbidge, Fowler and Hoyle, and by Cameron. The reviewed topics are (1) the nuclear physics input to the nucleosynthesis models (nuclear masses, fission, rates of β-decays, neutrino reactions, photoreactions, and nuclear charged particle-induced or neutron-induced reactions), (2) the nuclear physics and astrophysics aspects of the r-process, and (3) the same items for the p-process.

  9. 一种基于DSP/BIOS的跳频控制系统设计%Design on FH Control System based on DSP/BIOS

    Institute of Scientific and Technical Information of China (English)

    谈江海; 余金澳

    2013-01-01

    跳频通信由于其优良的抗干扰特性而成为当今军事通信的重要方式,跳频同步是跳频通信系统的关键技术之一,跳频控制系统的设计在整个通信系统中占有重要的位置。介绍了一种利用GPS信号来进行跳频同步的方法,对TOD、跳频图案等进行了相关设计;并详细介绍了工程研制项目中的实现过程,主要采用基于DSP/BIOS的方法来具体实现跳频控制系统。试验表明该设计可以做到快速、有效的跳频控制,该系统也在实际应用中发挥了重要作用。%HF communication is an important way in the military communication today for its good anti-jammingability, while HF synchronization is one of the key technologies in HF communication. HF control system occupies animportant position in communication system. This paper discusses a synchronization mode with GPS signal, gives the related designs on TOD and HF pattern, and describes in detail its imple-mentation in project development. The HF control system is developed with the way based on DSP/BIOS. Experimentindicates that this design could realize quick and efficient HF control, and this system could plays an important role in the practicalapplication.

  10. Intensive archaeological survey of the F/H Surface Enhancement Project Area, Savannah River Site, Aiken and Barnwell Counties, South Carolina

    Energy Technology Data Exchange (ETDEWEB)

    Sassaman, K.E.; Gillam, J.C.

    1993-08-01

    Twelve archaeological sites and four artifact occurrences were located by intensive survey of two tracts of land for the F and H Surface Enhancement Project on the Savannah River Site, Aiken and Barnwell Counties, South Carolina. Fieldwork in the 480-acre project area included surface reconnaissance of 3.6 linear kilometers of transects, 140 shovel tests along 4.2 linear kilometers of transects, an additional 162 shovel tests at sites and occurrences, and the excavation of six l {times} 2 m test units. All but one of the sites contained artifacts of the prehistoric era; the twelfth site consists of the remains of a twentieth-century home place. The historic site and six of the prehistoric sites consist of limited and/or disturbed contexts of archaeological deposits that have little research potential and are therefore considered ineligible for nomination to the National Register of Historic Places (NRHP). The remaining five sites have sufficient content and integrity to yield information important to ongoing investigations into upland site use. These sites (38AK146, 38AK535, 38AK539, 38AK541, and 38AK543) are thus deemed eligible for nomination to the NRHP and the Savannah River Archaeological Research Program (SRARP) recommends that they be preserved through avoidance or data recovery.

  11. Theoretical Studies of the Role of Vibrational Excitation on the Dynamics of the Hydrogen-Transfer Reaction of F(^2P) + HCl → FH + Cl({^2}P)

    Science.gov (United States)

    Ray, Sara E.; Vissers, Gé W. M.; McCoy, Anne B.

    2009-06-01

    Hydrogen-transfer reactions are probed through vibrational excitation of the HCl bond in the pre-reactive F\\cdotsHCl complex. Such open-shell species provide a challenge for quantum dynamical calculations due to the need to take into account multiple potential energy surfaces to accurately describe the system.A three-dimensional, fully-coupled potential energy surface has been constructed based on electronic energies calculated at the multireference configuration interaction+Davidson correction (MRCI+Q) level of theory with an aug-cc-pVnZ (n=2,3,4) basis. Spin orbit calculations have also been included. Here we present the results of time-dependent quantum wave packet calculations on the asymmetric hydrogen-transfer reaction of F(^2P) + HCl. In these calculations, the reaction is initiated by vibrationally exciting the HCl stretching motion in the pre-reactive F\\cdotsHCl complex. The wave packet is propagated on the coupled potential energy surfaces. Product state distributions were calculated for reactions initiated in the first three vibrationally excited states of HCl, v=1-3. M. P. Deskevich, M. Y. Hayes, K. Takahashi, R. T. Skodje, and D. J. Nesbitt J. Chem. Phys. 124 (22) 224303 (2006) M. P. Deskevich and D. J. Nesbitt private communication(2007)

  12. Dynamics of Ebola epidemics in West Africa 2014 [v2; ref status: indexed, http://f1000r.es/5fh

    Directory of Open Access Journals (Sweden)

    Robin J. Evans

    2015-05-01

    Full Text Available This paper investigates the dynamics of Ebola virus transmission in West Africa during 2014. The reproduction numbers for the total period of epidemic and for different consequent time intervals are estimated based on a simple linear model. It contains one major parameter - the average infectious period that defines the dynamics of epidemics. Numerical implementations are carried out on data collected from three countries Guinea, Sierra Leone and Liberia as well as the total data collected worldwide. Predictions are provided by considering different scenarios involving the average times of infectiousness for the next few months and the end of the current epidemic is estimated according to each scenario.

  13. Mechanistic effects of amino acids and glucose in a novel glutaric aciduria type 1 cell model.

    Directory of Open Access Journals (Sweden)

    Xi Fu

    Full Text Available Acute neurological crises involving striatal degeneration induced by a deficiency of glutaryl-CoA dehydrogenase (GCDH and the accumulation of glutaric (GA and 3-hydroxyglutaric acid (3-OHGA are considered to be the most striking features of glutaric aciduria type I (GA1. In the present study, we investigated the mechanisms of apoptosis and energy metabolism impairment in our novel GA1 neuronal model. We also explored the effects of appropriate amounts of amino acids (2 mM arginine, 2 mM homoarginine, 0.45 g/L tyrosine and 10 mM leucine and 2 g/L glucose on these cells. Our results revealed that the novel GA1 neuronal model effectively simulates the hypermetabolic state of GA1. We found that leucine, tyrosine, arginine, homoarginine or glucose treatment of the GA1 model cells reduced the gene expression of caspase-3, caspase-8, caspase-9, bax, fos, and jun and restored the intracellular NADH and ATP levels. Tyrosine, arginine or homoarginine treatment in particular showed anti-apoptotic effects; increased α-ketoglutarate dehydrogenase complex (OGDC, fumarase (FH, and citrate synthase (CS expression; and relieved the observed impairment in energy metabolism. To the best of our knowledge, this study is the first to investigate the protective mechanisms of amino acids and glucose in GA1 at the cellular level from the point of view of apoptosis and energy metabolism. Our data support the results of previous studies, indicating that supplementation of arginine and homoarginine as a dietary control strategy can have a therapeutic effect on GA1. All of these findings facilitate the understanding of cell apoptosis and energy metabolism impairment in GA1 and reveal new therapeutic perspectives for this disease.

  14. Mechanistic effects of amino acids and glucose in a novel glutaric aciduria type 1 cell model.

    Science.gov (United States)

    Fu, Xi; Gao, Hongjie; Tian, Fengyan; Gao, Jinzhi; Lou, Liping; Liang, Yan; Ning, Qin; Luo, Xiaoping

    2014-01-01

    Acute neurological crises involving striatal degeneration induced by a deficiency of glutaryl-CoA dehydrogenase (GCDH) and the accumulation of glutaric (GA) and 3-hydroxyglutaric acid (3-OHGA) are considered to be the most striking features of glutaric aciduria type I (GA1). In the present study, we investigated the mechanisms of apoptosis and energy metabolism impairment in our novel GA1 neuronal model. We also explored the effects of appropriate amounts of amino acids (2 mM arginine, 2 mM homoarginine, 0.45 g/L tyrosine and 10 mM leucine) and 2 g/L glucose on these cells. Our results revealed that the novel GA1 neuronal model effectively simulates the hypermetabolic state of GA1. We found that leucine, tyrosine, arginine, homoarginine or glucose treatment of the GA1 model cells reduced the gene expression of caspase-3, caspase-8, caspase-9, bax, fos, and jun and restored the intracellular NADH and ATP levels. Tyrosine, arginine or homoarginine treatment in particular showed anti-apoptotic effects; increased α-ketoglutarate dehydrogenase complex (OGDC), fumarase (FH), and citrate synthase (CS) expression; and relieved the observed impairment in energy metabolism. To the best of our knowledge, this study is the first to investigate the protective mechanisms of amino acids and glucose in GA1 at the cellular level from the point of view of apoptosis and energy metabolism. Our data support the results of previous studies, indicating that supplementation of arginine and homoarginine as a dietary control strategy can have a therapeutic effect on GA1. All of these findings facilitate the understanding of cell apoptosis and energy metabolism impairment in GA1 and reveal new therapeutic perspectives for this disease.

  15. GenBank blastx search result: AK059236 [KOME

    Lifescience Database Archive (English)

    Full Text Available AK059236 001-024-F01 AB016078.1 Rhodococcus sp. N-771 genes for nitrile hydratase r...egulator 2 and 1, amidase, nitrile hydratase alpha and beta subunits and nitrile hydratase activator, complete cds.|BCT BCT 8e-18 +3 ...

  16. GenBank blastx search result: AK243402 [KOME

    Lifescience Database Archive (English)

    Full Text Available AK243402 J100064O18 AB016078.1 AB016078 Rhodococcus sp. N-771 genes for nitrile hyd...ratase regulator 2 and 1, amidase, nitrile hydratase alpha and beta subunits and nitrile hydratase activator, complete cds. BCT 1e-27 1 ...

  17. Pre-sowing Seed Treatment with 24-Epibrassinolide Ameliorates Pesticide Stress in Brassica juncea L. through the Modulation of Stress Markers

    Directory of Open Access Journals (Sweden)

    Parvaiz Ahmad

    2016-11-01

    Full Text Available The present experiment was designed to assess the effects of seed soaking with 24-epibrassinolide (EBR on the physiology of Brassica juncea L. seedlings grown under imidacloprid (IMI toxicity. Application of EBR increased the length of seedlings, dry weight, and pigment contents, polyphenols, total phenols and organic acids under IMI toxicity. The expression of genes coding key enzymes of pigment, phenols, polyphenols and organic acid biosynthetic pathways was also studied including CHLASE (chlorophyllase, PSY (phytoene synthase, CHS (chalcone synthase and PAL (phenylalanine ammonialyase, CS (citrate synthase, SUCLG1 (succinyl Co-A ligase,, SDH (succinate dehydrogenase, FH (fumarate hydratase, MS (malate synthase. Multiple linear regression analysis revealed that IMI application regressed negatively on seedling length, dry weight and total chlorophyll content. However, EBR seed treatment regressed positively on all of the parameters studied. Moreover, interaction between IMI and EBR showed positive regression for growth parameters, content of pigments, total polyphenol, total phenol and malate, and expression of PSY and PAL. Negative interactions were noticed for the contents of fumarate, succinate and citrate, and expression of CHS and all genes studied related to organic acid metabolism. In conclusion, EBR enhanced the growth and contents of all studied metabolites by regulating the gene expression of B. juncea seedlings under IMI stress.

  18. Proteomic analysis in nitrogen-deprived Isochrysis galbana during lipid accumulation.

    Science.gov (United States)

    Song, Pingping; Li, Ling; Liu, Jianguo

    2013-01-01

    The differentially co-expressed proteins in N-deprived and N-enriched I. galbana were comparatively analyzed by using two dimensional electrophoresis (2-DE) and matrix-assisted laser desorption/ionization-time-of-flight/time-of-flight-mass spectrometry (MALDI-TOF/TOF-MS) with the aim of better understanding lipid metabolism in this oleaginous microalga. Forty-five of the 900 protein spots showed dramatic changes in N-deprived I. galbana compared with the N-enriched cells. Of these, 36 protein spots were analyzed and 27 proteins were successfully identified. The identified proteins were classified into seven groups by their molecular functions, including the proteins related to energy production and transformation, substance metabolism, signal transduction, molecular chaperone, transcription and translation, immune defense and cytoskeleton. These altered proteins slowed cell growth and photosynthesis of I. galbana directly or indirectly, but at the same time increased lipid accumulation. Eight key enzymes involved in lipid metabolism via different pathways were identified as glyceraldehyde-3-phosphate dehydrogenase (GAPDH), phosphoglycerate kinase (PGK), enolase, aspartate aminotransferase (AST), fumarate hydratase (FH), citrate synthase (CS), O-acetyl-serine lyase (OAS-L) and ATP sulfurylase (ATPS). The results suggested that the glycolytic pathway and citrate transport system might be the main routes for lipid anabolism in N-deprived I. galbana, and that the tricarboxylic acid (TCA) cycle, glyoxylate cycle and sulfur assimilation system might be the major pathways involved in lipid catabolism.

  19. Proteomic analysis in nitrogen-deprived Isochrysis galbana during lipid accumulation.

    Directory of Open Access Journals (Sweden)

    Pingping Song

    Full Text Available The differentially co-expressed proteins in N-deprived and N-enriched I. galbana were comparatively analyzed by using two dimensional electrophoresis (2-DE and matrix-assisted laser desorption/ionization-time-of-flight/time-of-flight-mass spectrometry (MALDI-TOF/TOF-MS with the aim of better understanding lipid metabolism in this oleaginous microalga. Forty-five of the 900 protein spots showed dramatic changes in N-deprived I. galbana compared with the N-enriched cells. Of these, 36 protein spots were analyzed and 27 proteins were successfully identified. The identified proteins were classified into seven groups by their molecular functions, including the proteins related to energy production and transformation, substance metabolism, signal transduction, molecular chaperone, transcription and translation, immune defense and cytoskeleton. These altered proteins slowed cell growth and photosynthesis of I. galbana directly or indirectly, but at the same time increased lipid accumulation. Eight key enzymes involved in lipid metabolism via different pathways were identified as glyceraldehyde-3-phosphate dehydrogenase (GAPDH, phosphoglycerate kinase (PGK, enolase, aspartate aminotransferase (AST, fumarate hydratase (FH, citrate synthase (CS, O-acetyl-serine lyase (OAS-L and ATP sulfurylase (ATPS. The results suggested that the glycolytic pathway and citrate transport system might be the main routes for lipid anabolism in N-deprived I. galbana, and that the tricarboxylic acid (TCA cycle, glyoxylate cycle and sulfur assimilation system might be the major pathways involved in lipid catabolism.

  20. Nuclear ARRB1 induces pseudohypoxia and cellular metabolism reprogramming in prostate cancer

    Science.gov (United States)

    Zecchini, Vincent; Madhu, Basetti; Russell, Roslin; Pértega-Gomes, Nelma; Warren, Anne; Gaude, Edoardo; Borlido, Joana; Stark, Rory; Ireland-Zecchini, Heather; Rao, Roheet; Scott, Helen; Boren, Joan; Massie, Charlie; Asim, Mohammad; Brindle, Kevin; Griffiths, John; Frezza, Christian; Neal, David E; Mills, Ian G

    2014-01-01

    Tumour cells sustain their high proliferation rate through metabolic reprogramming, whereby cellular metabolism shifts from oxidative phosphorylation to aerobic glycolysis, even under normal oxygen levels. Hypoxia-inducible factor 1A (HIF1A) is a major regulator of this process, but its activation under normoxic conditions, termed pseudohypoxia, is not well documented. Here, using an integrative approach combining the first genome-wide mapping of chromatin binding for an endocytic adaptor, ARRB1, both in vitro and in vivo with gene expression profiling, we demonstrate that nuclear ARRB1 contributes to this metabolic shift in prostate cancer cells via regulation of HIF1A transcriptional activity under normoxic conditions through regulation of succinate dehydrogenase A (SDHA) and fumarate hydratase (FH) expression. ARRB1-induced pseudohypoxia may facilitate adaptation of cancer cells to growth in the harsh conditions that are frequently encountered within solid tumours. Our study is the first example of an endocytic adaptor protein regulating metabolic pathways. It implicates ARRB1 as a potential tumour promoter in prostate cancer and highlights the importance of metabolic alterations in prostate cancer. PMID:24837709

  1. Catalytic Kinetics of Nitrile Hydratase Measured in Real-time by Ultraviolet Spectrometry%紫外光谱法实时测定腈水合酶的催化动力学

    Institute of Scientific and Technical Information of China (English)

    刘铭; 高毅; 曹竹安

    2005-01-01

    采用紫外光谱法研究了腈水合酶催化丙烯腈水合的过程, 在不同丙烯腈初始浓度下, 测定了催化过程中275 nm紫外吸光度的变化, 计算出丙烯酰胺的生成速率. 用Michaelis-Menten方程对不同丙烯腈浓度下的Nocardia sp.腈水合酶催化速率进行了拟合, 得到该酶以丙烯腈为底物的米氏常数(Km)为8.46 mmol/L, 单位质量腈水合酶的催化速率常数(kcat)为2 398 μmol/(min·mg).

  2. Effects of CD44 Ligation on Signaling and Metabolic Pathways in Acute Myeloid Leukemia

    KAUST Repository

    Madhoun, Nour Y.

    2017-04-01

    Acute myeloid leukemia (AML) is characterized by a blockage in the differentiation of myeloid cells at different stages. CD44-ligation using anti-CD44 monoclonal antibodies (mAbs) has been shown to reverse the blockage of differentiation and to inhibit the proliferation of blasts in most AML-subtypes. However, the molecular mechanisms underlying this property have not been fully elucidated. Here, we sought to I) analyze the effects of anti-CD44 mAbs on downstream signaling pathways, including the ERK1/2 (extracellular signal-regulated kinase 1 and 2) and mTOR (mammalian target of rapamycin) pathways and II) use state-of-the-art Nuclear Magnetic Resonance (NMR) technology to determine the global metabolic changes during differentiation induction of AML cells using anti-CD44 mAbs and other two previously reported differentiation agents. In the first objective (Chapter 4), our studies provide evidence that CD44-ligation with specific mAbs in AML cells induced an increase in ERK1/2 phosphorylation. The use of the MEK inhibitor (U0126) significantly inhibited the CD44-induced differentiation of HL60 cells, suggesting that ERK1/2 is critical for the CD44-triggered differentiation in AML. In addition, this was accompanied by a marked decrease in the phosphorylation of the mTORC1 and mTORC2 complexes, which are strongly correlated with the inhibition of the PI3K/Akt pathway. In the second objective (Chapter 5), 1H NMR experiments demonstrated that considerable changes in the metabolic profiles of HL60 cells were induced in response to each differentiation agent. These most notable metabolites that significantly changed upon CD44 ligation were involved in the tricarboxylic acid (TCA) cycle and glycolysis such as, succinate, fumarate and lactate. Therefore, we sought to analyze the mechanisms underlying their alterations. Our results revealed that anti-CD44 mAbs treatment induced upregulation in fumarate hydratase (FH) expression and its activity which was accompanied by a

  3. Development of an Amperometric Biosensor Platform for the Combined Determination of L-Malic, Fumaric, and L-Aspartic Acid.

    Science.gov (United States)

    Röhlen, Désirée L; Pilas, Johanna; Schöning, Michael J; Selmer, Thorsten

    2017-09-02

    Three amperometric biosensors have been developed for the detection of L-malic acid, fumaric acid, and L -aspartic acid, all based on the combination of a malate-specific dehydrogenase (MDH, EC 1.1.1.37) and diaphorase (DIA, EC 1.8.1.4). The stepwise expansion of the malate platform with the enzymes fumarate hydratase (FH, EC 4.2.1.2) and aspartate ammonia-lyase (ASPA, EC 4.3.1.1) resulted in multi-enzyme reaction cascades and, thus, augmentation of the substrate spectrum of the sensors. Electrochemical measurements were carried out in presence of the cofactor β-nicotinamide adenine dinucleotide (NAD(+)) and the redox mediator hexacyanoferrate (III) (HCFIII). The amperometric detection is mediated by oxidation of hexacyanoferrate (II) (HCFII) at an applied potential of + 0.3 V vs. Ag/AgCl. For each biosensor, optimum working conditions were defined by adjustment of cofactor concentrations, buffer pH, and immobilization procedure. Under these improved conditions, amperometric responses were linear up to 3.0 mM for L-malate and fumarate, respectively, with a corresponding sensitivity of 0.7 μA mM(-1) (L-malate biosensor) and 0.4 μA mM(-1) (fumarate biosensor). The L-aspartate detection system displayed a linear range of 1.0-10.0 mM with a sensitivity of 0.09 μA mM(-1). The sensor characteristics suggest that the developed platform provides a promising method for the detection and differentiation of the three substrates.

  4. Comprehensive Molecular Characterization of Papillary Renal Cell Carcinoma

    Science.gov (United States)

    Linehan, W. Marston; Spellman, Paul T.; Ricketts, Christopher J.; Creighton, Chad J.; Fei, Suzanne S.; Davis, Caleb; Wheeler, David A.; Murray, Bradley A.; Schmidt, Laura; Vocke, Cathy D.; Peto, Myron; Al Mamun, Abu Amar M.; Shinbrot, Eve; Sethi, Anurag; Brooks, Samira; Rathmell, W. Kimryn; Brooks, Angela N.; Hoadley, Katherine A.; Robertson, A. Gordon; Brooks, Denise; Bowlby, Reanne; Sadeghi, Sara; Shen, Hui; Weisenberger, Daniel J.; Bootwalla, Moiz; Baylin, Stephen B.; Laird, Peter W.; Cherniack, Andrew D.; Saksena, Gordon; Haake, Scott; Li, Jun; Liang, Han; Lu, Yiling; Mills, Gordon B.; Akbani, Rehan; Leiserson, Mark D.M.; Raphael, Benjamin J.; Anur, Pavana; Bottaro, Donald; Albiges, Laurence; Barnabas, Nandita; Choueiri, Toni K.; Czerniak, Bogdan; Godwin, Andrew K.; Hakimi, A. Ari; Ho, Thai; Hsieh, James; Ittmann, Michael; Kim, William Y.; Krishnan, Bhavani; Merino, Maria J.; Mills Shaw, Kenna R.; Reuter, Victor E.; Reznik, Ed; Shelley, Carl Simon; Shuch, Brian; Signoretti, Sabina; Srinivasan, Ramaprasad; Tamboli, Pheroze; Thomas, George; Tickoo, Satish; Burnett, Kenneth; Crain, Daniel; Gardner, Johanna; Lau, Kevin; Mallery, David; Morris, Scott; Paulauskis, Joseph D.; Penny, Robert J.; Shelton, Candace; Shelton, W. Troy; Sherman, Mark; Thompson, Eric; Yena, Peggy; Avedon, Melissa T.; Bowen, Jay; Gastier-Foster, Julie M.; Gerken, Mark; Leraas, Kristen M.; Lichtenberg, Tara M.; Ramirez, Nilsa C.; Santos, Tracie; Wise, Lisa; Zmuda, Erik; Demchok, John A.; Felau, Ina; Hutter, Carolyn M.; Sheth, Margi; Sofia, Heidi J.; Tarnuzzer, Roy; Wang, Zhining; Yang, Liming; Zenklusen, Jean C.; Zhang, Jiashan (Julia); Ayala, Brenda; Baboud, Julien; Chudamani, Sudha; Liu, Jia; Lolla, Laxmi; Naresh, Rashi; Pihl, Todd; Sun, Qiang; Wan, Yunhu; Wu, Ye; Ally, Adrian; Balasundaram, Miruna; Balu, Saianand; Beroukhim, Rameen; Bodenheimer, Tom; Buhay, Christian; Butterfield, Yaron S.N.; Carlsen, Rebecca; Carter, Scott L.; Chao, Hsu; Chuah, Eric; Clarke, Amanda; Covington, Kyle R.; Dahdouli, Mahmoud; Dewal, Ninad; Dhalla, Noreen; Doddapaneni, HarshaVardhan; Drummond, Jennifer; Gabriel, Stacey B.; Gibbs, Richard A.; Guin, Ranabir; Hale, Walker; Hawes, Alicia; Hayes, D. Neil; Holt, Robert A.; Hoyle, Alan P.; Jefferys, Stuart R.; Jones, Steven J.M.; Jones, Corbin D.; Kalra, Divya; Kovar, Christie; Lewis, Lora; Li, Jie; Ma, Yussanne; Marra, Marco A.; Mayo, Michael; Meng, Shaowu; Meyerson, Matthew; Mieczkowski, Piotr A.; Moore, Richard A.; Morton, Donna; Mose, Lisle E.; Mungall, Andrew J.; Muzny, Donna; Parker, Joel S.; Perou, Charles M.; Roach, Jeffrey; Schein, Jacqueline E.; Schumacher, Steven E.; Shi, Yan; Simons, Janae V.; Sipahimalani, Payal; Skelly, Tara; Soloway, Matthew G.; Sougnez, Carrie; Tam, Angela; Tan, Donghui; Thiessen, Nina; Veluvolu, Umadevi; Wang, Min; Wilkerson, Matthew D.; Wong, Tina; Wu, Junyuan; Xi, Liu; Zhou, Jane; Bedford, Jason; Chen, Fengju; Fu, Yao; Gerstein, Mark; Haussler, David; Kasaian, Katayoon; Lai, Phillip; Ling, Shiyun; Radenbaugh, Amie; Van Den Berg, David; Weinstein, John N.; Zhu, Jingchun; Albert, Monique; Alexopoulou, Iakovina; Andersen, Jeremiah J; Auman, J. Todd; Bartlett, John; Bastacky, Sheldon; Bergsten, Julie; Blute, Michael L.; Boice, Lori; Bollag, Roni J.; Boyd, Jeff; Castle, Erik; Chen, Ying-Bei; Cheville, John C.; Curley, Erin; Davies, Benjamin; DeVolk, April; Dhir, Rajiv; Dike, Laura; Eckman, John; Engel, Jay; Harr, Jodi; Hrebinko, Ronald; Huang, Mei; Huelsenbeck-Dill, Lori; Iacocca, Mary; Jacobs, Bruce; Lobis, Michael; Maranchie, Jodi K.; McMeekin, Scott; Myers, Jerome; Nelson, Joel; Parfitt, Jeremy; Parwani, Anil; Petrelli, Nicholas; Rabeno, Brenda; Roy, Somak; Salner, Andrew L.; Slaton, Joel; Stanton, Melissa; Thompson, R. Houston; Thorne, Leigh; Tucker, Kelinda; Weinberger, Paul M.; Winemiller, Cythnia; Zach, Leigh Anne; Zuna, Rosemary

    2016-01-01

    Background Papillary renal cell carcinoma, accounting for 15% of renal cell carcinoma, is a heterogeneous disease consisting of different types of renal cancer, including tumors with indolent, multifocal presentation and solitary tumors with an aggressive, highly lethal phenotype. Little is known about the genetic basis of sporadic papillary renal cell carcinoma; no effective forms of therapy for advanced disease exist. Methods We performed comprehensive molecular characterization utilizing whole-exome sequencing, copy number, mRNA, microRNA, methylation and proteomic analyses of 161 primary papillary renal cell carcinomas. Results Type 1 and Type 2 papillary renal cell carcinomas were found to be different types of renal cancer characterized by specific genetic alterations, with Type 2 further classified into three individual subgroups based on molecular differences that influenced patient survival. MET alterations were associated with Type 1 tumors, whereas Type 2 tumors were characterized by CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2-ARE pathway. A CpG island methylator phenotype (CIMP) was found in a distinct subset of Type 2 papillary renal cell carcinoma characterized by poor survival and mutation of the fumarate hydratase (FH) gene. Conclusions Type 1 and Type 2 papillary renal cell carcinomas are clinically and biologically distinct. Alterations in the MET pathway are associated with Type 1 and activation of the NRF2-ARE pathway with Type 2; CDKN2A loss and CIMP in Type 2 convey a poor prognosis. Furthermore, Type 2 papillary renal cell carcinoma consists of at least 3 subtypes based upon molecular and phenotypic features. PMID:26536169

  5. Stereochemistry of enzymatic water addition to C=C bonds.

    Science.gov (United States)

    Chen, Bi-Shuang; Otten, Linda G; Hanefeld, Ulf

    2015-01-01

    Water addition to carbon-carbon double bonds using hydratases is attracting great interest in biochemistry. Most of the known hydratases are involved in primary metabolism and to a lesser extent in secondary metabolism. New hydratases have recently been added to the toolbox, both from natural sources or artificial metalloenzymes. In order to comprehensively understand how the hydratases are able to catalyse the water addition to carbon-carbon double bonds, this review will highlight the mechanistic and stereochemical studies of the enzymatic water addition to carbon-carbon double bonds, focusing on the syn/anti-addition and stereochemistry of the reaction.

  6. TTCs for oral exposure: Identification of outliers in Cramer class I, II and III using the combined database of RepDose (FhG), Toxbase (TNO), Munro and ToxRefDB (USEPA)

    Science.gov (United States)

    The Thresholds of Toxicological Concern (TTC) are generic human exposure threshold for structural groups of chemicals below which no risk to human health is assumed and therefore no further testing is needed. Different thresholds have been developed for oral exposure e.g. for gen...

  7. TTCs for oral exposure: Identification of outliers in Cramer class I, II and III using the combined database of RepDose (FhG), Toxbase (TNO), Munro and ToxRefDB (USEPA)

    Science.gov (United States)

    The Thresholds of Toxicological Concern (TTC) are generic human exposure threshold for structural groups of chemicals below which no risk to human health is assumed and therefore no further testing is needed. Different thresholds have been developed for oral exposure e.g. for gen...

  8. Design of Key Blocks of a High Speed DS/FH Communication System for UAVs%无人机高速DS/FH混合扩频通信系统关键模块设计

    Institute of Scientific and Technical Information of China (English)

    王鹏宇

    2016-01-01

    针对UAV(Unmanned Aerial Vehicle,无人机)测控链路高抗干扰需求,给出了实现跳频速率20 000次/s的扩跳混合无人机测控数据链系统实现方案.系统采用跳频频率并行捕获模式.跳频源设计采用直接频率合成、DDS(Direct Digital Synthesis,直接数字频率合成)和PLL (Phase-Locked Loop,锁相环)相结合的混合频率合成技术.利用相位响应滤波器,通过正交调制技术完成MSK(Minimum Shift Keying,最小频移键控)、GMSK (GaussianMinimum Shift Keying,高斯最小频移键控)调制.通过推导得出2 bit差分解调输出与载波频率选择有关,且为四分之数据率的整数倍关系.然后通过实例分析给出了跳频频率间隔选取方法,即跳频间隔应当将临近跳频的主瓣分开,同时跳频载波频率应当设在其他跳频频谱的零点处.最后总结了高速扩跳频系统参数设计一般步骤.

  9. Energy Resonance and Inverse Population of the Product Vibrational States for the Reaction F+H2(v=0)→HF(v′)+H,LCAC-SW Theoretical Quantum Scattering Study

    Institute of Scientific and Technical Information of China (English)

    蔡政亭; 康从民; 马万勇; 冯大诚

    2001-01-01

    LCAC-SW (linear combination of arrangement channel-scattering wavefunction) method was used to calculate collinear state-to-state reaction probabilities for the reaction F+ H2(v =0)→ HF ( v ′) + H on the 6SEC potential energy surface. The results show that reaction probabilities P02 and P03 [ i. e. , v ′=2,3 for reaction F+ H-2(v = 0)→HF(v ′) + H] are primary, the population of product vibrational states is inverse and the reaction probabilities are oscillatory with collision energies,i.e., there is energy resonance in this reaction, which agrees with a new experiment.

  10. The Study of G Function Arithmetic of a HF High Speed FH CHESS Radio%短波高速跳频CHESS电台G函数算法研究

    Institute of Scientific and Technical Information of China (English)

    姚富强; 刘忠英

    2001-01-01

    本文深入研究了美国推出的短波高速跳频CHESS电台的G函数算法,涉及到跳频图案、信息调制与解调等.在介绍G函数算法原理的基础上,分析了G函数跳频图案的性能,并对其进行了检验,得出了一些有益的结论,提出了改进的方向.

  11. Evaluation of potential severe accidents during low power and shutdown operations at Surry, Unit-1: Analysis of core damage frequency from internal events during mid-loop operations. Appendices F-H, Volume 2, Part 4

    Energy Technology Data Exchange (ETDEWEB)

    Chu, T.L.; Musicki, Z.; Kohut, P.; Yang, J.; Bozoki, G.; Hsu, C.J.; Diamond, D.J. [Brookhaven National Lab., Upton, NY (United States); Bley, D.; Johnson, D. [PLG Inc., Newport Beach, CA (United States); Holmes, B. [AEA Technology, Dorset (United Kingdom)] [and others

    1994-06-01

    Traditionally, probabilistic risk assessments (PRA) of severe accidents in nuclear power plants have considered initiating events potentially occurring only during full power operation. Some previous screening analyses that were performed for other modes of operation suggested that risks during those modes were small relative to full power operation. However, more recent studies and operational experience have implied that accidents during low power and shutdown could be significant contributors to risk. Two plants, Surry (pressurized water reactor) and Grand Gulf (boiling water reactor), were selected as the plants to be studied. The objectives of the program are to assess the risks of severe accidents initiated during plant operational states other than full power operation and to compare the estimated core damage frequencies, important accident sequences and other qualitative and quantitative results with those accidents initiated during full power operation as assessed in NUREG-1150. The scope of the program includes that of a level-3 PRA. In phase 2, mid-loop operation was selected as the plant configuration to be analyzed based on the results of the phase 1 study. The objective of the phase 2 study is to perform a detailed analysis of the potential accident scenarios that may occur during mid-loop operation, and compare the results with those of NUREG-1150. The scope of the level-1 study includes plant damage state analysis, and uncertainty analysis. Volume 1 summarizes the results of the study. Internal events analysis is documented in Volume 2. It also contains an appendix that documents the part of the phase 1 study that has to do with POSs other than mid-loop operation. Internal fire and internal flood analyses are documented in Volumes 3 and 4. A separate study on seismic analysis, documented in Volume 5, was performed for the NRC by Future Resources Associates, Inc. Volume 6 documents the accident progression, source terms, and consequence analysis.

  12. Heterogeneity in rhesus macaque complement factor H binding to meningococcal factor H binding protein (FHbp) informs selection of primates to assess immunogenicity of FHbp-based vaccines.

    Science.gov (United States)

    Beernink, Peter T; Shaughnessy, Jutamas; Stefek, Heather; Ram, Sanjay; Granoff, Dan M

    2014-11-01

    Neisseria meningitidis causes disease only in humans. An important mechanism underlying this host specificity is the ability of the organism to resist complement by recruiting the complement downregulator factor H (FH) to the bacterial surface. In previous studies, binding of FH to one of the major meningococcal FH ligands, factor H binding protein (FHbp), was reported to be specific for human FH. Here we report that sera from 23 of 73 rhesus macaques (32%) tested had high FH binding to FHbp. Similar to human FH, binding of macaque FH to the meningococcal cell surface inhibited the complement alternative pathway by decreasing deposition of C3b. FH contains 20 domains (or short consensus repeats), with domains 6 and 7 being responsible for binding of human FH to FHbp. DNA sequence analyses of FH domains 6 and 7 from macaques with high or low FH binding showed a polymorphism at residue 352 in domain 6, with Tyr being associated with high binding and His with low binding. A recombinant macaque FH 6,7/Fc fragment with Tyr352 showed higher binding to FHbp than the corresponding fragment with His352. In previous studies in human FH transgenic mice, binding of FH to FHbp vaccines decreased protective antibody responses, and mutant FHbp vaccines with decreased FH binding elicited serum antibodies with greater protective activity. Thus, macaques with high FH binding to FHbp represent an attractive nonhuman primate model to investigate further the effects of FH binding on the immunogenicity of FHbp vaccines.

  13. A new autosomal STR nineplex for canine identification and parentage testing

    DEFF Research Database (Denmark)

    van Asch, Barbara; Alves, Cíntia; Gusmão, Leonor

    2009-01-01

    A single multiplex PCR assay capable of simultaneously amplifying nine canine-specific autosomal STR markers (FH3210, FH3241, FH2004, FH2658, FH4012, REN214L11, FH2010, FH2361 and the newly described C38) was developed for individual identification and parentage testing in domestic dogs. In order......-breed origin. Co-dominant inheritance of STR alleles was investigated in 101 father, mother and son trios. Expected heterozygosity values vary between 0.5648 for REN214L11 and 0.9050 for C38. The high level of genetic diversity observed for most markers provides this multiplex with a very high discriminating...

  14. Factor H binds to the hypervariable region of many Streptococcus pyogenes M proteins but does not promote phagocytosis resistance or acute virulence

    DEFF Research Database (Denmark)

    Gustafsson, Caj Ulrik Mattias; Lannergård, Jonas; Nilsson, Olof Rickard;

    2013-01-01

    Many pathogens express a surface protein that binds the human complement regulator factor H (FH), as first described for Streptococcus pyogenes and the antiphagocytic M6 protein. It is commonly assumed that FH recruited to an M protein enhances virulence by protecting the bacteria against...... immunochemical analysis indicated that FH binds solely to the hypervariable region (HVR) of an M protein, suggesting that selection has favored the ability of certain HVRs to bind FH. These FH-binding HVRs could be studied as isolated polypeptides that retain ability to bind FH, implying that an FH-binding HVR...... represents a distinct ligand-binding domain. The isolated HVRs specifically interacted with FH among all human serum proteins, interacted with the same region in FH and showed species specificity, but exhibited little or no antigenic cross-reactivity. Although these findings suggested that FH recruited...

  15. NCBI nr-aa BLAST: CBRC-CREM-01-1371 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-CREM-01-1371 ref|YP_926913.1| Phosphopyruvate hydratase [Shewanella amazonensi...s SB2B] gb|ABL99243.1| Phosphopyruvate hydratase [Shewanella amazonensis SB2B] YP_926913.1 6e-90 71% ...

  16. NCBI nr-aa BLAST: CBRC-CREM-01-1371 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-CREM-01-1371 ref|ZP_01109498.1| phosphopyruvate hydratase [Alteromonas macleodii 'Deep... ecotype'] gb|EAR06202.1| phosphopyruvate hydratase [Alteromonas macleodii 'Deep ecotype'] ZP_01109498.1 2e-88 70% ...

  17. NCBI nr-aa BLAST: CBRC-CREM-01-1371 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-CREM-01-1371 ref|ZP_01165062.1| phosphopyruvate hydratase [Oceanospirillum sp.... MED92] gb|EAR63059.1| phosphopyruvate hydratase [Oceanospirillum sp. MED92] ZP_01165062.1 2e-89 70% ...

  18. Sequence Classification: 652156 [

    Lifescience Database Archive (English)

    Full Text Available enoyl-CoA hydratase (unsaturated acyl-CoA hydratase) (crotonase) || http://www.ncbi.nlm.nih.gov/protein/72160471 ... ...Non-TMB TMH Non-TMB Non-TMB Non-TMB Non-TMB >gi|72160471|ref|YP_288128.1| probable

  19. Heterogeneity in Rhesus Macaque Complement Factor H Binding to Meningococcal Factor H Binding Protein (FHbp) Informs Selection of Primates To Assess Immunogenicity of FHbp-Based Vaccines

    OpenAIRE

    2014-01-01

    Neisseria meningitidis causes disease only in humans. An important mechanism underlying this host specificity is the ability of the organism to resist complement by recruiting the complement downregulator factor H (FH) to the bacterial surface. In previous studies, binding of FH to one of the major meningococcal FH ligands, factor H binding protein (FHbp), was reported to be specific for human FH. Here we report that sera from 23 of 73 rhesus macaques (32%) tested had high FH binding to FHbp....

  20. Investigation of solid phase upon {gamma}-irradiation of ferrihydrite-ethanol suspension

    Energy Technology Data Exchange (ETDEWEB)

    Jurkin, Tanja [Division of Materials Chemistry, Ruder Boskovic Institute, Bijenicka 54, HR-10002 Zagreb (Croatia); Zadro, Kreso [Department of Physics, Faculty of Science, University of Zagreb, Bijenicka 32, 10000 Zagreb (Croatia); Gotic, Marijan, E-mail: gotic@irb.h [Division of Materials Chemistry, Ruder Boskovic Institute, Bijenicka 54, HR-10002 Zagreb (Croatia); Music, Svetozar [Division of Materials Chemistry, Ruder Boskovic Institute, Bijenicka 54, HR-10002 Zagreb (Croatia)

    2011-07-15

    Ferrihydrite (FH) nanoparticles were synthesised and subjected to {gamma}-irradiation in the form of FH-ethanol suspension. The dose rate of {gamma}-radiation was {approx}16 kGy/h and the samples were irradiated to doses of up to 2590 kGy. {gamma}-irradiation of FH-ethanol suspensions did not cause the transformation of FH to any of the other iron oxide phases. Likewise, neither the Moessbauer and FT-IR spectroscopy nor the quantitative analysis using Energy Dispersive X-ray Spectroscopy gave any evidence of structural changes of FH upon {gamma}-irradiation. C, H analysis showed that the C concentration in FH gradually increased with dose and was higher in {gamma}-irradiated FH samples than in non-irradiated FH sample. This finding suggested that carbon in FH originated from ethanol degradation. The H concentration in FH gradually increased to the dose of up to 340 kGy and then slightly decreased. Magnetic measurements showed a progressive decrease in magnetisation with an increase in {gamma}-irradiation. The results of magnetic measurements and C, H analysis suggested the carbonisation of FH surface. It was supposed that {gamma}-irradiation of FH-ethanol suspension reductively decomposed ethanol thus generating unsaturated hydrocarbons and acetylides, which in turn formed a conjugate iron complex, thus carbonating the FH surface. The carbonisation of the FH surface prevented FH transformation to other iron oxide phases.

  1. Collagenolytic activities of the major secreted cathepsin L peptidases involved in the virulence of the helminth pathogen, Fasciola hepatica.

    Directory of Open Access Journals (Sweden)

    Mark W Robinson

    Full Text Available BACKGROUND: The temporal expression and secretion of distinct members of a family of virulence-associated cathepsin L cysteine peptidases (FhCL correlates with the entry and migration of the helminth pathogen Fasciola hepatica in the host. Thus, infective larvae traversing the gut wall secrete cathepsin L3 (FhCL3, liver migrating juvenile parasites secrete both FhCL1 and FhCL2 while the mature bile duct parasites, which are obligate blood feeders, secrete predominantly FhCL1 but also FhCL2. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that FhCL1, FhCL2 and FhCL3 exhibit differences in their kinetic parameters towards a range of peptide substrates. Uniquely, FhCL2 and FhCL3 readily cleave substrates with Pro in the P2 position and peptide substrates mimicking the repeating Gly-Pro-Xaa motifs that occur within the primary sequence of collagen. FhCL1, FhCL2 and FhCL3 hydrolysed native type I and II collagen at neutral pH but while FhCL1 cleaved only non-collagenous (NC, non-Gly-X-Y domains FhCL2 and FhCL3 exhibited collagenase activity by cleaving at multiple sites within the α1 and α2 triple helix regions (Col domains. Molecular simulations created for FhCL1, FhCL2 and FhCL3 complexed to various seven-residue peptides supports the idea that Trp67 and Tyr67 in the S2 subsite of the active sites of FhCL3 and FhCL2, respectively, are critical to conferring the unique collagenase-like activity to these enzymes by accommodating either Gly or Pro residues at P2 in the substrate. The data also suggests that FhCL3 accommodates hydroxyproline (Hyp-Gly at P3-P2 better than FhCL2 explaining the observed greater ability of FhCL3 to digest type I and II collagens compared to FhCL2 and why these enzymes cleave at different positions within the Col domains. CONCLUSIONS/SIGNIFICANCE: These studies further our understanding of how this helminth parasite regulates peptidase expression to ensure infection, migration and establishment in host tissues.

  2. Less pronounced response to exercise in healthy relatives to type 2 diabetic subjects compared with controls.

    Science.gov (United States)

    Ekman, C; Elgzyri, T; Ström, K; Almgren, P; Parikh, H; Dekker Nitert, Marloes; Rönn, T; Manderson Koivula, Fiona; Ling, C; Tornberg, Å B; Wollmer, P; Eriksson, K F; Groop, L; Hansson, O

    2015-11-01

    Healthy first-degree relatives with heredity of type 2 diabetes (FH+) are known to have metabolic inflexibility compared with subjects without heredity for diabetes (FH-). In this study, we aimed to test the hypothesis that FH+ individuals have an impaired response to exercise compared with FH-. Sixteen FH+ and 19 FH- insulin-sensitive men similar in age, peak oxygen consumption (V̇o2 peak), and body mass index completed an exercise intervention with heart rate monitored during exercise for 7 mo. Before and after the exercise intervention, the participants underwent a physical examination and tests for glucose tolerance and exercise capacity, and muscle biopsies were taken for expression analysis. The participants attended, on average, 39 training sessions during the intervention and spent 18.8 MJ on exercise. V̇o2 peak/kg increased by 14%, and the participants lost 1.2 kg of weight and 3 cm waist circumference. Given that the FH+ group expended 61% more energy during the intervention, we used regression analysis to analyze the response in the FH+ and FH- groups separately. Exercise volume had a significant effect on V̇o2 peak, weight, and waist circumference in the FH- group, but not in the FH+ group. After exercise, expression of genes involved in metabolism, oxidative phosphorylation, and cellular respiration increased more in the FH- compared with the FH+ group. This suggests that healthy, insulin-sensitive FH+ and FH- participants with similar age, V̇o2 peak, and body mass index may respond differently to an exercise intervention. The FH+ background might limit muscle adaptation to exercise, which may contribute to the increased susceptibility to type 2 diabetes in FH+ individuals.

  3. Determination of the structure and catalytic mechanism of sorghum bicolor caffeoyl-CoA O-methyltransferase

    Science.gov (United States)

    Although cold acclimation is a key process in plants from temperate climates, the mechanisms sensing low temperature remain obscure. Here, we show that the accumulation of the organic acid fumaric acid, mediated by the cytosolic fumarase FUM2, is essential for cold acclimation of metabolism in the c...

  4. Dicty_cDB: AFF860 [Dicty_cDB

    Lifescience Database Archive (English)

    Full Text Available quence qfei**ktkniw*ryshywlifkiiwws*fpy*fh*ck*tfcc*r*fl*sif*l**yycn istrirki*vvl**nwg*sctifiriayni...kiiwws*fpy*fh*ck*tfcc*r*fl*sif*l**yycn istrirki*vvl**nwg*sctifiriayniklclrliktnnn

  5. Reduced contribution of endothelin to the regulation of systemic and pulmonary vascular tone in severe familial hypercholesterolaemia

    NARCIS (Netherlands)

    S.B. Bender (Shawn ); V.J. de Beer (Vincent Jacob); D.L. Tharp (Darla); E.D. van Deel (Elza); D.K. Bowles; D.J.G.M. Duncker (Dirk); H. Laughlin (Harold); D. Merkus (Daphne)

    2014-01-01

    textabstractVascular dysfunction has been associated with familial hypercholesterolaemia (FH), a severe form of hyperlipidaemia. We recently demonstrated that swine with FH exhibit reduced exercise-induced systemic, but not pulmonary, vasodilatation involving reduced nitric oxide (NO) bioavailabilit

  6. Beta cell function and insulin sensitivity in women with polycystic ovary syndrome: influence of the family history of type 2 diabetes mellitus.

    Science.gov (United States)

    Vrbikova, Jana; Bendlova, Bela; Vankova, Marketa; Dvorakova, Katerina; Grimmichova, Tereza; Vondra, Karel; Pacini, Giovanni

    2009-09-01

    To study the impact of family history (FH) of type 2 diabetes mellitus on beta-cell compensatory mechanism in women with polycystic ovary syndrome (PCOS). A total of 70 women with PCOS, 14 with first-degree relative with type 2 diabetes mellitus (T2DM) (FH+), 56 with negative FH of T2DM (FH-) and 72 age and BMI matched control healthy women (CNT) underwent oral glucose tolerance test (OGTT). Insulin resistance was evaluated as oral glucose index (OGIS); insulin and C-peptide secretion as the insulinogenic index in 30th min of OGTT. Fasting blood glucose levels were significantly higher in FH+ than in FH- (p insulin was higher in FH+ than in CNT (p Insulin resistance and defective early-phase insulin secretion is present only in those PCOS-affected subjects who had positive FH of T2DM.

  7. The prevalence and prognostic importance of possible familial hypercholesterolemia in patients with myocardial infarction

    DEFF Research Database (Denmark)

    Rerup, Sofie Aagaard; Bang, Lia E; Mogensen, Ulrik M;

    2016-01-01

    AIMS: Familial hypercholesterolemia (FH) is a common genetic disorder causing accelerated atherosclerosis and premature cardiovascular disease. The aim of this study was to examine the prevalence and prognostic significance of possible FH in patients with myocardial infarction (MI). METHODS...

  8. [Familial hypercholesterolemia: why screening, counselling and treatment should be integrated].

    Science.gov (United States)

    Roeters van Lennep, Jeanine E; Visseren, Frank L J; Jira, Petr E

    2015-01-01

    Familial hypercholesterolemia (FH) is a monogenic autosomal dominant disorder. FH is the most common hereditary cause of raised serum cholesterol levels and is associated with an increased risk of premature cardiovascular disease (CVD). This disorder is known to have a genetic cause, and effective drug therapies exist for patients with FH. Successful cascade screening, within the framework of a national screening programme, gave the Netherlands an international role as model and pioneer as far as FH detection is concerned. With the ending of this screening programme as of 1 January 2014 the care for FH patients, including screening and counselling has had to be incorporated within the basic Dutch healthcare insurance system. It is essential that detection of FH should continue in as efficient and cost-effective a manner as possible. Our proposal is that this detection should be performed and co-ordinated by those treating patients with FH so that FH screening, counselling and treatment are integrated.

  9. Dicty_cDB: SLI236 [Dicty_cDB

    Lifescience Database Archive (English)

    Full Text Available DLIRNWSV*lnlg*ilvhyylvl *lllllvyfyqvliilrt*vvllqvf*qqqfschh*hqreqlenvyfyl*l*fh*l*hyl *hyllyfiki*mqmngvlvvni*...VGASGAIFGFLGVLLTDLIRNWSV*lnlg*ilvhyylvl *lllllvyfyqvliilrt*vvllqvf*qqqfschh*hqreqlenvyfyl*l*fh*l*hyl *hyllyf

  10. Archaeal characterization of bioaerosols from cage-housed and floor-housed poultry operations

    National Research Council Canada - National Science Library

    Just, Natasha; Blais Lecours, Pascale; Marcoux-Voiselle, Mélissa; Kirychuk, Shelley; Veillette, Marc; Singh, Baljit; Duchaine, Caroline

    2013-01-01

    Although bioaerosols from both cage-housed (CH) and floor-housed (FH) poultry operations are highly concentrated, the concentrations of dust, endotoxin, and bacteria are significantly higher in FH bioaerosols...

  11. Factor H binds to the hypervariable region of many Streptococcus pyogenes M proteins but does not promote phagocytosis resistance or acute virulence.

    Directory of Open Access Journals (Sweden)

    Mattias C U Gustafsson

    Full Text Available Many pathogens express a surface protein that binds the human complement regulator factor H (FH, as first described for Streptococcus pyogenes and the antiphagocytic M6 protein. It is commonly assumed that FH recruited to an M protein enhances virulence by protecting the bacteria against complement deposition and phagocytosis, but the role of FH-binding in S. pyogenes pathogenesis has remained unclear and controversial. Here, we studied seven purified M proteins for ability to bind FH and found that FH binds to the M5, M6 and M18 proteins but not the M1, M3, M4 and M22 proteins. Extensive immunochemical analysis indicated that FH binds solely to the hypervariable region (HVR of an M protein, suggesting that selection has favored the ability of certain HVRs to bind FH. These FH-binding HVRs could be studied as isolated polypeptides that retain ability to bind FH, implying that an FH-binding HVR represents a distinct ligand-binding domain. The isolated HVRs specifically interacted with FH among all human serum proteins, interacted with the same region in FH and showed species specificity, but exhibited little or no antigenic cross-reactivity. Although these findings suggested that FH recruited to an M protein promotes virulence, studies in transgenic mice did not demonstrate a role for bound FH during acute infection. Moreover, phagocytosis tests indicated that ability to bind FH is neither sufficient nor necessary for S. pyogenes to resist killing in whole human blood. While these data shed new light on the HVR of M proteins, they suggest that FH-binding may affect S. pyogenes virulence by mechanisms not assessed in currently used model systems.

  12. Unexpected Activity of a Novel Kunitz-type Inhibitor

    Science.gov (United States)

    Smith, David; Tikhonova, Irina G.; Jewhurst, Heather L.; Drysdale, Orla C.; Dvořák, Jan; Robinson, Mark W.; Cwiklinski, Krystyna; Dalton, John P.

    2016-01-01

    Kunitz-type (KT) protease inhibitors are low molecular weight proteins classically defined as serine protease inhibitors. We identified a novel secreted KT inhibitor associated with the gut and parenchymal tissues of the infective juvenile stage of Fasciola hepatica, a helminth parasite of medical and veterinary importance. Unexpectedly, recombinant KT inhibitor (rFhKT1) exhibited no inhibitory activity toward serine proteases but was a potent inhibitor of the major secreted cathepsin L cysteine proteases of F. hepatica, FhCL1 and FhCL2, and of human cathepsins L and K (Ki = 0.4-27 nm). FhKT1 prevented the auto-catalytic activation of FhCL1 and FhCL2 and formed stable complexes with the mature enzymes. Pulldown experiments from adult parasite culture medium showed that rFhKT1 interacts specifically with native secreted FhCL1, FhCL2, and FhCL5. Substitution of the unusual P1 Leu15 within the exposed reactive loop of FhKT1 for the more commonly found Arg (FhKT1Leu15/Arg15) had modest adverse effects on the cysteine protease inhibition but conferred potent activity against the serine protease trypsin (Ki = 1.5 nm). Computational docking and sequence analysis provided hypotheses for the exclusive binding of FhKT1 to cysteine proteases, the importance of the Leu15 in anchoring the inhibitor into the S2 active site pocket, and the inhibitor's selectivity toward FhCL1, FhCL2, and human cathepsins L and K. FhKT1 represents a novel evolutionary adaptation of KT protease inhibitors by F. hepatica, with its prime purpose likely in the regulation of the major parasite-secreted proteases and/or cathepsin L-like proteases of its host. PMID:27422822

  13. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population

    DEFF Research Database (Denmark)

    Nordestgaard, Børge G; Chapman, M John; Humphries, Steve E

    2013-01-01

    The first aim was to critically evaluate the extent to which familial hypercholesterolaemia (FH) is underdiagnosed and undertreated. The second aim was to provide guidance for screening and treatment of FH, in order to prevent coronary heart disease (CHD).......The first aim was to critically evaluate the extent to which familial hypercholesterolaemia (FH) is underdiagnosed and undertreated. The second aim was to provide guidance for screening and treatment of FH, in order to prevent coronary heart disease (CHD)....

  14. Continuous measurements of instantaneous heart rate and its fluctuations before and after hatching in chickens.

    Science.gov (United States)

    Moriya, K; Pearson, J T; Burggren, W W; Ar, A; Tazawa, H

    2000-03-01

    There has been considerable interest in heart rate (fh) fluctuations in relation to cardiovascular control systems and foetal conditions during pregnancy in mammals. Prominent fluctuations in fh also occur in avian embryos, which are an important experimental model for studying developmental physiology. The present study determined the instantaneous fh of seven chick embryos continuously from the last stage of prenatal development (day 18), throughout the pipping (perinatal) period (days 19-21) until hatching and, subsequently, of newly hatched chicks (up to day 2). The distinctive patterns of instantaneous fh fluctuations took the form of specific changes within a broad mean fh baseline. Cyclic oscillations (ultradian rhythm) occurred until an early stage of the perinatal period, when the fh baseline started rising. Subsequently, the baseline dropped and respiratory arrhythmia began to appear concomitant with external pipping. During the final stage of external pipping, when the fh baseline rose again prior to hatching, three unique patterns of instantaneous fh fluctuations were evident: relatively long-lasting cyclic small accelerations, irregular intermittent large accelerations and short-term repeated large accelerations. Furthermore, repeated alternate occurrences of the latter two types of acceleration formed an additional oscillating pattern with a period of 10-15 min. During the early period after hatching, when the fh baseline reached its maximum, instantaneous fh changed relatively slowly accompanied by transient rapid decelerations, probably due to augmented vagal tone. Subsequently, the mean fh baseline dropped to its minimum, and a circadian rhythm and three types of previously reported fh fluctuations (types I-III) appeared. Developmental patterns of mean fh and the appearance of distinctive patterns of instantaneous fluctuations in fh and circadian rhythms were not influenced by an ultimate failure of hatching after a normal development. The

  15. A novel, inducible, citral lyase purified from spores of Penicillium digitatum

    NARCIS (Netherlands)

    Wolken, W.A.M.; Loo, W.J.V. van; Tramper, J.; Werf, M.J. van der

    2002-01-01

    A novel lyase, combining hydratase and aldolase activity, that converts citral into methylheptenone and acetaldehyde, was purified from spores of Penicillium digitatum. Remarkably, citral lyase activity was induced 118-fold by incubating nongerminating spores with the substrate, citral. This cofacto

  16. A novel, inducible, citral lyase purified from spores of Penicillium digitatum

    NARCIS (Netherlands)

    Wolken, W.A.M.; Loo, W.J.V. van; Tramper, J.; Werf, M.J. van der

    2002-01-01

    A novel lyase, combining hydratase and aldolase activity, that converts citral into methylheptenone and acetaldehyde, was purified from spores of Penicillium digitatum. Remarkably, citral lyase activity was induced 118-fold by incubating nongerminating spores with the substrate, citral. This

  17. Isolation and characterization of Rhodococcus ruber CGMCC3090 ...

    African Journals Online (AJOL)

    STORAGESEVER

    2009-10-19

    Oct 19, 2009 ... nitrile hydratase was abundantly produced in this strain and that it mediated monohydrolysis. The ...... TLC: Rf = 0.32 (petroleum ether/ethyl acetate/methanol = .... hydrolysis of aromatic dinitriles using a whole cell catalyst.

  18. Evaluation of the Chemical and Mechanical Properties of Hardening High-Calcium Fly Ash Blended Concrete

    Directory of Open Access Journals (Sweden)

    Wei-Jie Fan

    2015-09-01

    Full Text Available High-calcium fly ash (FH is the combustion residue from electric power plants burning lignite or sub-bituminous coal. As a mineral admixture, FH can be used to produce high-strength concrete and high-performance concrete. The development of chemical and mechanical properties is a crucial factor for appropriately using FH in the concrete industry. To achieve sustainable development in the concrete industry, this paper presents a theoretical model to systematically evaluate the property developments of FH blended concrete. The proposed model analyzes the cement hydration, the reaction of free CaO in FH, and the reaction of phases in FH other than free CaO. The mutual interactions among cement hydration, the reaction of free CaO in FH, and the reaction of other phases in FH are also considered through the calcium hydroxide contents and the capillary water contents. Using the hydration degree of cement, the reaction degree of free CaO in FH, and the reaction degree of other phases in FH, the proposed model evaluates the calcium hydroxide contents, the reaction degree of FH, chemically bound water, porosity, and the compressive strength of hardening concrete with different water to binder ratios and FH replacement ratios. The evaluated results are compared to experimental results, and good consistencies are found.

  19. Evaluation of the Chemical and Mechanical Properties of Hardening High-Calcium Fly Ash Blended Concrete.

    Science.gov (United States)

    Fan, Wei-Jie; Wang, Xiao-Yong; Park, Ki-Bong

    2015-09-07

    High-calcium fly ash (FH) is the combustion residue from electric power plants burning lignite or sub-bituminous coal. As a mineral admixture, FH can be used to produce high-strength concrete and high-performance concrete. The development of chemical and mechanical properties is a crucial factor for appropriately using FH in the concrete industry. To achieve sustainable development in the concrete industry, this paper presents a theoretical model to systematically evaluate the property developments of FH blended concrete. The proposed model analyzes the cement hydration, the reaction of free CaO in FH, and the reaction of phases in FH other than free CaO. The mutual interactions among cement hydration, the reaction of free CaO in FH, and the reaction of other phases in FH are also considered through the calcium hydroxide contents and the capillary water contents. Using the hydration degree of cement, the reaction degree of free CaO in FH, and the reaction degree of other phases in FH, the proposed model evaluates the calcium hydroxide contents, the reaction degree of FH, chemically bound water, porosity, and the compressive strength of hardening concrete with different water to binder ratios and FH replacement ratios. The evaluated results are compared to experimental results, and good consistencies are found.

  20. Coronary Heart Disease in Familial Hypercholesterolemia

    NARCIS (Netherlands)

    J. Versmissen (Jorie)

    2012-01-01

    textabstractFamilial hypercholesterolemia (FH) (OMIM #143890) is an autosomal dominant disorder present in 1:500 Caucasians. FH is caused by defective low-density lipoprotein (LDL) receptors, leading to a diminished uptake of LDL cholesterol by the liver. As a result, FH patients have high LDL chole

  1. The relationship of a family history for hypertension, myocardial infarction, or stroke with cardiovascular physiology in young women.

    Science.gov (United States)

    McBride, Carole A; Hale, Sarah A; Subramanian, Meenakumari; Badger, Gary J; Bernstein, Ira M

    2014-04-01

    Cardiovascular disease (CVD) and preeclampsia share several pathophysiologic risk factors. We examined family history (FH) and physiologic status in 60 healthy, nulliparous women to determine the relationship between FH and known risk factors for CVD. Data are presented as mean ± standard error (SE). Decreased uterine blood flow was observed in women with FH of hypertension (+FH: 21.5 ± 1.7, no FH: 33.3 ± 9.0 mL/min; P = .04). Women reporting an FH of stroke showed increased alpha- and beta-adrenergic response, as measured by Valsalva maneuver (α: FH: 24.7 ± 1.9, -FH: 18.9 ± 1.1 mm Hg, P = .02; β: FH: 22.0 ± 2.1, -FH: 16.9 ± 1.4 mm Hg; P = .04), and increased cardiac output (4.83 ± 0.22 vs 4.31 ± 0.12 L/min; P = .01). We identified no significant physiologic associations linked to an FH of myocardial infarction. Our observations show significant differences in physiologic characteristics in women with specific CVD family histories. These data, coupled with known heritable contributions to CVD and preeclampsia, suggest a distinct physiologic phenotype that may link preeclampsia risk with FH of CVD, independent of pregnancy.

  2. Familial hypercholesterolemia: Screening, treatment and follow-up from pregnancy into young adulthood

    NARCIS (Netherlands)

    Kusters, D.M.

    2016-01-01

    In part 1, the consequences of familial hypercholesterolemia (FH) during pregnancy for the unborn child are explored. Part II comprises several studies on the screening, diagnosis and follow-up of children with FH. The treatment of children with FH is studied in part III, with the most important

  3. Familial hypercholesterolaemia in children and adolescents

    DEFF Research Database (Denmark)

    Wiegman, Albert; Gidding, Samuel S; Watts, Gerald F

    2015-01-01

    Familial hypercholesterolaemia (FH) is a common genetic cause of premature coronary heart disease (CHD). Globally, one baby is born with FH every minute. If diagnosed and treated early in childhood, individuals with FH can have normal life expectancy. This consensus paper aims to improve awareness...

  4. Arabidopsis group le formins localize to specific cell membrane domains, interact with actin-binding proteins and cause defects in cell expansion upon aberrant expression

    NARCIS (Netherlands)

    Deeks, M.J.; Cvrcková, F.; Machesky, L.M.; Mikitová, V.; Ketelaar, T.; Zársky, V.; Davies, B.; Hussey, P.J.

    2005-01-01

    ¿ The closely related proteins AtFH4 and AtFH8 represent the group Ie clade of Arabidopsis formin homologues. The subcellular localization of these proteins and their ability to affect the actin cytoskeleton were examined. ¿ AtFH4 protein activity was identified using fluorimetric techniques. Intera

  5. Pludselig uventet hjertedød hos en 18-årig kvinde med familiær hyperkolesterolæmi

    DEFF Research Database (Denmark)

    Risgaard, Bjarke; Jabbari, Reza; Bundgaard, Henning;

    2013-01-01

    Familial hypercholesterolaemia (FH) is a well-defined but underdiagnosed dyslipidaemia occurring in 1:500 persons. We report a case where an 18-year-old woman with an untreated FH dies a sudden cardiac death due to acute myocardial infarction. In patients with FH atherosclerotic manifestations...

  6. Familial hypercholesterolaemia

    DEFF Research Database (Denmark)

    Versmissen, Jorie; Vongpromek, Ranitha; Yahya, Reyhana

    2016-01-01

    cholesterol efflux capacity between male familial hypercholesterolaemia (FH) patients with and without CHD relative to their non-FH brothers, and examined HDL constituents including sphingosine-1-phosphate (S1P) and its carrier apolipoprotein M (apoM). RESULTS: Seven FH patients were asymptomatic and six had...

  7. Pludselig uventet hjertedød hos en 18-årig kvinde med familiær hyperkolesterolæmi

    DEFF Research Database (Denmark)

    Risgaard, Bjarke; Jabbari, Reza; Bundgaard, Henning

    2013-01-01

    Familial hypercholesterolaemia (FH) is a well-defined but underdiagnosed dyslipidaemia occurring in 1:500 persons. We report a case where an 18-year-old woman with an untreated FH dies a sudden cardiac death due to acute myocardial infarction. In patients with FH atherosclerotic manifestations...

  8. Construction of Frequency Hopping Sequence Set Based upon Generalized Cyclotomy

    CERN Document Server

    Liu, Fang; Zhou, Zhengchun; Tang, Xiaohu

    2010-01-01

    Frequency hopping (FH) sequences play a key role in frequency hopping spread spectrum communication systems. It is important to find FH sequences which have simultaneously good Hamming correlation, large family size and large period. In this paper, a new set of FH sequences with large period is proposed, and the Hamming correlation distribution of the new set is investigated. The construction of new FH sequences is based upon Whiteman's generalized cyclotomy. It is shown that the proposed FH sequence set is optimal with respect to the average Hamming correlation bound.

  9. Examination of the Feynman-Hibbs Approach in the Study of NeN-Coronene Clusters at Low Temperatures.

    Science.gov (United States)

    Rodríguez-Cantano, Rocío; Pérez de Tudela, Ricardo; Bartolomei, Massimiliano; Hernández, Marta I; Campos-Martínez, José; González-Lezana, Tomás; Villarreal, Pablo; Hernández-Rojas, Javier; Bretón, José

    2016-07-14

    Feynman-Hibbs (FH) effective potentials constitute an appealing approach for investigations of many-body systems at thermal equilibrium since they allow us to easily include quantum corrections within standard classical simulations. In this work we apply the FH formulation to the study of NeN-coronene clusters (N = 1-4, 14) in the 2-14 K temperature range. Quadratic (FH2) and quartic (FH4) contributions to the effective potentials are built upon Ne-Ne and Ne-coronene analytical potentials. In particular, a new corrected expression for the FH4 effective potential is reported. FH2 and FH4 cluster energies and structures-obtained from energy optimization through a basin-hopping algorithm as well as classical Monte Carlo simulations-are reported and compared with reference path integral Monte Carlo calculations. For temperatures T > 4 K, both FH2 and FH4 potentials are able to correct the purely classical calculations in a consistent way. However, the FH approach fails at lower temperatures, especially the quartic correction. It is thus crucial to assess the range of applicability of this formulation and, in particular, to apply the FH4 potentials with great caution. A simple model of N isotropic harmonic oscillators allows us to propose a means of estimating the cutoff temperature for the validity of the method, which is found to increase with the number of atoms adsorbed on the coronene molecule.

  10. Suitability of teriparatide and level of acceptance of pharmacotherapeutic recommendations in a healthcare management areaSuitability of teriparatide and level of acceptance of pharmacotherapeutic recommendations in a healthcare management area DOI:\t10.7399/fh.2016.40.4.9953

    Directory of Open Access Journals (Sweden)

    Maria Rosa Cantudo-Cuenca

    2016-07-01

    Full Text Available Objective: To analyse the suitability of teriparatide prescriptions for osteoporosis treatment in a health management area, as well as the level of acceptance of pharmacotherapeutic recommendations made to physicians. Design: A prospective interventional study conducted from february 2015 to june 2015. Setting: South Seville Health Management Area. Participants: Patients receiving teriparatide. Main measurements: Suitability of teriparatide prescriptions according to Clinical Practice Guidelines and level of acceptance of pharmacotherapeutic recommendations. Results: Teriparatide prescriptions were unsuitable in 45 patients (68.2%; 11 due to no indication, 17 patients did not have previous treatments with first-line drugs, 6 due to contraindications and 9 patients were treated for more than 24 months with the drug. Besides, 4 prescriptions were unsuitable because of combination with other therapies. The acceptance of pharmacotherapeutic recommendations was 64.4%, leading to teriparatide discontinuation in 21 patients (72.4%, and a switch to alendronate or ibandronate in another 8 patients. Conclusions: A high percentage of teriparatide prescriptions is unsuitable in our health care management area, but it has decreased after pharmacist intervention.

  11. Ethanol-induced autonomic responses and risk taking increase in young adults with a positive family history of alcohol problems.

    Science.gov (United States)

    Caneto, Florencia; Pautassi, Ricardo Marcos; Pilatti, Angelina

    2018-01-01

    The mechanisms that underlie the greater prevalence of alcohol use disorders in individuals with a positive family history (FH+) of alcohol abuse are still under investigation. These subjects may exhibit differential sensitivity to alcohol's effects on psychomotor stimulation and impulsivity. Alcohol-induced psychomotor stimulation, measured as the heart rate (HR) response, is a proxy for the positive rewarding effects of the drug. We analyzed alcohol-induced effects on time perception (Time Production Task), risk taking (Balloon Analogue Risk Task [BART]), and HR in FH+ and FH- participants. In the FH+ and FH- groups, women and men received 0.6 and 0.7g/kg alcohol, respectively. The alcohol dose yielded a breath alcohol concentration of 0.08% throughout the experiment. The control groups received placebo, and the subjective perception of alcohol intoxication was assessed. Alcohol intoxication significantly increased HR and the adjusted average number of pumps on the BART (a measure of risk taking) in FH+ men and women but not in FH- participants. Behavioral impulsivity was unaffected by alcohol or a FH of alcohol abuse. FH- but not FH+ participants who received alcohol reported significantly greater subjective perception of alcohol's effects than their placebo counterparts. These results indicate that FH+ individuals presented heightened sensitivity to alcohol-induced HR stimulation and alcohol-induced risk taking compared with their FH- counterparts. FH+ subjects, however, were insensitive to the subjective effects of alcohol. This idiosyncratic response pattern may be a likely pathway by which a FH of alcohol problems promotes alcohol drinking. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Defining the Binding Region in Factor H to Develop a Therapeutic Factor H-Fc Fusion Protein against Non-Typeable Haemophilus influenzae.

    Science.gov (United States)

    Wong, Sandy M; Shaughnessy, Jutamas; Ram, Sanjay; Akerley, Brian J

    2016-01-01

    Non-typeable Haemophilus influenzae (NTHi) cause a range of illnesses including otitis media, sinusitis, and exacerbation of chronic obstructive pulmonary disease, infections that contribute to the problem of antibiotic resistance and are themselves often intractable to standard antibiotic treatment regimens. We investigated a strategy to exploit binding of the complement inhibitor Factor H (FH) to NTHi as a functional target for an immunotherapeutic containing the NTHi binding domain of FH fused to the Fc domain of IgG1. Chimeric proteins containing the regions that most FH-binding bacteria use to engage human FH, domains 6 and 7 (FH6,7/Fc) and/or 18 through 20 (FH18-20/Fc), were evaluated for binding to NTHi. FH6,7/Fc bound strongly to each of seven NTHi clinical isolates tested and efficiently promoted complement-mediated killing by normal human serum. FH18-20/Fc bound weakly to three of the strains but did not promote complement dependent killing. Outer-membrane protein P5 has been implicated in FH binding by NTHi, and FH6,7/Fc binding was greatly diminished in five of seven P5 deficient isogenic mutant strains tested, implicating an alternative FH binding protein in some strains. Binding of FH18-20/Fc was decreased in the P5 mutant of one strain. A murine model was used to evaluate potential therapeutic application of FH6,7/Fc. FH6,7/Fc efficiently promoted binding of C3 to NTHi exposed to mouse serum, and intranasal delivery of FH6,7/Fc resulted in significantly enhanced clearance of NTHi from the lung. Moreover, a P5 deficient mutant was attenuated for survival in the lung model, suggesting that escape mutants lacking P5 would be less likely to replace strains susceptible to FH6,7/Fc. These results provide evidence for the potential utility of FH6,7/Fc as a therapeutic against NTHi lung infection. FH binding is a common property of many respiratory tract pathogens and FH/Fc chimeras may represent promising alternative or adjunctive therapeutics against such

  13. Defining the binding region in factor H to develop a therapeutic factor H-Fc fusion protein against nontypeable Haemophilus influenzae

    Directory of Open Access Journals (Sweden)

    Sandy M. Wong

    2016-04-01

    Full Text Available Nontypeable Haemophilus influenzae (NTHi cause a range of illnesses including otitis media, sinusitis, and exacerbation of chronic obstructive pulmonary disease, infections that contribute to the problem of antibiotic resistance and are themselves often intractable to standard antibiotic treatment regimens. We investigated a strategy to exploit binding of the complement inhibitor Factor H (FH to NTHi as a functional target for an immunotherapeutic containing the NTHi binding domain of FH fused to the Fc domain of IgG1. Chimeric proteins containing the regions that most FH-binding bacteria use to engage human FH, domains 6 and 7 (FH6,7/Fc and/or 18 through 20 (FH18-20/Fc, were evaluated for binding to NTHi. FH6,7/Fc bound strongly to each of seven NTHi clinical isolates tested and efficiently promoted complement-mediated killing by normal human serum. FH18-20/Fc bound weakly to three of the strains but did not promote complement dependent killing. Outer-membrane protein P5 has been implicated in FH binding by NTHi, and FH6,7/Fc binding was greatly diminished in five of seven P5 deficient isogenic mutant strains tested, implicating an alternative FH binding protein in some strains. Binding of FH18-20/Fc was decreased in the P5 mutant of one strain. A murine model was used to evaluate potential therapeutic application of FH6,7/Fc. FH6,7/Fc efficiently promoted binding of C3 to NTHi exposed to mouse serum, and intranasal delivery of FH6,7/Fc resulted in significantly enhanced clearance of NTHi from the lung. Moreover, a P5 deficient mutant was attenuated for survival in the lung model, suggesting that escape mutants lacking P5 would be less likely to replace strains susceptible to FH6,7/Fc. These results provide evidence for the potential utility of FH6,7/Fc as a therapeutic against NTHi lung infection. FH binding is a common property of many respiratory tract pathogens and FH/Fc chimeras may represent promising alternative or adjunctive

  14. Examination of the Feynman-Hibbs Approach in the Study of Ne$_N$-Coronene Clusters at Low Temperatures

    CERN Document Server

    Rodríguez-Cantano, R; Bartolomei, M; Hernández, M I; Campos-Martínez, J; González-Lezana, T; Villarreal, P; Hernández-Rojas, J; Bretón, J

    2016-01-01

    Feynman-Hibbs (FH) effective potentials constitute an appealing approach for investigations of many-body systems at thermal equilibrium since they allow us to easily include quantum corrections within standard classical simulations. In this work we apply the FH formulation to the study of Ne$_N$-coronene clusters ($N=$ 1-4, 14) in the 2-14 K temperature range. Quadratic (FH2) and quartic (FH4) contributions to the effective potentials are built upon Ne-Ne and Ne-coronene analytical potentials. In particular, a new corrected expression for the FH4 effective potential is reported. FH2 and FH4 cluster energies and structures -obtained from energy optimization through a basin-hoping algorithm as well as classical Monte Carlo simulations- are reported and compared with reference path integral Monte Carlo calculations. For temperatures $T> \\approx 4$ K, both FH2 and FH4 potentials are able to correct the purely classical calculations in a consistent way. However, the FH approach fails at lower temperatures, especia...

  15. Impact of family hypertension history on exercise-induced cardiac remodeling.

    Science.gov (United States)

    Baggish, Aaron L; Weiner, Rory B; Yared, Kibar; Wang, Francis; Kupperman, Eli; Hutter, Adolph M; Picard, Michael H; Wood, Malissa J

    2009-07-01

    Left ventricular (LV) hypertrophy is a well-established, but highly variable, finding among exercise-trained persons. The causes for the variability in LV remodeling in response to exercise training remain incompletely understood. The present study sought to determine whether a family history of hypertension is a determinant of the cardiac response to exercise training. The cardiac parameters in 60 collegiate rowers (30 men/30 women; age 19.8 +/- 1.1 years) with (family history positive [FH+], n = 22) and without (family history negative [FH-], n = 38) a FH of hypertension were studied with echocardiography before and after 90 days of rowing training. The LV mass increased significantly in both groups. However, the LV mass increased significantly more in FH- persons (Delta 17 +/- 5 g/m(2)) than in FH+ persons (Delta 9 +/- 6 g/m(2), p hypertrophy between the 2 groups. FH- athletes experienced eccentric LV hypertrophy (relative wall thickness index 0.39 +/- 0.4) characterized by LV dilation. In contrast, FH+ athletes developed concentric LV hypertrophy (relative wall thickness index 0.44 +/- 0.3; p eccentric LV remodeling in FH- athletes was associated with a more robust enhancement of LV diastolic function than the concentric LV remodeling that occurred in FH+ athletes. In conclusion, these findings suggest that patterns of exercise-induced LV remodeling are strongly associated with FH history status.

  16. Environment and feeding change the ability of heart rate to predict metabolism in resting Steller sea lions (Eumetopias jubatus).

    Science.gov (United States)

    Young, Beth L; Rosen, David A S; Haulena, Martin; Hindle, Allyson G; Trites, Andrew W

    2011-01-01

    The ability to use heart rate (fh) to predict oxygen consumption rates ([Formula: see text]) in Steller sea lions and other pinnipeds has been investigated in fasting animals. However, it is unknown whether established fh:[Formula: see text] relationships hold under more complex physiological situations, such as when animals are feeding or digesting. We assessed whether fh could accurately predict [Formula: see text] in trained Steller sea lions while fasting and after being fed. Using linear mixed-effects models, we derived unique equations to describe the fh:[Formula: see text] relationship for fasted sea lions resting on land and in water. Feeding did not significantly change the fh:[Formula: see text] relationship on land. However, Steller sea lions in water displayed a different fh:[Formula: see text] relationship after consuming a 4-kg meal compared with the fasting condition. Incorporating comparable published fh:[Formula: see text] data from Steller sea lions showed a distinct effect of feeding after a 6-kg meal. Ultimately, our study illustrated that both feeding and physical environment are statistically relevant when deriving [Formula: see text] from telemetered fh, but that only environment affects the practical ability to predict metabolism from fh. Updating current bioenergetic models with data gathered using these predictive fh:[Formula: see text] equations will yield more accurate estimates of metabolic rates of free-ranging Steller sea lions under a variety of physiological, behavioral, and environmental states.

  17. Quantification of fumarate and investigation of endogenous and exogenous fumarate stability in rat plasma by LC-MS/MS.

    Science.gov (United States)

    Shi, Yao; Tse, Susanna; Rago, Brian; Yapa, Udeni; Li, Fumin; Fast, Douglas M

    2016-04-01

    Fumaric acid is a commonly used excipient in pharmaceutical products. It is not known if its presence may lead to fluctuation of endogenous fumarate levels. An LC-MS/MS method was developed and validated to quantify fumarate in support of a toxicokinetics study. Stability evaluation showed that endogenous fumarate was stable for 6 h at room temperature, while exogenously added fumaric acid was converted to malate within 1 h due to the presence of fumarase. Citric acid, a fumarase inhibitor, prevented the conversion of added fumaric acid in rat plasma. The method was validated in citric acid stabilized rat plasma using a surrogate matrix approach. A discrepancy in stability was observed between endogenous fumarate and exogenously added fumaric acid.

  18. Clinical management of familial hypercholesterolemia: new insights from international guidelines and recent studies

    Directory of Open Access Journals (Sweden)

    Anthony S. Wierzbicki

    2014-12-01

    Full Text Available This review article assesses the clinical features, diagnosis and management of familial hypercholesterolemia (FH. FH is mostly an autosomally dominantly inherited with an incidence of 1 in 250. Tendon xanthomata are pathognomonic. Untreated FH is associated with 100-200 fold increase in risk of cardiovascular disease (CVD. FH is diagnosed by screening for elevated low density lipoprotein cholesterol (LDL-C and confirmed by DNA techniques. Once index cases have been identified cascade family screening should occur. FH is primarily treated with high dose statin therapy. This reduces progression of surrogate markers of coronary arterial disease and registry studies show a 70% long-term decrease in CVD mortality. The justification for other lipidlowering therapies e.g. ezetimibe relies on the high population attributable risk of LDL-C in FH. Novel therapies with greater LDL-C reducing actions such as proprotein convertase subtilisin kexin-9 inhibitors show promise in FH Children with FH should be identified through cascade screening but drug treatment is dependent on LDL-C and family history. They should be managed in specialist paediatric units or in family clinics. Cases of homozygous FH are rare. This orphan condition should be managed in specialist centers with a combination of drug therapy, apheresis and liver transplantation. Novel therapies for the treatment of homozygous FH such as mipomersen and lomitapide are gradually coming into use FH is a common underdiagnosed condition. Current, let alone future, therapies are extremely effective in reducing both LDL-C and CVD events in patients with FH. Identification and treatment of FH should be a feature of preventative CVD medicine programmes.

  19. Glutamate-119 of the large alpha-subunit is the catalytic base in the hydration of 2-trans-enoyl-coenzyme A catalyzed by the multienzyme complex of fatty acid oxidation from Escherichia coli.

    Science.gov (United States)

    He, X Y; Yang, S Y

    1997-09-09

    Glu139 of the large alpha-subunit of the multienzyme complex of fatty acid oxidation from Escherichia coli was identified as the catalytic residue of enoyl-CoA hydratase [Yang, S.-Y., He, X.-Y., & Schulz, H. (1995) Biochemistry 34, 6441-6447]. To determine whether any of the other conserved protic residues is directly involved in the hydratase catalysis, the multienzyme complexes with either an alpha/Asp69 --> Asn or an alpha/Glu119 --> Gln mutation were overproduced and characterized. The catalytic properties of 3-ketoacyl-CoA thiolase and l-3-hydroxyacyl-CoA dehydrogenase of the mutant complexes were almost unaffected. The amidation of Asp69 and Glu119 caused a 7.6- and 88-fold decrease, respectively, in the kcat of enoyl-CoA hydratase without a significant change in the Km value of the hydratase as well as a 5.9- and 62-fold increase, respectively, in the Km of Delta3-cis-Delta2-trans-enoyl-CoA isomerase with a very small decrease in the kcat of the latter enzyme. The data suggest that the carboxyl group of Glu119 is particularly important to the catalytic activity of enoyl-CoA hydratase. Furthermore, the wild-type hydratase shows a bell-shaped pH dependence of the kcat/Km with pKa values of 5.9 and 9.2, whereas the Glu119 --> Gln mutant hydratase has only a single pKa of 9.5. A simple explanation for these observations is that a deprotonated Glu119 and a protonated Glu139 are required for the high kcat of the enoyl-CoA hydratase. The results of site-directed mutagenesis studies, together with the structural information about the spatial arrangement of two conserved glutamate residues of rat liver enoyl-CoA hydratase [Engel, C. K., Mathieu, M., Zeelen, J. P., Hiltunen, J. K., and Wierenga, R. K. (1996) EMBO J. 15, 5135-5145] to which Glu119 and Glu139 of the large alpha-subunit correspond, lead to the conclusion that the gamma-carboxyl group of Glu119 serves as the second general acid-base functional group in catalyzing the hydration of 2-trans-enoyl-CoA.

  20. Tellurite enters Escherichia coli mainly through the PitA phosphate transporter

    OpenAIRE

    Elías, Alex O; Abarca, María José; Montes, Rebecca A; Chasteen, Thomas G; Pérez-Donoso, José M.; Vásquez, Claudio C.

    2012-01-01

    Several transporters suspected to be involved in tellurite uptake in Escherichia coli were analyzed. Results showed that the PitA phosphate transporter was related to tellurite uptake. Escherichia coli ΔpitA was approximately four-fold more tolerant to tellurite, and cell viability remained almost unchanged during prolonged exposure to the toxicant as compared with wild type or ΔpitB cells. Notably, reduced thiols (toxicant targets) as well as superoxide dismutase, catalase, and fumarase C ac...

  1. 3-D Enzymatic Nanomaterial Architectures for Energy Harvesting

    Science.gov (United States)

    2016-06-30

    Demonstration of physical interactions between consecutive enzymes of the citric acid cycle and of the aspartate-malate shuttle. A study involving fumarase...glycolysis, TCA cycle , fatty acid oxidation, electron transport chain, antibiotic biosynthesis, urea cycle and cyclic AMP degradation.[3] We have...oxidation, amino acid metabolism, lipid biosynthesis and the tricarboxylic acid (TCA) cycle .5,11 Several enzymes of the TCA cycle participate in

  2. Structural studies of MFE-1: the 1.9 A crystal structure of the dehydrogenase part of rat peroxisomal MFE-1.

    Science.gov (United States)

    Taskinen, Jukka P; Kiema, Tiila R; Hiltunen, J Kalervo; Wierenga, Rik K

    2006-01-27

    The 1.9 A structure of the C-terminal dehydrogenase part of the rat peroxisomal monomeric multifunctional enzyme type 1 (MFE-1) has been determined. In this construct (residues 260-722 and referred to as MFE1-DH) the N-terminal hydratase part of MFE-1 has been deleted. The structure of MFE1-DH shows that it consists of an N-terminal helix, followed by a Rossmann-fold domain (domain C), followed by two tightly associated helical domains (domains D and E), which have similar topology. The structure of MFE1-DH is compared with the two known homologous structures: human mitochondrial 3-hydroxyacyl-CoA dehydrogenase (HAD; sequence identity is 33%) (which is dimeric and monofunctional) and with the dimeric multifunctional alpha-chain (alphaFOM; sequence identity is 28%) of the bacterial fatty acid beta-oxidation alpha2beta2-multienzyme complex. Like MFE-1, alphaFOM has an N-terminal hydratase part and a C-terminal dehydrogenase part, and the structure comparisons show that the N-terminal helix of MFE1-DH corresponds to the alphaFOM linker helix, located between its hydratase and dehydrogenase part. It is also shown that this helix corresponds to the C-terminal helix-10 of the hydratase/isomerase superfamily, suggesting that functionally it belongs to the N-terminal hydratase part of MFE-1.

  3. Expression, purification, cocrystallization and preliminary crystallographic analysis of sucrose octasulfate/human complement regulator factor H SCRs 6–8

    Energy Technology Data Exchange (ETDEWEB)

    Prosser, Beverly E.; Johnson, Steven; Roversi, Pietro [The Sir William Dunn School of Pathology, The University of Oxford, South Parks Road, Oxford OX1 3RE (United Kingdom); Clark, Simon J. [Faculty of Life Sciences, Manchester University, Michael Smith Building, Oxford Road, Manchester M13 9PT (United Kingdom); Tarelli, Edward [Medical Biomics Centre, St George’s, University of London, Cranmer Terrace, London SW17 0RE (United Kingdom); Sim, Robert B. [The MRC Immunochemistry Unit, The University of Oxford, South Parks Road, Oxford OX1 3RE (United Kingdom); Day, Antony J. [Faculty of Life Sciences, Manchester University, Michael Smith Building, Oxford Road, Manchester M13 9PT (United Kingdom); Lea, Susan M., E-mail: susan.lea@bnc.ox.ac.uk [The Sir William Dunn School of Pathology, The University of Oxford, South Parks Road, Oxford OX1 3RE (United Kingdom)

    2007-06-01

    The crystallization of human complement regulator FH-678{sub 402H} with a glycosaminoglycan analogue is described. Human plasma protein complement factor H (FH) is an inhibitor of the spontaneously activated alternative complement pathway. An allotypic variant of FH, 402His, has been associated with age-related macular degeneration, the leading cause of blindness in the elderly. Crystals of FH domains 6–8 (FH678) containing 402His have been grown in the presence of a polyanionic sucrose octasulfate ligand (an analogue of the natural glycosaminoglycan ligands of FH) using both native and selenomethionine-derivatized protein. Native data sets diffracting to 2.3 Å and SeMet data sets of up to 2.8 Å resolution have been collected. An anomalous difference Patterson map reveals self- and cross-peaks from two incorporated Se atoms. The corresponding selenium substructure has been solved.

  4. Excretory/secretory products of Fasciola hepatica but not recombinant phosphoglycerate kinase induce death of human hepatocyte cells.

    Science.gov (United States)

    Bąska, Piotr; Norbury, Luke J; Wiśniewski, Marcin; Januszkiewicz, Kamil; Wędrychowicz, Halina

    2013-06-01

    The liver fluke Fasciola hepatica infects a wide range of hosts, and has a considerable impact on the agriculture industry, mainly through infections of sheep and cattle. Further, human infection is now considered of public health importance and is hyperendemic in some regions. The fluke infection causes considerable damage to the hosts' liver. However, the mechanisms of liver destruction have not yet been completely elucidated. In the present report we incubated a human liver cell line in the presence of either F. hepatica excretory/secretory material (FhES) or recombinant phosphoglycerate kinase (FhPGK). Dosedependent cytotoxicity in the presence of FhES was observed, indicating that FhES is capable of killing human hepatocytes, supporting a role for FhES in damaging host liver cells during infection; while treatment with a recombinant intracellular protein - FhPGK, had no impact on cell survival.

  5. Microbes bind complement inhibitor factor H via a common site.

    Directory of Open Access Journals (Sweden)

    T Meri

    Full Text Available To cause infections microbes need to evade host defense systems, one of these being the evolutionarily old and important arm of innate immunity, the alternative pathway of complement. It can attack all kinds of targets and is tightly controlled in plasma and on host cells by plasma complement regulator factor H (FH. FH binds simultaneously to host cell surface structures such as heparin or glycosaminoglycans via domain 20 and to the main complement opsonin C3b via domain 19. Many pathogenic microbes protect themselves from complement by recruiting host FH. We analyzed how and why different microbes bind FH via domains 19-20 (FH19-20. We used a selection of FH19-20 point mutants to reveal the binding sites of several microbial proteins and whole microbes (Haemophilus influenzae, Bordetella pertussis, Pseudomonas aeruginosa, Streptococcus pneumonia, Candida albicans, Borrelia burgdorferi, and Borrelia hermsii. We show that all studied microbes use the same binding region located on one side of domain 20. Binding of FH to the microbial proteins was inhibited with heparin showing that the common microbial binding site overlaps with the heparin site needed for efficient binding of FH to host cells. Surprisingly, the microbial proteins enhanced binding of FH19-20 to C3b and down-regulation of complement activation. We show that this is caused by formation of a tripartite complex between the microbial protein, FH, and C3b. In this study we reveal that seven microbes representing different phyla utilize a common binding site on the domain 20 of FH for complement evasion. Binding via this site not only mimics the glycosaminoglycans of the host cells, but also enhances function of FH on the microbial surfaces via the novel mechanism of tripartite complex formation. This is a unique example of convergent evolution resulting in enhanced immune evasion of important pathogens via utilization of a "superevasion site."

  6. Severe familial hypercholesterolemia impairs the regulation of coronary blood flow and oxygen supply during exercise.

    Science.gov (United States)

    Bender, Shawn B; de Beer, Vincent J; Tharp, Darla L; Bowles, Douglas K; Laughlin, M Harold; Merkus, Daphne; Duncker, Dirk J

    2016-11-01

    Accelerated development of coronary atherosclerosis is a defining characteristic of familial hypercholesterolemia (FH). However, the recent data highlight a significant cardiovascular risk prior to the development of critical coronary stenosis. We, therefore, examined the hypothesis that FH produces coronary microvascular dysfunction and impairs coronary vascular control at rest and during exercise in a swine model of FH. Coronary vascular responses to drug infusions and exercise were examined in chronically instrumented control and FH swine. FH swine exhibited ~tenfold elevation of plasma cholesterol and diffuse coronary atherosclerosis (20-60 % plaque burden). Similar to our recent findings in the systemic vasculature in FH swine, coronary smooth muscle nitric oxide sensitivity was increased in vivo and in vitro with maintained endothelium-dependent vasodilation in vivo in FH. At rest and during exercise, FH swine exhibited increased myocardial O2 extraction resulting in reduced coronary venous SO2 and PO2 versus control. During exercise in FH swine, the transmural distribution of coronary blood flow was unchanged; however, a shift toward anaerobic cardiac metabolism was revealed by increased coronary arteriovenous H(+) concentration gradient. This shift was associated with a worsening of cardiac efficiency (relationship between cardiac work and O2 consumption) in FH during exercise owing, in part, to a generalized reduction in stroke volume which was associated with increased left atrial pressure in FH. Our data highlight a critical role for coronary microvascular dysfunction as a contributor to impaired myocardial O2 balance, cardiac ischemia, and impaired cardiac function prior to the development of critical coronary stenosis in FH.

  7. My Approach to the Patient With Familial Hypercholesterolemia

    Science.gov (United States)

    Safarova, Maya S.; Kullo, Iftikhar J.

    2017-01-01

    Familial hypercholesterolemia (FH), a relatively common Mendelian genetic disorder, is associated with a dramatically increased lifetime risk of premature atherosclerotic cardiovascular disease due to elevated plasma low-density lipoprotein cholesterol (LDL-C) levels. The diagnosis of FH is based on clinical presentation or genetic testing. Early identification of patients with FH is of great public health importance because preventive strategies can lower the absolute lifetime cardiovascular risk and screening can detect affected relatives. However, low awareness, detection, and control of FH pose hurdles in the prevention of FH-related cardiovascular events. Of the estimated 0.65 million to 1 million patients with FH in the United States, less than 10% carry a diagnosis of FH. Based on registry data, a substantial proportion of patients with FH are receiving no or inadequate lipid-lowering therapy. Statins remain the mainstay of treatment for patients with FH. Lipoprotein apheresis and newly approved lipid-lowering drugs are valuable adjuncts to statin therapy, particularly when the LDL-C–lowering response is suboptimal. Monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 provide an additional approximately 60% lowering of LDL-C levels and are approved for use in patients with FH. For homozygous FH, 2 new drugs that work independent of the LDL receptor pathway are available: an apolipoprotein B antisense oligonucleotide (mipomersen) and a microsomal triglyceride transfer protein inhibitor (lomitapide). This review attempts to critically examine the available data to provide a summary of the current evidence for managing patients with FH, including screening, diagnosis, treatment, and surveillance. PMID:27261867

  8. On Analog of Fourier Transform in Interior of the Light Cone

    Directory of Open Access Journals (Sweden)

    Tatyana Shtepina

    2014-01-01

    Full Text Available We introduce an analog of Fourier transform Fhρ in interior of light cone that commutes with the action of the Lorentz group. We describe some properties of Fhρ, namely, its action on pseudoradial functions and functions being products of pseudoradial function and space hyperbolic harmonics. We prove that Fhρ-transform gives a one-to-one correspondence on each of the irreducible components of quasiregular representation. We calculate the inverse transform too.

  9. Dicty_cDB: VSG271 [Dicty_cDB

    Lifescience Database Archive (English)

    Full Text Available date 2001. 3.22 Translated Amino Acid sequence eiq**invnisr*ifr*f**w*rcisrlwirkk**k**fik*fh**fww*gr**q****k ...q**invxisr*ifr*f**w*rcisrlwirkk**k**fik*fh**fww*gr**q** **kfhxyxyxn*intqyk*ttqln Frame B: kynnklmstladrflddf...ENSTXTTTXTK*thninklln*i Translated Amino Acid sequence (All Frames) Frame A: eiq*...*invnisr*ifr*f**w*rcisrlwirkk**k**fik*fh**fww*gr**q****k fhyynyyn*intqyk*TTQLNKHNINNLISFLTIKKKKXEKK--- ---ex

  10. Reduced contribution of endothelin to the regulation of systemic and pulmonary vascular tone in severe familial hypercholesterolaemia.

    Science.gov (United States)

    Bender, Shawn B; de Beer, Vincent J; Tharp, Darla L; van Deel, Elza D; Bowles, Douglas K; Duncker, Dirk J; Laughlin, M Harold; Merkus, Daphne

    2014-04-15

    Vascular dysfunction has been associated with familial hypercholesterolaemia (FH), a severe form of hyperlipidaemia. We recently demonstrated that swine with FH exhibit reduced exercise-induced systemic, but not pulmonary, vasodilatation involving reduced nitric oxide (NO) bioavailability. Since NO normally limits endothelin (ET) action, we examined the hypothesis that reduced systemic vasodilatation during exercise in FH swine results from increased ET-mediated vasoconstriction. Systemic and pulmonary vascular responses to exercise were examined in chronically instrumented normal and FH swine in the absence and presence of the ETA/B receptor antagonist tezosentan. Intrinsic reactivity to ET was further assessed in skeletal muscle arterioles. FH swine exhibited ∼9-fold elevation in total plasma cholesterol versus normal swine. Similar to our recent findings, systemic, not pulmonary, vasodilatation during exercise was reduced in FH swine. Blockade of ET receptors caused marked systemic vasodilatation at rest and during exercise in normal swine that was significantly reduced in FH swine. The reduced role of ET in FH swine in vivo was not the result of decreased arteriolar ET responsiveness, as responsiveness was increased in isolated arterioles. Smooth muscle ET receptor protein content was unaltered by FH. However, circulating plasma ET levels were reduced in FH swine. ET receptor antagonism caused pulmonary vasodilatation at rest and during exercise in normal, but not FH, swine. Therefore, contrary to our hypothesis, FH swine exhibit a generalised reduction in the role of ET in regulating vascular tone in vivo probably resulting from reduced ET production. This may represent a unique vascular consequence of severe familial hypercholesterolaemia.

  11. An investigation of nitrile transforming enzymes in the chemo-enzymatic synthesis of the taxol sidechain.

    Science.gov (United States)

    Wilding, Birgit; Veselá, Alicja B; Perry, Justin J B; Black, Gary W; Zhang, Meng; Martínková, Ludmila; Klempier, Norbert

    2015-07-28

    Paclitaxel (taxol) is an antimicrotubule agent widely used in the treatment of cancer. Taxol is prepared in a semisynthetic route by coupling the N-benzoyl-(2R,3S)-3-phenylisoserine sidechain to the baccatin III core structure. Precursors of the taxol sidechain have previously been prepared in chemoenzymatic approaches using acylases, lipases, and reductases, mostly featuring the enantioselective, enzymatic step early in the reaction pathway. Here, nitrile hydrolysing enzymes, namely nitrile hydratases and nitrilases, are investigated for the enzymatic hydrolysis of two different sidechain precursors. Both sidechain precursors, an openchain α-hydroxy-β-amino nitrile and a cyanodihydrooxazole, are suitable for coupling to baccatin III directly after the enzymatic step. An extensive set of nitrilases and nitrile hydratases was screened towards their activity and selectivity in the hydrolysis of two taxol sidechain precursors and their epimers. A number of nitrilases and nitrile hydratases converted both sidechain precursors and their epimers.

  12. [Transformation of 2- and 4-cyanopyridines by free and immobilized cells of nitrile-hydrolyzing bacteria].

    Science.gov (United States)

    Maksimova, Iu G; Vasil'ev, D M; Ovechkina, G V; Maksimov, A Iu; Demakov, V A

    2013-01-01

    The transformation dynamics of 2- and 4-cyanopyridines by cells suspended and adsorbed on inorganic carriers has been studied in the Rhodococcus ruber gt 1 strain possessing nitrile hydratase activity and the Pseudomonas fluorescens C2 strain containing nitrilase. It was shown that both nitrile hydratase and nitrilase activities of immobilized cells against 2-cyanopyridine were 1.5-4 times lower compared to 4-cyanopyridine and 1.6-2 times lower than the activities of free cells against 2-cyanpopyridine. The possibility of obtaining isonicotinic acid during the combined conversion of 4-cyanopyridine by a mixed suspension of R. ruber gt 1 cells with a high level of nitrile hydratase activity and R. erythropolis 11-2 cells with a pronounced activity of amidase has been shown. Immobilization of Rhodococcus cells on raw coal and Pseudomonas cells on china clay was shown to yield a heterogeneous biocatalyst for the efficient transformation of cyanopyridines into respective amides and carbonic acids.

  13. Affinity purification of human factor H on polypeptides derived from streptococcal m protein: enrichment of the Y402 variant.

    Directory of Open Access Journals (Sweden)

    O Rickard Nilsson

    Full Text Available Recent studies indicate that defective activity of complement factor H (FH is associated with several human diseases, suggesting that pure FH may be used for therapy. Here, we describe a simple method to isolate human FH, based on the specific interaction between FH and the hypervariable region (HVR of certain Streptococcus pyogenes M proteins. Special interest was focused on the FH polymorphism Y402H, which is associated with the common eye disease age-related macular degeneration (AMD and has also been implicated in the binding to M protein. Using a fusion protein containing two copies of the M5-HVR, we found that the Y402 and H402 variants of FH could be efficiently purified by single-step affinity chromatography from human serum containing the corresponding protein. Different M proteins vary in their binding properties, and the M6 and M5 proteins, but not the M18 protein, showed selective binding of the FH Y402 variant. Accordingly, chromatography on a fusion protein derived from the M6-HVR allowed enrichment of the Y402 protein from serum containing both variants. Thus, the exquisite binding specificity of a bacterial protein can be exploited to develop a simple and robust procedure to purify FH and to enrich for the FH variant that protects against AMD.

  14. Affinity purification of human factor H on polypeptides derived from streptococcal m protein: enrichment of the Y402 variant.

    Science.gov (United States)

    Nilsson, O Rickard; Lannergård, Jonas; Morgan, B Paul; Lindahl, Gunnar; Gustafsson, Mattias C U

    2013-01-01

    Recent studies indicate that defective activity of complement factor H (FH) is associated with several human diseases, suggesting that pure FH may be used for therapy. Here, we describe a simple method to isolate human FH, based on the specific interaction between FH and the hypervariable region (HVR) of certain Streptococcus pyogenes M proteins. Special interest was focused on the FH polymorphism Y402H, which is associated with the common eye disease age-related macular degeneration (AMD) and has also been implicated in the binding to M protein. Using a fusion protein containing two copies of the M5-HVR, we found that the Y402 and H402 variants of FH could be efficiently purified by single-step affinity chromatography from human serum containing the corresponding protein. Different M proteins vary in their binding properties, and the M6 and M5 proteins, but not the M18 protein, showed selective binding of the FH Y402 variant. Accordingly, chromatography on a fusion protein derived from the M6-HVR allowed enrichment of the Y402 protein from serum containing both variants. Thus, the exquisite binding specificity of a bacterial protein can be exploited to develop a simple and robust procedure to purify FH and to enrich for the FH variant that protects against AMD.

  15. Perinatal complications and genetic loading in schizophrenia: preliminary findings.

    Science.gov (United States)

    Schwarzkopf, S B; Nasrallah, H A; Olson, S C; Coffman, J A; McLaughlin, J A

    1989-03-01

    History of perinatal complications (PCs) and first degree family history (FH) of psychiatric illness were examined in groups of schizophrenic/schizoaffective (n = 21) and bipolar (n = 10) patients. PCs were significantly more frequent in the schizophrenic and schizoaffective patients than in bipolar patients. An inverse relationship was found between PCs and FH status, with FH-positive patients having significantly fewer PCs than the FH-negative group. This relationship persisted when the bipolar patients were excluded. Findings emphasize the etiological importance of genetics and perinatal events in the psychoses, and support the validity of a familial/sporadic distinction.

  16. Novel Frequency Hopping Sequences Generator Based on AES Algorithm

    Institute of Scientific and Technical Information of China (English)

    李振荣; 庄奕琪; 张博; 张超

    2010-01-01

    A novel frequency hopping(FH) sequences generator based on advanced encryption standard(AES) iterated block cipher is proposed for FH communication systems.The analysis shows that the FH sequences based on AES algorithm have good performance in uniformity, correlation, complexity and security.A high-speed, low-power and low-cost ASIC of FH sequences generator is implemented by optimizing the structure of S-Box and MixColumns of AES algorithm, proposing a hierarchical power management strategy, and applying ...

  17. Fasciola hepatica tegumental antigens indirectly induce an M2 macrophage-like phenotype in vivo.

    Science.gov (United States)

    Adams, P N; Aldridge, A; Vukman, K V; Donnelly, S; O'Neill, S M

    2014-10-01

    The M2 subset of macrophages has a critical role to play in host tissue repair, tissue fibrosis and modulation of adaptive immunity during helminth infection. Infection with the helminth, Fasciola hepatica, is associated with M2 macrophages in its mammalian host, and this response is mimicked by its excretory-secretory products (FhES). The tegumental coat of F. hepatica (FhTeg) is another major source of immune-modulatory molecules; we have previously shown that FhTeg can modulate the activity of both dendritic cells and mast cells inhibiting their ability to prime a Th1 immune response. Here, we report that FhTeg does not induce Th2 immune responses but can induce M2-like phenotype in vivo that modulates cytokine production from CD4(+) cells in response to anti-CD3 stimulation. FhTeg induces a RELMα expressing macrophage population in vitro, while in vivo, the expression of Arg1 and Ym-1/2 but not RELMα in FhTeg-stimulated macrophages was STAT6 dependent. To support this finding, FhTeg induces RELMα expression in vivo prior to the induction of IL-13. FhTeg can induce IL-13-producing peritoneal macrophages following intraperitoneal injection This study highlights the important role of FhTeg as an immune-modulatory source during F. hepatica infection and sheds further light on helminth-macrophage interactions.

  18. Molecular and Biochemical Analysis of Chalcone Synthase from Freesia hybrid in flavonoid biosynthetic pathway.

    Directory of Open Access Journals (Sweden)

    Wei Sun

    Full Text Available Chalcone synthase (CHS catalyzes the first committed step in the flavonoid biosynthetic pathway. In this study, the cDNA (FhCHS1 encoding CHS from Freesia hybrida was successfully isolated and analyzed. Multiple sequence alignments showed that both the conserved CHS active site residues and CHS signature sequence were found in the deduced amino acid sequence of FhCHS1. Meanwhile, crystallographic analysis revealed that protein structure of FhCHS1 is highly similar to that of alfalfa CHS2, and the biochemical analysis results indicated that it has an enzymatic role in naringenin biosynthesis. Moreover, quantitative real-time PCR was performed to detect the transcript levels of FhCHS1 in flowers and different tissues, and patterns of FhCHS1 expression in flowers showed significant correlation to the accumulation patterns of anthocyanin during flower development. To further characterize the functionality of FhCHS1, its ectopic expression in Arabidopsis thaliana tt4 mutants and Petunia hybrida was performed. The results showed that overexpression of FhCHS1 in tt4 mutants fully restored the pigmentation phenotype of the seed coats, cotyledons and hypocotyls, while transgenic petunia expressing FhCHS1 showed flower color alteration from white to pink. In summary, these results suggest that FhCHS1 plays an essential role in the biosynthesis of flavonoid in Freesia hybrida and may be used to modify the components of flavonoids in other plants.

  19. Dependence of microbial magnetite formation on humic substance and ferrihydrite concentrations

    Science.gov (United States)

    Piepenbrock, Annette; Dippon, Urs; Porsch, Katharina; Appel, Erwin; Kappler, Andreas

    2011-11-01

    Iron mineral (trans)formation during microbial Fe(III) reduction is of environmental relevance as it can influence the fate of pollutants such as toxic metal ions or hydrocarbons. Magnetite is an important biomineralization product of microbial iron reduction and influences soil magnetic properties that are used for paleoclimate reconstruction and were suggested to assist in the localization of organic and inorganic pollutants. However, it is not well understood how different concentrations of Fe(III) minerals and humic substances (HS) affect magnetite formation during microbial Fe(III) reduction. We therefore used wet-chemical extractions, magnetic susceptibility measurements and X-ray diffraction analyses to determine systematically how (i) different initial ferrihydrite (FH) concentrations and (ii) different concentrations of HS (i.e. the presence of either only adsorbed HS or adsorbed and dissolved HS) affect magnetite formation during FH reduction by Shewanella oneidensis MR-1. In our experiments magnetite formation did not occur at FH concentrations lower than 5 mM, even though rapid iron reduction took place. At higher FH concentrations a minimum fraction of Fe(II) of 25-30% of the total iron present was necessary to initiate magnetite formation. The Fe(II) fraction at which magnetite formation started decreased with increasing FH concentration, which might be due to aggregation of the FH particles reducing the FH surface area at higher FH concentrations. HS concentrations of 215-393 mg HS/g FH slowed down (at partial FH surface coverage with sorbed HS) or even completely inhibited (at complete FH surface coverage with sorbed HS) magnetite formation due to blocking of surface sites by adsorbed HS. These results indicate the requirement of Fe(II) adsorption to, and subsequent interaction with, the FH surface for the transformation of FH into magnetite. Additionally, we found that the microbially formed magnetite was further reduced by strain MR-1 leading to

  20. New Approaches in Detection and Treatment of Familial Hypercholesterolemia

    OpenAIRE

    Hartgers, Merel L.; Ray, Kausik K.; Hovingh, G. Kees

    2015-01-01

    Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder that clinically leads to increased low density lipoprotein-cholesterol (LDL-C) levels. As a consequence, FH patients are at high risk for cardiovascular disease (CVD). Mutations are found in genes coding for the LDLR, apoB, and PCSK9, although FH cannot be ruled out in the absence of a mutation in one of these genes. It is pivotal to diagnose FH at an early age, since lipid lowering results in a decreased risk of car...

  1. Mutations causative of familial hypercholesterolaemia

    DEFF Research Database (Denmark)

    Benn, Marianne; Watts, Gerald F; Tybjærg-Hansen, Anne

    2016-01-01

    AIMS: Ideally, familial hypercholesterolaemia (FH) is diagnosed by testing for mutations that decrease the catabolism of low-density lipoprotein (LDL) cholesterol; however, genetic testing is not universally available. The aim of the present study was to assess the frequency and predictors of FH....... The prevalence of the four FH mutations was 0.18% (1:565), suggesting a total prevalence of FH mutations of 0.46% (1:217). Using the Dutch Lipid Clinic Network (DLCN) criteria, odds ratios for an FH mutation were 439 (95% CI: 170-1 138) for definite FH, 90 (53-152) for probable FH, and 18 (13-25) for possible FH......-cholesterol concentration to discriminate between mutation carriers and non-carriers was 4.4 mmol/L. CONCLUSION: Familial hypercholesterolaemia-causing mutations are estimated to occur in 1:217 in the general population and are best identified by a definite or probable phenotypic diagnosis of FH based on the DLCN criteria...

  2. Dicty_cDB: CFG407 [Dicty_cDB

    Lifescience Database Archive (English)

    Full Text Available slated Amino Acid sequence k*kk*yyf*qyylyyylvklnhihl*nvwigilvqihvqhtqetidfmnnkamvsyskev nsqnhtqlnwvnhvaqhkee...fh*nhtlihhllmmvihtiqlafhfkdsiem nsmllly Frame B: k*kk*yyf*qyylyyylvklnhihl*nvwigilvqihvqhtqetidfmnnkamvsyske

  3. Factor H specifically capture novel Factor H-binding proteins of Streptococcus suis and contribute to the virulence of the bacteria.

    Science.gov (United States)

    Li, Quan; Ma, Caifeng; Fu, Yang; He, Yanan; Yu, Yanfei; Du, Dechao; Yao, Huochun; Lu, Chengping; Zhang, Wei

    2017-03-01

    Factor H (FH), a regulatory protein of the complement system, can bind specifically to factor H-binding proteins (FHBPs) of Streptococcus suis serotype 2 (SS2), which contribute to evasion of host innate immune defenses. In the present study, we aimed to identify novel FHBPs and characterize the biological functions of FH in SS2 pathogenesis. Here, a method that combined proteomics and Far-western blotting was developed to identify the surface FHBPs of SS2. With this method, fourteen potential novel FHBPs were identified among SS2 surface proteins. We selected eight newly identified proteins and further confirmed their binding activity to FH. The binding of SS2 to immobilized FH decreased dramatically after pre-incubation with anti-FHBPs polyclonal antibodies. We showed for the first time that SS2 also interact specifically with mouse FH. Furthermore, we found that FH play an important role in adherence and invasion of SS2 to HEp-2 cells. Additionally, using a mouse model of intraperitoneal challenge, we confirmed that SS2 pre-incubated with FH enhanced bacteremia and brain invasion, compared with SS2 not pretreated with FH. Taken together, this study provides a useful method to characterize the host-bacteria interactions. These results first indicated that binding of FH to the cell surface improved the adherence and invasion of SS2 to HEp-2 cells, promoting SS2 to resist killing and leading to enhance virulence. Copyright © 2016 Elsevier GmbH. All rights reserved.

  4. Analysis of mutations causing familial hypercholesterolaemia in black South African patients of different ancestry

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    U K Ibe

    2017-02-01

    Full Text Available Background. Familial hypercholesterolaemia (FH is usually caused by mutations in three genes (LDLR, APOB and PCSK9. Objective. To identify the spectrum of FH-causing mutations in black South African (SA patients. Methods. DNA samples of 16 unrelated South African FH patients with elevated low-density lipoprotein cholesterol levels, tendon xanthomas and corneal arcus (3 clinically homozygous FH and 13 heterozygous FH of ethnic African origin were screened for mutations in the LDLR (coding region, promoter and intron/exon boundaries, APOB (part of exon 26 and PCSK9 genes (exon 7, using high-resolution melting. Results. Eight LDLR mutations were identified, for an overall detection rate of 8/19 predicted FH-causing alleles (42.1%. The previously reported six base pair deletion p.(D47_G48del was found in two patients, and two novel variants (c.1187-25T>C and c.1664T>G p.(L555R were found, both predicted to be pathogenic using in silico web-based predictive algorithms. No pathogenic variants in APOB or PCSK9 were found. Conclusions. These findings contribute to the knowledge of allelic heterogeneity in the spectrum of FH-causing mutations in black SA patients, signifying their ancestral diversity. The relatively low overall detection rate may reflect locus heterogeneity of the FH phenotype in black SA FH patients.

  5. The Impact of Lipoprotein-Associated Oxidative Stress on Cell-Specific Microvesicle Release in Patients with Familial Hypercholesterolemia

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    M. H. Nielsen

    2016-01-01

    Full Text Available Objective. Microvesicles (MVs are small cell-derived particles shed upon activation. Familial hypercholesterolemia (FH particularly when associated with Achilles tendon xanthomas (ATX predisposes to atherosclerosis, possibly through oxLDL-C interaction with the CD36 receptor. To investigate the hypothesis that MVs derived from cells involved in atherosclerosis are increased in FH and that CD36 expressing MVs (CD36+ MVs may be markers of oxLDL-C-induced cell activation, cell-specific MVs were measured in FH patients with and without ATX and their association with atherogenic lipid profile was studied. Approach and Results. Thirty FH patients with and without ATX and twenty-three controls were included. Plasma concentrations of MVs and CD36+ MVs derived from platelets (PMVs, erythrocytes (ErytMVs, monocytes (MMVs, and endothelial cells (EMVs, as well as tissue factor-positive cells (TF+ MVs, were measured by flow cytometry. Total MVs, MMVs, EMVs, ErytMVs, and TF+ MVs were significantly increased in FH patients, compared to controls. CD36+ MVs derived from endothelial cells and monocytes were significantly higher in FH patients and oxLDL-C predicted all the investigated cell-specific CD36+ MVs in FH patients with ATX. Conclusions. MVs derived from cells involved in atherosclerosis were increased in FH and may contribute to elevated atherothrombosis risk. The increased cell-specific CD36+ MVs observed in FH may represent markers of oxLDL-C-induced cell activation.

  6. Dicty_cDB: SSL761 [Dicty_cDB

    Lifescience Database Archive (English)

    Full Text Available LKKCPKGFSFFGSIG CDDFIKNYSKKYPDVEIGGRHTDSFTLF--- ---NHHSHFTHLLLLCYECFENTGY*i*wifiqhsdlyivkw*nl**gyshstyfevsei...vekvskrififwfnwm **fh*klfkeisrc*nwwssyrlfyiiw--- ---NHHSHFTHLLLLCYECFENTGY*i*wifiqhsdlyivkw*nl**gyshstyfevse

  7. A comparative study of nitrilases identified by genome mining.

    Science.gov (United States)

    Kaplan, Ondřej; Veselá, Alicja B; Petříčková, Alena; Pasquarelli, Fabrizia; Pičmanová, Martina; Rinágelová, Anna; Bhalla, Tek Chand; Pátek, Miroslav; Martínková, Ludmila

    2013-07-01

    Escherichia coli strains expressing different nitrilases transformed nitriles or KCN. Six nitrilases (from Aspergillus niger (2), A. oryzae, Neurospora crassa, Arthroderma benhamiae, and Nectria haematococca) were arylacetonitrilases, two enzymes (from A. niger and Penicillium chrysogenum) were cyanide hydratases and the others (from P. chrysogenum, P. marneffei, Gibberella moniliformis, Meyerozyma guilliermondi, Rhodococcus rhodochrous, and R. ruber) preferred (hetero)aromatic nitriles as substrates. Promising nitrilases for the transformation of industrially important substrates were found: the nitrilase from R. ruber for 3-cyanopyridine, 4-cyanopyridine and bromoxynil, the nitrilases from N. crassa and A. niger for (R,S)-mandelonitrile, and the cyanide hydratase from A. niger for KCN and 2-cyanopyridine.

  8. Biodégradation des cyanures libres par le champignon Fusarium solani: relation avec le pH et la distribution des espèces cyanurées en solution

    Science.gov (United States)

    Dumestre, Alain; Bousserrhine, Noureddine; Berthelin, Jacques

    1997-07-01

    Free cyanide biodégradation by Fusarium solani, a fungi isolated from cyanide-contaminated soils. involves a cyanide hydrolyzing enzyme. cyanide hydratase (EC 4.2.1.66). This enzyme specifically seems to convert cyanhydric acid (HCN) to formamide but not the cyanide ion (CN -). Hence. the rate of free cyanide biodégradation is a function of the equilibrium HCN/CN - in solution. A better understanding of cyanide hydratase properties allows the definition of optimal conditions of F.solani biodégradation activity. and the proposition of a biological treatment of cyanide-contaminated alkaline soils and effluents.

  9. Segregation of a latent high adiposity phenotype in families with a history of type 2 diabetes mellitus implicates rare obesity-susceptibility genetic variants with large effects in diabetes-related obesity.

    Directory of Open Access Journals (Sweden)

    Arthur B Jenkins

    Full Text Available BACKGROUND: We recently reported significantly greater weight gain in non-diabetic healthy subjects with a 1(st degree family history (FH+ of type 2 diabetes mellitus (T2DM than in a matched control group without such history (FH- during voluntary overfeeding, implying co-inheritance of susceptibilities to T2DM and obesity. We have estimated the extent and mode of inheritance of susceptibility to increased adiposity in FH+. METHODS: Normoglycaemic participants were categorised either FH+ (≥1 1(st degree relative with T2DM, 50 F/30 M, age 45 ± 14 (SD yr or FH- (71F/51M, age 43 ± 14 yr. Log-transformed anthropometric measurements (height, hip and waist circumferences and lean, bone and fat mass (Dual Energy X-ray Absorptiometry data were analysed by rotated Factor Analysis. The age- and gender-adjusted distributions of indices of adiposity in FH+ were assessed by fits to a bimodal model and by relative risk ratios (RR, FH+/FH- and interpreted in a purely genetic model of FH effects. RESULTS: The two orthogonal factors extracted, interpretable as Frame and Adiposity accounted for 80% of the variance in the input data. FH+ was associated with significantly higher Adiposity scores (p<0.01 without affecting Frame scores. Adiposity scores in FH+ conformed to a bimodal normal distribution, consistent with dominant expression of major susceptibility genes with 59% (95% CI 40%, 74% of individuals under the higher mode. Calculated risk allele frequencies were 0.09 (0.02, 0.23 in FH-, 0.36 (0.22, 0.48 in FH+ and 0.62 (0.36, 0.88 in unobserved T2DM-affected family members. CONCLUSIONS: The segregation of Adiposity in T2DM-affected families is consistent with dominant expression of rare risk variants with major effects, which are expressed in over half of FH+ and which can account for most T2DM-associated obesity in our population. The calculated risk allele frequency in FH- suggests that rare genetic variants could also account for a substantial fraction

  10. Protection against Schistosoma mansoni infection using a Fasciola hepatica-derived fatty acid binding protein from different delivery systems.

    Science.gov (United States)

    Vicente, Belén; López-Abán, Julio; Rojas-Caraballo, Jose; del Olmo, Esther; Fernández-Soto, Pedro; Muro, Antonio

    2016-04-18

    Schistosomiasis is a water-borne disease afflicting over 261 million people in many areas of the developing countries with high morbidity and mortality. The control relies mainly on treatment with praziquantel. Fatty acid binding proteins (FABP) have demonstrated high levels of immune-protection against trematode infections. This study reports the immunoprotection induced by cross-reacting Fasciola hepatica FABP, native (nFh12) and recombinantly expressed using two different expression systems Escherichia coli (rFh15) and baculovirus (rFh15b) against Schistosoma mansoni infection. BALB/c mice were vaccinated with native nFh12 or recombinant rFh15 and rFh15 FABP from F. hepatica formulated in adjuvant adaptation (ADAD) system with natural or chemical synthesised immunomodulators (PAL and AA0029) and then challenged with 150 cercariae of S. mansoni. Parasite burden, hepatic lesions and antibody response were studied in vaccination trials. Furthermore differences between rFh15 and rFh15b immunological responses (cytokine production, splenocyte population and antibody levels) were studied. Vaccination with nFh12 induced significant reductions in worm burden (83%), eggs in tissues (82-92%) and hepatic lesions (85%) compared to infected controls using PAL. Vaccination with rFh15 showed lower total worm burden (56-64%), eggs in the liver (21-61%), eggs in the gut (30-77%) and hepatic damage (67-69%) using PAL and AA0029 as immunomodulators. In contrast, mice vaccinated with rFh15b showed only reductions in eggs trapped in the liver and intestine (53 and 60%, respectively), and hepatic lesions (45%). We observed a significant rise in TNFα, IL-6, IL-2, IL-4 and high antibody response (IgG, IgG1, IgG2a, IgM and IgE) in mice immunised with either rFh15 or rFh15b. Moreover, mice immunised with rFh15b showed an increase in IFNγ and a decrease in B220 cells compared to untreated mice, and less production of IgG1 and IgM than in mice immunised by rFh15. Higher level of

  11. Folded-back solution structure of monomeric factor H of human complement by synchrotron X-ray and neutron scattering, analytical ultracentrifugation and constrained molecular modelling.

    Science.gov (United States)

    Aslam, M; Perkins, S J

    2001-06-22

    Factor H (FH) is a regulatory cofactor for the protease factor I in the breakdown of C3b in the complement system of immune defence, and binds to heparin and other polyanionic substrates. FH is composed of 20 short consensus/complement repeat (SCR) domains, for which the overall arrangement in solution is unknown. As previous studies had shown that FH can form monomeric or dimeric structures, X-ray and neutron scattering was accordingly performed with FH in the concentration range between 0.7 and 14 mg ml(-1). The radius of gyration of FH was determined to be 11.1-11.3 nm by both methods, and the radii of gyration of the cross-section were 4.4 nm and 1.7 nm. The distance distribution function P(r) showed that the overall length of FH was 38 nm. The neutron data showed that FH was monomeric with a molecular mass of 165,000(+/-17,000) Da. Analytical ultracentrifugation data confirmed this, where sedimentation equilibrium curve fits gave a mean molecular mass of 155,000(+/-3,000) Da. Sedimentation velocity experiments using the g*(s) derivative method showed that FH was monodisperse and had a sedimentation coefficient of 5.3(+/-0.1) S. In order to construct a full model of FH for scattering curve and sedimentation coefficient fits, homology models were constructed for 17 of the 20 SCR domains using knowledge of the NMR structures for FH SCR-5, SCR-15 and SCR-16, and vaccinia coat protein SCR-3 and SCR-4. Molecular dynamics simulations were used to generate a large conformational library for each of the 19 SCR-SCR linker peptides. Peptides from these libraries were combined with the 20 SCR structures in order to generate stereochemically complete models for the FH structure. Using an automated constrained fit procedure, the analysis of 16,752 possible FH models showed that only those models in which the 20 SCR domains were bent back upon themselves were able to account for the scattering and sedimentation data. The best-fit models showed that FH had an overall length

  12. The meningococcal vaccine candidate neisserial surface protein A (NspA binds to factor H and enhances meningococcal resistance to complement.

    Directory of Open Access Journals (Sweden)

    Lisa A Lewis

    Full Text Available Complement forms an important arm of innate immunity against invasive meningococcal infections. Binding of the alternative complement pathway inhibitor factor H (fH to fH-binding protein (fHbp is one mechanism meningococci employ to limit complement activation on the bacterial surface. fHbp is a leading vaccine candidate against group B Neisseria meningitidis. Novel mechanisms that meningococci employ to bind fH could undermine the efficacy of fHbp-based vaccines. We observed that fHbp deletion mutants of some meningococcal strains showed residual fH binding suggesting the presence of a second receptor for fH. Ligand overlay immunoblotting using membrane fractions from one such strain showed that fH bound to a approximately 17 kD protein, identified by MALDI-TOF analysis as Neisserial surface protein A (NspA, a meningococcal vaccine candidate whose function has not been defined. Deleting nspA, in the background of fHbp deletion mutants, abrogated fH binding and mAbs against NspA blocked fH binding, confirming NspA as a fH binding molecule on intact bacteria. NspA expression levels vary among strains and expression correlated with the level of fH binding; over-expressing NspA enhanced fH binding to bacteria. Progressive truncation of the heptose (Hep I chain of lipooligosaccharide (LOS, or sialylation of lacto-N-neotetraose LOS both increased fH binding to NspA-expressing meningococci, while expression of capsule reduced fH binding to the strains tested. Similar to fHbp, binding of NspA to fH was human-specific and occurred through fH domains 6-7. Consistent with its ability to bind fH, deleting NspA increased C3 deposition and resulted in increased complement-dependent killing. Collectively, these data identify a key complement evasion mechanism with important implications for ongoing efforts to develop meningococcal vaccines that employ fHbp as one of its components.

  13. The extent of familial hypercholesterolemia instruction in US schools and colleges of medicine, pharmacy, and osteopathic medicine.

    Science.gov (United States)

    Withycombe, Bethany; Winden, Janae C; Hassanyn, Reem; Duell, P Barton; Ito, Matthew K

    2015-01-01

    Familial hypercholesterolemia (FH) is a common autosomal codominant disease characterized by extreme plasma cholesterol concentrations and high risk of early heart disease. FH is underdiagnosed and severely undertreated. This may be due in part to gaps in FH education within medical and pharmacy training programs. To assess the extent to which FH is covered in professional curriculums in accredited schools and colleges of medicine, pharmacy, and osteopathic medicine in the United States. An 18-question survey was distributed via e-mail to 288 US schools and colleges of medicine, pharmacy, and osteopathic medicine. Fifty-six of 288 (19.4%) programs responded to the survey. Three were excluded from analysis because of lack of program accreditation and FH instruction. Overall, 43% indicated that FH instruction at their respective institution was perceived to be adequate. More than 90% of the programs indicated that the following topics were covered within the curriculum: FH pathophysiology; associated morbidity and mortality; guideline-recommended low-density lipoprotein cholesterol goals and risk factor management; consequences of poor lipid management; and the screening, diagnosis, and treatment of adult patients. However, instruction was lacking for FH screening methods as one-third of the programs covered cascade screening and only half of the programs reported distinguishing between heterozygous and homozygous FH including differences in treatment approach. The results suggested important gaps in the coverage of FH in the curriculum, and strategies need to be developed to ensure that FH instruction is sufficient within these professional programs. Copyright © 2015 National Lipid Association. Published by Elsevier Inc. All rights reserved.

  14. Dynamics of ferrihydrite-bound organic carbon during microbial Fe reduction

    Science.gov (United States)

    Adhikari, Dinesh; Zhao, Qian; Das, Kamol; Mejia, Jacqueline; Huang, Rixiang; Wang, Xilong; Poulson, Simon R.; Tang, Yuanzhi; Roden, Eric E.; Yang, Yu

    2017-09-01

    The dynamics of iron (Fe)-bound organic carbon (OC) during dissimilatory microbial Fe(III) reduction has the potential to play an important role in regulating the biogeochemical cycling of carbon (C) in permanently or transiently anoxic soils and sediments. In this study, we investigated the release and transformation of ferrihydrite (Fh)-bound OC during microbial reduction of Fe by Shewanella putrefaciens strain CN32 under a fixed Fe concentration of 13 mM and varying C/Fe molar ratios. We found that reduction of Fe and reductive release of OC was dependent on the C/Fe molar ratio, with high C/Fe ratio enhancing both reduction of Fe and release of OC. For Fh-OC co-precipitates with C/Fe ratio of 3.7, 54.7% of Fh-bound OC was released to solution phase when 25.1% of Fe was reduced. The presence of OC inhibited the transformation of Fh to more crystalline Fe phases both in the bulk and on the surface. Upon reduction, Fh-bound OC became more concentrated on the surface of Fh-OC co-precipitates, and surface components were enriched with carboxylic functional groups. Reduction increased the lability of Fh-bound OC for Fh-OC co-precipitate with C/Fe ratio of 3.7, and aromatic OC was preferentially retained within the co-precipitates. Our results indicate that microbial reduction altered the quantity and composition of OC released from Fh-OC co-precipitates, depending on the C/Fe ratio and associations between Fe and OC. Assuming higher availability of released OC compared to original Fh-bound OC, reduction of Fh can likely lead to enhanced degradation of OC and result in a shorter residence time for OC in soils and sediments.

  15. Fecal assays detect hypersensitivity to cow's milk protein and gluten in adults with irritable bowel syndrome.

    Science.gov (United States)

    Carroccio, Antonio; Brusca, Ignazio; Mansueto, Pasquale; Soresi, Maurizio; D'Alcamo, Alberto; Ambrosiano, Giuseppe; Pepe, Ilenia; Iacono, Giuseppe; Lospalluti, Maria Letizia; La Chiusa, Stella M; Di Fede, Gaetana

    2011-11-01

    Some patients with irritable bowel syndrome (IBS)-like symptoms suffer from food hypersensitivity (FH); their symptoms improve when they are placed on elimination diets. No assays identify patients with FH with satisfactory levels of sensitivity. We determined the frequency of FH among patients with symptoms of IBS and the ability of fecal assays for tryptase, eosinophil cationic protein (ECP), or calprotectin to diagnose FH. The study included 160 patients with IBS, 40 patients with other gastrointestinal diseases, and 50 healthy individuals (controls). At the start of the study, patients completed a symptom severity questionnaire, fecal samples were assayed, and levels of specific immunoglobulin E were measured. Patients were observed for 4 weeks, placed on an elimination diet (without cow's milk and derivatives, wheat, egg, tomato, and chocolate) for 4 weeks, and kept a diet diary. Those who reported improvements after the elimination diet period were then diagnosed with FH, based on the results of a double-blind, placebo-controlled, oral food challenge (with cow's milk proteins and then with wheat proteins). Forty of the patients with IBS (25%) were found to have FH. Levels of fecal ECP and tryptase were significantly higher among patients with IBS and FH than those without FH. The ECP assay was the most accurate assay for diagnosis of FH, showing 65% sensitivity and 91% specificity. Twenty-five percent of patients with IBS have FH. These patients had increased levels of fecal ECP and tryptase, indicating that they might cause inflammation in patients with IBS. Fecal assays for ECP could be used to identify FH in patients with IBS. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

  16. A cytologic assay for diagnosis of food hypersensitivity in patients with irritable bowel syndrome.

    Science.gov (United States)

    Carroccio, Antonio; Brusca, Ignazio; Mansueto, Pasquale; Pirrone, Giuseppe; Barrale, Maria; Di Prima, Lidia; Ambrosiano, Giuseppe; Iacono, Giuseppe; Lospalluti, Maria Letizia; La Chiusa, Stella M; Di Fede, Gaetana

    2010-03-01

    A percentage of patients with symptoms of irritable bowel syndrome (IBS) suffer from food hypersensitivity (FH) and improve on a food-elimination diet. No assays have satisfactory levels of sensitivity for identifying patients with FH. We evaluated the efficacy of an in vitro basophil activation assay in the diagnosis of FH in IBS-like patients. Blood samples were collected from 120 consecutive patients diagnosed with IBS according to Rome II criteria. We analyzed in vitro activation of basophils by food allergens (based on levels of CD63 expression), as well as total and food-specific immunoglobulin (Ig)E levels in serum. Effects of elimination diets and double-blind food challenges were used as standards for FH diagnosis. Twenty-four of the patients (20%) had FH (cow's milk and/or wheat hypersensitivity); their symptom scores improved significantly when they were placed on an elimination diet. Patients with FH differed from other IBS patients in that they had a longer duration of clinical history, a history of FH as children, and an increased frequency of self-reported FH; they also had hypersensitivities to other antigens (eg, egg or soy). The basophil activation assay diagnosed FH with 86% sensitivity, 88% specificity, and 87% accuracy; this level of sensitivity was significantly higher than that of serum total IgE or food-specific IgE assays. A cytometric assay that quantifies basophils after stimulation with food antigens based on cell-surface expression of CD63 had high levels of sensitivity, specificity, and accuracy in diagnosing FH. This assay might be used to diagnose FH in patients with IBS-like symptoms. Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

  17. Design of meningococcal factor H binding protein mutant vaccines that do not bind human complement factor H.

    Science.gov (United States)

    Pajon, Rolando; Beernink, Peter T; Granoff, Dan M

    2012-08-01

    Meningococcal factor H binding protein (fHbp) is a human species-specific ligand for the complement regulator, factor H (fH). In recent studies, fHbp vaccines in which arginine at position 41 was replaced by serine (R41S) had impaired fH binding. The mutant vaccines elicited bactericidal responses in human fH transgenic mice superior to those elicited by control fHbp vaccines that bound human fH. Based on sequence similarity, fHbp has been classified into three variant groups. Here we report that although R41 is present in fHbp from variant groups 1 and 2, the R41S substitution eliminated fH binding only in variant group 1 proteins. To identify mutants in variant group 2 with impaired fH binding, we generated fHbp structural models and predicted 63 residues influencing fH binding. From these, we created 11 mutants with one or two amino acid substitutions in a variant group 2 protein and identified six that decreased fH binding. Three of these six mutants retained conformational epitopes recognized by all six anti-fHbp monoclonal antibodies (MAbs) tested and elicited serum complement-mediated bactericidal antibody titers in wild-type mice that were not significantly different from those obtained with the control vaccine. Thus, fHbp amino acid residues that affect human fH binding differ across variant groups. This result suggests that fHbp sequence variation induced by immune selection also affects fH binding motifs via coevolution. The three new fHbp mutants from variant group 2, which do not bind human fH, retained important epitopes for eliciting bactericidal antibodies and may be promising vaccine candidates.

  18. Biochemical Characterization and Differential Expression of a 16.5-Kilodalton Tegument-Associated Antigen from the Liver Fluke Fasciola hepatica

    Science.gov (United States)

    Gaudier, José F.; Cabán-Hernández, Kimberly; Osuna, Antonio

    2012-01-01

    A cDNA encoding a 16.5-kDa protein termed FhTP16.5 was identified by immunoscreening of a cDNA library from Fasciola hepatica adult flukes using pooled sera from rabbits infected with F. hepatica for 4 weeks. Quantitative reverse transcriptase PCR (qPCR) analysis revealed that FhTP16.5 is not expressed in unembryonated eggs. It is poorly expressed in miracidia and highly expressed at the juvenile and adult stages; however, significant differences were found between the expression levels of FhTP16.5 in juveniles versus adult flukes. Recombinant FhTP16.5 was expressed at high levels in Escherichia coli, purified by affinity chromatography, and used to raise anti-FhTP16.5 polyclonal antibodies in rabbits. Immunoblot analysis using the anti-FhTP16.5 IgG antibody identified FhTP16.5 in crude and tegumental extracts and in excretory-secretory products of F. hepatica. The protein was not detected in crude extracts of Schistosoma mansoni or Schistosoma japonicum. Antibodies to FhTP16.5 were detected in the sera of rabbits at 3 to 12 weeks of F. hepatica infection as well as in the sera of humans with chronic fascioliasis; these findings suggest that FhTP16.5 could be a good antigen for serodiagnosis of fascioliasis. Immunohistochemistry demonstrated that FhTP16.5 localizes to the surface of the tegument of various developmental stages and in parenchymal tissues of the adult fluke. Such specific localization makes FhTP16.5 an attractive target for immunoprophylaxis or chemotherapy. PMID:22278327

  19. Deep-diving sea lions exhibit extreme bradycardia in long-duration dives.

    Science.gov (United States)

    McDonald, Birgitte I; Ponganis, Paul J

    2014-05-01

    Heart rate and peripheral blood flow distribution are the primary determinants of the rate and pattern of oxygen store utilisation and ultimately breath-hold duration in marine endotherms. Despite this, little is known about how otariids (sea lions and fur seals) regulate heart rate (fH) while diving. We investigated dive fH in five adult female California sea lions (Zalophus californianus) during foraging trips by instrumenting them with digital electrocardiogram (ECG) loggers and time depth recorders. In all dives, dive fH (number of beats/duration; 50±9 beats min(-1)) decreased compared with surface rates (113±5 beats min(-1)), with all dives exhibiting an instantaneous fH below resting (100 m) consisted of: (1) an initial rapid decline in fH resulting in the lowest instantaneous fH of the dive at the end of descent, often below 10 beats min(-1) in dives longer than 6 min in duration; (2) a slight increase in fH to ~10-40 beats min(-1) during the bottom portion of the dive; and (3) a gradual increase in fH during ascent with a rapid increase prior to surfacing. Thus, fH regulation in deep-diving sea lions is not simply a progressive bradycardia. Extreme bradycardia and the presumed associated reductions in pulmonary and peripheral blood flow during late descent of deep dives should (a) contribute to preservation of the lung oxygen store, (b) increase dependence of muscle on the myoglobin-bound oxygen store, (c) conserve the blood oxygen store and (d) help limit the absorption of nitrogen at depth. This fH profile during deep dives of sea lions may be characteristic of deep-diving marine endotherms that dive on inspiration as similar fH profiles have been recently documented in the emperor penguin, another deep diver that dives on inspiration.

  20. Influence of family history of dementia in the development and progression of late-onset Alzheimer's disease.

    Science.gov (United States)

    Scarabino, Daniela; Gambina, Giuseppe; Broggio, Elisabetta; Pelliccia, Franca; Corbo, Rosa Maria

    2016-03-01

    Family history of dementia (FH) is a recognized risk factor for developing late-onset Alzheimer's disease (AD). We asked whether having FH increases AD risk and influences disease severity (age at onset and cognitive impairment) in 420 AD patients and 109 controls with (FH+) or without (FH-). The relationships of APOE and other AD risk genes with FH were analyzed as well. The proportion of APOE e4 allele carriers was higher among the FH+ than the FH- AD patients (49.6% vs. 38.9%; P = 0.04). The distribution of the risk genotypes of nine AD susceptibility genes previously examined (CHAT, CYP17, CYP19, ESR1, FSHR, P53, P73, P21, PPARG) did not differ between the FH+ and the FH- AD patients, indicating that none contributed significantly to familial clustering of disease. FH was associated with an increased AD risk (odds ratio [OR] 2.71, 95% confidence interval [CI] 1.44-5.09; P = 0.002) independent of carrying the APOE e4 allele (OR 2.61, 95%CI 1.53-4.44; P = 0.0004). Having a first-degree relative or a parent with dementia was significantly associated with AD risk (OR 2.9, 95%CI 1.3-6.4; P = 0.009 and OR 2.7, 95%CI 1.1-6.2; P = 0.02) but having a sibling with dementia was not (OR 1.7, 95%CI 0.2 to 14.7; P = 0.6). Among the FH+ AD patients, having one or both parents affected seemed to raise the risk of earlier onset age (P = 0.02) and greater cognitive impairment (P = 0.02) than having only an affected sibling, whereas having two or more affected relatives did not. © 2015 Wiley Periodicals, Inc.

  1. Efficacy of Targeted Complement Inhibition in Experimental C3 Glomerulopathy

    Science.gov (United States)

    Ruseva, Marieta M.; Peng, Tao; Lasaro, Melissa A.; Bouchard, Keith; Liu-Chen, Susan; Sun, Fang; Yu, Zhao-Xue; Marozsan, Andre; Wang, Yi

    2016-01-01

    C3 glomerulopathy refers to renal disorders characterized by abnormal accumulation of C3 within the kidney, commonly along the glomerular basement membrane (GBM). C3 glomerulopathy is associated with complement alternative pathway dysregulation, which includes functional defects in complement regulator factor H (FH). There is no effective treatment for C3 glomerulopathy. We investigated the efficacy of a recombinant mouse protein composed of domains from complement receptor 2 (CR2) and FH (CR2-FH) in two models of C3 glomerulopathy with either preexisting or triggered C3 deposition along the GBM. FH-deficient mice spontaneously develop renal pathology associated with abnormal C3 accumulation along the GBM and secondary plasma C3 deficiency. CR2-FH partially restored plasma C3 levels in FH-deficient mice 2 hours after intravenous injection. CR2-FH specifically targeted glomerular C3 deposits, reduced the linear C3 reactivity assessed with anti-C3 and anti-C3b/iC3b/C3c antibodies, and prevented further spontaneous accumulation of C3 fragments along the GBM. Reduction in glomerular C3d and C9/C5b-9 reactivity was observed after daily administration of CR2-FH for 1 week. In a second mouse model with combined deficiency of FH and complement factor I, CR2-FH prevented de novo C3 deposition along the GBM. These data show that CR2-FH protects the GBM from both spontaneous and triggered C3 deposition in vivo and indicate that this approach should be tested in C3 glomerulopathy. PMID:26047789

  2. Association of coronary heart disease with age-adjusted aortocoronary calcification in patients with familial hypercholesterolaemia

    DEFF Research Database (Denmark)

    Jensen, J M; Gerdes, Lars Ulrik; Jensen, H K

    2000-01-01

    OBJECTIVES: Existing algorithms of risk of coronary heart disease (CHD) do not pertain to patients with familial hypercholesterolaemia (FH), whose arteries have been exposed to hypercholesterolaemia since birth. We studied a cohort of FH patients to compare four diagnostic models of CHD: traditio...

  3. Sudden cardiac death in young adults

    DEFF Research Database (Denmark)

    Larsen, Maiken K; Nissen, Peter H; Kristensen, Ingrid B;

    2012-01-01

    Familial hypercholesterolemia (FH) is a genetic disorder that may lead to premature coronary heart disease (CHD) and sudden cardiac death (SCD). Mutations in the LDLR or APOB genes cause FH. We have screened the LDLR and the ligand-binding region of APOB genes in 52 cases of SCD. Deceased patients...... premature CHD and SCD....

  4. Lipoprotein(a) levels in familial hipercholesterolaemia: an important predictor for cardiovascular disease independent of the type of LDL-receptor mutation

    Science.gov (United States)

    To determine the relationship between lipoprotein(a) [Lp(a)] and cardiovascular disease (CVD) in a large cohort of heterozygous familial hypercholesterolemia (FH) patients. Lipoprotein(a) is considered a cardiovascular risk factor. Nevertheless, the role of Lp(a) as a predictor of CVD in FH has been...

  5. 46 CFR 12.25-10 - General requirements.

    Science.gov (United States)

    2010-10-01

    ..., ordinary seaman, wiper, and steward's department (F.H.) endorsements do not require an exam. Holders of.... MMCs or MMDs endorsed as steward's department (F.H.) will authorize the holder's service in any capacity in the steward's department. (See § 12.02-11(b) of this part for unqualified ratings in the...

  6. Esophageal acid sensitivity and mucosal integrity in patients with functional heartburn.

    Science.gov (United States)

    Weijenborg, P W; Smout, A J P M; Bredenoord, A J

    2016-11-01

    Patients with functional heartburn (FH) experience troublesome heartburn that is not related to gastroesophageal reflux. The etiology of the heartburn sensation in FH patients is unknown. In patients with reflux disease, esophageal hypersensitivity seems associated with impaired mucosal integrity. We aimed to determine esophageal sensitivity and mucosal integrity in FH and non-erosive reflux disease (NERD) patients. In this prospective experimental study, we performed an acid perfusion test and upper endoscopy with biopsies in 12 patients with NERD and nine patients with FH. Mucosal integrity was measured during endoscopy using electrical tissue impedance spectroscopy and biopsy specimens were analyzed in Ussing chambers for transepithelial electrical resistance and transepithelial permeability. Lag time to heartburn perception was significantly longer in FH patients (median 12 min) than in NERD patients (median 3 min). Once perceived, intensity of heartburn was scored equal with median visual analog scale 6.5 and 7.1 respectively. Esophageal mucosal integrity was also comparable between FH and NERD patients, both in vivo extracellular impedance and ex vivo transepithelial resistance and permeability were similar. Patients with FH did not show acid hypersensitivity as seen in patients with NERD. However, once perceived, intensity of heartburn is similar. Esophageal mucosal integrity is similar between NERD and FH patients, and is therefore unlikely to be the underlying cause of the observed difference in esophageal acid perception. © 2016 John Wiley & Sons Ltd.

  7. No certain predictors for mutation status in a Danish cohort with familial hypercholesterolemia: a descriptive study

    DEFF Research Database (Denmark)

    Nybo, Mads; Brusgaard, Klaus; Hansen, Annebirthe Bo

    2007-01-01

    OBJECTIVE: In order to enable clinicians to refer the right persons suspected of familial hypercholesterolemia (FH) for mutation screening, a retrospective study was conducted in a Danish FH cohort. DESIGN AND METHODS: The study comprised 643 probands and 395 relatives, of which 421 individuals had...

  8. Characterization of a disease-causing Glu119-Lys mutation in the low-density lipoprotein receptor gene in two Danish families with heterozygous familial hypercholesterolemia

    DEFF Research Database (Denmark)

    Jensen, H K; Jensen, T G; Jensen, L G

    1994-01-01

    Mutations in the gene for the low-density lipoprotein receptor (LDL receptor) cause the autosomal dominant inherited disease familial hypercholesterolemia (FH). In 15 Danish patients with heterozygous FH we have screened exon 4 of the LDL receptor gene for point mutations and small rearrangements...

  9. Familial Hypercholesterolemia: The Lipids or the Genes?

    Directory of Open Access Journals (Sweden)

    Nemer Georges M

    2011-04-01

    Full Text Available Abstract Familial Hypercholesterolemia (FH is a common cause of premature cardiovascular disease and is often undiagnosed in young people. Although the disease is diagnosed clinically by high LDL cholesterol levels and family history, to date there are no single internationally accepted criteria for the diagnosis of FH. Several genes have been shown to be involved in FH; yet determining the implications of the different mutations on the phenotype remains a hard task. The polygenetic nature of FH is being enhanced by the discovery of new genes that serve as modifiers. Nevertheless, the picture is still unclear and many unknown genes contributing to the phenotype are most likely involved. Because of this evolving polygenetic nature, the diagnosis of FH by genetic testing is hampered by its cost and effectiveness. In this review, we reconsider the clinical versus genetic nomenclature of FH in the literature. After we describe each of the genetic causes of FH, we summarize the known correlation with phenotypic measures so far for each genetic defect. We then discuss studies from different populations on the genetic and clinical diagnoses of FH to draw helpful conclusions on cost-effectiveness and suggestions for diagnosis.

  10. 肝片吸虫抗原基因的克隆与筛选%CLONING AND SCREENING OF ANTIGEN GENE OF FASCIOLA HEPATICA

    Institute of Scientific and Technical Information of China (English)

    张西玉; 徐恒; 吴峰; 郑莉

    2000-01-01

    提取肝片吸虫总RNA,经oligo(dT)-纤维素柱分离得到mRNA,反转录合成cDNA后,连接Eco RI人工合成接头,酶切后克隆到表达型质粒载体pGEX-1λT,转化大肠杆菌JM107菌株构建肝片吸虫cDNA文库(文库大小约为2.1×105).用免疫印迹筛选出5个阳性克隆,分别命名为:pFH2,pFH4,pFH16,pFH21和pFH29.其中pFH21印迹信号最强.Eco RI酶切pFH21显示:插入片段大小约为1.0kb.重组子pFH21经SDS-PAGE电泳显示:表达有一个重组蛋白,分子量约为48kD.

  11. Family history of Type 1 diabetes affects insulin secretion in patients with 'Type 2' diabetes.

    Science.gov (United States)

    Lundgren, V M; Andersen, M K; Isomaa, B; Tuomi, T

    2013-05-01

    The aim was to evaluate the impact of family history of diabetes on the phenotype of patients diagnosed with Type 2 diabetes and the frequency of susceptibility genotypes. Patients with Type 2 diabetes with family history for both Type 1 and Type 2 diabetes (FH(MIX, n) = 196) or Type 2 diabetes only (FH(T2), n = 139) matched for age, sex, BMI and age at diagnosis, underwent an oral glucose tolerance test and a combined glucagon test and insulin tolerance test. Glutamic acid decarboxylase (GAD) antibodies and major Type 1 and Type 2 diabetes susceptibility gene variants were analysed. Patients were stratified into groups according to family history or GAD antibody positivity (GADA+, GADA-) or a combination of these (GADA+/FH(MIX), GADA+/FH(T2), GADA-/FH(MIX), GADA-/FH(T2)). Compared with other patients, those with FH(MIX) more often had GAD antibodies (14.3 vs. 4.3%, P = 0.003), and those with both FH(MIX) and GAD antibodies had the highest frequency of insulin deficiency (stimulated serum C-peptide insulin deficiency. A family history for both type 1 and type 2 diabetes was associated with higher prevalence of GAD antibodies and HLA-DQB1 risk genotypes than a family history of type 2 diabetes only, and was associated with earlier and more severe development of insulin deficiency, which was only partially explained by GAD antibodies and HLA. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.

  12. Extreme phenotypes in hypercholesterolemia : From genotype to therapy

    NARCIS (Netherlands)

    Sjouke, B.

    2017-01-01

    Familial hypercholesterolemia (FH) is an inherited disorder of cholesterol metabolism, resulting in increased LDL-cholesterol levels and, as a consequence, an increased risk for coronary heart disease. Recently, many causal FH mutations in different genes have been identified and advances in genetic

  13. Family history of alcohol dependence modulates functional neurophysiology in mood/anxiety disorders

    NARCIS (Netherlands)

    Sjoerds, Z.; van Tol, M.J.; van den Brink, W.; van der Wee, N.J.A.; Aleman, A.; Beekman, A.T.F.; Penninx, B.W.J.H.; Veltman, D.J.

    2013-01-01

    Background. A family history (FH) of alcohol dependence (AD) not only increases the risk for AD, but is also associated with an increased risk for mood and anxiety disorders. However, it is unknown how a FH of AD affects neural substrates in patients with mood and anxiety disorders. In this study we

  14. Can Multiple Lifestyle Behaviours Be Improved in People with Familial Hypercholesterolemia? Results of a Parallel Randomised Controlled Trial

    NARCIS (Netherlands)

    Broekhuizen, K.; Poppel, M.N.M. van; Koppes, L.L.; Kindt, I.; Brug, J.; Mechelen, W. van

    2012-01-01

    Objective: To evaluate the efficacy of an individualised tailored lifestyle intervention on physical activity, dietary intake, smoking and compliance to statin therapy in people with Familial Hypercholesterolemia (FH). Methods: Adults with FH (n = 340) were randomly assigned to a usual care control

  15. Gene-load score of the renin-angiotensin-aldosterone system is associated with coronary heart disease in familial hypercholesterolaemia

    NARCIS (Netherlands)

    J.B. van der Net (Jeroen); J. van Etten (Jeroen); M. Yazdanpanah (Mojgan); G.M. Dallinga-Thie (Geesje); J.J.P. Kastelein (John); J.C. Defesche (Joep); R.P. Koopmans (Richard); E.W. Steyerberg (Ewout); E.J.G. Sijbrands (Eric)

    2008-01-01

    textabstractAims: Familial hypercholesterolaemia (FH) is characterized by premature coronary heart disease (CHD). However, the incidence of CHD varies considerably among FH patients. Genetic variation in the renin-angiotensin-aldosterone system (RAAS) and the adrenalin/noradrenalin system may be of

  16. Clinical characteristics and evaluation of LDL-cholesterol treatment of the Spanish Familial Hypercholesterolemia Longitudinal Cohort Study (SAFEHEART

    Directory of Open Access Journals (Sweden)

    Piedecausa Mar

    2011-06-01

    Full Text Available Abstract Aim Familial hypercholesterolemia (FH patients are at high risk for premature coronary heart disease (CHD. Despite the use of statins, most patients do not achieve an optimal LDL-cholesterol goal. The aims of this study are to describe baseline characteristics and to evaluate Lipid Lowering Therapy (LLT in FH patients recruited in SAFEHEART. Methods and Results A cross-sectional analysis of cases recruited in the Spanish FH cohort at inclusion was performed. Demographic, lifestyle, medical and therapeutic data were collected by specific surveys. Blood samples for lipid profile and DNA were obtained. Genetic test for FH was performed through DNA-microarray. Data from 1852 subjects (47.5% males over 19 years old were analyzed: 1262 (68.1%, mean age 45.6 years had genetic diagnosis of FH and 590 (31.9%, mean age 41.3 years were non-FH. Cardiovascular disease was present in 14% of FH and in 3.2% of non-FH subjects (P Conclusion Although most of this high risk population is receiving LLT, prevalence of cardiovascular disease and LDL-c levels are still high and far from the optimum LDL-c therapeutic goal. However, LDL-c levels could be reduced by using more intensive LLT such as combined therapy with maximum statin dose and ezetimibe.

  17. HEART UK statement on the management of homozygous familial hypercholesterolaemia in the United Kingdom.

    Science.gov (United States)

    France, Michael; Rees, Alan; Datta, Dev; Thompson, Gilbert; Capps, Nigel; Ferns, Gordon; Ramaswami, Uma; Seed, Mary; Neely, Dermot; Cramb, Robert; Shoulders, Carol; Barbir, Mahmoud; Pottle, Alison; Eatough, Ruth; Martin, Steven; Bayly, Graham; Simpson, Bill; Halcox, Julian; Edwards, Ray; Main, Linda; Payne, Jules; Soran, Handrean

    2016-12-01

    This consensus statement addresses the current three main modalities of treatment of homozygous familial hypercholesterolaemia (HoFH): pharmacotherapy, lipoprotein (Lp) apheresis and liver transplantation. HoFH may cause very premature atheromatous arterial disease and death, despite treatment with Lp apheresis combined with statin, ezetimibe and bile acid sequestrants. Two new classes of drug, effective in lowering cholesterol in HoFH, are now licensed in the United Kingdom. Lomitapide is restricted to use in HoFH but, may cause fatty liver and is very expensive. PCSK9 inhibitors are quite effective in receptor defective HoFH, are safe and are less expensive. Lower treatment targets for lipid lowering in HoFH, in line with those for the general FH population, have been proposed to improve cardiovascular outcomes. HEART UK presents a strategy combining Lp apheresis with pharmacological treatment to achieve these targets in the United Kingdom (UK). Improved provision of Lp apheresis by use of existing infrastructure for extracorporeal treatments such as renal dialysis is promoted. The clinical management of adults and children with HoFH including advice on pregnancy and contraception are addressed. A premise of the HEART UK strategy is that the risk of early use of drug treatments beyond their licensed age restriction may be balanced against risks of liver transplantation or ineffective treatment in severely affected patients. This may be of interest beyond the UK.

  18. Using Early Standardized Language Measures to Predict Later Language and Early Reading Outcomes in Children at High Risk for Language-Learning Impairments

    Science.gov (United States)

    Flax, Judy F.; Realpe-Bonilla, Teresa; Roesler, Cynthia; Choudhury, Naseem; Benasich, April

    2009-01-01

    The aim of the study was to examine the profiles of children with a family history (FH+) of language-learning impairments (LLI) and a control group of children with no reported family history of LLI (FH-) and identify which language constructs (receptive or expressive) and which ages (2 or 3 years) are related to expressive and receptive language…

  19. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: Consensus Statement of the European Atherosclerosis Society

    NARCIS (Netherlands)

    Nordestgaard, B.G.; Chapman, M.J.; Humphries, S.E.; Ginsberg, H.N.; Masana, L.; Descamps, O.S.; Wiklund, O.; Hegele, R.A.; Raal, F.J.; Defesche, J.C.; Wiegman, A.; Santos, R.D.; Watts, G.F.; Parhofer, K.G.; Hovingh, G.K.; Kovanen, P.T.; Boileau, C.; Averna, M.; Boren, J.; Bruckert, E.; Catapano, A.L.; Kuivenhoven, J.A.; Pajukanta, P.; Ray, K.; Stalenhoef, A.F.H.; Stroes, E.; Taskinen, M.R.; Tybjaerg-Hansen, A.; Consensus, P. European Athero

    2013-01-01

    AIMS: The first aim was to critically evaluate the extent to which familial hypercholesterolaemia (FH) is underdiagnosed and undertreated. The second aim was to provide guidance for screening and treatment of FH, in order to prevent coronary heart disease (CHD). METHODS AND RESULTS: Of the theoretic

  20. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population : guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society

    NARCIS (Netherlands)

    Nordestgaard, Borge G.; Chapman, M. John; Humphries, Steve E.; Ginsberg, Henry N.; Masana, Luis; Descamps, Olivier S.; Wiklund, Olov; Hegele, Robert A.; Raal, Frederick J.; Defesche, Joep C.; Wiegman, Albert; Santos, Raul D.; Watts, Gerald F.; Parhofer, Klaus G.; Hovingh, G. Kees; Kovanen, Petri T.; Boileau, Catherine; Averna, Maurizio; Boren, Jan; Bruckert, Eric; Catapano, Alberico L.; Kuivenhoven, Jan Albert; Pajukanta, Paeivi; Ray, Kausik; Stalenhoef, Anton F. H.; Stroes, Erik; Taskinen, Marja-Riitta; Tybjaerg-Hansen, Anne

    2013-01-01

    AIMS: The first aim was to critically evaluate the extent to which familial hypercholesterolaemia (FH) is underdiagnosed and undertreated. The second aim was to provide guidance for screening and treatment of FH, in order to prevent coronary heart disease (CHD). METHODS AND RESULTS: Of the theoretic

  1. Colesevelam added to combination therapy with a statin and ezetimibe in patients with familial hypercholesterolemia: a 12-week, multicenter, randomized, double-blind, controlled trial.

    NARCIS (Netherlands)

    Huijgen, R.; Abbink, E.J.; Bruckert, E.; Stalenhoef, A.F.H.; Imholz, B.P.; Durrington, P.N.; Trip, M.D.; Eriksson, M.; Visseren, F.L.; Schaefer, J.R.; Kastelein, J.J.

    2010-01-01

    BACKGROUND: Familial hypercholesterolemia (FH) has been associated with increased cardiovascular risk when untreated or when normal LDL-C concentrations are not reached. Some patients with FH do not reach LDL-C goals despite intensive combination therapy. OBJECTIVE: This study assessed the efficacy

  2. AcEST: DK953947 [AcEST

    Lifescience Database Archive (English)

    Full Text Available 45/81 (55%) Frame = +3 Query: 315 HDLICTLCANSTALWIYAIVWLLANVNGWETNVFVTXXXXXXXXXX... = +3 Query: 288 FHILQVC*GHDLICTLCANSTALWIYAIVWLLANVNGWETNVFVTXXXXXXXXXXGTKMQ 467 FH V D T+ S LW++ +++LL N+N...+3 Query: 288 FHILQVC*GHDLICTLCANSTALWIYAIVWLLANVNGWETNVFVTXXXXXXXXXXGTKMQ 467 FH V D T+ S LW++ +++LL N+NGW

  3. Body mass index and annual increase of body mass index in long-term childhood cancer survivors; relationship to treatment

    NARCIS (Netherlands)

    Brouwer, Cornelia A J; Gietema, Jourik A; Vonk, Judith M; Tissing, W J E; Boezen, Hendrika M; Zwart, Nynke; Postma, Aleida

    2012-01-01

    PURPOSE: Evaluation of body mass index (BMI) at final height (FH) and annual BMI increase in adult childhood cancer survivors (CCS) after treatment with anthracyclines, platinum, and/or radiotherapy. METHODS: BMI (weight/height²) was calculated retrospectively from diagnosis until FH. The prevalence

  4. Cholesterol Levels in Genetically Determined Familial Hypercholesterolaemia in Russian Karelia

    Directory of Open Access Journals (Sweden)

    V. A. Korneva

    2017-01-01

    Full Text Available Familial hypercholesterolaemia (FH is a rare disease that tends to be diagnosed lately. In Russia, the genetic and phenotypic characteristics of the disease are not well defined. We investigated 102 patients with definite FH. In 52 of these patients (50.9% genetic analysis was performed, revealing pathogenic mutations of the low density lipoprotein (LDL receptor gene in 22 patients. We report here five mutations of the LDL receptor gene found in the Karelian FH sample for the first time. The detection rate of mutations in definite FH patients was 42.3%. Two groups of patients with a definite diagnosis of FH according to the Dutch Lipid Clinic Network criteria were compared: the first group had putatively functionally important LDL receptor gene mutations, while in the second group LDL receptor gene mutations were excluded by single-strand conformation polymorphism analysis. Total and LDL cholesterol levels were higher in the group with LDL receptor mutations compared to the mutation-free population. The frequency of mutations in patients with LDL cholesterol > 6.5 mmol/L was more than 3 times higher than that in patients with LDL < 6.5 mmol/L. Total and LDL cholesterol levels and the frequency of coronary heart disease and myocardial infarction were higher in the group with definite FH compared to groups with probable and possible FH. Cholesterol figures in FH patients of different age and sex from the Karelian population were comparable.

  5. Gclust Server: 77003 [Gclust Server

    Lifescience Database Archive (English)

    Full Text Available 77003 ATH_AT5G54650_15239699 Cluster Sequences - 900 Fh5 (FORMIN HOMOLOGY5); actin ...OLOGY5); actin binding Number of Sequences 1 Homologs 1 ...Link to cluster sequences Cluster Sequences Link to related sequences - Sequence length 900 Representative annotation Fh5 (FORMIN HOM

  6. Gclust Server: 76964 [Gclust Server

    Lifescience Database Archive (English)

    Full Text Available 76964 ATH_AT5G54650_30696498 Cluster Sequences - 900 Fh5 (FORMIN HOMOLOGY5); actin ...OLOGY5); actin binding Number of Sequences 1 Homologs 1 ...Link to cluster sequences Cluster Sequences Link to related sequences - Sequence length 900 Representative annotation Fh5 (FORMIN HOM

  7. The Influence of an Educational Computer Game on Children's Cultural Identities

    Science.gov (United States)

    Chen, Hsiang-Ping; Lien, Chi-Jui; Annetta, Len; Lu, Yu-Ling

    2010-01-01

    This study develops an educational computer game, FORmosaHope (FH), to explore the influences that an educational computer game might have on children's cultural identities. FH is a role-playing game, in which children can actively explore a mini-world to learn about science, technology, and society. One hundred and thirty sixth-graders, about…

  8. Fasciola hepatica saposin-like-2 protein based ELISA for the serodiagnosis of chronic human fascioliasis

    Science.gov (United States)

    Figueroa-Santiago, Olgary; Delgado, Bonnibel; Espino, Ana M.

    2011-01-01

    An indirect enzyme-linked immunosorbent assay (ELISA) was developed and evaluated for its diagnostic ability to detect human IgG antibodies against Fasciola hepatica saposin-like protein-2. The assay was compared with an indirect ELISA with excretory-secretory products (FhES) from adult F. hepatica. In an analysis of the sera of 37 patients infected with F. hepatica, 40 patients with other parasitic infections, and 50 healthy controls, the sensitivity of both ELISA assays was 100%. However, the FhSAP2-based ELISA was more specific (95.6%) than the FhES-ELISA (91.9%). These results demonstrated that FhSAP2 can be used in the serodiagnosis of chronic human fascioliasis with additional advantage that is relative cheap and easy to produce. Studies are in progress to evaluate this FhSAP2-ELISA assay in a large-scale prevalence surveys in endemic areas. PMID:21683266

  9. The role of heparan sulfate as determining pathogenic factor in complement factor H-associated diseases.

    Science.gov (United States)

    Loeven, Markus A; Rops, Angelique L W M M; Berden, Jo H M; Daha, Mohamed R; Rabelink, Ton J; van der Vlag, Johan

    2015-02-01

    Complement factor H (FH) systemically inhibits excessive complement activation in the microenvironment of host cells, but for instance not on microbes. This self-recognition is mediated by two binding sites that recognize distinctly sulfated heparan sulfate (HS) domains. The interaction with HS not only concentrates FH on host cells, but directly affects its activity, evoking novel models of conformational activation. Genetic aberrations in the HS-binding domains systemically disturb the protective function of FH, yet the resulting loss of complement control affects mainly ocular and renal tissues. Recent results suggest that the specific expression of HS domains in these tissues restricts the interaction of HS to a single binding site within FH. This lack of redundancy could predispose eyes and kidneys to complement-mediated damage, making HS a central determinant for FH-associated diseases. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. Lipoprotein apheresis and new therapies for severe familial hypercholesterolemia in adults and children.

    Science.gov (United States)

    Page, Michael M; Bell, Damon A; Hooper, Amanda J; Watts, Gerald F; Burnett, John R

    2014-06-01

    Familial hypercholesterolemia (FH), the most common and severe monogenic form of hypercholesterolemia, is an autosomal co-dominant disease characterized by an increased plasma low density lipoprotein (LDL)-cholesterol concentration and premature coronary heart disease (CHD). The clinical phenotype depends on the gene involved and severity of mutation (or mutations) present. Patients with homozygous or compound heterozygous FH have severe hypercholesterolemia (LDL-cholesterol >13 mmol/L) due to a gene dosing effect and without treatment have accelerated atherosclerotic CHD from birth, and frequently die of CHD before age 30. Cholesterol-lowering therapies have been shown to reduce both mortality and major adverse cardiovascular events in individuals with FH. Lipoprotein apheresis concomitant with lipid-lowering therapy is the treatment of choice for homozygous FH. This article describes the rationale and role of lipoprotein apheresis in the treatment of severe FH and outlines the recent advances in new pharmacotherapies for this condition.

  11. Familial hypercholesterolemia in the danish general population

    DEFF Research Database (Denmark)

    Benn, Marianne; Watts, Gerald F; Tybjaerg-Hansen, Anne

    2012-01-01

    receptor (LDLR) and apolipoprotein B (APOB) genes. Objective: We employed this tool to investigate the prevalence of FH and the associations between FH and coronary artery disease and cholesterol-lowering medication in the Copenhagen General Population Study. Setting: The study was of an unselected......, community-based population comprising 69,016 participants. Main Outcome Measures: FH (definite/probable) was defined as a Dutch Lipid Clinic Network score higher than 5. Coronary artery disease was myocardial infarction or angina pectoris. Results: The prevalence of FH was 0.73% (one in 137.......8-13.8). Conclusion: The prevalence of FH appears to be higher than commonly perceived in a general population of white Danish individuals, with at least half of affected subjects not receiving cholesterol-lowering medication. The very high risk of coronary artery disease irrespective of use of medication reflects...

  12. Familial hypercholesterolaemia reduces the quality of life of patients not reaching treatment targets

    DEFF Research Database (Denmark)

    Mortensen, Gitte Lee; Madsen, Ivan Bredbjerg; Kruse, Charlotte

    2016-01-01

    INTRODUCTION: Familial hypercholesterolaemia (FH) is the most common monogenic disorder associated with premature cardiovascular disease. If untreated, life expectancy in heterozygous FH patients is shortened by 20-30 years compared with the general population. Nevertheless, treatment goals...... are only met in approximately 50% of patients. This comparative study examined the quality of life (QoL) impact of FH in patients who had and had not reached the target of treatment. METHODS: Two qualitative focus group interviews were carried out with a total of ten FH patients. A semi......-structured interview guide included questions identified in a preceding literature study. The data were analysed using a medical anthropological approach. RESULTS: While having FH did not have much impact on well-treated patients' QoL, patients who had not reached the treatment target had markedly more concerns...

  13. Cipher quasi-chaotic code for frequency hopping communications

    Institute of Scientific and Technical Information of China (English)

    王宏霞; 何晨; 虞厥邦

    2004-01-01

    The chaotic frequency hopping (FH) communication systems have been presented so far. The chaotic sequences possesses good randomness and sensitive dependence on initial conditions, which is quite advantageous to run the FH codes in code-division multiple access (CDMA) systems. But the finite precision of computation and the fact of the low-dimensional chaos predicted easily cause difficulty in chaotic application. In this paper, some disadvantages associated with the conventional FH codes and the chaotic code scrambled by m-sequences are reviewed briefly. In order to overcome these drawbacks to some extents, a new higher performance FH code called cipher quasi-chaotic (CQC) code is proposed,which is generated by combining the clock-controlled stream cipher technique and chaotic dynamics. Performance analysis applying in FH communication systems of this kind of code is given. The privacy of the CQC sequence is also analyzed.

  14. Biocatalytic Synthesis of Highly Enantiopure 1,4-Benzodioxane-2-carboxylic Acid and Amide

    Institute of Scientific and Technical Information of China (English)

    LIU Jun; WANG De-Xian; ZHENG Qi-Yu; WANG Mei-Xiang

    2006-01-01

    Catalyzed by Rhodococcus erythropolis A J270, a nitrile hydratase and amidase containing microbial whole-cell catalyst, at 10 ℃ and with the use of methanol as a co-solvent, nitrile and amide biotransformations produce 2S-1,4-benzodioxane-2-carboxamide and 2R-1,4-benzodioxane-2-carboxylic acid in high yields with excellent enantioselectivity.

  15. Disease: H01352 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available lex of the fatty acid beta-oxidation cycle. Human TFP is an octamer composed of four alpha-subunits harbor...ing long-chain enoyl-CoA hydratase and long-chain L-3-hydroxyacyl-CoA dehydrogenase

  16. Bioinspired catalytic nitrile hydration by dithiolato, sulfinato/thiolato, and sulfenato/sulfinato ruthenium complexes.

    Science.gov (United States)

    Kumar, Davinder; Masitas, César A; Nguyen, Tho N; Grapperhaus, Craig A

    2013-01-11

    A series of Ru(II) catalysts inspired by the metalloenzyme nitrile hydratase catalyze the hydration of benzonitrile with up to 242 turnovers under neutral conditions with very low catalysts loading. Catalysts with an oxidized sulfur environment are less susceptible to product inhibition increasing the catalytic efficiency at low nitrile : water ratios.

  17. Gclust Server: 9975 [Gclust Server

    Lifescience Database Archive (English)

    Full Text Available 9975 Bja_bll4497=nthB Cluster Sequences - 219 nitrile hydratase subunit beta 11 1.0...0e-50 0.0 0.0 0.0 33.33 16.13 0.0 Show 9975 Cluster ID 9975 Sequence ID Bja_bll4497=nthB Link to cluster seq

  18. AcEST: BP914175 [AcEST

    Lifescience Database Archive (English)

    Full Text Available Escherichia coli (strain UTI89 / UPEC) GN=fumC PE=4 SV=1 Length = 467 Score = 52....ERINQLLNE 404 >tr|Q0THL7|Q0THL7_ECOL5 Fumarate hydratase class II OS=Escherichia coli O6:K15:H31 (strain 536 / UPEC

  19. Toxicological investigation of di(isodecyl)phthalate in rats

    NARCIS (Netherlands)

    van den Ham WA; Jansen EHJM; de Fluiter P; van Leeuwen FXR

    1992-01-01

    In a study in which male rats have been exposed to 0, 20, 60, 200, 600 and 2000 mg di(isodecyl)phthalate (DIDP)kg diet for 2 weeks, body weight and liver weight and a number of enzyme parameters (palmitoyl coenzyme-A oxidase (PCO), enoyl coenzyme-A hydratase (ECH), carnitine acetyl transferase (CAT)

  20. Toxicological investigation of di(isononyl]phthalate in rats

    NARCIS (Netherlands)

    Jansen EHJM; van den Ham WA; de Fluiter P; van Leeuwen FXR

    1992-01-01

    In a study in which male rats have been exposed to 0,20, 60, 200, 600 and 2000 mg di(isononyl)phthalate (DINP)/kg diet for 2 weeks, body weight and liver weight and a number of enzyme parameters (palmitoyl coenzyme-A oxidase (PCO), enoyl coenzyme-A hydratase (ECH), carnitine acetyl transferase (CAT)

  1. Toxicological investigation of dibutylphthalate in rats

    NARCIS (Netherlands)

    Jansen EHJM; van den Ham WA; de Fluiter P; van Leeuwen FXR

    1993-01-01

    In a study in which male rats have been exposed to 0, 20, 60, 200, 600 and 2000 mg dibutylphthalate (DBP)/kg diet for 2 weeks, body weight and liver weight and a number of enzyme parameters which are related with peroxisome proliferation (palmitoyl coenzyme-A oxidase (PCO, enoyl coenzyme-A hydratase

  2. Sequence Classification: 893466 [

    Lifescience Database Archive (English)

    Full Text Available nd enoyl-CoA hydratase activities; Fox2p || http://www.ncbi.nlm.nih.gov/protein/6322861 ... ...unctional enzyme of the peroxisomal fatty acid beta-oxidation pathway; has 3-hydroxyacyl-CoA dehydrogenase a

  3. AcEST: DK950379 [AcEST

    Lifescience Database Archive (English)

    Full Text Available D Urocanate hydratase OS=Bacillus halodurans ... 31 2.6 sp|A5D7F6|MAML2_BOVIN Mastermind-like protein 2 OS=B...EAMLAFQRRGA 315 >sp|A5D7F6|MAML2_BOVIN Mastermind-like protein 2 OS=Bos taurus GN

  4. Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations

    NARCIS (Netherlands)

    Evenepoel, Lucie; Papathomas, Thomas G.; Krol, Niels; Korpershoek, Esther; De Krijger, Ronald R.; Persu, Alexandre; Dinjens, Winand N M

    2015-01-01

    The tricarboxylic acid, or Krebs, cycle is central to the cellular metabolism of sugars, lipids, and amino acids; it fuels the mitochondrial respiratory chain for energy generation. In the past decade, mutations in the Krebs-cycle enzymes succinate dehydrogenase, fumarate hydratase, and isocitrate

  5. GenBank blastx search result: AK243510 [KOME

    Lifescience Database Archive (English)

    Full Text Available AK243510 J100075B22 AF013216.1 AF013216 Myxococcus xanthus Dog (dog), isocitrate lyase (icl), Mls (mls), Ufo... (ufo), fumarate hydratase (fhy), and proteosome major subunit (clpP) genes, complete cds; and acyl-CoA oxidase (aco) gene, partial cds. BCT 2e-87 1 ...

  6. GenBank blastn search result: AK241214 [KOME

    Lifescience Database Archive (English)

    Full Text Available AK241214 J065122P06 AF013216.1 AF013216 Myxococcus xanthus Dog (dog), isocitrate lyase (icl), Mls (mls), Ufo... (ufo), fumarate hydratase (fhy), and proteosome major subunit (clpP) genes, complete cds; and acyl-CoA oxidase (aco) gene, partial cds. BCT 8e-18 1 -1 ...

  7. GenBank blastx search result: AK241214 [KOME

    Lifescience Database Archive (English)

    Full Text Available AK241214 J065122P06 AF013216.1 AF013216 Myxococcus xanthus Dog (dog), isocitrate lyase (icl), Mls (mls), Ufo... (ufo), fumarate hydratase (fhy), and proteosome major subunit (clpP) genes, complete cds; and acyl-CoA oxidase (aco) gene, partial cds. BCT 1e-151 1 ...

  8. GenBank blastx search result: AK243527 [KOME

    Lifescience Database Archive (English)

    Full Text Available AK243527 J100075P16 AF013216.1 AF013216 Myxococcus xanthus Dog (dog), isocitrate lyase (icl), Mls (mls), Ufo... (ufo), fumarate hydratase (fhy), and proteosome major subunit (clpP) genes, complete cds; and acyl-CoA oxidase (aco) gene, partial cds. BCT 1e-143 1 ...

  9. GenBank blastx search result: AK287540 [KOME

    Lifescience Database Archive (English)

    Full Text Available AK287540 J065011K01 AF013216.1 AF013216 Myxococcus xanthus Dog (dog), isocitrate lyase (icl), Mls (mls), Ufo... (ufo), fumarate hydratase (fhy), and proteosome major subunit (clpP) genes, complete cds; and acyl-CoA oxidase (aco) gene, partial cds. BCT 0.0 0 ...

  10. A Novel Factor H-Fc Chimeric Immunotherapeutic Molecule against Neisseria gonorrhoeae.

    Science.gov (United States)

    Shaughnessy, Jutamas; Gulati, Sunita; Agarwal, Sarika; Unemo, Magnus; Ohnishi, Makoto; Su, Xia-Hong; Monks, Brian G; Visintin, Alberto; Madico, Guillermo; Lewis, Lisa A; Golenbock, Douglas T; Reed, George W; Rice, Peter A; Ram, Sanjay

    2016-02-15

    Neisseria gonorrhoeae, the causative agent of the sexually transmitted infection gonorrhea, has developed resistance to almost every conventional antibiotic. There is an urgent need to develop novel therapies against gonorrhea. Many pathogens, including N. gonorrhoeae, bind the complement inhibitor factor H (FH) to evade complement-dependent killing. Sialylation of gonococcal lipooligosaccharide, as occurs in vivo, augments binding of human FH through its domains 18-20 (FH18-20). We explored the use of fusing FH18-20 with IgG Fc (FH18-20/Fc) to create a novel anti-infective immunotherapeutic. FH18-20 also binds to select host glycosaminoglycans to limit unwanted complement activation on host cells. To identify mutation(s) in FH18-20 that eliminated complement activation on host cells, yet maintained binding to N. gonorrhoeae, we created four mutations in domains 19 or 20 described in atypical hemolytic uremic syndrome that prevented binding of mutated fH to human erythrocytes. One of the mutant proteins (D to G at position 1119 in domain 19; FHD1119G/Fc) facilitated complement-dependent killing of gonococci similar to unmodified FH18-20/Fc but, unlike FH18-20/Fc, did not lyse human erythrocytes. FHD1119G/Fc bound to all (100%) of 15 sialylated clinical N. gonorrhoeae isolates tested (including three contemporary ceftriaxone-resistant strains), mediated complement-dependent killing of 10 of 15 (67%) strains, and enhanced C3 deposition (≥10-fold above baseline levels) on each of the five isolates not directly killed by complement. FHD1119G/Fc facilitated opsonophagocytic killing of a serum-resistant strain by human polymorphonuclear neutrophils. FHD1119G/Fc administered intravaginally significantly reduced the duration and burden of gonococcal infection in the mouse vaginal colonization model. FHD1119G/Fc represents a novel immunotherapeutic against multidrug-resistant N. gonorrhoeae.

  11. Differences in various biochemical and clinical parameters with respect to family history of Non Communicable Diseases in fourth year MBBS students of Karachi, Pakistan

    Science.gov (United States)

    Basit, Khalid Abdul; Fawwad, Asher; Munir, Muhammad Asadullah; Siddiqui, Iftikhar Ahmed; Siddiqui, Sidra; Basit, Abdul

    2015-01-01

    Objective: To observe the differences of various biochemical and clinical parameters with respect to Family History (FH) of Non-communicable Diseases (NCDs) in fourth year Bachelor of Medicine, Bachelor of Surgery (MBBS) students. Methods: This observational study was conducted at Baqai Institute of Diabetology & Endocrinology from December 2013 to January 2014. Total 50 medical students from Dow University of Health Sciences (DUHS) participated in the study. Statistical Package for Social Sciences (SPSS) version 13 was used to analyze the data. For cross tabulation and mean comparison z-test and t test were applied. Results: Out of 50 subjects, there were 26 (52%) females. Mean age of the study population was 21.56 ± 0.90 years. Mean serum cholesterol levels with positive FH of NCDs was significantly higher than negative FH of NCDs (p=0.005). Mean value of low density lipoprotein (LDL) of positive family history of NCDs was found higher than those with negative FH (p=0.006) being statistically significant. The insulin levels in subjects with positive FH of NCDs were higher than subjects with negative FH of NCDs (p=0.685). However, serum leptin and plasma renin showed no significant difference with the negative FH of NCDs being higher compared to positive FH of NCDs (p=0.068) and (p=0.884) respectively. However, Waist circumference, Body mass index and central obesity in subjects with positive FH of NCDs shows increasing trend but no statistically significant difference (p > 0.05) was observed. Conclusion: In our study of various biochemical and clinical parameters with respect to FH of NCDs, Serum Cholesterol and LDL levels were observed higher and statistically significant. PMID:26430439

  12. UDP-galactose 4'-epimerase from the liver fluke, Fasciola hepatica: biochemical characterization of the enzyme and identification of inhibitors.

    Science.gov (United States)

    Zinsser, Veronika L; Lindert, Steffen; Banford, Samantha; Hoey, Elizabeth M; Trudgett, Alan; Timson, David J

    2015-03-01

    Leloir pathway enzyme uridine diphosphate (UDP)-galactose 4'-epimerase from the common liver fluke Fasciola hepatica (FhGALE) was identified and characterized. The enzyme can be expressed in, and purified from, Escherichia coli. The recombinant enzyme is active: the K(m) (470 μM) is higher than the corresponding human enzyme (HsGALE), whereas the k(cat) (2.3 s(-1)) is substantially lower. FhGALE binds NAD(+) and has shown to be dimeric by analytical gel filtration. Like the human and yeast GALEs, FhGALE is stabilized by the substrate UDP-galactose. Molecular modelling predicted that FhGALE adopts a similar overall fold to HsGALE and that tyrosine 155 is likely to be the catalytically critical residue in the active site. In silico screening of the National Cancer Institute Developmental Therapeutics Program library identified 40 potential inhibitors of FhGALE which were tested in vitro. Of these, 6 showed concentration-dependent inhibition of FhGALE, some with nanomolar IC50 values. Two inhibitors (5-fluoroorotate and N-[(benzyloxy)carbonyl]leucyltryptophan) demonstrated selectivity for FhGALE over HsGALE. These compounds also thermally destabilized FhGALE in a concentration-dependent manner. Interestingly, the selectivity of 5-fluoroorotate was not shown by orotic acid, which differs in structure by 1 fluorine atom. These results demonstrate that, despite the structural and biochemical similarities of FhGALE and HsGALE, it is possible to discover compounds which preferentially inhibit FhGALE.

  13. Mutations of factor H impair regulation of surface-bound C3b by three mechanisms in atypical hemolytic uremic syndrome.

    Science.gov (United States)

    Lehtinen, Markus J; Rops, Angelique L; Isenman, David E; van der Vlag, Johan; Jokiranta, T Sakari

    2009-06-05

    Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy associated with mutations in complement proteins, most frequently in the main plasma alternative pathway regulator factor H (FH). The hotspot for the FH mutations is in domains 19-20 (FH19-20) that are indispensable for FH activity on C3b bound covalently to host cells. In aHUS, down-regulation of cell-bound C3b by FH is impaired, but it is not clear whether this is due to an altered FH binding to surface-bound C3b or to cell surface structures. To explore the molecular pathogenesis of aHUS we tested binding of 14 FH19-20 point mutants to C3b and its C3d fragment, mouse glomerular endothelial cells (mGEnC-1), and heparin. The cell binding correlated well, but not fully, with heparin binding and the cell binding site was overlapping but distinct from the C3b/C3d binding site that was shown to extend to domain 19. Our results show that aHUS-associated FH19-20 mutants have different combinations of three primary defects: impaired binding to C3b/C3d, impaired binding to the mGEnC-1 cells/heparin, and, as a novel observation, an enhanced mGEnC-1 cell or heparin binding. We propose a model of the molecular pathogenesis of aHUS where all three mechanisms lead eventually to impaired control of C3b on the endothelial cell surfaces. Based on the results with the aHUS patient mutants and the overlap in FH19-20 binding sites for mGEnC-1/heparin and C3b/C3d we conclude that binding of FH19-20 to C3b/C3d is essential for target discrimination by the alternative pathway.

  14. New Approaches in Detection and Treatment of Familial Hypercholesterolemia.

    Science.gov (United States)

    Hartgers, Merel L; Ray, Kausik K; Hovingh, G Kees

    2015-12-01

    Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder that clinically leads to increased low density lipoprotein-cholesterol (LDL-C) levels. As a consequence, FH patients are at high risk for cardiovascular disease (CVD). Mutations are found in genes coding for the LDLR, apoB, and PCSK9, although FH cannot be ruled out in the absence of a mutation in one of these genes. It is pivotal to diagnose FH at an early age, since lipid lowering results in a decreased risk of cardiovascular complications especially if initiated early, but unfortunately FH is largely underdiagnosed. While a number of clinical criteria are available, identification of a pathogenic mutation in any of the three aforementioned genes is seen by many as a way to establish a definitive diagnosis of FH. It should be remembered that clinical treatment is based on LDL-C levels and not solely on presence or absence of genetic mutations as LDL-C is what drives risk. Traditionally, mutation detection has been done by means of dideoxy sequencing. However, novel molecular testing methods are gradually being introduced. These next generation sequencing-based methods are likely to be applied on broader scale once their efficacy and effect on cost are being established. Statins are the first-line therapy of choice for FH patients as they have been proven to reduce CVD risk across a range of conditions including hypercholesterolemia (though not specifically tested in FH). However, in a significant proportion of FH patients LDL-C goals are not met, despite the use of maximal statin doses and additional lipid-lowering therapies. This underlines the need for additional therapies, and inhibition of PCSK9 and CETP is among the most promising new therapeutic options. In this review, we aim to provide an overview of the latest information about the definition, diagnosis, screening, and current and novel therapies for FH.

  15. Differences in various biochemical and clinical parameters with respect to family history of Non Communicable Diseases in fourth year MBBS students of Karachi, Pakistan.

    Science.gov (United States)

    Basit, Khalid Abdul; Fawwad, Asher; Munir, Muhammad Asadullah; Siddiqui, Iftikhar Ahmed; Siddiqui, Sidra; Basit, Abdul

    2015-01-01

    To observe the differences of various biochemical and clinical parameters with respect to Family History (FH) of Non-communicable Diseases (NCDs) in fourth year Bachelor of Medicine, Bachelor of Surgery (MBBS) students. This observational study was conducted at Baqai Institute of Diabetology & Endocrinology from December 2013 to January 2014. Total 50 medical students from Dow University of Health Sciences (DUHS) participated in the study. Statistical Package for Social Sciences (SPSS) version 13 was used to analyze the data. For cross tabulation and mean comparison z-test and t test were applied. Out of 50 subjects, there were 26 (52%) females. Mean age of the study population was 21.56 ± 0.90 years. Mean serum cholesterol levels with positive FH of NCDs was significantly higher than negative FH of NCDs (p=0.005). Mean value of low density lipoprotein (LDL) of positive family history of NCDs was found higher than those with negative FH (p=0.006) being statistically significant. The insulin levels in subjects with positive FH of NCDs were higher than subjects with negative FH of NCDs (p=0.685). However, serum leptin and plasma renin showed no significant difference with the negative FH of NCDs being higher compared to positive FH of NCDs (p=0.068) and (p=0.884) respectively. However, Waist circumference, Body mass index and central obesity in subjects with positive FH of NCDs shows increasing trend but no statistically significant difference (p > 0.05) was observed. In our study of various biochemical and clinical parameters with respect to FH of NCDs, Serum Cholesterol and LDL levels were observed higher and statistically significant.

  16. Staphylococcal Ecb protein and host complement regulator factor H enhance functions of each other in bacterial immune evasion.

    Science.gov (United States)

    Amdahl, Hanne; Jongerius, Ilse; Meri, Taru; Pasanen, Tanja; Hyvärinen, Satu; Haapasalo, Karita; van Strijp, Jos A; Rooijakkers, Suzan H; Jokiranta, T Sakari

    2013-08-15

    Staphylococcus aureus is a major human pathogen causing more than a tenth of all septicemia cases and often superficial and deep infections in various tissues. One of the immune evasion strategies of S. aureus is to secrete proteins that bind to the central complement opsonin C3b. One of these, extracellular complement binding protein (Ecb), is known to interfere directly with functions of C3b. Because C3b is also the target of the physiological plasma complement regulator, factor H (FH), we studied the effect of Ecb on the complement regulatory functions of FH. We show that Ecb enhances acquisition of FH from serum onto staphylococcal surfaces. Ecb and FH enhance mutual binding to C3b and also the function of each other in downregulating complement activation. Both Ecb and the C-terminal domains 19-20 of FH bind to the C3d part of C3b. We show that the mutual enhancing effect of Ecb and FH on binding to C3b depends on binding of the FH domain 19 to the C3d part of C3b next to the binding site of Ecb on C3d. Our results show that Ecb, FH, and C3b form a tripartite complex. Upon exposure of serum-sensitive Haemophilus influenzae to human serum, Ecb protected the bacteria, and this effect was enhanced by the addition of the C-terminal domains 19-20 of FH. This finding indicates that the tripartite complex formation could give additional protection to bacteria and that S. aureus is thereby able to use host FH and bacterial Ecb in a concerted action to eliminate C3b at the site of infection.

  17. Addition of a novel, protective family history category allows better profiling of cardiovascular risk and atherosclerotic burden in the general population. The Asklepios Study.

    Directory of Open Access Journals (Sweden)

    Caroline M Van daele

    Full Text Available OBJECTIVES: Whereas the importance of family history (FH is widely recognized in cardiovascular risk assessment, its full potential could be underutilized, when applied with its current simple guidelines-based definition (cFH: presence of premature cardiovascular disease (CVD in a first-degree relative. We tested the added value of a new, extended family history definition (eFH, also taking into account later onset of disease, second-degree relatives and number of affected relatives, on profiling cardiovascular risk and atherosclerotic burden in the general population. DESIGN: Longitudinal population study. SETTING: Random, representative population sample from Erpe-Mere and Nieuwerkerken (Belgium, primary care. SUBJECTS: 2524 male/female volunteers, aged 35-55 years, free from overt CVD. MAIN OUTCOME MEASURES: Subjects were extensively phenotyped including presence of atherosclerosis (ultrasound and a newly developed FH questionnaire (4 generations. RESULTS: Compared to cFH, eFH was superior in predicting an adverse risk profile (glycemic state, elevated blood pressure, lipid abnormalities, presence of metabolic syndrome components and presence of atherosclerosis (all age & sex-adjusted p<0.05. Unlike cFH, eFH remained a significant predictor of subclinical atherosclerosis after adjusting for confounders. Most relations with eFH were not graded but showed clear informational breakpoints, with absence of CVD (including late onset in any first-degree relative being a negative predictor of atherosclerosis, and a particularly interesting phenotype for further study. CONCLUSIONS: A novel, extended FH definition is superior to the conventional definition in profiling cardiovascular risk and atherosclerotic burden in the general population. There remain clear opportunities to refine and increase the performance and informational content of this simple, readily-available inexpensive tool.

  18. Height outcome of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

    Institute of Scientific and Technical Information of China (English)

    Feng Yun-lin; Zhu Hui-juan; Gong Feng-ying; Li Nai-shi; Pan Hui; Lu Zhao-lin; Shi Yi-fan

    2007-01-01

    Objective: To retrospectively investigate the height outcome of patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD).Methods: The 135 CAH patients with 21-OHD diagnosed in our hospital from Jan 1980 to Oct 2006 were retrospectively analyzed.The investigated parameters included final height(FH), FH standard deviation score(FH SDS), target height SDS (TH SDS), difference between TH and FH (TH-FH), FH SDS-TH SDS, the age of onset of sexual development, and the difference between bone age and chronological age(BA-CA) when patients got the FH.Results: Among the 135 patients, female/male=108/27.Mean FH was (156.84±5.4) cm (n=14) and (150.8±6.8) cm (n=76) for males and females, respectively.Mean FH SDS was (-0.6±0.8) (n=13) and (0.2±1.2) (n=54) for males and females, respectively.Sexual development began at (5.2±1.7) years old (y/o) (n=13) and (7.9±3.2) y/o (n=43) in males and females, respectively.Conclusions: The FH of CAH patients with 21-OHD was lower than that of the normal range.Effect of the disease on the height growth in male patients was more severe than that in females.All patients began sexual development much earlier than the normal age-matched group.Male patients began their sexual development even earlier.

  19. Secreted aspartic protease 2 of Candida albicans inactivates factor H and the macrophage factor H-receptors CR3 (CD11b/CD18) and CR4 (CD11c/CD18).

    Science.gov (United States)

    Svoboda, Eliška; Schneider, Andrea E; Sándor, Noémi; Lermann, Ulrich; Staib, Peter; Kremlitzka, Mariann; Bajtay, Zsuzsa; Barz, Dagmar; Erdei, Anna; Józsi, Mihály

    2015-11-01

    The opportunistic pathogenic yeast Candida albicans employs several mechanisms to interfere with the human complement system. This includes the acquisition of host complement regulators, the release of molecules that scavenge complement proteins or block cellular receptors, and the secretion of proteases that inactivate complement components. Secreted aspartic protease 2 (Sap2) was previously shown to cleave C3b, C4b and C5. C. albicans also recruits the complement inhibitor factor H (FH), but yeast-bound FH can enhance the antifungal activity of human neutrophils via binding to complement receptor type 3 (CR3). In this study, we characterized FH binding to human monocyte-derived macrophages. Inhibition studies with antibodies and siRNA targeting CR3 (CD11b/CD18) and CR4 (CD11c/CD18), as well as analysis of colocalization of FH with these integrins indicated that both function as FH receptors on macrophages. Preincubation of C. albicans yeast cells with FH induced increased production of IL-1β and IL-6 in macrophages. Furthermore, FH enhanced zymosan-induced production of these cytokines. C. albicans Sap2 cleaved FH, diminishing its complement regulatory activity, and Sap2-treatment resulted in less detectable CR3 and CR4 on macrophages. These data show that FH enhances the activation of human macrophages when bound on C. albicans. However, the fungus can inactivate both FH and its receptors on macrophages by secreting Sap2, which may represent an additional means for C. albicans to evade the host innate immune system.

  20. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease

    Science.gov (United States)

    Nordestgaard, Børge G.; Chapman, M. John; Humphries, Steve E.; Ginsberg, Henry N.; Masana, Luis; Descamps, Olivier S.; Wiklund, Olov; Hegele, Robert A.; Raal, Frederick J.; Defesche, Joep C.; Wiegman, Albert; Santos, Raul D.; Watts, Gerald F.; Parhofer, Klaus G.; Hovingh, G. Kees; Kovanen, Petri T.; Boileau, Catherine; Averna, Maurizio; Borén, Jan; Bruckert, Eric; Catapano, Alberico L.; Kuivenhoven, Jan Albert; Pajukanta, Päivi; Ray, Kausik; Stalenhoef, Anton F. H.; Stroes, Erik; Taskinen, Marja-Riitta; Tybjærg-Hansen, Anne

    2013-01-01

    Aims The first aim was to critically evaluate the extent to which familial hypercholesterolaemia (FH) is underdiagnosed and undertreated. The second aim was to provide guidance for screening and treatment of FH, in order to prevent coronary heart disease (CHD). Methods and results Of the theoretical estimated prevalence of 1/500 for heterozygous FH, <1% are diagnosed in most countries. Recently, direct screening in a Northern European general population diagnosed approximately 1/200 with heterozygous FH. All reported studies document failure to achieve recommended LDL cholesterol targets in a large proportion of individuals with FH, and up to 13-fold increased risk of CHD. Based on prevalences between 1/500 and 1/200, between 14 and 34 million individuals worldwide have FH. We recommend that children, adults, and families should be screened for FH if a person or family member presents with FH, a plasma cholesterol level in an adult ≥8 mmol/L(≥310 mg/dL) or a child ≥6 mmol/L(≥230 mg/dL), premature CHD, tendon xanthomas, or sudden premature cardiac death. In FH, low-density lipoprotein cholesterol targets are <3.5 mmol/L(<135 mg/dL) for children, <2.5 mmol/L(<100 mg/dL) for adults, and <1.8 mmol/L(<70 mg/dL) for adults with known CHD or diabetes. In addition to lifestyle and dietary counselling, treatment priorities are (i) in children, statins, ezetimibe, and bile acid binding resins, and (ii) in adults, maximal potent statin dose, ezetimibe, and bile acid binding resins. Lipoprotein apheresis can be offered in homozygotes and in treatment-resistant heterozygotes with CHD. Conclusion Owing to severe underdiagnosis and undertreatment of FH, there is an urgent worldwide need for diagnostic screening together with early and aggressive treatment of this extremely high-risk condition. PMID:23956253

  1. Comparison of Carotid Intima-Media Thickness in Pediatric Patients with Metabolic Syndrome, Heterozygous Familial Hyperlipidemia and Normals

    Directory of Open Access Journals (Sweden)

    Arvind Vijayasarathi

    2014-01-01

    Full Text Available Background. Our goal was to compare the carotid intimal-medial thickness (CIMT of untreated pediatric patients with metabolic syndrome (MS, heterozygous familial hyperlipidemia (heFH, and MS+heFH against one another and against a control group consisting of healthy, normal body habitus children. Methods. Our population consisted of untreated pediatric patients (ages 5–20 yrs who had CIMT measured in a standardized manner. Results. Our population included 57 with MS, 23 with heFH, and 10 with MS+heFH. The control group consisted of 84 children of the same age range. Mean CIMT for the MS group was 469.8 μm (SD = 67, 443.8 μm (SD = 61 for the heFH group, 478.3 μm (SD = 70 for the MS+heFH group, and 423.2 μm (SD = 45 for the normal control group. Significance differences between groups occurred for heFH versus MS (P=0.022, heFH versus control (P=0.038, MS versus control (P=9.0E-10, and MS+heFH versus control (P=0.003. Analysis showed significant negative correlation between HDL and CIMT (r=-0.32,  P=0.03 but not for LDL, triglycerides, BP, waist circumference, or BMI. Conclusion. For pediatric patients, the thickest CIMT occurred for patients with MS alone or for those with MS+heFH. This indicates that MS, rather than just elevated LDL, accounts for more rapid thickening of CIMT in this population.

  2. Functional comparison of the binding of factor H short consensus repeat 6 (SCR 6) to factor H binding protein from Neisseria meningitidis and the binding of factor H SCR 18 to 20 to Neisseria gonorrhoeae porin.

    Science.gov (United States)

    Shaughnessy, Jutamas; Lewis, Lisa A; Jarva, Hanna; Ram, Sanjay

    2009-05-01

    Both Neisseria meningitidis and Neisseria gonorrhoeae recruit the alternative pathway complement inhibitory protein factor H (fH) to their surfaces to evade complement-dependent killing. Meningococci bind fH via fH binding protein (fHbp), a surface-exposed lipoprotein that is subdivided into three variant families based on one classification scheme. Chimeric proteins that comprise contiguous domains of fH fused to murine Fc were used to localize the binding site for all three fHbp variants on fH to short consensus repeat 6 (SCR 6). As expected, fH-like protein 1 (FHL-1), which contains fH SCR 6, also bound to fHbp-expressing meningococci. Using site-directed mutagenesis, we identified histidine 337 and histidine 371 in SCR 6 as important for binding to fHbp. These findings may provide the molecular basis for recent observations that demonstrated human-specific fH binding to meningococci. Differences in the interactions of fHbp variants with SCR 6 were evident. Gonococci bind fH via their porin (Por) molecules (PorB.1A or PorB.1B); sialylation of lipooligosaccharide enhances fH binding. Both sialylated PorB.1B- and (unsialylated) PorB.1A-bearing gonococci bind fH through SCR 18 to 20; PorB.1A can also bind SCR 6, but only weakly, as evidenced by a low level of binding of FHL-1 relative to that of fH. Using isogenic strains expressing either meningococcal fHbp or gonococcal PorB.1B, we discovered that strains expressing gonococcal PorB.1B in the presence of sialylated lipooligosaccharide bound more fH, more effectively limited C3 deposition, and were more serum resistant than their isogenic counterparts expressing fHbp. Differences in fH binding to these two related pathogens may be important for modulating their individual responses to host immune attack.

  3. Following Enzyme Activity with Infrared Spectroscopy

    Directory of Open Access Journals (Sweden)

    Saroj Kumar

    2010-03-01

    Full Text Available Fourier transform infrared (FTIR spectroscopy provides a direct, "on-line" monitor of enzymatic reactions. Measurement of enzymatic activity is based on the fact that the infrared spectra of reactants and products of an enzymatic reaction are usually different. Several examples are given using the enzymes pyruvate kinase, fumarase and alcohol dehydrogenase. The main advantage of the infrared method is that it observes the reaction of interest directly, i.e.,no activity assay is required to convert the progress of the reaction into an observable quantity.

  4. [Metabolism of Yarrowia lipolytica grown on ethanol under conditions promoting the production of alpha-ketoglutaric and citric acids: a comparative study of the central metabolism enzymes].

    Science.gov (United States)

    Il'chenko, A P; Cherniavskaia, O G; Shishkanova, N V; Finogenova, T V

    2002-01-01

    A comparative study of the enzymes of the tricarboxylic acid (TCA) and glyoxylate cycles in the mutant Yarrowia lipolytica strain N1 capable of producing alpha-ketoglutaric acid (KGA) and citric acid showed that almost all enzymes of the TCA cycle are more active under conditions promoting the production of KGA. The only exception was citrate synthase, whose activity was higher in yeast cells producing citric acid. The production of both acids was accompanied by suppression of the glyoxylate cycle enzymes. The activities of malate dehydrogenase, aconitase, NADP-dependent isocitrate dehydrogenase, and fumarase were higher in cells producing KGA than in cells producing citric acid.

  5. Rapid onset pressor response to exercise in young women with a family history of hypertension.

    Science.gov (United States)

    Matthews, Evan L; Greaney, Jody L; Wenner, Megan M

    2017-09-01

    What is the central question of this study? Alterations in blood pressure control at exercise onset are apparent in older adults with established cardiovascular disease. It is currently not known whether these alterations are evident in young adults with a family history of hypertension. What is the main finding and its importance? We demonstrate that young women with a family history of hypertension display a larger change in blood pressure within the first 10 s of isometric exercise. These data suggest altered blood pressure control in young women with a family history of hypertension. Hypertensive adults demonstrate atypical increases in blood pressure (BP) and muscle sympathetic nerve activity (MSNA) at the immediate onset of static muscle contraction. However, it is unknown whether these abnormal responses occur in young, otherwise healthy adults at risk for developing future disease, such as those with a family history of hypertension (+FH). We tested the hypothesis that +FH young women have exaggerated increases in BP and MSNA at the onset of static muscle contraction compared with those without a family history of hypertension (-FH). We retrospectively examined beat-by-beat BP and MSNA during the initial 30 s of isometric handgrip exercise (30% of maximal voluntary contraction) in 16 +FH (22 ± 2 years old, 22 ± 3 kg m(-2) ) and 16 -FH (22 ± 3 years old, 22 ± 3 kg m(-2) ) women. Resting mean arterial pressure (+FH 80 ± 11 mmHg versus -FH 84 ± 13 mmHg), MSNA burst frequency (+FH 7 ± 3 bursts min(-1) versus -FH 9 ± 5 bursts min(-1) ) and burst incidence [+FH 12 ± 4 bursts (100 heart beats)(-1) versus -FH 12 ± 8 bursts (100 heart beats)(-1) ] were similar between groups (all P > 0.05). Within the first 10 s of exercise, changes in mean arterial pressure (+FH Δ8 ± 6 mmHg versus -FH Δ3 ± 2 mmHg, P < 0.05) and heart rate (+FH Δ8 ± 5 beats min(-1) versus -FH Δ4 ± 4 beats min(-1) , P < 0

  6. Improved access to life insurance after genetic diagnosis of familial hypercholesterolaemia: cross-sectional postal questionnaire study.

    Science.gov (United States)

    Huijgen, Roeland; Homsma, Sietske J M; Hutten, Barbara A; Kindt, Iris; Vissers, Maud N; Kastelein, John J P; van Rijckevorsel, Jan L A

    2012-07-01

    A decade ago, in the initial stage of genetic testing for familial hypercholesterolaemia (FH) in The Netherlands, it was reported that such screening decreased access to affordable life insurance for mutation carriers. In 2003, in order to improve access to insurance for FH mutation carriers, insurers agreed to underwrite according to a set of guidelines. In this cross-sectional study, we assessed whether access to insurance has improved since the advent of these guidelines. We approached 2825 subjects that had participated in the genetic testing for FH between 1998 and 2003. We compared unconditional acceptance rates before and after FH diagnosis and before and after the guidelines were issued by means of logistic regression analysis. Our study outcome pertains to 414 FH patients who applied for life insurance. Unconditional acceptance of a policy before DNA diagnosis and before the issue of guidelines occurred in 182 out of 255 (71%) cases, versus 27 out of 35 (77%) cases after DNA diagnosis, but before the issue of guidelines. De facto, 107 out of 124 (86%) patients received unconditional acceptance after DNA diagnosis and after the issue of guidelines (P for trend=0.002). Access to life insurance improved for FH patients after molecular diagnosis and it improved even further after the guidelines were issued. Therefore, we argue that limited access to life insurance on the basis of 'DNA discrimination' is no longer a valid argument against genetic cascade testing for FH, at least not in our country.

  7. The Effect of Simulated Flash-Heat Pasteurization on Immune Components of Human Milk

    Science.gov (United States)

    Daniels, Brodie; Schmidt, Stefan; King, Tracy; Israel-Ballard, Kiersten; Amundson Mansen, Kimberly; Coutsoudis, Anna

    2017-01-01

    A pasteurization temperature monitoring system has been designed using FoneAstra, a cellphone-based networked sensing system, to monitor simulated flash-heat (FH) pasteurization. This study compared the effect of the FoneAstra FH (F-FH) method with the Sterifeed Holder method currently used by human milk banks on human milk immune components (immunoglobulin A (IgA), lactoferrin activity, lysozyme activity, interleukin (IL)-8 and IL-10). Donor milk samples (N = 50) were obtained from a human milk bank, and pasteurized. Concentrations of IgA, IL-8, IL-10, lysozyme activity and lactoferrin activity were compared to their controls using the Student’s t-test. Both methods demonstrated no destruction of interleukins. While the Holder method retained all lysozyme activity, the F-FH method only retained 78.4% activity (p < 0.0001), and both methods showed a decrease in lactoferrin activity (71.1% Holder vs. 38.6% F-FH; p < 0.0001) and a decrease in the retention of total IgA (78.9% Holder vs. 25.2% F-FH; p < 0.0001). Despite increased destruction of immune components compared to Holder pasteurization, the benefits of F-FH in terms of its low cost, feasibility, safety and retention of immune components make it a valuable resource in low-income countries for pasteurizing human milk, potentially saving infants’ lives. PMID:28241418

  8. Highly active mesoporous ferrihydrite supported pt catalyst for formaldehyde removal at room temperature.

    Science.gov (United States)

    Yan, Zhaoxiong; Xu, Zhihua; Yu, Jiaguo; Jaroniec, Mietek

    2015-06-01

    Ferrihydrite (Fh) supported Pt (Pt/Fh) catalyst was first prepared by combining microemulsion and NaBH4 reduction methods and investigated for room-temperature removal of formaldehyde (HCHO). It was found that the order of addition of Pt precursor and ferrihydrite in the preparation process has an important effect on the microstructure and performance of the catalyst. Pt/Fh was shown to be an efficient catalyst for complete oxidation of HCHO at room temperature, featuring higher activity than magnetite supported Pt (Pt/Fe3O4). Pt/Fh and Pt/Fe3O4 exhibited much higher catalytic activity than Pt supported over calcined Fh and TiO2. The abundance of surface hydroxyls, high Pt dispersion and excellent adsorption performance of Fh are responsible for superior catalytic activity and stability of the Pt/Fh catalyst. This work provides some indications into the design and fabrication of the cost-effective and environmentally benign catalysts with excellent adsorption and catalytic oxidation performances for HCHO removal at room temperature.

  9. Interpretative comments specifically suggesting specialist referral increase the detection of familial hypercholesterolaemia.

    Science.gov (United States)

    Bender, Robert; Edwards, Glenn; McMahon, Jenny; Hooper, Amanda J; Watts, Gerald F; Burnett, John R; Bell, Damon A

    2016-08-01

    Familial hypercholesterolaemia (FH) is an under-diagnosed inherited condition characterised by elevated low density lipoprotein (LDL)-cholesterol and premature coronary artery disease. The requesting general practitioner of individuals with extremely elevated LDL-cholesterol measured by St John of God Pathology receives an interpretative comment on the lipid results highlighting possible FH. We sought to determine whether specifically recommending referral to the regional Lipid Disorders Clinic (LDC) increased referral and FH detection rates. A prospective case-control study of individuals with LDL-cholesterol ≥6.5 mmol/L was conducted. All individuals received an interpretative comment highlighting the possibility of FH. The cases comment also suggested LDC referral, and a subset of cases received the LDC's fax number (fax-cases) in addition. There were 231 individuals with an LDL-cholesterol ≥6.5 mmol/L; 96 (42%) controls and 135 (58%) cases, of which 99 were fax-cases. Twenty-four (18%) cases were referred to clinic compared with eight (8%) controls (p = 0.035). After specialist review and genetic testing, four probable and four definite FH individuals were detected amongst controls, compared with seven possible, eight probable and nine definite FH amongst cases. Genetic testing was performed in 31 (94%) individuals, 13 (42%) had a causative mutation identified. Interpretative commenting specifically recommending specialist review augments the detection of FH in the community.

  10. Differential expression and localization of saposin-like protein 2 of Fasciola hepatica.

    Science.gov (United States)

    Cabán-Hernández, Kimberly; Espino, Ana M

    2013-12-01

    FhSAP2 is a novel antigen isolated from the adult fluke of Fasciola hepatica. Based on sequence similarity with amoebapores and other related proteins, it belongs to the saposin-like protein (SAPLIP) family. FhSAP2 has been shown to be highly immunogenic and capable of inducing protective immune responses in mice and rabbits challenged with F. hepatica. Moreover, FhSAP2 is also reactive with sera from humans with chronic fascioliasis. In the present study, we investigated the expression of FhSAP2 in various developmental stages of F. hepatica by qPCR and demonstrated that FhSAP2-mRNA species are up-regulated in undeveloped eggs, newly excysted juveniles, and adults, but down-regulated in the miracidium stage. Monoclonal antibodies against FhSAP2 were produced, and two clones that are positive to F. hepatica whole-body extract, but not reactive with extracts from other trematodes, were selected, expanded and used for histolocalization studies. Confocal immunofluorescence revealed the presence of native FhSAP2 in epithelial cells surrounding the gut, toward the outermost part of the tegument, and toward the tegumental cells of both adults and newly excysted juveniles.

  11. 324 Building B-Cell Pressurized Water Reactor Spent Fuel Packaging & Shipment RL Readiness Assessment Final Report [SEC 1 Thru 3

    Energy Technology Data Exchange (ETDEWEB)

    HUMPHREYS, D C

    2002-08-01

    A parallel readiness assessment (RA) was conducted by independent Fluor Hanford (FH) and U. S. Department of Energy, Richland Operations Office (RL) team to verify that an adequate state of readiness had been achieved for activities associated with the packaging and shipping of pressurized water reactor fuel assemblies from B-Cell in the 324 Building to the interim storage area at the Canister Storage Building in the 200 Area. The RL review was conducted in parallel with the FH review in accordance with the Joint RL/FH Implementation Plan (Appendix B). The RL RA Team members were assigned a FH RA Team counterpart for the review. With this one-on-one approach, the RL RA Team was able to assess the FH Team's performance, competence, and adherence to the implementation plan and evaluate the level of facility readiness. The RL RA Team agrees with the FH determination that startup of the 324 Building B-Cell pressurized water reactor spent nuclear fuel packaging and shipping operations can safely proceed, pending completion of the identified pre-start items in the FH final report (see Appendix A), completion of the manageable list of open items included in the facility's declaration of readiness, and execution of the startup plan to operations.

  12. Joint impact of physical activity and family history on the development of diabetes among urban adults in Mainland China: a pooled analysis of community-based prospective cohort studies.

    Science.gov (United States)

    Xu, Fei; Wang, Youfa; Ware, Robert S; Tse, Lap Ah; Wang, Zhiyong; Hong, Xin; Dunstan, David W; Owen, Neville

    2015-03-01

    To examine the joint influences of physical activity (PA) and family history (FH) of diabetes on subsequent type 2 diabetes (T2D), the authors pooled and analyzed data from 2 community-based urban adult prospective cohort studies in 2011 in Nanjing, China. Among 4550 urban participants, the 3-year cumulative incidence of T2D was 5.1%. After adjustment for potential confounders, compared with those with FH+ and insufficient PA, the adjusted odds ratio (95% confidence interval) of developing T2D was 0.42 (0.18, 0.98) for participants with sufficient PA and FH+, 0.32 (0.22, 0.46) for participants with insufficient PA and FH-, and 0.15 (0.08, 0.28) for participants with sufficient PA and FH-. Such significant graduated associations between PA/FH and risk of developing T2D were also identified in either men or women, separately. Sufficient PA and FH- may jointly reduce the risk of developing T2D in urban Chinese adults. © 2012 APJPH.

  13. Emerging LDL therapies: Mipomersen-antisense oligonucleotide therapy in the management of hypercholesterolemia.

    Science.gov (United States)

    Toth, Peter P

    2013-01-01

    Familial hypercholesterolemia (FH) is characterized by severe elevations in low-density lipoprotein cholesterol (LDL-C) and poses considerable treatment challenges. Substantive LDL-C reductions are difficult to achieve with standard therapies, and many patients with FH do not tolerate currently available lipid-lowering medications. Mipomersen is an antisense oligonucleotide injectable drug that was recently approved by the Food and Drug Administration for the treatment of homozygous FH. It is complementary in sequence to a segment of the human apolipoprotein (Apo) B-100 messenger RNA and specifically binds to it, blocking translation of the gene product. Reducing the production of Apo B-100 reduces hepatic production of very low-density lipoprotein, consequently decreasing circulating levels of atherogenic very low-density lipoprotein remnants, intermediate-density lipoproteins, LDL, and lipoprotein(a) particles. Results from a pivotal trial conducted in patients with homozygous FH, and supporting trials in patients with heterozygous FH with coronary artery disease (CAD) (LDL-C ≥ 100 mg/dL, triglycerides 100 mg/dL in homozygous FH and severe hypercholesterolemia populations. The main on-treatment adverse events were mild-to-moderate injection site reactions and flu-like symptoms. Available data regarding the efficacy, safety and tolerability of mipomersen, including results at up to 104 weeks of therapy, support the use of mipomersen for the treatment of FH. Copyright © 2013 National Lipid Association. Published by Elsevier Inc. All rights reserved.

  14. The Effect of Simulated Flash-Heat Pasteurization on Immune Components of Human Milk

    Directory of Open Access Journals (Sweden)

    Brodie Daniels

    2017-02-01

    Full Text Available A pasteurization temperature monitoring system has been designed using FoneAstra, a cellphone-based networked sensing system, to monitor simulated flash-heat (FH pasteurization. This study compared the effect of the FoneAstra FH (F-FH method with the Sterifeed Holder method currently used by human milk banks on human milk immune components (immunoglobulin A (IgA, lactoferrin activity, lysozyme activity, interleukin (IL-8 and IL-10. Donor milk samples (N = 50 were obtained from a human milk bank, and pasteurized. Concentrations of IgA, IL-8, IL-10, lysozyme activity and lactoferrin activity were compared to their controls using the Student’s t-test. Both methods demonstrated no destruction of interleukins. While the Holder method retained all lysozyme activity, the F-FH method only retained 78.4% activity (p < 0.0001, and both methods showed a decrease in lactoferrin activity (71.1% Holder vs. 38.6% F-FH; p < 0.0001 and a decrease in the retention of total IgA (78.9% Holder vs. 25.2% F-FH; p < 0.0001. Despite increased destruction of immune components compared to Holder pasteurization, the benefits of F-FH in terms of its low cost, feasibility, safety and retention of immune components make it a valuable resource in low-income countries for pasteurizing human milk, potentially saving infants’ lives.

  15. PFAPA syndrome is not a sporadic disease.

    Science.gov (United States)

    Cochard, Marie; Clet, Johanna; Le, Lan; Pillet, Pascal; Onrubia, Xavier; Guéron, Thierry; Faouzi, Mohammed; Hofer, Michaël

    2010-10-01

    To determine whether PFAPA (periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis) patients have a positive family history (FH) for recurrent fever syndromes. For all patients with PFAPA seen in two paediatric rheumatology centres (Romandy, Switzerland and Bordeaux, France), parents were interviewed to record the FH for periodic fever. As controls, we interviewed a group of children without history of recurrent fever. We recruited 84 patients with PFAPA and 47 healthy children. The FH for recurrent fever (without an infectious cause and recurring for at least half a year) was positive in 38/84 (45%), and was positive for PFAPA (diagnosis confirmed by a physician) in 10/84 (12%) of the PFAPA patients. For 29 of the 38 patients with positive FH, the affected person was a sibling or a parent. None of the healthy children had a positive FH for recurrent fever or PFAPA. A positive FH for rheumatological diseases was seen in both groups of children. These data show that a significant percentage of PFAPA patients present a positive FH of recurrent fever and PFAPA. This familial susceptibility suggests a potential genetic origin for this syndrome.

  16. A comparison between two different in vitro basophil activation tests for gluten- and cow's milk protein sensitivity in irritable bowel syndrome (IBS)-like patients.

    Science.gov (United States)

    Carroccio, Antonio; Brusca, Ignazio; Mansueto, Pasquale; D'alcamo, Alberto; Barrale, Maria; Soresi, Maurizio; Seidita, Aurelio; La Chiusa, Stella M; Iacono, Giuseppe; Sprini, Delia

    2013-06-01

    The diagnosis of food hypersensitivity (FH) in adult patients with gastrointestinal symptoms, beyond the immediate IgE-mediated clinical manifestations, is very often difficult. The aims of our study were to: 1) evaluate the frequency of FH in patients with irritable bowel syndrome (IBS)-like clinical presentation; and 2) compare the diagnostic accuracy of two different methods of in vitro basophil activation tests. Three hundred and five patients (235 females, age range 18-66 years) were included and underwent a diagnostic elimination diet and successive double-blind placebo-controlled (DBPC) challenges. Two different methods of in vitro basophil activation tests (BAT) (CD63 expression after in vitro wheat or cow's milk proteins stimulation) were evaluated: one was performed on separated leukocytes, and the other on whole blood. Ninety patients of the 305 studied (29.5%) were positive to the challenges and were diagnosed as suffering from FH. BAT on separate leukocytes showed a sensitivity of 86% and a specificity of 91% in FH diagnosis. BAT on whole blood showed a sensitivity of 15%-20% and a specificity of 73% in FH diagnosis (p<0.0001 compared to the other method). About one third of the IBS patients included in the study were suffering from FH and were cured on the elimination diet. The BAT based on CD63 detection on whole blood samples did not work in FH diagnosis and showed a significantly lower sensitivity, specificity and diagnostic accuracy than the assay based on separated leukocytes.

  17. A comparative assessment of information-exploitation techniques for GPR data inversion

    Science.gov (United States)

    Salucci, M.; Tenuti, L.; Poli, L.; Oliveri, G.; Massa, A.

    2015-11-01

    The inversion of Ground Penetrating Radar (GPR) data requires the development of suitable information-exploitation techniques that are able to extract as much as possible information on the unknown targets from the available measurements. An innovative singlefrequency (SF) inversion technique based on a deterministic conjugate-gradient (CG) minimization and the iterative multi-scaling approach (IMSA) is described. It is then shown how to improve the performances of the SF-IMSA-CG method by the introduction of an external frequency hopping (FH) iterative loop. On the one hand, the proposed FH-IMSA-CG method allows to exploit the intrinsic frequency diversity of wideband GPR measurements thanks to the FH strategy. On the other hand, the IMSA approach guarantees a significant reduction of the problem unknowns, providing an increased resolution within the identified regions of interest (RoIs). A numerical comparison shows the advantages of the FH-IMSA-CG over its single-frequency version. Moreover, the benefits of integrating the IMSA within the FH are verified by directly comparing the FH-IMSA-CG with its single-resolution (BARE) version (FH-BARE-CG).

  18. Rates of oxygen uptake increase independently of changes in heart rate in late stages of development and at hatching in the green iguana, Iguana iguana.

    Science.gov (United States)

    Sartori, Marina R; Abe, Augusto S; Crossley, Dane A; Taylor, Edwin W

    2017-03-01

    Oxygen consumption (VO2), heart rate (fH), heart mass (Mh) and body mass (Mb) were measured during embryonic incubation and in hatchlings of green iguana (Iguana iguana). Mean fH and VO2 were unvarying in early stage embryos. VO2 increased exponentially during the later stages of embryonic development, doubling by the end of incubation, while fH was constant, resulting in a 2.7-fold increase in oxygen pulse. Compared to late stage embryos, the mean inactive level of VO2 in hatchlings was 1.7 fold higher, while fH was reduced by half resulting in a further 3.6 fold increase in oxygen pulse. There was an overall negative correlation between mean fH and VO2 when data from hatchlings was included. Thus, predicting metabolic rate as VO2 from measurements of fH is not possible in embryonic reptiles. Convective transport of oxygen to supply metabolism during embryonic incubation was more reliably indicated as an index of cardiac output (COi) derived from the product of fH and Mh. However, a thorough analysis of factors determining rates of oxygen supply during development and eclosion in reptiles will require cannulation of blood vessels that proved impossible in the present study, to determine oxygen carrying capacity by the blood and arteriovenous oxygen content difference (A-V diff), plus patterns of blood flow. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. 6th Hellenic Congress in Athens, of the Hellenic Atherosclerosis Society, on the 04-06 December 2014 Novel Pharmacologic Treatments of Familial Hypercholesterolaemia

    Science.gov (United States)

    Athyros, VG

    2015-01-01

    Familial hypercholesterolaemia (FH) is the most common inherited monogenic lipid disorder. It is caused by mutations of genes related to low density lipoprotein (LDL) receptors, apolipoprotein B or proprotein convertase subtilisin/kexin type 9 (PCSK9). Homozygous FH (HoFH; 1/400,000 births) is treated by LDL apheresis. Recently lomitapide has been used for the treatment of HoFH as a monotherapy or in addition to LDL apheresis. Heterozygous FH (HeFH), 1/250-1/200 births, is associated with an increased cardiovascular disease (CVD) risk. The main treatment for HeFH has been high doses of high intensity statins plus ezetimibe. However, this is not usually enough to attain LDL-C targets, especially in those with overt CVD or equivalents (LDL-C goal ofevolocumab and alirocumab). These antibodies have been shown in phase II and III trials to be safe and to produce reductions in LDL-C levels by around 60% either as monotherapy or on top of optimal therapy with statins and ezetimibe. These antibodies are administered subcutaneously every 2 weeks with an automatic device. Anti-PCSK9 antibodies are expected to be licensed soon (? in 2015) and are considered by many as “the statins of the 21st century”. PMID:26664657

  20. Inheritance pattern of familial hypercholesterolemia and markers of cardiovascular risk.

    Science.gov (United States)

    Kusters, D Meeike; Avis, Hans J; Braamskamp, Marjet J; Huijgen, Roeland; Wijburg, Frits A; Kastelein, John J; Wiegman, Albert; Hutten, Barbara A

    2013-09-01

    Studies in children and adults have resulted in conflicting evidence in the quest for the answer to the hypothesis that offspring from hypercholesterolemic mothers might have an increased cardiovascular risk. Previous studies might have suffered from limitations such as cohort size and clinical sampling bias. We therefore explored this hypothesis in large cohorts of both subjects with familial hypercholesterolemia (FH) and unaffected siblings in a wide age range. In three cohorts (cohort 1: n = 1,988, aged 0-18 years; cohort 2: n = 300, 8-30 years; cohort 3: n = 369, 18-60 years), we measured lipid and lipoproteins as well as carotid intima-media thickness (c-IMT) in offspring from FH mothers versus FH fathers. For LDL cholesterol, triglycerides (TGs), and c-IMT, we performed a pooled analysis. No significant differences could be observed in c-IMT, lipid, or lipoprotein levels from offspring of FH mothers versus FH fathers. Pooled analyses showed no significant differences for either LDL cholesterol [mean difference 0.02 (-0.06,0.11) mmol/l, P = 0.60], TGs [mean difference 0.07 (0.00,0.14) mmol/l, P = 0.08], or c-IMT [mean difference -0.00 (-0.01,0.01) mm, P = 0.86]. Our data do not support the hypothesis that cardiovascular risk markers are different between offspring from FH mothers and FH fathers.

  1. Inheritance pattern of familial hypercholesterolemia and markers of cardiovascular risk[S

    Science.gov (United States)

    Kusters, D. Meeike; Avis, Hans J.; Braamskamp, Marjet J.; Huijgen, Roeland; Wijburg, Frits A.; Kastelein, John J.; Wiegman, Albert; Hutten, Barbara A.

    2013-01-01

    Studies in children and adults have resulted in conflicting evidence in the quest for the answer to the hypothesis that offspring from hypercholesterolemic mothers might have an increased cardiovascular risk. Previous studies might have suffered from limitations such as cohort size and clinical sampling bias. We therefore explored this hypothesis in large cohorts of both subjects with familial hypercholesterolemia (FH) and unaffected siblings in a wide age range. In three cohorts (cohort 1: n = 1,988, aged 0–18 years; cohort 2: n = 300, 8–30 years; cohort 3: n = 369, 18–60 years), we measured lipid and lipoproteins as well as carotid intima-media thickness (c-IMT) in offspring from FH mothers versus FH fathers. For LDL cholesterol, triglycerides (TGs), and c-IMT, we performed a pooled analysis. No significant differences could be observed in c-IMT, lipid, or lipoprotein levels from offspring of FH mothers versus FH fathers. Pooled analyses showed no significant differences for either LDL cholesterol [mean difference 0.02 (−0.06,0.11) mmol/l, P = 0.60], TGs [mean difference 0.07 (0.00,0.14) mmol/l, P = 0.08], or c-IMT [mean difference −0.00 (−0.01,0.01) mm, P = 0.86]. Our data do not support the hypothesis that cardiovascular risk markers are different between offspring from FH mothers and FH fathers. PMID:23833242

  2. Staphylococcus aureus surface protein SdrE binds complement regulator factor H as an immune evasion tactic.

    Directory of Open Access Journals (Sweden)

    Julia A Sharp

    Full Text Available Similar to other highly successful invasive bacterial pathogens, Staphylococcus aureus recruits the complement regulatory protein factor H (fH to its surface to inhibit the alternative pathway of complement. Here, we report the identification of the surface-associated protein SdrE as a fH-binding protein using purified fH overlay of S. aureus fractionated cell wall proteins and fH cross-linking to S. aureus followed by mass spectrometry. Studies using recombinant SdrE revealed that rSdrE bound significant fH whether from serum or as a purified form, in both a time- and dose-dependent manner. Furthermore, rSdrE-bound fH exhibited cofactor functionality for factor I (fI-mediated cleavage of C3b to iC3b which correlated positively with increasing amounts of fH. Expression of SdrE on the surface of the surrogate bacterium Lactococcus lactis enhanced recruitment of fH which resulted in increased iC3b generation. Moreover, surface expression of SdrE led to a reduction in C3-fragment deposition, less C5a generation, and reduced killing by polymorphonuclear cells. Thus, we report the first identification of a S. aureus protein associated with the staphylococcal surface that binds factor H as an immune evasion mechanism.

  3. Comparison of purified 12 kDa and recombinant 15 kDa Fasciola hepatica antigens related to a Schistosoma mansoni fatty acid binding protein

    Directory of Open Access Journals (Sweden)

    George V. Hillyer

    1995-04-01

    Full Text Available Vaccines in schistosomiasis using homologous antigens have been studied extensively in experimentally infected mammalian hosts. Vaccines using heterologous antigens have received comparatively less attention. This review summarizes recent work on a heterologous 12 kDa Fasciola hepatica antigenic polypeptide which cross reacts with Schistosoma mansoni. A cDNA has been cloned and sequenced, and the predicted amino acid sequence of the recombinant protein has been shown to have significant (44 identity with a 14 kDa S. mansoni fatty acid binding protein. Thus in the parasitic trematodes fatty acid binding proteins may be potential vaccine candidates. The F. hepatica recombinant protein has been overexpressed and purified and denoted rFh15. Preliminary rFh15 migrates more slowly (i.e. may be slightly larger than nFh12 on SDS-PAGE and has a predicted pI of 6.01 vs. observed pI of 5.45. Mice infected with F. hepatica develop antibodies to nFh12 by 2 weeks of infection vs. 6 weeks of infection to rFh15; on the other hand, mice with schistosomiasis mansoni develop antibodies to both nFh12 and rFh15 by 6 weeks of infection. Both the F. hepatica and S. mansoni cross-reactive antigens may be cross-protective antigens with the protection inducing capability against both species.

  4. Improved access to life insurance after genetic diagnosis of familial hypercholesterolaemia: cross-sectional postal questionnaire study

    Science.gov (United States)

    Huijgen, Roeland; Homsma, Sietske JM; Hutten, Barbara A; Kindt, Iris; Vissers, Maud N; Kastelein, John JP; van Rijckevorsel, Jan LA

    2012-01-01

    A decade ago, in the initial stage of genetic testing for familial hypercholesterolaemia (FH) in The Netherlands, it was reported that such screening decreased access to affordable life insurance for mutation carriers. In 2003, in order to improve access to insurance for FH mutation carriers, insurers agreed to underwrite according to a set of guidelines. In this cross-sectional study, we assessed whether access to insurance has improved since the advent of these guidelines. We approached 2825 subjects that had participated in the genetic testing for FH between 1998 and 2003. We compared unconditional acceptance rates before and after FH diagnosis and before and after the guidelines were issued by means of logistic regression analysis. Our study outcome pertains to 414 FH patients who applied for life insurance. Unconditional acceptance of a policy before DNA diagnosis and before the issue of guidelines occurred in 182 out of 255 (71%) cases, versus 27 out of 35 (77%) cases after DNA diagnosis, but before the issue of guidelines. De facto, 107 out of 124 (86%) patients received unconditional acceptance after DNA diagnosis and after the issue of guidelines (P for trend=0.002). Access to life insurance improved for FH patients after molecular diagnosis and it improved even further after the guidelines were issued. Therefore, we argue that limited access to life insurance on the basis of ‘DNA discrimination' is no longer a valid argument against genetic cascade testing for FH, at least not in our country. PMID:22293687

  5. Coronary Heart Disease, Peripheral Arterial Disease, and Stroke in Familial Hypercholesterolaemia: Insights From the SAFEHEART Registry (Spanish Familial Hypercholesterolaemia Cohort Study).

    Science.gov (United States)

    Pérez de Isla, Leopoldo; Alonso, Rodrigo; Mata, Nelva; Saltijeral, Adriana; Muñiz, Ovidio; Rubio-Marin, Patricia; Diaz-Diaz, José L; Fuentes, Francisco; de Andrés, Raimundo; Zambón, Daniel; Galiana, Jesús; Piedecausa, Mar; Aguado, Rocio; Mosquera, Daniel; Vidal, José I; Ruiz, Enrique; Manjón, Laura; Mauri, Marta; Padró, Teresa; Miramontes, José P; Mata, Pedro

    2016-09-01

    Heterozygous familial hypercholesterolemia (FH) is the most common premature atherosclerotic cardiovascular disease (ASCVD)-related monogenic disorder, and it is associated with ischemic heart disease. There is limited information whether FH increases the risk of peripheral arterial and cerebrovascular disease. Our aim was to analyze ASCVD prevalence and characteristics in different arterial territories in a large FH population, to compare them with an unaffected control population and to determine which factors are associated to ASCVD. SAFEHEART (Spanish Familial Hypercholesterolaemia Cohort Study) is an ongoing registry of molecularly defined patients with heterozygous FH in Spain. ASCVD in the different arterial territories was analyzed, as well as individual characteristics, genetic variables, and lipid-lowering therapies. The study recruited 4132 subjects (3745 ≥18 years); 2,752 of those enrolled were molecularly diagnosed FH cases. Median age was 44.0 years (45.9% men) and 40 years (46.6% men) in FH patients and unaffected relatives (P50 mg/dL were independently associated with ASCVD. The prevalence of ASCVD is higher, and the involvement of the arterial territories is different in FH patients when compared with their unaffected relatives. Age, male sex, increased body mass index, hypertension, type 2 diabetes mellitus, smoking habit, and lipoprotein(a) >50 mg/dL were independently associated to ASCVD. URL: https://www.clinicaltrials.gov. Unique identifier: NCT02693548. © 2016 American Heart Association, Inc.

  6. Behavioral Impulsivity and Risk-Taking Trajectories Across Early Adolescence in Youths With and Without Family Histories of Alcohol and Other Drug Use Disorders.

    Science.gov (United States)

    Dougherty, Donald M; Lake, Sarah L; Mathias, Charles W; Ryan, Stacy R; Bray, Bethany C; Charles, Nora E; Acheson, Ashley

    2015-08-01

    Youths with family histories of alcohol and other drug use disorders (FH+) are at increased susceptibility for developing substance use disorders relative to those without such histories (FH-). This vulnerability may be related to impaired adolescent development of impulse control and elevated risk-taking. However, no previous studies have prospectively examined impulse control and risk-taking in FH+ youth across adolescence. A total of 386 pre-adolescents (305 FH+, 81 FH-; aged 10 to 12) with no histories of regular alcohol or other drug use were compared on behavioral measures of impulsivity including delay discounting, response initiation (Immediate Memory Task), response inhibition impulsivity (GoStop Impulsivity Paradigm), and risk-taking (Balloon Analogue Risk Task-Youth). Youths completed these laboratory tasks every 6 months, allowing for the examination of 10- to 15-year-olds. Hierarchical linear modeling was used to characterize the development of impulse control and risk-taking as shown in performance of these tasks throughout adolescence. We found that (i) FH+ youths had increased levels of delay discounting and response inhibition impulsivity at study entry; (ii) regardless of FH status, all youths had relatively stable delay discounting across time, improvements in response inhibition and response initiation impulsivity, and increased risk-taking; and (iii) although FH+ youths had increased response inhibition impulsivity at pre-adolescence, these differences were negligible by mid-adolescence. Heightened delay discounting in FH+ pre-adolescents coupled with normal adolescent increases in risk-taking may contribute to their increased susceptibility toward problem substance use in adolescence. Copyright © 2015 by the Research Society on Alcoholism.

  7. Fasciola hepatica Surface Coat Glycoproteins Contain Mannosylated and Phosphorylated N-glycans and Exhibit Immune Modulatory Properties Independent of the Mannose Receptor.

    Science.gov (United States)

    Ravidà, Alessandra; Aldridge, Allison M; Driessen, Nicole N; Heus, Ferry A H; Hokke, Cornelis H; O'Neill, Sandra M

    2016-04-01

    Fascioliasis, caused by the liver fluke Fasciola hepatica, is a neglected tropical disease infecting over 1 million individuals annually with 17 million people at risk of infection. Like other helminths, F. hepatica employs mechanisms of immune suppression in order to evade its host immune system. In this study the N-glycosylation of F. hepatica's tegumental coat (FhTeg) and its carbohydrate-dependent interactions with bone marrow derived dendritic cells (BMDCs) were investigated. Mass spectrometric analysis demonstrated that FhTeg N-glycans comprised mainly of oligomannose and to a lesser extent truncated and complex type glycans, including a phosphorylated subset. The interaction of FhTeg with the mannose receptor (MR) was investigated. Binding of FhTeg to MR-transfected CHO cells and BMDCs was blocked when pre-incubated with mannan. We further elucidated the role played by MR in the immunomodulatory mechanism of FhTeg and demonstrated that while FhTeg's binding was significantly reduced in BMDCs generated from MR knockout mice, the absence of MR did not alter FhTeg's ability to induce SOCS3 or suppress cytokine secretion from LPS activated BMDCs. A panel of negatively charged monosaccharides (i.e. GlcNAc-4P, Man-6P and GalNAc-4S) were used in an attempt to inhibit the immunoregulatory properties of phosphorylated oligosaccharides. Notably, GalNAc-4S, a known inhibitor of the Cys-domain of MR, efficiently suppressed FhTeg binding to BMDCs and inhibited the expression of suppressor of cytokine signalling (SOCS) 3, a negative regulator the TLR and STAT3 pathway. We conclude that F. hepatica contains high levels of mannose residues and phosphorylated glycoproteins that are crucial in modulating its host's immune system, however the role played by MR appears to be limited to the initial binding event suggesting that other C-type lectin receptors are involved in the immunomodulatory mechanism of FhTeg.

  8. Pooling and expanding registries of familial hypercholesterolaemia to assess gaps in care and improve disease management and outcomes: Rationale and design of the global EAS Familial Hypercholesterolaemia Studies Collaboration.

    Science.gov (United States)

    Vallejo-Vaz, Antonio J; Akram, Asif; Kondapally Seshasai, Sreenivasa Rao; Cole, Della; Watts, Gerald F; Hovingh, G Kees; Kastelein, John J P; Mata, Pedro; Raal, Frederick J; Santos, Raul D; Soran, Handrean; Freiberger, Tomas; Abifadel, Marianne; Aguilar-Salinas, Carlos A; Alnouri, Fahad; Alonso, Rodrigo; Al-Rasadi, Khalid; Banach, Maciej; Bogsrud, Martin P; Bourbon, Mafalda; Bruckert, Eric; Car, Josip; Ceska, Richard; Corral, Pablo; Descamps, Olivier; Dieplinger, Hans; Do, Can T; Durst, Ronen; Ezhov, Marat V; Fras, Zlatko; Gaita, Dan; Gaspar, Isabel M; Genest, Jaques; Harada-Shiba, Mariko; Jiang, Lixin; Kayikcioglu, Meral; Lam, Carolyn S P; Latkovskis, Gustavs; Laufs, Ulrich; Liberopoulos, Evangelos; Lin, Jie; Lin, Nan; Maher, Vincent; Majano, Nelson; Marais, A David; März, Winfried; Mirrakhimov, Erkin; Miserez, André R; Mitchenko, Olena; Nawawi, Hapizah; Nilsson, Lennart; Nordestgaard, Børge G; Paragh, György; Petrulioniene, Zaneta; Pojskic, Belma; Reiner, Željko; Sahebkar, Amirhossein; Santos, Lourdes E; Schunkert, Heribert; Shehab, Abdullah; Slimane, M Naceur; Stoll, Mario; Su, Ta-Chen; Susekov, Andrey; Tilney, Myra; Tomlinson, Brian; Tselepis, Alexandros D; Vohnout, Branislav; Widén, Elisabeth; Yamashita, Shizuya; Catapano, Alberico L; Ray, Kausik K

    2016-12-01

    The potential for global collaborations to better inform public health policy regarding major non-communicable diseases has been successfully demonstrated by several large-scale international consortia. However, the true public health impact of familial hypercholesterolaemia (FH), a common genetic disorder associated with premature cardiovascular disease, is yet to be reliably ascertained using similar approaches. The European Atherosclerosis Society FH Studies Collaboration (EAS FHSC) is a new initiative of international stakeholders which will help establish a global FH registry to generate large-scale, robust data on the burden of FH worldwide. The EAS FHSC will maximise the potential exploitation of currently available and future FH data (retrospective and prospective) by bringing together regional/national/international data sources with access to individuals with a clinical and/or genetic diagnosis of heterozygous or homozygous FH. A novel bespoke electronic platform and FH Data Warehouse will be developed to allow secure data sharing, validation, cleaning, pooling, harmonisation and analysis irrespective of the source or format. Standard statistical procedures will allow us to investigate cross-sectional associations, patterns of real-world practice, trends over time, and analyse risk and outcomes (e.g. cardiovascular outcomes, all-cause death), accounting for potential confounders and subgroup effects. The EAS FHSC represents an excellent opportunity to integrate individual efforts across the world to tackle the global burden of FH. The information garnered from the registry will help reduce gaps in knowledge, inform best practices, assist in clinical trials design, support clinical guidelines and policies development, and ultimately improve the care of FH patients. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  9. A novel targeted inhibitor of the alternative pathway of complement and its therapeutic application in ischemia/reperfusion injury.

    Science.gov (United States)

    Huang, Yuxiang; Qiao, Fei; Atkinson, Carl; Holers, V Michael; Tomlinson, Stephen

    2008-12-01

    Bioavailability and therapeutic efficacy of soluble Crry, a mouse inhibitor of all complement activation pathways, is significantly enhanced when linked to a fragment of complement receptor 2 (CR2), a receptor that targets C3 activation products. In this study, we characterize alternative pathway-specific inhibitors consisting of a single or dimeric N-terminal region of mouse factor H (fH; short consensus repeats 1-5) linked to the same CR2 fragment (CR2-fH and CR2-fHfH). Both CR2-fH and CR2-fHfH were highly effective at inhibiting the alternative pathway in vitro and demonstrated a higher specific activity than CR2-Crry. CR2-fH was also more effective than endogenous serum fH in blocking target deposition of C3. Target binding and complement inhibitory activity of CR2-fH/CR2-fHfH was dependent on CR2- and C3-mediated interactions. The alternative pathway of complement plays a role in intestine ischemia/reperfusion injury. However, serum fH fails to provide protection against intestine ischemia/reperfusion injury although it can bind to and provide cell surfaces with protection from complement and is present in plasma at a high concentration. In a mouse model, CR2-fH and CR2-fHfH provided complete protection from local (intestine) and remote (lung) injury. CR2-fH targeted to the site of local injury and greatly reduced levels of tissue C3 deposition. Thus, the targeting mechanism significantly enhances alternative pathway-specific complement inhibitory activity of the N-terminal domain of fH and has the potential to reduce side effects that may be associated with systemic complement blockade. The data further indicate alternative pathway dependence for local and remote injury following intestinal ischemia/reperfusion in a clinically relevant therapeutic paradigm.

  10. Biochemical and molecular characterization of a flavonoid 3-O-glycosyltransferase responsible for anthocyanins and flavonols biosynthesis in Freesia hybrida

    Directory of Open Access Journals (Sweden)

    Wei eSun

    2016-03-01

    Full Text Available The glycosylation of flavonoids increases their solubility and stability in plants. Flowers accumulate anthocyanidin and flavonol glycosides which are synthesized by UDP-sugar flavonoid glycosyltransferases (UFGTs. In our previous study, a cDNA clone (Fh3GT1 encoding UFGT was isolated from Freesia hybrida, which was preliminarily proved to be invovled in cyanidin 3-O-glucoside biosynthesis. Here, a variety of anthocyanin and flavonol glycosides were detected in flowers and other tissues of F. hybrida, implying the versatile roles of Fh3GT1 in flavonoids biosynthesis. To further unravel its multi-functional roles, integrative analysis between gene expression and metabolites was investigated. The results showed expression of Fh3GT1 was positively related to the accumulation of anthocyanins and flavonol glycosides, suggesting its potential roles in the biosynthesis of both flavonoid glycosides. Subsequently, biochemical analysis results revealed that a broad range of flavonoid substrates including flavonoid not naturally occurred in F. hybrida could be recognized by the recombinant Fh3GT1. Both UDP-glucose and UDP-galactose could be used as sugar donors by recombinant Fh3GT1, although UDP-galactose was transferred with relatively low activity. Furthermore, regiospecificity analysis demonstrated that Fh3GT1 was able to glycosylate delphinidin at the 3-, 4'- and 7- positions in a sugar-dependent manner. And the introduction of Fh3GT1 into Arabidopsis UGT78D2 mutant successfully restored the anthocyanins and flavonols phenotypes caused by lost-of-function of the 3GT, indicating that Fh3GT1 functions as a flavonoid 3-O-glucosyltransferase in vivo. In summary, these results demonstrate that Fh3GT1 is a flavonoid 3-O-glycosyltransferase using UDP-glucose as the preferred sugar donor and may involve in flavonoid glycosylation in F. hybrida.

  11. Perbandingan Karkas Dari Beberapa Bangsa Sapi

    Directory of Open Access Journals (Sweden)

    Cut Aida Fitri

    2002-04-01

    Full Text Available ABSTRACT. The objective of this research was determined how far the comparisons of carcass of those three species. This research were used 57 fattening cow. Which consisting of 19 Aceh (SA cow. 19 Brahman cross (BX cow and 19 Friesian Holstein (FH, for 90 days observation time. The attributes that observed include: percentage of carcass weight, percentage of meat weight, percentage of added result, percentage of bone weight, percentage of fat. From each of those multi special of cow, considering each of their weight before cutter. The result of this research are: mean (± SE of their life weight are: SA 316.00  ± 9.68 kg, BX: 410.16 ± 9.53 kg and FH: 414.37 ± 10.12 kg. Mean (± SE of carcass percentage are: FH: 53.33 ± 0.83%, SA 55.75 ± 0.67% and BX: 56.28 ± 0.74. Mean (± SE of meat weight percentage : FH: 69.15 ± 0.74%, BX: 70.91 ± 1.18% and SA: 72.67 ± 1.08%. Mean (± SE of added result percentage: FH: 25.22  ± 0.57%, BX: 25.33 ± 0.47% and SA: 25.74 ± 0.74%. Mean (± SE of bone weight  percentage: SA: 16.75 ± 00.58%, BX: 19.24 ± 0.72% and FH: 20.91 ± 0.74%. Mean (±SE of fat percentage: SA: 6.94 ± 0.75% , BX: 17.84 ± 0.55%, and FH: 8.21 ± 0.49%. The result of ‘T’ test of SA carcass, meat and fat weight percentage were not significantly different with BX. SA added result percentage was not significantly different with BX and FH. SA bone weight percentage was signicantly different (P < 0.05 with BX. SA carcass, meats and fat weight percentage were significantly different (P < 0.05 with FH. SA bone weight percentage was not significantly different with FH. Carcass weight percentage of BX was signicantly different (P < 0.05 with FH. Meat, added result meat, bones and fat weight percentage of BX were not sifnificantly different with FH.

  12. Chemosensitization of Breast Cancer Cells to Chemotherapeutic Agents by 3,3’-Diindolylmethane (DIM)

    Science.gov (United States)

    2007-08-01

    cancer cells. Front Biosci 2005;10:236-43. 34. Rahman KM, Aranha O, Sarkar FH. Indole-3-carbinol (I3C) induces apoptosis in tumorigenic but not in...by AKT and NF-kappaB pathways in prostate cancer cells. Front Biosci 2005;10:236-43. 27. Rahman KM, Aranha O, Sarkar FH. Indole-3-carbinol (I3C...breast cancer cells. Cancer research 1999;59:1244-51. 45. Rahman KM, Aranha O, Glazyrin A, Chinni SR, Sarkar FH. Translocation of Bax to mitochondria

  13. Synthesis and Characterization of Rare Earth Complexes of Ferrocenylcarbonylhydrazine

    Institute of Scientific and Technical Information of China (English)

    边占喜; 董彬; 李保国

    2002-01-01

    Rare earth complexes of ferrocenylcarbonylhydrazine Ln(FH)x(ClO4)3*nH2O (where Ln = La, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, x=3; Ln = Er, Tm, Yb, Lu, x=4; n=2~6, FH=ferrocenylcarbonylhydrazin) were synthesized and characterized by elemental analyses, MS, IR and 1H NMR spectra. The ligand FH is bidentate, coordinating through the carbonyl oxygen and the amino nitrogen atom. The redox properties of the ligand and its complexes were investigated using cyclic voltammetric method. The solid state fluorescence spectra of Sm, Tb and Dy complexes were also studied.

  14. Modelo de suplementação nutricional com fatores hepatotróficos aumenta proliferação celular em fígado de ratos sadios

    Directory of Open Access Journals (Sweden)

    T.P.A. Aloia

    2010-08-01

    Full Text Available Foram avaliados dois protocolos de administração, em ratos sadios, de uma solução de fatores hepatotróficos (FH, composta por aminoácidos, vitaminas, sais minerais, glicose, insulina, glucagon e triiodotironina (T3. A solução foi administrada durante 10 dias, 40mg/kg/dia, i.p., em duas, grupo 2xFH (n=15, ou três doses, grupo 3xFH (n=15, diárias. Foram observados os efeitos na proliferação celular dos hepatócitos, na angiogênese e na matriz extracelular hepática, assim como as possíveis reações adversas. Os animais dos grupos 2xFH e 3xFH apresentaram aumento da massa hepática de 30,1% e 22,5%, respectivamente, em relação ao grupo-controle (CT; n=15. O índice de proliferação hepatocelular foi maior nos grupos 2xFH (1,4% e 3xFH (1,2% em relação ao grupo CT (0,53%, e a densitometria relativa do fator de crescimento do endotélio vascular pelo imunoblot não revelou diferença estatística entre os três grupos. Nos grupos 2xFH e 3xFH, houve redução do colágeno intersticial em relação ao grupo CT. A solução de FH estimulou o crescimento hepático e reduziu o volume de colágeno perissinusoidal. A administração em três doses diárias resultou em mortalidade de 26,7%, possivelmente pelo excessivo estresse da manipulação e pela menor adaptação fisiológica dos ratos, o que não ocorreu nos grupos 2xFH e CT. Para esse tipo de abordagem em ratos, o procedimento experimental mais apropriado, seguro, com melhor chance de adaptação dos animais e com resultados significativos é a aplicação dos FH em duas doses diárias.

  15. Synthetic coprecipitates of exopolysaccharides and ferrihydrite. Part II: Siderophore-promoted dissolution

    Science.gov (United States)

    Mikutta, Christian; Kretzschmar, Ruben

    2008-02-01

    Ferrihydrite (Fh) coprecipitated with exopolymers of plants and microbes may differ in its geochemical reactivity from its abiotic counterpart. We synthesized Fh in the presence and absence of acid polysaccharides (polygalacturonic acid (PGA), alginate, xanthan) and characterized the physical and structural properties of the precipitates formed [Mikutta C., Mikutta R., Bonneville S., Wagner F., Voegelin A., Christl I. and Kretzschmar R. (2008) Synthetic coprecipitates of exopolysaccharides and ferrihydrite. Part I: Characterization. Geochim. Cosmochim. Acta]. In this paper, we focus on the reactivity of PGA and alginate coprecipitates and pure Fh, and studied their interaction with the microbial siderophore desferrioxamine B (DFOB) in the presence and absence of low molecular weight organic (LMWO) acid anions (malate, citrate). Batch adsorption and dissolution experiments were performed in the dark at pH 7 in 10 mM NaClO 4 background electrolyte. In the dissolution experiments, different modes of ligand addition were applied (single, simultaneous, stepwise). With an estimated Langmuir sorption maximum of 15 mmol/mol Fe, a PGA coprecipitate with 11% C org sorbed about four times as much DFOB as pure Fh, and the amount of DFOB sorbed was ˜4-fold larger than estimated from the sum of DFOB sorption to pure Fh and PGA alone. The apparent initial dissolution rates, Rapp-initial, and pseudo-first order rate coefficients, k, of the coprecipitates exceeded those of pure Fh by up to two orders of magnitude. Citrate and malate exerted a strong synergistic effect on the DFOB-promoted dissolution of pure Fh, whereas synergistic effects of both anions were absent or negligible for the coprecipitates. Rapp-initial of the citrate and DFOB-promoted dissolution of PGA coprecipitates increased with increasing molar C/Fe ratio of the coprecipitates, independent of the charge of the LMWO ligand. Our results indicate that polyuronates stabilize Fh particles sterically and /or

  16. Improving detection of familial hypercholesterolaemia in primary care using electronic audit and nurse-led clinics.

    Science.gov (United States)

    Green, Peter; Neely, Dermot; Humphries, Steve E

    2016-06-01

    In the UK fewer than 15% of familial hypercholesterolemia (FH) cases are diagnosed, representing a major gap in coronary heart disease prevention. We wished to support primary care doctors within the Medway Clinical Commissioning Group (CCG) to implement NICE guidance (CG71) and consider the possibility of FH in adults who have raised total cholesterol concentrations, thereby improving the detection of people with FH. Utilizing clinical decision support software (Audit+) we developed an FH Audit Tool and implemented a systematic audit of electronic medical records within GP practices, first identifying all patients diagnosed with FH or possible FH and next electronically flagging patients with a recorded total cholesterol of >7.5 mmol L(-1) or LDL-C > 4.9 mmol L(-1) (in adults), for further assessment. After a 2-year period, a nurse-led clinic was introduced to screen more intensely for new FH index cases. We evaluated if these interventions increased the prevalence of FH closer to the expected prevalence from epidemiological studies. The baseline prevalence of FH within Medway CCG was 0.13% (1 in 750 persons). After 2 years, the recorded prevalence of diagnosed FH increased by 0.09% to 0.22% (1 in 450 persons). The nurse advisor programme ran for 9 months (October 2013-July 2014) and during this time, the recorded prevalence of patients diagnosed with FH increased to 0.28% (1 in 357 persons) and the prevalence of patients 'at risk and unscreened' reduced from 0.58% to 0.14%. Our study shows that two simple interventions increased the detection of FH. This systematic yet simple electronic case-finding programme with nurse-led review allowed the identification of new index cases, more than doubling the recorded prevalence of detected disease to 1 in 357 (0.28%). This study shows that primary care has an important role in identifying patients with this condition. © 2015 The Authors. Journal of Evaluation in Clinical Practice published by John Wiley

  17. Improving detection of familial hypercholesterolaemia in primary care using electronic audit and nurse‐led clinics

    Science.gov (United States)

    Neely, Dermot; Humphries, Steve E.; Saunders, Tanya; Gray, Val; Gordon, Louise; Payne, Jules; Carter, Slade; Neuwirth, Clare; Rees, Alan; Gallagher, Hazel

    2015-01-01

    Abstract Rationale, aims and objectives In the UK fewer than 15% of familial hypercholesterolemia (FH) cases are diagnosed, representing a major gap in coronary heart disease prevention. We wished to support primary care doctors within the Medway Clinical Commissioning Group (CCG) to implement NICE guidance (CG71) and consider the possibility of FH in adults who have raised total cholesterol concentrations, thereby improving the detection of people with FH. Methods Utilizing clinical decision support software (Audit+) we developed an FH Audit Tool and implemented a systematic audit of electronic medical records within GP practices, first identifying all patients diagnosed with FH or possible FH and next electronically flagging patients with a recorded total cholesterol of >7.5 mmol L−1 or LDL‐C > 4.9 mmol L−1 (in adults), for further assessment. After a 2‐year period, a nurse‐led clinic was introduced to screen more intensely for new FH index cases. We evaluated if these interventions increased the prevalence of FH closer to the expected prevalence from epidemiological studies. Results The baseline prevalence of FH within Medway CCG was 0.13% (1 in 750 persons). After 2 years, the recorded prevalence of diagnosed FH increased by 0.09% to 0.22% (1 in 450 persons). The nurse advisor programme ran for 9 months (October 2013–July 2014) and during this time, the recorded prevalence of patients diagnosed with FH increased to 0.28% (1 in 357 persons) and the prevalence of patients ‘at risk and unscreened’ reduced from 0.58% to 0.14%. Conclusions Our study shows that two simple interventions increased the detection of FH. This systematic yet simple electronic case‐finding programme with nurse‐led review allowed the identification of new index cases, more than doubling the recorded prevalence of detected disease to 1 in 357 (0.28%). This study shows that primary care has an important role in identifying patients with this condition. PMID

  18. On the convergence of nonlinear Beltrami type operators

    Directory of Open Access Journals (Sweden)

    Riccardo De Arcangelis

    1986-11-01

    Full Text Available One of the results proved is the following: if (fh is a sequence of K-quasiregular mappings, converging to f  in L1loc , whose jacobians verify a weak integrability condition, then the solutions of Dirichlet problems for the nonlinear Laplace-Beltrami operator associated to each fh converge to the solution of the Dirichlet problem for the nonlinear Laplace-Beltrami operator associated to f. Such result is deduced as a particular case of a more general theorem concerning nonlinear operators. The case of K-quasiconformal functions fh is also treated. A class of weighted Sobolev spaces associated to quasiconformal mappings is studied.

  19. Specific combination of compound heterozygous mutations in 17β-hydroxysteroid dehydrogenase type 4 (HSD17B4 defines a new subtype of D-bifunctional protein deficiency

    Directory of Open Access Journals (Sweden)

    McMillan Hugh J

    2012-11-01

    Full Text Available Abstract Background D-bifunctional protein (DBP deficiency is typically apparent within the first month of life with most infants demonstrating hypotonia, psychomotor delay and seizures. Few children survive beyond two years of age. Among patients with prolonged survival all demonstrate severe gross motor delay, absent language development, and severe hearing and visual impairment. DBP contains three catalytically active domains; an N-terminal dehydrogenase, a central hydratase and a C-terminal sterol carrier protein-2-like domain. Three subtypes of the disease are identified based upon the domain affected; DBP type I results from a combined deficiency of dehydrogenase and hydratase activity; DBP type II from isolated hydratase deficiency and DBP type III from isolated dehydrogenase deficiency. Here we report two brothers (16½ and 14 years old with DBP deficiency characterized by normal early childhood followed by sensorineural hearing loss, progressive cerebellar and sensory ataxia and subclinical retinitis pigmentosa. Methods and results Biochemical analysis revealed normal levels of plasma VLCFA, phytanic acid and pristanic acid, and normal bile acids in urine; based on these results no diagnosis was made. Exome analysis was performed using the Agilent SureSelect 50Mb All Exon Kit and the Illumina HiSeq 2000 next-generation-sequencing (NGS platform. Compound heterozygous mutations were identified by exome sequencing and confirmed by Sanger sequencing within the dehydrogenase domain (c.101C>T; p.Ala34Val and hydratase domain (c.1547T>C; p.Ile516Thr of the 17β-hydroxysteroid dehydrogenase type 4 gene (HSD17B4. These mutations have been previously reported in patients with severe-forms of DBP deficiency, however each mutation was reported in combination with another mutation affecting the same domain. Subsequent studies in fibroblasts revealed normal VLCFA levels, normal C26:0 but reduced pristanic acid beta-oxidation activity. Both DBP

  20. Analysis of metabolites in plasma reveals distinct metabolic features between Dahl salt-sensitive rats and consomic SS.13(BN) rats.

    Science.gov (United States)

    Wang, Le; Hou, Entai; Wang, Zhengjun; Sun, Na; He, Liqing; Chen, Lan; Liang, Mingyu; Tian, Zhongmin

    2014-07-18

    Salt-sensitive hypertension is a major risk factor for cardiovascular disorders. Our previous proteomic study revealed substantial differences in several proteins between Dahl salt-sensitive (SS) rats and salt-insensitive consomic SS.13(BN) rats. Subsequent experiments indicated a role of fumarase insufficiency in the development of hypertension in SS rats. In the present study, a global metabolic profiling study was performed using gas chromatography/mass spectrometry (GC/MS) in plasma of SS rats (n=9) and SS.13(BN) rats (n=8) on 0.4% NaCl diet, designed to gain further insights into the relationship between alterations in cellular intermediary metabolism and predisposition to hypertension. Principal component analysis of the data sets revealed a clear clustering and separation of metabolic profiles between SS rats and SS.13(BN) rats. 23 differential metabolites were identified (PSS rats. Pyruvate, which connects TCA cycle and glycolysis, was also increased in SS rats. Moreover, lower activity levels of fumarase, aconitase, α-ketoglutarate dehydrogenase and succinyl-CoA synthetase were detected in the heart, liver or skeletal muscles of SS rats. The distinct metabolic features in SS and SS.13(BN) rats indicate abnormalities of TCA cycle in SS rats, which may play a role in predisposing SS rats to developing salt-sensitive hypertension.

  1. Decreasing the mitochondrial synthesis of malate in potato tubers does not affect plastidial starch synthesis, suggesting that the physiological regulation of ADPglucose pyrophosphorylase is context dependent.

    Science.gov (United States)

    Szecowka, Marek; Osorio, Sonia; Obata, Toshihiro; Araújo, Wagner L; Rohrmann, Johannes; Nunes-Nesi, Adriano; Fernie, Alisdair R

    2012-12-01

    Modulation of the malate content of tomato (Solanum lycopersicum) fruit by altering the expression of mitochondrially localized enzymes of the tricarboxylic acid cycle resulted in enhanced transitory starch accumulation and subsequent effects on postharvest fruit physiology. In this study, we assessed whether such a manipulation would similarly affect starch biosynthesis in an organ that displays a linear, as opposed to a transient, kinetic of starch accumulation. For this purpose, we used RNA interference to down-regulate the expression of fumarase in potato (Solanum tuberosum) under the control of the tuber-specific B33 promoter. Despite displaying similar reductions in both fumarase activity and malate content as observed in tomato fruit expressing the same construct, the resultant transformants were neither characterized by an increased flux to, or accumulation of, starch, nor by alteration in yield parameters. Since the effect in tomato was mechanistically linked to derepression of the reaction catalyzed by ADP-glucose pyrophosphorylase, we evaluated whether the lack of effect on starch biosynthesis was due to differences in enzymatic properties of the enzyme from potato and tomato or rather due to differential subcellular compartmentation of reductant in the different organs. The results are discussed in the context both of current models of metabolic compartmentation and engineering.

  2. Efficient aspartic acid production by a psychrophile-based simple biocatalyst.

    Science.gov (United States)

    Tajima, Takahisa; Hamada, Mai; Nakashimada, Yutaka; Kato, Junichi

    2015-10-01

    We previously constructed a Psychrophile-based Simple bioCatalyst (PSCat) reaction system, in which psychrophilic metabolic enzymes are inactivated by heat treatment, and used it here to study the conversion of aspartic acid from fumaric acid mediated by the activity of aspartate ammonia-lyase (aspartase). In Escherichia coli, the biosynthesis of aspartic acid competes with that of L-malic acid produced from fumaric acid by fumarase. In this study, E. coli aspartase was expressed in psychrophilic Shewanella livingstonensis Ac10 heat treated at 50 °C for 15 min. The resultant PSCat could convert fumaric acid to aspartic acid without the formation of L-malic acid because of heat inactivation of psychrophilic fumarase activity. Furthermore, alginate-immobilized PSCat produced high yields of aspartic acid and could be re-used nine times. The results of our study suggest that PSCat can be applied in biotechnological production as a new approach to increase the yield of target compounds.

  3. The Effect of Simulated Flash-Heat Pasteurization on Immune Components of Human Milk.

    Science.gov (United States)

    Daniels, Brodie; Schmidt, Stefan; King, Tracy; Israel-Ballard, Kiersten; Amundson Mansen, Kimberly; Coutsoudis, Anna

    2017-02-22

    A pasteurization temperature monitoring system has been designed using FoneAstra, a cellphone-based networked sensing system, to monitor simulated flash-heat (FH) pasteurization. This study compared the effect of the FoneAstra FH (F-FH) method with the Sterifeed Holder method currently used by human milk banks on human milk immune components (immunoglobulin A (IgA), lactoferrin activity, lysozyme activity, interleukin (IL)-8 and IL-10). Donor milk samples (N = 50) were obtained from a human milk bank, and pasteurized. Concentrations of IgA, IL-8, IL-10, lysozyme activity and lactoferrin activity were compared to their controls using the Student's t-test. Both methods demonstrated no destruction of interleukins. While the Holder method retained all lysozyme activity, the F-FH method only retained 78.4% activity (p milk, potentially saving infants' lives.

  4. Disease: H00441 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available H00441 Progressive osseous heteroplasia (POH) Progressive osseous heteroplasia (POH... PMID:8126048 (description) Kaplan FS, Craver R, MacEwen GD, Gannon FH, Finkel G, Hahn G, Tabas J, Gardner RJ, Zasloff MA Progress

  5. The Impact of Lipoprotein-Associated Oxidative Stress on Cell-Specific Microvesicle Release in Patients with Familial Hypercholesterolemia

    DEFF Research Database (Denmark)

    Nielsen, M H; Irvine, H; Vedel, S;

    2016-01-01

    was studied. Approach and Results. Thirty FH patients with and without ATX and twenty-three controls were included. Plasma concentrations of MVs and CD36+ MVs derived from platelets (PMVs), erythrocytes (ErytMVs), monocytes (MMVs), and endothelial cells (EMVs), as well as tissue factor-positive cells (TF+ MVs......Objective. Microvesicles (MVs) are small cell-derived particles shed upon activation. Familial hypercholesterolemia (FH) particularly when associated with Achilles tendon xanthomas (ATX) predisposes to atherosclerosis, possibly through oxLDL-C interaction with the CD36 receptor. To investigate...... the hypothesis that MVs derived from cells involved in atherosclerosis are increased in FH and that CD36 expressing MVs (CD36+ MVs) may be markers of oxLDL-C-induced cell activation, cell-specific MVs were measured in FH patients with and without ATX and their association with atherogenic lipid profile...

  6. Caracterizacion del plano oclusal y diferentes marcos dentoesqueleticos en escolares entre 5 y 6 anos.(Articulo de Investigacion: Cientifica y Tecnologica)

    National Research Council Canada - National Science Library

    Arenas, Cristina; Giralda, Andres; Mustafa, Nancy; Seidel, Cristina

    2012-01-01

    .... Las variables analizadas fueron: el Marco Dental, Kim, el Plano Oclusal y el plano FH que se determino utilizando el porion anatomico y orbital como puntos de referencia, y los planos oclusales considerando la denticion decidua y mixta respectivamente...

  7. Drug: D06666 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available KP Peptide Treatment of diseases caused by human papillomavirus recombinant vaccine CAS: 295371-00-5 PubChem: 47208317 ... ...FH MHGDTPTLHE YMLDLQPETT DLYCYEQLND SSEEEDEIDG PAGQAEPDRA HYNIVTFCCK CDSTLRLCVQ STHVDIRTLE DLLMGTLGIV CPICSQ

  8. Strategies for Dense Optical CDMA Communication Systems

    Institute of Scientific and Technical Information of China (English)

    WANG Yu-bao; LIN Jin-tong

    2005-01-01

    In this paper,we have formulated a strategy that the limited available code sequences in pure Direct-Sequence(DS)or Frequency-Hopping(FH)system can be reused to realize dense optical CDMA:the strategy of novel hybrid DS/FH system.In which,the case that there are n users employing the same FH pattern but different DS code patterns is considered.On the condition that the impact of channel noises is neglected,the upper bound probability of error is evaluated based on the stationary random process theory.The results show that the hybrid system is suitable for Dense Optical CDMA(DOCDMA)communication.Moreover,the problems such as the link-impairment,dispersion of group velocity,etc.in the pure(DS or FH)system can be solved effectively.

  9. Genetics Home Reference: gastrointestinal stromal tumor

    Science.gov (United States)

    ... L, Gaal J, Korpershoek E, van Nederveen FH, Kelly L, Schiavon G, Verweij J, Mathijssen RH, den ... stem cell factor receptor. Biochem Biophys Res Commun. 2005 Nov 11;337(1):1-13. Review. Citation ...

  10. Pregnancy in a Woman with Homozygous Familial Hypercholesterolemia Not on Low-Density Lipoprotein Apheresis

    Directory of Open Access Journals (Sweden)

    Akl C. Fahed

    2012-11-01

    Full Text Available Pregnancy in women with homozygous familial hypercholesterolemia (FH has been rarely reported and might pose risks on the mother and her fetus. Although most reported cases remained on low-density lipoprotein (LDL apheresis, there are no clear guidelines regarding the management of this entity. We report the first case of an uncomplicated pregnancy in a 24-year-old homozygous FH woman who was not maintained on LDL apheresis. FH expresses a wide variability in the phenotype, and management of homozygous FH cases who desire to become pregnant should be individualized based on preconceptional assessment with frequent antenatal follow-up. Decisions on management should be made after weighing the risks versus benefits of LDL apheresis.

  11. Heart rate regulation and extreme bradycardia in diving emperor penguins.

    Science.gov (United States)

    Meir, Jessica U; Stockard, Torre K; Williams, Cassondra L; Ponganis, Katherine V; Ponganis, Paul J

    2008-04-01

    To investigate the diving heart rate (f(H)) response of the emperor penguin (Aptenodytes forsteri), the consummate avian diver, birds diving at an isolated dive hole in McMurdo Sound, Antarctica were outfitted with digital electrocardiogram recorders, two-axis accelerometers and time depth recorders (TDRs). In contrast to any other freely diving bird, a true bradycardia (f(H) significantly emperor penguins. Maximum instantaneous surface interval f(H) in this study is the highest ever recorded for emperor penguins (256 beats min(-1)), equivalent to f(H) at V(O(2)) max., presumably facilitating oxygen loading and post-dive metabolism. The classic Scholander-Irving dive response in these emperor penguins contrasts with the absence of true bradycardia in diving ducks, cormorants, and other penguin species.

  12. The Impact of Lipoprotein-Associated Oxidative Stress on Cell-Specific Microvesicle Release in Patients with Familial Hypercholesterolemia

    DEFF Research Database (Denmark)

    Nielsen, M H; Irvine, H; Vedel, S

    2016-01-01

    Objective. Microvesicles (MVs) are small cell-derived particles shed upon activation. Familial hypercholesterolemia (FH) particularly when associated with Achilles tendon xanthomas (ATX) predisposes to atherosclerosis, possibly through oxLDL-C interaction with the CD36 receptor. To investigate...

  13. Dicty_cDB: AFI509 [Dicty_cDB

    Lifescience Database Archive (English)

    Full Text Available TTCATCTTCTAGTTTTAAAAATAAAAGAAAACTNAACAATAAATAAAA sequence update 2001. 6. 2 Translated Amino Acid sequence *invnisr*ifr*f**w*rcisrlwi...rame C: *invnisr*ifr*f**w*rcisrlwirkk**r**fik*fh**fww*gr**q****kfhyy nyynyyykykyk

  14. Coupling Microbial Growth with Nanoparticles: A Universal Strategy To Produce Functional Fungal Hyphae Macrospheres.

    Science.gov (United States)

    Zhu, Wen-Kun; Cong, Huai-Ping; Guan, Qing-Fang; Yao, Wei-Tang; Liang, Hai-Wei; Wang, Wei; Yu, Shu-Hong

    2016-05-25

    Macroscale assembly of nanoscale building blocks is an intriguing way to translate the unique characteristics of individual nanoparticles into macroscopic materials. However, the lack of the efficient universal assembly strategy seriously hinders the possibility of macroscale architectures in practical applications. Herein, we develop a general, environment-friendly, and scalable microbial growth method for the construction of macroscopic composite assemblies with excellent mechanical strength by in situ integrating various types of nanoparticles into fungal hyphae (FH) macrospheres. Notably, the size of the FH-based composite spheres and the loading amount of the nanoparticles with different dimensions can be well tuned by controlling the cultivation time and the dosage of nanoparticles, respectively. Interestingly, bifunctional FH-based core-shell macrospheres can also be achieved by programmed assembling two different kinds of nanoparticles in the cultivation process. The produced multifunctional FH-based composite spheres exhibit wide potential applications in magnetic actuation, photothermal therapy, and contaminant adsorption, etc.

  15. Neutrophils contribute to fracture healing by synthesizing fibronectin+ extracellular matrix rapidly after injury

    NARCIS (Netherlands)

    Bastian, Okan W.; Koenderman, Leo; Alblas, Jacqueline; Leenen, Luke P H; Blokhuis, Taco J.

    2016-01-01

    The role of inflammatory cells in bone regeneration remains unclear. We hypothesize that leukocytes contribute to fracture healing by rapidly synthesizing an "emergency extracellular matrix (ECM)" before stromal cells infiltrate the fracture hematoma (FH) and synthesize the eventual collagenous bone

  16. Dicty_cDB: SFL389 [Dicty_cDB

    Lifescience Database Archive (English)

    Full Text Available rkesllfkmicyfilrikrrdqle rch*echvamkinh*vnqivsn*yhqesikhfsfkpihqmkwqvg*kqlrkdqnia...qcc*ss*cyrsfktsfhgfgmdssnltxiqaar Frame C: kti*k*fh*kiyhqhygnxqikrvn*rnkdm**rigrkesllfkmicyfilrikrrdqle rch*...echvamkinh*vnqivsn*yhqesikhfsfkpihqmkwqvg*kqlrkdqniaqyhn hsilnmrymlisiqqlvslvyqkn

  17. Selection of individuals for genetic testing for familial hypercholesterolaemia : development and external validation of a prediction model for the presence of a mutation causing familial hypercholesterolaemia

    NARCIS (Netherlands)

    Besseling, Joost; Reitsma, Johannes B; Gaudet, Daniel; Brisson, Diane; Kastelein, John J P; Hovingh, G Kees; Hutten, Barbara A

    2017-01-01

    AIMS: Familial hypercholesterolaemia (FH) is an autosomal dominant disease that warrants early diagnosis to prevent premature cardiovascular disease (CVD). However, genetic testing to make a definite diagnosis is costly, and careful selection of eligible subjects is important. Unfortunately,

  18. The effect of triclabendazole (Fasinex) in children with fasciolosis.

    Science.gov (United States)

    Yilmaz, H; Oner, A F; Akdeniz, H; Arslan, S

    1998-08-01

    Three children infected with Fasciola hepatica (FH) were treated with triclabendazole (TCZ; Fasinex). In the first two patients, firstly, albendazole (Andazole) was administered, but did not stop the excretion of FH eggs. To these two patients, TCZ was administered in a single oral dose of 10 mg/kg postprandially. Two month later, very few eggs were found in stool samples. So, the same dose of triclabendazole was secondly given to the patients. After this therapy. FH eggs have not been found in the repeated stool examinations for a follow up of one year. To the third patient, TCZ was administered in a single oral dose of 10 mg/kg together with food. This patient has remained free of complaints and stool samples were free from FH eggs for two months. In conclusion, TCZ may be used as a treatment of choice for human fasciolosis both in adults, and children.

  19. Family history of alcoholism and the stability of personality in young adulthood.

    Science.gov (United States)

    Larkins, Jenny M; Sher, Kenneth J

    2006-12-01

    The authors examined the magnitude and durability of personality differences related to family history of alcoholism (FH) and the development of alcohol use disorders (AUDs) in late adolescence and early adulthood. Data were taken from a longitudinal sample (N = 487; approximately half FH-positive [+]) who completed the Eysenck Personality Questionnaire (H. J. Eysenck & S. B. G. Eysenck, 1975) at 3 points spanning 11 years (participants were 18 years old at baseline). Hierarchical linear analyses showed that FH+ participants had higher levels of neuroticism and psychoticism over the study period, independent of AUD. Despite relatively large mean decreases in neuroticism (as well as extraversion), the magnitude of the between-groups differences found at age 18 were maintained over the next decade. These changes thus reflect stable underlying differences in personality and not artifacts of higher rates of AUDs in FH+ individuals, recently living in an alcoholic home, vulnerability to the developmental challenge of leaving home, and/or a developmental lag.

  20. First insight into CD59-like molecules of adult Fasciola hepatica.

    Science.gov (United States)

    Shi, Yunliang; Toet, Hayley; Rathinasamy, Vignesh; Young, Neil D; Gasser, Robin B; Beddoe, Travis; Huang, Weiyi; Spithill, Terry W

    2014-09-01

    The present study focussed on investigating CD59-like molecules of Fasciola hepatica. A cDNA encoding a CD59-like protein (termed FhCD59-1) identified previously in the membrane fraction of the F. hepatica tegument was isolated. This homologue was shown to encode a predicted open reading frame (ORF) of 122 amino acids (aa) orthologous to human CD59 with a 25 aa signal peptide, a mature protein containing 10 cysteines and a conserved CD59/Ly-6 family motif "CCXXXXCN". An analysis of cDNAs from two different adult specimens of F. hepatica revealed seven variable types of FhCD59-1 sequences, designated FhCD59-1.1 to FhCD59-1.7, which had 94.3-99.7% amino acid sequence identity upon pairwise comparison. Molecular modeling of FhCD59-1.1 with human CD59 confirmed the presence of the three-finger protein domain found in the CD59 family and predicted three disulphide bonds in the F. hepatica sequence. The interrogation of F. hepatica databases identified two additional sequences, designated FhCD59-2 and FhCD59-3, which had only 23.4-29.5% amino acid identity to FhCD59-1.1. Orthologues of the inferred CD59 protein sequences of F. hepatica were also identified in other flatworms, including Fasciola gigantica, Fascioloides magna, Schistosoma haematobium, Schistosoma japonicum, Schistosoma mansoni, Clonorchis sinensis, Opisthorchis viverrini, Taenia solium, Echinococcus granulosus and the free living Schmidtea mediterannea. The results revealed a considerable degree of sequence complexity in the CD59-like sequence families in F. hepatica and flatworms. Phylogenetic analysis of CD59-like aa sequences from F. hepatica and flatworms showed that FhCD59-2 clustered with the known surface-associated protein SmCD59-2 of S. mansoni. Relatively well-supported clades specific to schistosomes, fasciolids and opisthorchiids were identified. The qPCR analysis of gene transcription showed that the relative expression of these 3 FhCD59-like sequences varied by 11-47-fold during fluke

  1. Characterization and differential expression of cathepsin L3 alleles from Fasciola hepatica.

    Science.gov (United States)

    Zawistowska-Deniziak, A; Wasyl, K; Norbury, L J; Wesołowska, A; Bień, J; Grodzik, M; Wiśniewski, M; Bąska, P; Wędrychowicz, H

    2013-07-01

    Fasciola hepatica infections cause significant global problems in veterinary and human medicine, including causing huge losses in cattle and sheep production. F. hepatica host infection is a multistage process and flukes express papain-like cysteine proteases, termed cathepsins, which play pivotal roles in virulence through host entry, tissue migration and immune evasion. Expression of these proteases is developmentally regulated. Recent studies indicate that excystment of infective larvae is dependent on cysteine proteases and together FhCL3 and FhCB account for over 80% of total protease activity detectable in newly excysted juvenile (NEJ) fluke. This paper focuses on members of the cathepsin L gene family, specifically those belonging to the CL3 clade. The cDNA of two novel cathepsin L3 proteases--FhCL3-1 and FhCL3-2 were cloned. The mRNA transcript expression levels for these enzymes were significantly different at various time points in life development stages obtained in vitro, from dormant metacercariae to NEJ 24h after excystment. Maximum expression levels were observed in NEJ immediately after excystment. In all stages examined by Real Time PCR, FhCL3-2 was expressed at a higher level compared to FhCL3-1 which was expressed only at very low levels. Western blot and immunohistochemical analysis also indicated higher expression of the FhCL3-2 allele and its secretory nature. The ability of antibody responses from rats and sheep challenged with F. hepatica to recognize recombinant FhCL3-1 and FhCL3-2 was shown to differ. Differences were also confirmed through the use of anti-rFhCL3-1 and anti-rFhCL3-2 sera in Western blot analysis of juvenile excretory/secretory (ES) material separated by 2D electrophoresis. These results indicate analysis of relative expression of parasite virulence factors from different populations is required, as this will likely impact the effectiveness of vaccines based on these antigens.

  2. White Matter Hyperintensities on T2-Weighted MRI Images among DNA-Verified Older Familial Hypercholesterolemia Patients

    Energy Technology Data Exchange (ETDEWEB)

    Hyttinen, L. (Dept. of Internal Medicine, North Karelia Central Hospital, Joensuu (Finland)); Autti, T.; Soljanlahti, S. (Medical Imaging Center, Helsinki Univ. Central Hospital, Helsinki (Finland)); Rauma, S. (Dept. of Radiology, North Karelia Central Hospital, Joensuu (Finland)); Vuorio, A.F. (Dept. of Medicine, Univ. of Helsinki, Helsinki (Finland)); Strandberg, T.E. (Dept. of Health Sciences/Geriatrics, Univ. of Oulu, Oulu (Finland))

    2009-04-15

    Background: Familial hypercholesterolemia (FH) is a genetic disorder, causing an increased risk of coronary heart disease (CHD) if untreated. Silent brain infarctions and white matter hyperintensities (WMHIs) observed on T2-weighted magnetic resonance images (MRI) are associated with increased risk for stroke and myocardial infarction. Age is a strong predictor of WMHIs. Purpose: To use MRI to assess the presence of clinically silent brain lesions in older FH patients, and to compare the occurrence and size of these lesions in older FH patients with middle-aged FH patients and healthy controls. Material and Methods: A total of 43 older (age = 65 years) FH patients with the same FH North Karelia mutation, living in Finland, were identified. In this comprehensive cohort, 1.5T brain MRI was available for 33 individuals (age 65-84 years, M/F 9/24, mean duration of statin treatment 15.3 years). This group was divided into two age categories: 65-74 years (FHe1 group, n=23) and 75-84 years (FHe2 group, n=10). Infarcts, including lacunas, and WMHIs on T2-weighted images were recorded. Data from brain MRI were compared to those of a group of middle-aged FH patients with CHD (n=19, age 48-64 years) and with middle-aged healthy controls (n=29, age 49-63 years). Results: Only two (6%) of the older FH patients had clinically silent brain infarcts detected by MRI. The amount of large WMHIs (>5 mm in diameter) was similar in the FHe1 group compared with the groups of middle-aged FH patients and healthy controls, even though the FHe1 group was 13 years older. The total amount of WMHIs and the amount of large WMHIs were greatest in the FHe2 group. Conclusion: FH patients aged 65 to 74 years receiving long-term statin treatment (15 years) did not have more WMHIs on brain MRI compared to middle-aged FH patients and healthy controls.

  3. The detection of heterozygous familial hypercholesterolemia in Ireland.

    LENUS (Irish Health Repository)

    O'Kane, Maurice J

    2012-05-01

    Heterozygous familial hypercholesterolemia (HeFH) is an autosomal dominant condition with a population prevalence of 1 in 500, and is associated with significant cardiovascular morbidity and mortality. It may be caused by mutations in the low-density lipoprotein (LDL) receptor, apolipoprotein B100 (Apo B100), or proprotein convertase subtilisin\\/kexin type 9 (PCSK9) genes, with over 1,000 causative mutations described. Statin therapy in HeFH is considered effective and safe. Audit data suggest that approximately 80% of the putative HeFH population remains unidentified and, therefore, there is a need to develop a strategy for the identification of affected individuals so that early lipid-lowering treatment may be offered. There is good evidence showing the effectiveness and acceptability of HeFH screening programs in Europe. The authors describe a protocol for an all island approach to HeFH detection in the Republic of Ireland\\/Northern Ireland. Index cases will be identified by opportunistic screening using the Simon Broome, or Make Early Diagnosis to Prevent Early Death (MedPed) and World Health Organization (WHO) criteria. Patients identified as "definite," "probable," or "possible" HeFH criteria will be offered genetic testing. The authors expect causative mutations to be identified in approximately 80% of patients with "definite" HeFH but in only approximately 20% of patients with "possible" HeFH. Cascade screening will be undertaken in first-degree relatives of the index case using genetic testing (where a causative mutation has been identified), or otherwise using LDL cholesterol concentration. The establishment of a HeFH screening program on an all-island basis will require: expansion of the existing molecular genetics diagnostic services, the establishment of a cohort of nurses\\/genetic counselors, a HeFH database to support cascade testing, the development of a network of lipid clinics (in a primary or secondary care setting), and an educational

  4. A forkhead gene related to HNF-3beta is required for gastrulation and axis formation in the ascidian embryo.

    Science.gov (United States)

    Olsen, C L; Jeffery, W R

    1997-09-01

    We have isolated a member of the HNF-3/forkhead gene family in ascidians as a means to determine the role of winged-helix genes in chordate development. The MocuFH1 gene, isolated from a Molgula oculata cDNA library, exhibits a forkhead DNA-binding domain most similar to zebrafish axial and rodent HNF-3beta. MocuFH1 is a single copy gene but there is at least one other related forkhead gene in the M. oculata genome. The MocuFH1 gene is expressed in the presumptive endoderm, mesenchyme and notochord cells beginning during the late cleavage stages. During gastrulation, MocuFH1 expression occurs in the prospective endoderm cells, which invaginate at the vegetal pole, and in the presumptive notochord and mesenchyme cells, which involute over the anterior and lateral lips of the blastopore, respectively. However, this gene is not expressed in the presumptive muscle cells, which involute over the posterior lip of the blastopore. MocuFH1 expression continues in the same cell lineages during neurulation and axis formation, however, during the tailbud stage, MocuFH1 is also expressed in ventral cells of the brain and spinal cord. The functional role of the MocuFH1 gene was studied using antisense oligodeoxynucleotides (ODNs), which transiently reduce MocuFH1 transcript levels during gastrulation. Embryos treated with antisense ODNs cleave normally and initiate gastrulation. However, gastrulation is incomplete, some of the endoderm and notochord cells do not enter the embryo and undergo subsequent movements, and axis formation is abnormal. In contrast, the prospective muscle cells, which do not express MocuFH1, undergo involution and later express muscle actin and acetylcholinesterase, markers of muscle cell differentiation. The results suggest that MocuFH1 is required for morphogenetic movements of the endoderm and notochord precursor cells during gastrulation and axis formation. The effects of inhibiting MocuFH1 expression on embryonic axis formation in ascidians are

  5. The Role of SDF-1alpha and CXCR4 in Metastatic Breast Cancer

    Science.gov (United States)

    2006-08-01

    cancer cells. Nutr Cancer 2004;48:84–94. 5. Rahman KM, Aranha O, Glazyrin A, Chinni SR, Sarkar FH. Translocation of Bax to mitochondria induces...KM, Aranha O, Sarkar FH. Indole-3-carbinol (I3C) induces apoptosis in tumorigenic but not in non- tumorigenic breast epithelial cells. Nutr Cancer...Rahman KM, Aranha O, Glazyrin A, et al. Translocation of Bax to mitochondria induces apoptotic cell death in indole-3-carbinol (I3C) treated breast

  6. Blunted hypothalamic–pituitary–adrenocortical axis responsivity to stress in persons with a family history of alcoholism

    OpenAIRE

    Sorocco, Kristen H.; Lovallo, William R.; Vincent, Andrea S.; Collins, Frank L.

    2005-01-01

    Abstinent alcoholics show a blunted stress cortisol response that may be a consequence of drinking or a preexisting risk marker. We tested cortisol responses to psychological stress in 186 18–30 year-old, healthy social drinkers having no personal history of alcohol or drug dependence, 91 of whom had one or two alcoholic parents (FH+) and 95 having no family alcoholism for two generations (FH−). We predicted that, similar to alcoholic patients, the FH+ would have reduced stress cortisol respo...

  7. The relationship between heart rate and rate of oxygen consumption in Galapagos marine iguanas (Amblyrhynchus cristatus) at two different temperatures.

    Science.gov (United States)

    Butler, Patrick J; Frappell, Peter B; Wang, Tobias; Wikelski, Martin

    2002-07-01

    To enable the use of heart rate (fH) for estimating field metabolic rate (FMR) in free-ranging Galapagos marine iguanas Amblyrhynchus cristatus, we determined the relationships between fH and mass-specific rate of oxygen consumption (sVO2) in seven iguanas before and during exercise on a treadmill and during the post-exercise period. The experiments were conducted at 27 and 35 degrees C, which are the temperatures that represent the lowest and highest average body temperatures of these animals in the field during summer. There were linear and significant relationships between fH and sVO2 at both temperatures (r(2)=0.86 and 0.91 at 27 degrees C and 36 degrees C, respectively). The slopes of the two regression lines did not differ, but there were significant differences in their intercepts. Thus, while heart rate can be used to predict FMR, the effects of temperature on the intercept of the regression must be taken into account when converting fH to sVO2. On the basis of our data, this can be achieved by applying the following formula: sVO2=0.0113fH-0.2983Q(10)((T(b)-27)/10). The increase in sVO2 with elevated body temperature results from an increase in fH, with no significant change in mass-specific oxygen pulse (sO(2) pulse; cardiac stroke volume times the difference in oxygen content between arterial and mixed venous blood). However, during exercise at both temperatures, increases in fH are insufficient to provide all of the additional O(2) required and there are also significant increases in the sO(2) pulses. This creates the situation whereby the same fH at the two temperatures can represent different values of sVO2.

  8. Air Vehicle Integration and Technology Research (AVIATR). Task Order 0003: Condition-Based Maintenance Plus Structural Integrity (CBM+SI) Demonstration (April 2011 to August 2011)

    Science.gov (United States)

    2011-08-01

    FSMP "Items of Criticality" Lists (Serv Life < 32000 FH) Risk Document Total Before Triage Triage Projet Control Points CONTROL POINT DOWN-SELECT...34Items of Criticality" Lists (Serv Life < 32K FH) Risk Document Total before Triage Triage (none yet performed ) Projet Control Points 5 Approved...analysis. However, since both codes use different probabilistic analysis strategies and different ways to manage the statistical distributions, their

  9. Physics and Chemistry of MW Discharge in Gas Flows

    Science.gov (United States)

    2007-11-02

    Imhof R.E., Read F.H. Measured lifetimes of the uC Π 3 state of N2 and the +Σga 3 state of H2 - J. Phys., 1971, v.B4(8), pp.1063-1069 15. Chen S.T...Radiative lifetimes of ions measured with the photoelectron spectrometer - Chem. Phys. Lett., 1975, v.30(3), pp.344-346 44. Smith A.J., Read F.H., Imhof

  10. Gene fusion detection in formalin-fixed paraffin-embedded benign fibrous histiocytomas using fluorescence in situ hybridization and RNA sequencing.

    Science.gov (United States)

    Walther, Charles; Hofvander, Jakob; Nilsson, Jenny; Magnusson, Linda; Domanski, Henryk A; Gisselsson, David; Tayebwa, Johnbosco; Doyle, Leona A; Fletcher, Christopher D M; Mertens, Fredrik

    2015-09-01

    Benign fibrous histiocytomas (FH) can be subdivided into several morphological and clinical subgroups. Recently, gene fusions involving either one of two protein kinase C genes (PRKCB and PRKCD) or the ALK gene were described in FH. We here wanted to evaluate the frequency of PRKCB and PRKCD gene fusions in FH. Using interphase fluorescence in situ hybridization on sections from formalin-fixed paraffin-embedded (FFPE) tumors, 36 cases could be analyzed. PRKCB or PRKCD rearrangements were seen in five tumors: 1/7 regular, 0/3 aneurysmal, 0/6 cellular, 2/7 epithelioid, 0/1 atypical, 2/10 deep, and 0/2 metastatic lesions. We also evaluated the status of the ALK gene in selected cases, finding rearrangements in 3/7 epithelioid and 0/1 atypical lesions. To assess the gene fusion status of FH further, deep sequencing of RNA (RNA-Seq) was performed on FFPE tissue from eight cases with unknown gene fusion status, as well as on two FH and six soft tissue sarcomas with known gene fusions; of the latter eight positive controls, the expected fusion transcript was found in all but one, while 2/8 FH with unknown genetic status showed fusion transcripts, including a novel KIRREL/PRKCA chimera. Thus, also a third member of the PRKC family is involved in FH tumorigenesis. We conclude that gene fusions involving PRKC genes occur in several morphological (regular, cellular, aneurysmal, epithelioid) and clinical (cutaneous, deep) subsets of FH, but they seem to account for only a minority of the cases. In epithelioid lesions, however, rearrangements of PRKC or ALK were seen, as mutually exclusive events, in the majority (5/7) of cases. Finally, the study also shows that RNA-Seq is a promising tool for identifying gene fusions in FFPE tissues.

  11. The use of low density lipoprotein receptor activity of lymphocytes to determine the prevalence of familial hypercholesterolaemia in a rural South African community.

    Science.gov (United States)

    Steyn, K; Weight, M J; Dando, B R; Christopher, K J; Rossouw, J E

    1989-01-01

    The diagnosis of heterozygous familial hypercholesterolaemia in three rural South African communities in which hypercholesterolaemia is very prevalent could be confirmed by the measurement of low density lipoprotein (LDL) receptor activity in circulating lymphocytes. A nominal cut off point could be proposed which separated the LDL receptor activity of 24 clinically diagnosed heterozygous FH patients and 31 healthy people. LDL receptor activity was measured as total degradation of 125I-LDL and expressed as ng LDL/mg cell protein/6 hours. The cut off point was set at 970 ng/mg protein/6 hours. This proposed cut off point was tested by assaying the LDL receptor of three homozygous FH patients and seven of their obligate heterozygous FH first degree relatives. The three homozygous FH patients showed no receptor activity and the activity of the seven obligate heterozygous first degree relatives fell below the proposed cut off point. To determine the prevalence of FH in the study population, all persons aged 15 to 24 years whose total cholesterol levels fell above the 80th centile for their age and sex, as well as their families, were approached (n = 114). The LDL receptor activity in lymphocytes of 77 of these persons aged 15 to 24 years was determined after applying the exclusion criteria. Ten of the 77 participants had LDL receptor activity below 970 ng LDL/mg protein/6 hours and were therefore diagnosed as being heterozygous FH patients. The calculation of the prevalence (corrected for exclusions) revealed that one in 71 of the 15 to 24 year old permanent residents in the predominantly Afrikaans speaking community suffered from heterozygous FH. This is higher than any FH prevalence previously reported for any group. PMID:2918524

  12. Arsenic retention and transport behavior in the presence of typical anionic and nonionic surfactants.

    Science.gov (United States)

    Liang, Chuan; Wang, Xianliang; Peng, Xianjia

    2016-01-01

    The massive production and wide use of surfactants have resulted in a large amount of surfactant residuals being discharged into the environment, which could have an impact on arsenic behavior. In the present study, the influence of the anionic surfactant sodium dodecyl benzene sulfonate (SDBS) and nonionic surfactant polyethylene glycol octylphenyl ether (Triton X-100) on arsenic behavior was investigated in batch and column tests. The presence of SDBS and Triton X-100 reduced arsenic retention onto ferrihydrite (FH), enhanced arsenic transport through FH coated sand (FH-sand) columns and promoted arsenic release from the FH surface. With coexisting surfactants in solution, the equilibrium adsorbed amount of arsenic on FH decreased by up to 29.7% and the adsorption rate decreased by up to 52.3%. Pre-coating with surfactants caused a decrease in the adsorbed amount and adsorption rate of arsenic by up to 15.1% and 58.3%, respectively. Because of the adsorption attenuation caused by surfactants, breakthrough of As(V) and As(III) with SDBS in columns packed with FH-sand was 23.8% and 14.3% faster than that in those without SDBS, respectively. In columns packed with SDBS-coated FH-sand, transport of arsenic was enhanced to a greater extent. Breakthrough of As(V) and As(III) was 52.4% and 43.8% faster and the cumulative retention amount was 44.5% and 57.3% less than that in pure FH-sand column systems, respectively. Mobilization of arsenic by surfactants increased with the increase of the initial adsorbed amount of arsenic. The cumulative release amount of As(V) and As(III) from the packed column reached 10.8% and 36.0%, respectively.

  13. PFAPA syndrome is not a sporadic disease

    OpenAIRE

    Cochard, Marie; Clet, Johanna; Le, Lan; Pillet, Pascal; Onrubia, Xavier; Guéron, Thierry; Faouzi, Mohammed; Hofer, Michaël

    2017-01-01

    Objectives. To determine whether PFAPA (periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis) patients have a positive family history (FH) for recurrent fever syndromes. Method. For all patients with PFAPA seen in two paediatric rheumatology centres (Romandy, Switzerland and Bordeaux, France), parents were interviewed to record the FH for periodic fever. As controls, we interviewed a group of children without history of recurrent fever. Results. We recruited 84 patients with...

  14. Estimating the prevalence of heterozygous familial hypercholesterolaemia: a systematic review and meta-analysis

    Science.gov (United States)

    Akioyamen, Leo E; Genest, Jacques; Shan, Shubham D; Reel, Rachel L; Albaum, Jordan M; Chu, Anna; Tu, Jack V

    2017-01-01

    Objectives Heterozygous familial hypercholesterolaemia (FH) confers a significant risk for premature cardiovascular disease (CVD). However, the estimated prevalence of FH varies substantially among studies. We aimed to provide a summary estimate of FH prevalence in the general population and assess variations in frequency across different sociodemographic characteristics. Setting, participants and outcome measures We searched MEDLINE, EMBASE, Global Health, the Cochrane Library, PsycINFO and PubMed for peer-reviewed literature using validated strategies. Results were limited to studies published in English between January 1990 and January 2017. Studies were eligible if they determined FH prevalence using clinical criteria or DNA-based analyses. We determined a pooled point prevalence of FH in adults and children and assessed the variation of the pooled frequency by age, sex, geographical location, diagnostic method, study quality and year of publication. Estimates were pooled using random-effects meta-analysis. Differences by study-level characteristics were investigated through subgroups, meta-regression and sensitivity analyses. Results The pooled prevalence of FH from 19 studies including 2 458 456 unique individuals was 0.40% (95% CI 0.29% to 0.52%) which corresponds to a frequency of 1 in 250 individuals. FH prevalence was found to vary by age and geographical location but not by any other covariates. Results were consistent in sensitivity analyses. Conclusions Our systematic review suggests that FH is a common disorder, affecting 1 in 250 individuals. These findings underscore the need for early detection and management to decrease CVD risk. PMID:28864697

  15. On the Cauchy problem for a doubly nonlinear degenerate parabolic equation with strongly nonlinear sources

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    In this article, we consider the existence of local and global solution to the Cauchy problem of a doubly nonlinear equation. By introducing the norms |||f|||h and <f>h, we give the suffcient and necessary conditions on the initial value to the existence of local solution of doubly nonlinear equation. Moreover some results on the global existence and nonexistence of solutions are considered.

  16. Comparative evaluation of selected vegetable oils and Terpenes on Transdermal permeation of Ketorolac Tromethamine

    Directory of Open Access Journals (Sweden)

    Goudanavar Prakash

    2011-12-01

    Full Text Available A reservoir type transdermal patch for delivery of ketorolac tromethamine (KT, a potent analgesic agent was studied. Studies were carried out to investigate the effect of permeation enhancers on the in vitro permeation of KT across rat skin. Films were prepared by using hydroxy propyl methyl cellulose (HPMC and polyvinylalcohol (PVA polymers by incorporating glycerine as plasticizers using solvent casting method. A total of fourteen formulations were prepared by using same drug polymer ratio of 1:1 and incorporated different terpenes and vegetable oils as permeation enhancers in same concentrations. The prepared systems released the drug in the following order: FP2 > FP3 > FH2 > FP5 > FH3 > FP4 > FH5 > FH4 > FH6 > FP6 > FH7 > FP7 > FH1 > FH1. The various permeation parameters such as enhancement ratio and percent of drug permeated were determined for all the formulations. The maximum percent of drug permeation was observed with PVA monolithic system containing 10% d-limonene. Permeation enhancement of KT with different enhancers followed the order: d-limonene > cineole > olive oil > menthol >linseed oil > sunflower oil. The in vitro release studies revealed that terpenes showed better permeation enhancement than vegetable oils and the release was sustained up to 24 h and it follows zero-order kinetics. All the films were found to be stable at 37°C and 45°C with respect to their physical parameters. A reservoir type transdermal patch for delivery of KT thus appears to be feasible of delivering KT across skin.

  17. What is the actual epidemiology of familial hypercholesterolemia in Italy? Evidence from a National Primary Care Database.

    Science.gov (United States)

    Guglielmi, Valeria; Bellia, Alfonso; Pecchioli, Serena; Medea, Gerardo; Parretti, Damiano; Lauro, Davide; Sbraccia, Paolo; Federici, Massimo; Cricelli, Iacopo; Cricelli, Claudio; Lapi, Francesco

    2016-11-15

    There are some inconsistencies on prevalence estimates of familial hypercholesterolemia (FH) in general population across Europe due to variable application of its diagnostic criteria. We aimed to investigate the FH epidemiology in Italy applying the Dutch Lipid Clinical Network (DLCN) score, and two alternative diagnostic algorithms to a primary care database. We performed a retrospective population-based study using the Health Search IMS Health Longitudinal Patient Database (HSD) and including active (alive and currently registered with their general practitioners (GPs)) patients on December 31, 2014. Cases of FH were identified by applying DLCN score. Two further algorithms, based on either ICD9CM coding for FH or some clinical items adopted by the DLCN, were tested towards DLCN itself as gold standard. We estimated a prevalence of 0.01% for "definite" and 0.18% for "definite" plus "probable" cases as per the DLCN. Algorithms 1 and 2 reported a FH prevalence of 0.9 and 0.13%, respectively. Both algorithms resulted in consistent specificity (1: 99.10%; 2: 99.9%) towards DLCN, but Algorithm 2 considerably better identified true positive (sensitivity=85.90%) than Algorithm 1 (sensitivity=10.10%). The application of DLCN or valid diagnostic alternatives in the Italian primary care setting provides estimates of FH prevalence consistent with those reported in other screening studies in Caucasian population. These diagnostic criteria should be therefore fostered among GPs. In the perspective of FH new therapeutic options, the epidemiological picture of FH is even more relevant to foresee the costs and to plan affordable reimbursement programs in Italy. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  18. Understanding Forest Health with Remote Sensing-Part II—A Review of Approaches and Data Models

    Directory of Open Access Journals (Sweden)

    Angela Lausch

    2017-02-01

    Full Text Available Stress in forest ecosystems (FES occurs as a result of land-use intensification, disturbances, resource limitations or unsustainable management, causing changes in forest health (FH at various scales from the local to the global scale. Reactions to such stress depend on the phylogeny of forest species or communities and the characteristics of their impacting drivers and processes. There are many approaches to monitor indicators of FH using in-situ forest inventory and experimental studies, but they are generally limited to sample points or small areas, as well as being time- and labour-intensive. Long-term monitoring based on forest inventories provides valuable information about changes and trends of FH. However, abrupt short-term changes cannot sufficiently be assessed through in-situ forest inventories as they usually have repetition periods of multiple years. Furthermore, numerous FH indicators monitored in in-situ surveys are based on expert judgement. Remote sensing (RS technologies offer means to monitor FH indicators in an effective, repetitive and comparative way. This paper reviews techniques that are currently used for monitoring, including close-range RS, airborne and satellite approaches. The implementation of optical, RADAR and LiDAR RS-techniques to assess spectral traits/spectral trait variations (ST/STV is described in detail. We found that ST/STV can be used to record indicators of FH based on RS. Therefore, the ST/STV approach provides a framework to develop a standardized monitoring concept for FH indicators using RS techniques that is applicable to future monitoring programs. It is only through linking in-situ and RS approaches that we will be able to improve our understanding of the relationship between stressors, and the associated spectral responses in order to develop robust FH indicators.

  19. Identification of the major proteins of an immune modulating fraction from adult Fasciola hepatica released by Nonidet P40

    OpenAIRE

    Morphew, R.M.; Hamilton, C M; Wright, H. A.; Dowling, D. J.; O’Neill, S. M.; Brophy, P.M.

    2012-01-01

    Fasciola hepatica NP-40 released antigens (FhTeg) exhibit potent Th1 immunosuppressive properties in vitro and in vivo. However, the protein composition of this active fraction, responsible for Th1 immune modulatory activity, has yet to be resolved. Therefore, FhTeg, a Nonidet P-40 extract, was subjected to a proteomic analysis in order to identify individual protein components. This was performed using an in house F. hepatica EST database following 2D electrophoresis combined with de novo se...

  20. Family history of cancer and risk for esophageal and gastric cancer in Shanxi, China

    Directory of Open Access Journals (Sweden)

    Goldstein Alisa

    2009-08-01

    Full Text Available Abstract Background Family history (FH by different relative types and risk of upper gastrointestinal (UGI cancers has been only rarely reported; the data on UGI cancer survival are sparse. Methods 600 esophageal squamous cell carcinoma (ESCC cases, 598 gastric cardia adenocarcinoma cases, and 316 gastric non-cardia adenocarcinoma cases, and 1514 age-, gender-, and neighborhood-matched controls were asked for FH in first degree relatives and non-blood relatives. Odds ratios (ORs and 95% confidence intervals (CIs from logistic regressions, and hazard ratios (HRs from Cox proportional hazard regressions were estimated. Results Increased ESCC risk was associated with FH of any cancer (OR = 1.72, 95% CI = 1.39–2.12, FH of any UGI cancer (OR = 2.28, 95%CI = 1.77–2.95 and FH of esophageal cancer (OR = 2.84, 95%CI = 2.09–3.86, but not FH of non-UGI cancer. Individuals with two or more affected first-degree relatives had 10-fold increased ESCC risk. FH of gastric cardia cancer was associated with an increased risk of all three cancers. Cancer in non-blood relatives was not associated with risk of any UGI cancer. FH of UGI cancer was associated with a poorer survival rate among younger ESCC cases (HR = 1.82, 95%CI = 1.01–3.29. Conclusion These data provide strong evidence that shared susceptibility is involved in esophageal carcinogenesis and also suggest a role in prognosis.

  1. Relationship between parameters of electrical impedance spectroscopy and frost hardiness in stems and needles of Pinus bun(g)eana

    Institute of Scientific and Technical Information of China (English)

    Yaqing LI; Gang ZHANG; Shupeng QUE; Liang ZHU; Bao DI; Xiumei JIN

    2009-01-01

    We studied the frost hardiness (FH) in stems and needles of different Pinus bungeana provenances during frost hardening by means of electrical impedance spectroscopy (EIS) and conventional electrolytic leakage (EL) and compared the regression equations of the two methods in order to optimize the EIS method for studying FH on plants. During frost hardening, EIS and EL were applied to one-year old stems and needles of P. bungeana in an 8-year provenance field trial at the Thirteen Tombs Nursery in Beijing within the provenances of Mangshan of Beijing, Liangdang of Gansu and Xiaoyi of Shanxi provinces, China. A double-DCE model and Model-A were used, respectively, for the EIS analysis of stems and needles that were not exposed to a controlled freezing treatment. After controlled freezing tests, the FH of stems and needles were assessed by EIS and EL. Without controlled freezing tests, the relaxation time (τ1) of stems and the specific intracellular resistance (ri) of stems and needles displayed a statistically significant correlation with FH (R2 =0.79-0.86); after controlled freezing tests, specific extracellular resistance (re) of the stems and needles, the cell membrane time constant (τm) of needles displayed an even higher correlation with FH (R2 = 0.92-0.94). There were significant relationship between EIS and EL in assessing the FH of stems and needles of P, bungeana, but EIS underestimated FH more than EL did. EIS is one of the more promising methods for assessing FH, especially without employing a controlled freezing test.

  2. Optimizing Treatment of Familial Hypercholesterolemia in Children and Adolescents

    OpenAIRE

    Luirink, Ilse K.; Hutten, Barbara A; Wiegman, Albert

    2015-01-01

    Cardiovascular disease (CVD) is still the most prominent cause of death and morbidity in the world, and one of the major risk factors for developing CVD is hypercholesterolemia. Familial hypercholesterolemia (FH) is a dominantly inherited disorder characterized by markedly elevated plasma low-density lipoprotein cholesterol and premature coronary heart disease. Currently, several treatment options are available for children with FH. Lifestyle adjustments are the first step in treatment. If th...

  3. Factor H-related protein 5 interacts with pentraxin 3 and the extracellular matrix and modulates complement activation.

    Science.gov (United States)

    Csincsi, Ádám I; Kopp, Anne; Zöldi, Miklós; Bánlaki, Zsófia; Uzonyi, Barbara; Hebecker, Mario; Caesar, Joseph J E; Pickering, Matthew C; Daigo, Kenji; Hamakubo, Takao; Lea, Susan M; Goicoechea de Jorge, Elena; Józsi, Mihály

    2015-05-15

    The physiological roles of the factor H (FH)-related proteins are controversial and poorly understood. Based on genetic studies, FH-related protein 5 (CFHR5) is implicated in glomerular diseases, such as atypical hemolytic uremic syndrome, dense deposit disease, and CFHR5 nephropathy. CFHR5 was also identified in glomerular immune deposits at the protein level. For CFHR5, weak complement regulatory activity and competition for C3b binding with the plasma complement inhibitor FH have been reported, but its function remains elusive. In this study, we identify pentraxin 3 (PTX3) as a novel ligand of CFHR5. Binding of native CFHR5 to PTX3 was detected in human plasma and the interaction was characterized using recombinant proteins. The binding of PTX3 to CFHR5 is of ∼2-fold higher affinity compared with that of FH. CFHR5 dose-dependently inhibited FH binding to PTX3 and also to the monomeric, denatured form of the short pentraxin C-reactive protein. Binding of PTX3 to CFHR5 resulted in increased C1q binding. Additionally, CFHR5 bound to extracellular matrix in vitro in a dose-dependent manner and competed with FH for binding. Altogether, CFHR5 reduced FH binding and its cofactor activity on pentraxins and the extracellular matrix, while at the same time allowed for enhanced C1q binding. Furthermore, CFHR5 allowed formation of the alternative pathway C3 convertase and supported complement activation. Thus, CFHR5 may locally enhance complement activation via interference with the complement-inhibiting function of FH, by enhancement of C1q binding, and by activating complement, thereby contributing to glomerular disease.

  4. HELP LDL apheresis reduces plasma pentraxin 3 in familial hypercholesterolemia.

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    Michela Zanetti

    Full Text Available BACKGROUND: Pentraxin 3 (PTX3, a key component of the humoral arm of innate immunity, is secreted by vascular cells in response to injury, possibly aiming at tuning arterial activation associated with vascular damage. Severe hypercholesterolemia as in familial hypercholesterolemia (FH promotes vascular inflammation and atherosclerosis; low-density lipoprotein (LDL apheresis is currently the treatment of choice to reduce plasma lipids in FH. HELP LDL apheresis affects pro- and antiinflammatory biomarkers, however its effects on PTX3 levels are unknown. We assessed the impact of FH and of LDL removal by HELP apheresis on PTX3. METHODS: Plasma lipids, PTX3, and CRP were measured in 19 patients with FH undergoing chronic HELP LDL apheresis before and after treatment and in 20 control subjects. In the patients assessment of inflammation and oxidative stress markers included also plasma TNFα, fibrinogen and TBARS. RESULTS: At baseline, FH patients had higher (p = 0.0002 plasma PTX3 than matched control subjects. In FH PTX3 correlated positively (p≤0.05 with age, gender and CRP and negatively (p = 0.01 with HELP LDL apheresis vintage. The latter association was confirmed after correction for age, gender and CRP. HELP LDL apheresis acutely reduced (p≤0.04 plasma PTX3, CRP, fibrinogen, TBARS and lipids, but not TNFα. No association was observed between mean decrease in PTX3 and in LDL cholesterol. PTX3 paralleled lipids, oxidative stress and inflammation markers in time-course study. CONCLUSION: FH is associated with increased plasma PTX3, which is acutely reduced by HELP LDL apheresis independently of LDL cholesterol, as reflected by the lack of association between change in PTX3 and in LDL levels. These results, together with the finding of a negative relationship between PTX3 and duration of treatment suggest that HELP LDL apheresis may influence both acutely and chronically cardiovascular outcomes in FH by modulating PTX3.

  5. COMPARATIVE EFFECT OF APHERESIS vs ATORVASTATIN/APHERESIS ON MARKERS OF INFLAMMATION IN PATIENTS WITH FAMILIAL HYPERCHOLESTEROLEMIA

    OpenAIRE

    Puntoni, Mariarita; Sbrana, Francesco; Bigazzi, Federico; Minichilli, Fabrizio; Sampietro, Tiziana

    2011-01-01

    Objective: Patients with Familial Hypercholesterolemia (FH) have increased cardiovascular events. Clinical trials have demonstrated that lowering circulating lipid levels by LDL-apheresis has beneficial effects on prognosis. However, whether apheresis vascular effects in FH are related to modulation of pro- and anti-inflammatory cytokines, and whether the combination of apheresis with atorvastatin is able to enhance the putative anti-inflammatory effect of apheresis remains unknown. We examin...

  6. Diagnosis scoring for clinical identification of children with heterozygous familial hypercholesterolemia.

    Science.gov (United States)

    Benlian, Pascale; Turquet, Anne; Carrat, Fabrice; Amsellem, Sabine; Sanchez, Lydie; Briffaut, Dorothée; Girardet, Jean Philippe

    2009-04-01

    Familial hypercholesterolemia (FH) is a frequent monogenic condition characterized by progressive atherosclerosis requiring preventive therapy from childhood. In a pediatric setting, heterozygous FH (hFH) in children may not be identified from common forms of hypercholesterolemia (HC). To elaborate a clinical scoring system for the diagnosis of hFH, defined by the presence of a disease-causing mutation of the gene for the low-density lipoprotein receptor (LDLR). A total of 100 unrelated children (6 +/-3 years old, 43 boys, 57 girls) with type IIa HC (LDLC >130 mg/dL) and complete genetic testing (at loci for genes for LDLR, apolipoprotein B, proprotein convertase subtilisin-like kesin type 9, and apolipoprotein E) were selected for score elaboration. Of 60 criteria from clinical records and family questionnaires, predictors of having hFH were estimated by logistic regression analysis. Scores were validated in 38 other unrelated children with HC. Three independent predictors of hFH were identified according to the LDLR genotype (50 Microt+/50 Microt-): low-density lipoprotein cholesterol before (262 vs 178 mg/dL, P < 0.001) and after (225 vs 142 mg/dL, P < 0.001) 3 months or more of a lipid-lowering diet, combined with parental statin usage (odds ratio 6.2; 95% confidence interval 1.4-28.3; P = 0.018). High precision and accuracy of the scoring system (area under the receiver operating characteristic curve = 0.94; 95% confidence interval 0.91-0.98) were translated into 4 probability classes (definite/probable/possible/improbable hFH) with a false-negative rate of 12%. A score distinguishing hFH from common HC provides a simple tool for appropriate clinical decision and care in high-risk children.

  7. The rulB gene of plasmid pWW0 is a hotspot for the site-specific insertion of integron-like elements found in the chromosomes of environmental Pseudomonas fluorescens group bacteria.

    Science.gov (United States)

    Rhodes, Glenn; Bosma, Hester; Studholme, David; Arnold, Dawn L; Jackson, Robert W; Pickup, Roger W

    2014-08-01

    The rulAB operon of Pseudomonas spp. confers fitness traits on the host and has been suggested to be a hotspot for insertion of mobile elements that carry avirulence genes. Here, for the first time, we show that rulB on plasmid pWW0 is a hotspot for the active site-specific integration of related integron-like elements (ILEs) found in six environmental pseudomonads (strains FH1-FH6). Integration into rulB on pWW0 occurred at position 6488 generating a 3 bp direct repeat. ILEs from FH1 and FH5 were 9403 bp in length and contained eight open reading frames (ORFs), while the ILE from FH4 was 16 233 bp in length and contained 16 ORFs. In all three ILEs, the first 5.1 kb (containing ORFs 1-4) were structurally conserved and contained three predicted site-specific recombinases/integrases and a tetR homologue. Downstream of these resided ORFs of the 'variable side' with structural and sequence similarity to those encoding survival traits on the fitness enhancing plasmid pGRT1 (ILE(FH1) and ILE(FH5)) and the NR-II virulence region of genomic island PAGI-5 (ILE(FH4)). Collectively, these ILEs share features with the previously described type III protein secretion system effector ILEs and are considered important to host survival and transfer of fitness enhancing and (a)virulence genes between bacteria.

  8. Molecular characterization of Iranian patients with possible familial hypercholesterolemia.

    Science.gov (United States)

    Farrokhi, E; Shayesteh, F; Asadi Mobarakeh, S; Roghani Dehkordi, F; Ghatreh Samani, K; Hashemzadeh Chaleshtori, M

    2011-07-01

    Familial hypercholesterolemia (FH) is an autosomal dominant disorder of lipoprotein metabolism caused mainly by mutations in the low-density lipoprotein receptor (LDLR) and apolipoprotein B 100 (APOB) genes. Until now, the molecular basis of FH has been demonstrated in detail in many populations, but there is still very limited Molecular data concerning FH in Iran. The aim of this study was to characterize the LDLR and APOB gene mutations in an Iranian population. A total of 30 non-related Iranian possible FH subjects were studied. Diagnosis of FH was based on the Dutch Lipid Clinic Network diagnostic criteria. All samples were initially tested for three common APOB gene mutations including R3500Q, R3500 W and R3531C using PCR-RFLP assay. Subsequently, promoter and coding region of the LDLR gene was screened by PCR-SSCP analysis and positive results were confirmed by DNA sequencing. Four previously reported polymorphisms 1413G > A, 1725C > T, 1773T > C and 2140 + 5G > A were found in ~17% (5/30) of population studied. Moreover, no variation was found in APOB gene. Our data indicated that LDLR and APOB gene mutations have not contribution to possible FH in Iranian population studied here. However, we examined three common APOB mutations and LDLR in only 30 patients, and to determine the role of these genes in developing FH in Iran, more FH samples and populations needed to be investigated for the mutations of the related genes.

  9. Physically Protected Spread Spectrum Communications

    Science.gov (United States)

    2016-04-14

    for the FH system in those days was because of implementation issues, such as a frequency -ringing problem , which occurred whenever a frequency was...PS-TR-2016-0046 HAS BEEN REVIEWED AND IS APPROVED FOR PUBLICATION IN ACCORDANCE WITH ASSIGNED DISTRIBUTION STATEMENT. KHANH PHAM PAUL D. LEVAN...keying (MPSK) and M-ary quadrature amplitude-shift keying (MQAM) for a slow frequency hopping (FH) spread spectrum (SS) system because, recently

  10. [Femoral hernia in elderly and senile patients, peculiarities of surgical tactics].

    Science.gov (United States)

    Vorovs'kyĭ, O O

    2014-01-01

    The results of surgical treatment of 74 elderly and senile patients, suffering femoral hernia (FH), were analyzed. In 39 (52.7%) of them intestinal incarceration was noted. The most effective procedures have appeared those, which incorporate application of polypropylene implants for the femoral ring strengthening while hernioplasty performing in elderly and senile patients. Application of transabdominal preperitoneal endovideohemioplasty constitutes a perspective direction in surgical treatment of FH.

  11. Genetic testing of Korean familial hypercholesterolemia using whole-exome sequencing.

    Directory of Open Access Journals (Sweden)

    Soo Min Han

    Full Text Available Familial hypercholesterolemia (FH is a genetic disorder with an increased risk of early-onset coronary artery disease. Although some clinically diagnosed FH cases are caused by mutations in LDLR, APOB, or PCSK9, mutation detection rates and profiles can vary across ethnic groups. In this study, we aimed to provide insight into the spectrum of FH-causing mutations in Koreans. Among 136 patients referred for FH, 69 who met Simon Broome criteria with definite family history were enrolled. By whole-exome sequencing (WES analysis, we confirmed that the 3 known FH-related genes accounted for genetic causes in 23 patients (33.3%. A substantial portion of the mutations (19 of 23 patients, 82.6% resulted from 17 mutations and 2 copy number deletions in LDLR gene. Two mutations each in the APOB and PCSK9 genes were verified. Of these anomalies, two frameshift deletions in LDLR and one mutation in PCSK9 were identified as novel causative mutations. In particular, one novel mutation and copy number deletion were validated by co-segregation in their relatives. This study confirmed the utility of genetic diagnosis of FH through WES.

  12. Toxoplasma gondii profilin acts primarily to sequester G-actin while formins efficiently nucleate actin filament formation in vitro.

    Science.gov (United States)

    Skillman, Kristen M; Daher, Wassim; Ma, Christopher I; Soldati-Favre, Dominique; Sibley, L David

    2012-03-27

    Apicomplexan parasites employ gliding motility that depends on the polymerization of parasite actin filaments for host cell entry. Despite this requirement, parasite actin remains almost entirely unpolymerized at steady state; formation of filaments required for motility relies on a small repertoire of actin-binding proteins. Previous studies have shown that apicomplexan formins and profilin exhibit canonical functions on heterologous actins from higher eukaryotes; however, their biochemical properties on parasite actins are unknown. We therefore analyzed the impact of T. gondii profilin (TgPRF) and FH1-FH2 domains of two formin isoforms in T. gondii (TgFRM1 and TgFRM2) on the polymerization of T. gondii actin (TgACTI). Our findings based on in vitro assays demonstrate that TgFRM1-FH1-FH2 and TgFRM2-FH1-FH2 dramatically enhanced TgACTI polymerization in the absence of profilin, making them the sole protein factors known to initiate polymerization of this normally unstable actin. In addition, T. gondii formin domains were shown to both initiate polymerization and induce bundling of TgACTI filaments; however, they did not rely on TgPRF for these activities. In contrast, TgPRF sequestered TgACTI monomers, thus inhibiting polymerization even in the presence of formins. Collectively, these findings provide insight into the unusual control mechanisms of actin dynamics within the parasite.

  13. The molecular basis of familial hypercholesterolemia in Lebanon: spectrum of LDLR mutations and role of PCSK9 as a modifier gene.

    Science.gov (United States)

    Abifadel, Marianne; Rabès, Jean-Pierre; Jambart, Sélim; Halaby, Georges; Gannagé-Yared, Marie-Hélène; Sarkis, Antoine; Beaino, Ghada; Varret, Mathilde; Salem, Nabiha; Corbani, Sandra; Aydénian, Hermine; Junien, Claudine; Munnich, Arnold; Boileau, Catherine

    2009-07-01

    Autosomal dominant hypercholesterolemia (ADH), a major risk for coronary heart disease, is associated with mutations in the genes encoding the low-density lipoproteins receptor (LDLR), its ligand apolipoprotein B (APOB) or PCSK9 (Proprotein Convertase Subtilin Kexin 9). Familial hypercholesterolemia (FH) caused by mutation in the LDLR gene is the most frequent form of ADH. The incidence of FH is particularly high in the Lebanese population presumably as a result of a founder effect. In this study we characterize the spectrum of the mutations causing FH in Lebanon: we confirm the very high frequency of the LDLR p.Cys681X mutation that accounts for 81.5 % of the FH Lebanese probands recruited and identify other less frequent mutations in the LDLR. Finally, we show that the p.Leu21dup, an in frame insertion of one leucine to the stretch of 9 leucines in exon 1 of PCSK9, known to be associated with lower LDL-cholesterol levels in general populations, is also associated with a reduction of LDL-cholesterol levels in FH patients sharing the p.C681X mutation in the LDLR. Thus, by studying for the first time the impact of PCSK9 polymorphism on LDL-cholesterol levels of FH patients carrying a same LDLR mutation, we show that PCSK9 might constitute a modifier gene in familial hypercholesterolemia.

  14. Vascular and baroreceptor abnormalities in young males with a family history of hypertension.

    Science.gov (United States)

    Boutcher, Yati N; Park, Young J; Boutcher, Stephen H

    2009-12-01

    Vascular and baroreceptor abnormalities in 44 young males, mean age 21 years, comprising of offspring with (FH(+); n = 22) and without (FH(-); n = 22) hypertensive parents, were investigated. Peak forearm blood flow (FBF), which was defined as the highest blood flow obtained following reactive hyperaemia, was assessed using strain gauge plethysmography following 5 min of ischemia. Cardiopulmonary baroreceptor sensitivity was assessed using lower body negative pressure for 5 min at -20 mmHg and was determined by calculating change of stroke volume and forearm vascular resistance (FVR) to lower body negative pressure. Carotid baroreceptor sensitivity was assessed using neck suction at -20, -40, -60, and -80 mmHg and was calculated by dividing RR interval by systolic blood pressure. Augmentation index, a measure of wave reflection, was assessed using applanation tonometry and was calculated as the ratio of augmented pressure and pulse pressure. Peak FBF of FH(+) was 19% lower than the FH(-) (p = 0.02). Also FH(+) had 17% higher peak FVR compared to FH(-) (p = 0.04). However, there were no significant differences between groups for cardiopulmonary, carotid baroreceptor sensitivity, and augmentation index. These results suggest that peripheral vascular dysfunction appears earlier than abnormal baroreceptor sensitivity in young males with a family history of hypertension.

  15. Metabolic rate and vascular function are reduced in women with a family history of type 2 diabetes mellitus.

    Science.gov (United States)

    Olive, Jennifer L; Ballard, Kevin D; Miller, James J; Milliner, Beth A

    2008-06-01

    Metabolic and vascular abnormalities have been found in individuals with type 2 diabetes mellitus (T2D). Family history is often associated with increased risk of the development of T2D. We sought to determine if young, sedentary, insulin-sensitive individuals with a family history of T2D (FH+) have a reduced resting energy expenditure (REE) and vascular endothelial function compared with individuals who have no family history of T2D (FH-). The REE was determined in 18 FH+ individuals and 15 FH- individuals using indirect open-circuit calorimetry. Vascular endothelial function was measured via flow-mediated dilation (FMD) of the brachial artery. C-reactive protein and interleukin-6 were also measured to look at vascular inflammation. Body composition was measured via bioelectrical impedance analysis to determine fat-free mass and fat mass for each individual. Insulin resistance was calculated using the homeostasis model assessment equation and fasting insulin and glucose concentrations. Subjects (n = 42) were approximately 26 years old and had normal fasting serum insulin or glucose concentrations. The REE normalized for body weight (kilocalories per day per kilogram body weight) was significantly reduced in the FH+ women compared with FH- women (P history of T2D have reduced whole-body metabolic rate and vascular endothelial function compared with those with no family history of disease. These differences in whole-body metabolic rate and vascular endothelial function were not present in male subjects.

  16. Radiation effects on the fluoxetine hydrochloride toxicity in the presence of domestic sewage

    Energy Technology Data Exchange (ETDEWEB)

    Silva, Vanessa H. Ogihara; Borrely, Sueli I., E-mail: vanessa.ogihara@usp.br [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil); Campos, Fabio; Piveli, Roque P. [Universidade de Sao Paulo (USP), Sao Paulo, SP (Brazil). Escola Politecnica. Centro Tecnologico de Hidraulica

    2013-07-01

    The sanitation field is directly related to environmental quality and health. The improvements in wastewater treatment systems provide benefits to the environment and their population. It is clearly understood that the conventional wastewater treatment does not remove many micropollutants, including some medicinal products, and that these products can be toxic to living organisms. The goal of this research was the assessment of toxicity of fluoxetine hydrochloride (FH) as well as the irradiation application to remove FH from waters. The FH was irradiated in water solutions and also contained in domestic sewage. Both types of samples were irradiated at a Dynamitron® Electron Beam Accelerator (EBA). The Vibrio fischeri bacteria was applied as biological assay to the samples (water solution of FH; untreated sewage and the mixture of untreated sewage + FH). The efficiency was 1.44% to 26.21% less toxic after treatments. UV-Vis Spectrometry showed the degradation of FH by radiation. 2.5 kGy was a suitable dose that could be suggested for environmental application of Electron Beam Technology. (author)

  17. Familial hypercholesterolemia in primary care in Germany. Diabetes and cardiovascular risk evaluation: Targets and Essential Data for Commitment of Treatment (DETECT) study.

    Science.gov (United States)

    Schmidt, Nina; Schmidt, Burkhard; Dressel, Alexander; Gergei, Ingrid; Klotsche, Jens; Pieper, Lars; Scharnagl, Hubert; Kleber, Marcus E; März, Winfried; Lehnert, Hendrik; Pittrow, David; Stalla, Günter; Wittchen, Hans-Ulrich; Grammer, Tanja B

    2017-08-19

    Familial hypercholesterolemia (FH) is an inherited disorder of lipoprotein metabolism characterised by impaired removal of low-density lipoproteins (LDL) from the circulation, which leads to an increased risk of cardiovascular disease (CVD). This risk can be significantly lowered by early diagnosis and treatment. In Germany, reliable estimates of the prevalence of FH are lacking. We therefore examined the prevalence rate of FH in Germany in a primary care based cohort. We utilized records of 4722 participants in the DETECT study, in whom complete data on blood lipids and medical history were available. Prevalence rates were assessed using the Dutch Lipid Clinics Network (DLCN) and the US-MEDPED criteria. We stratified for gender and age. Group differences were analyzed using Chi(2) and ANOVA tests. Using the DLCN (probable or definite FH) and the US.MEDPED criteria yielded prevalence rates of 1:278 and 1:295, respectively. The established diagnostic scores used in this analysis identify different patients. In women below 50 years of age, the LDL-C concentration is lower than in men, leading to the possibility of under-diagnosing FH in this group because women under the age of 50 are less likely to reach a higher DLCN-Score. FH has a higher than expected prevalence in Germany. Clinical diagnostic algorithms may not be concordant. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Structural determinants of host specificity of complement Factor H recruitment by Streptococcus pneumoniae.

    Science.gov (United States)

    Achila, David; Liu, Aizhuo; Banerjee, Rahul; Li, Yue; Martinez-Hackert, Erik; Zhang, Jing-Ren; Yan, Honggao

    2015-01-15

    Many human pathogens have strict host specificity, which affects not only their epidemiology but also the development of animal models and vaccines. Complement Factor H (FH) is recruited to pneumococcal cell surface in a human-specific manner via the N-terminal domain of the pneumococcal protein virulence factor choline-binding protein A (CbpAN). FH recruitment enables Streptococcus pneumoniae to evade surveillance by human complement system and contributes to pneumococcal host specificity. The molecular determinants of host specificity of complement evasion are unknown. In the present study, we show that a single human FH (hFH) domain is sufficient for tight binding of CbpAN, present the crystal structure of the complex and identify the critical structural determinants for host-specific FH recruitment. The results offer new approaches to the development of better animal models for pneumococcal infection and redesign of the virulence factor for pneumococcal vaccine development and reveal how FH recruitment can serve as a mechanism for both pneumococcal complement evasion and adherence.

  19. Association of Peripheral Arterial and Cardiovascular Diseases in Familial Hypercholesterolemia

    Directory of Open Access Journals (Sweden)

    Carolina Pereira

    2014-08-01

    Full Text Available Background: Familial hypercholesterolemia (FH is an autosomal dominant genetic disease characterized by an elevation in the serum levels of total cholesterol and of low-density lipoproteins (LDL- c. Known to be closely related to the atherosclerotic process, FH can determine the development of early obstructive lesions in different arterial beds. In this context, FH has also been proposed to be a risk factor for peripheral arterial disease (PAD. Objective: This observational cross-sectional study assessed the association of PAD with other manifestations of cardiovascular disease (CVD, such as coronary artery and cerebrovascular disease, in patients with heterozygous FH. Methods: The diagnosis of PAD was established by ankle-brachial index (ABI values ≤ 0.90. This study assessed 202 patients (35% of men with heterozygous FH (90.6% with LDL receptor mutations, mean age of 51 ± 14 years and total cholesterol levels of 342 ± 86 mg /dL. Results: The prevalences of PAD and previous CVD were 17% and 28.2 %, respectively. On multivariate analysis, an independent association between CVD and the diagnosis of PAD was observed (OR = 2.50; 95% CI: 1.004 - 6.230; p = 0.049. Conclusion: Systematic screening for PAD by use of ABI is feasible to assess patients with FH, and it might indicate an increased risk for CVD. However, further studies are required to determine the role of ABI as a tool to assess the cardiovascular risk of those patients.

  20. Two Years after Molecular Diagnosis of Familial Hypercholesterolemia: Majority on Cholesterol-Lowering Treatment but a Minority Reaches Treatment Goal

    Science.gov (United States)

    Huijgen, Roeland; Kindt, Iris; Verhoeven, Sjoerd B. J.; Sijbrands, Eric J. G.; Vissers, Maud N.; Kastelein, John J. P.; Hutten, Barbara A.

    2010-01-01

    Background The risk of premature cardiovascular disease in patients with familial hypercholesterolemia (FH) can be profoundly reduced by cholesterol-lowering therapy, and current guidelines for FH advocate ambitious low-density lipoprotein cholesterol (LDL-C) goals. In the present study, we determined whether these goals are reflected in current clinical practice once FH has been diagnosed. Methodology/Principal Findings In 2008, we sent questionnaires to all subjects (aged 18–65 years) who were molecularly diagnosed with FH in the year 2006 through the screening program in the Netherlands. Of these 1062 subjects, 781 completed the questionnaire (46% males; mean age: 42±12 years; mean LDL-C at molecular diagnosis (baseline): 4.1±1.3 mmol/L). The number of persons that used cholesterol-lowering therapy increased from 397 (51%) at baseline to 636 (81%) after diagnosis. Mean treated LDL-C levels decreased significantly to 3.2±1.1 mmol/L two years after diagnosis. Only 22% achieved the LDL-C target level of ≤2.5 mmol/L. Conclusions/Significance The proportion of patients using cholesterol-lowering medication was significantly increased after FH diagnosis through genetic cascade screening. The attained LDL-C levels were lower than those reported in previous surveys on medication use in FH, which could reflect the effect of more stringent lipid target levels. However, only a minority of the medication users reached the LDL-C target. PMID:20169164

  1. Association of Peripheral Arterial and Cardiovascular Diseases in Familial Hypercholesterolemia

    Energy Technology Data Exchange (ETDEWEB)

    Pereira, Carolina [Instituto do Coração HCFMUSP, São Paulo, SP (Brazil); Hospital Israelita Albert Einstein, São Paulo, SP (Brazil); Miname, Marcio [Instituto do Coração HCFMUSP, São Paulo, SP (Brazil); Makdisse, Marcia [Hospital Israelita Albert Einstein, São Paulo, SP (Brazil); Kalil, Roberto Filho [Instituto do Coração HCFMUSP, São Paulo, SP (Brazil); Santos, Raul D., E-mail: rdsf@cardiol.br [Instituto do Coração HCFMUSP, São Paulo, SP (Brazil); Hospital Israelita Albert Einstein, São Paulo, SP (Brazil)

    2014-08-15

    Familial hypercholesterolemia (FH) is an autosomal dominant genetic disease characterized by an elevation in the serum levels of total cholesterol and of low-density lipoproteins (LDL- c). Known to be closely related to the atherosclerotic process, FH can determine the development of early obstructive lesions in different arterial beds. In this context, FH has also been proposed to be a risk factor for peripheral arterial disease (PAD). This observational cross-sectional study assessed the association of PAD with other manifestations of cardiovascular disease (CVD), such as coronary artery and cerebrovascular disease, in patients with heterozygous FH. The diagnosis of PAD was established by ankle-brachial index (ABI) values ≤ 0.90. This study assessed 202 patients (35% of men) with heterozygous FH (90.6% with LDL receptor mutations), mean age of 51 ± 14 years and total cholesterol levels of 342 ± 86 mg /dL. The prevalences of PAD and previous CVD were 17% and 28.2 %, respectively. On multivariate analysis, an independent association between CVD and the diagnosis of PAD was observed (OR = 2.50; 95% CI: 1.004 - 6.230; p = 0.049). Systematic screening for PAD by use of ABI is feasible to assess patients with FH, and it might indicate an increased risk for CVD. However, further studies are required to determine the role of ABI as a tool to assess the cardiovascular risk of those patients.

  2. Common Patterns of Congenital Lower Extremity Shortening: Diagnosis, Classification, and Follow-up.

    Science.gov (United States)

    Bedoya, Maria A; Chauvin, Nancy A; Jaramillo, Diego; Davidson, Richard; Horn, B David; Ho-Fung, Victor

    2015-01-01

    Congenital lower limb shortening is a group of relatively rare, heterogeneous disorders. Proximal focal femoral deficiency (PFFD) and fibular hemimelia (FH) are the most common pathologic entities in this disease spectrum. PFFD is characterized by variable degrees of shortening or absence of the femoral head, with associated dysplasia of the acetabulum and femoral shaft. FH ranges from mild hypoplasia to complete absence of the fibula with variable shortening of the tibia. The development of the lower limb requires complex and precise gene interactions. Although the etiologies of PFFD and FH remain unknown, there is a strong association between the two disorders. Associated congenital defects in the lower extremity are found in more than 50% of patients with PFFD, ipsilateral FH being the most common. FH also has a strong association with shortening and bowing of the tibia and with foot deformities such as absence of the lateral rays of the foot. Early diagnosis and radiologic classification of these abnormalities are imperative for appropriate management and surgical planning. Plain radiography remains the main diagnostic imaging modality for both PFFD and FH, and appropriate description of the osseous abnormalities seen on radiographs allows accurate classification, prognostic evaluation, and surgical planning. Minor malformations may commonly be misdiagnosed.

  3. The Plasmodium falciparum blood stages acquire factor H family proteins to evade destruction by human complement.

    Science.gov (United States)

    Rosa, Thiago F A; Flammersfeld, Ansgar; Ngwa, Che J; Kiesow, Meike; Fischer, Rainer; Zipfel, Peter F; Skerka, Christine; Pradel, Gabriele

    2016-04-01

    The acquisition of regulatory proteins is a means of blood-borne pathogens to avoid destruction by the human complement. We recently showed that the gametes of the human malaria parasite Plasmodium falciparum bind factor H (FH) from the blood meal of the mosquito vector to assure successful sexual reproduction, which takes places in the mosquito midgut. While these findings provided a first glimpse of a complex mechanism used by Plasmodium to control the host immune attack, it is hitherto not known, how the pathogenic blood stages of the malaria parasite evade destruction by the human complement. We now show that the human complement system represents a severe threat for the replicating blood stages, particularly for the reinvading merozoites, with complement factor C3b accumulating on the surfaces of the intraerythrocytic schizonts as well as of free merozoites. C3b accumulation initiates terminal complement complex formation, in consequence resulting in blood stage lysis. To inactivate C3b, the parasites bind FH as well as related proteins FHL-1 and CFHR-1 to their surface, and FH binding is trypsin-resistant. Schizonts acquire FH via two contact sites, which involve CCP modules 5 and 20. Blockage of FH-mediated protection via anti-FH antibodies results in significantly impaired blood stage replication, pointing to the plasmodial complement evasion machinery as a promising malaria vaccine target.

  4. Recruitment of Factor H as a Novel Complement Evasion Strategy for Blood-Stage Plasmodium falciparum Infection.

    Science.gov (United States)

    Kennedy, Alexander T; Schmidt, Christoph Q; Thompson, Jennifer K; Weiss, Greta E; Taechalertpaisarn, Tana; Gilson, Paul R; Barlow, Paul N; Crabb, Brendan S; Cowman, Alan F; Tham, Wai-Hong

    2016-02-01

    The human complement system is the frontline defense mechanism against invading pathogens. The coexistence of humans and microbes throughout evolution has produced ingenious molecular mechanisms by which microorganisms escape complement attack. A common evasion strategy used by diverse pathogens is the hijacking of soluble human complement regulators to their surfaces to afford protection from complement activation. One such host regulator is factor H (FH), which acts as a negative regulator of complement to protect host tissues from aberrant complement activation. In this report, we show that Plasmodium falciparum merozoites, the invasive form of the malaria parasites, actively recruit FH and its alternative spliced form FH-like protein 1 when exposed to human serum. We have mapped the binding site in FH that recognizes merozoites and identified Pf92, a member of the six-cysteine family of Plasmodium surface proteins, as its direct interaction partner. When bound to merozoites, FH retains cofactor activity, a key function that allows it to downregulate the alternative pathway of complement. In P. falciparum parasites that lack Pf92, we observed changes in the pattern of C3b cleavage that are consistent with decreased regulation of complement activation. These results also show that recruitment of FH affords P. falciparum merozoites protection from complement-mediated lysis. Our study provides new insights on mechanisms of immune evasion of malaria parasites and highlights the important function of surface coat proteins in the interplay between complement regulation and successful infection of the host.

  5. From gas-phase to liquid-water chemical reactions: the fluorine atom plus water trimer system.

    Science.gov (United States)

    Li, Guoliang; Li, Qian-Shu; Xie, Yaoming; Schaefer, Henry F

    2015-09-14

    The potential energy profile for the F+(H2 O)3 →HF+(H2 O)2 OH reaction has been investigated using the "gold standard" CCSD(T) method with correlation-consistent basis sets up to cc-pVQZ. Four different reaction pathways have been found and these are related, both geometrically and energetically. The entrance complexes F⋅⋅⋅(H2 O)3 for all four reaction pathways are found lying ca. 7 kcal mol(-1) below the separated reactants F+(H2 O)3 . The four reaction barriers on their respective reaction coordinates lie ca. 4 kcal mol(-1) below the reactants. There are also corresponding exit complexes HF⋅⋅⋅(H2 O)2 OH, lying about 13 kcal mol(-1) below the separated products HF+(H2 O)2 OH. Compared with analogous F+(H2 O)2 and F+H2 O reactions, the F+(H2 O)3 reaction is somewhat similar to the former but qualitatively different from the latter. It may be reasonable to predict that the reactions between atomic fluorine and water tetramer (or even larger water clusters) may be similar to the F+(H2 O)3 reaction.

  6. A targeted inhibitor of the complement alternative pathway reduces RPE injury and angiogenesis in models of age-related macular degeneration.

    Science.gov (United States)

    Rohrer, Bärbel; Long, Qin; Coughlin, Beth; Renner, Brandon; Huang, Yuxiang; Kunchithapautham, Kannan; Ferreira, Viviana P; Pangburn, Michael K; Gilkeson, Gary S; Thurman, Joshua M; Tomlinson, Stephen; Holers, V Michael

    2010-01-01

    Genetic variations in complement factor H (fH), an inhibitor of the complement alternative pathway (CAP), and oxidative stress are associated with age-related macular degeneration (AMD). Recently, novel complement therapeutics have been created with the capacity to be "targeted" to sites of complement activation. One example is our recombinant form of fH, CR2-fH, which consists of the N-terminus of mouse fH that contains the CAP-inhibitory domain, linked to a complement receptor 2 (CR2) targeting fragment that binds complement activation products. CR2-fH was investigated in vivo in the mouse model of choroidal neovascularization (CNV) and in vitro in oxidatively stressed RPE cell monolayers. RPE deterioration and CNV development were found to require CAP activation, and specific CAP inhibition by CR2-fH reduced the loss of RPE integrity and angiogenesis in CNV. In both the in vivo and in vitro paradigm of RPE damage, a model requiring molecular events known to be involved in AMD, complement-dependent VEGF production, was confirmed. These data may open new avenues for AMD treatment strategies.

  7. Brain atrophy rates in first degree relatives at risk for Alzheimer's.

    Science.gov (United States)

    Lampert, Erika J; Roy Choudhury, Kingshuk; Hostage, Christopher A; Rathakrishnan, Bharath; Weiner, Michael; Petrella, Jeffrey R; Doraiswamy, P Murali

    2014-01-01

    A positive family history (FH) raises the risk for late-onset Alzheimer's disease though, other than the known risk conferred by apolipoprotein ε4 (ApoE4), much of the genetic variance remains unexplained. We examined the effect of family history on longitudinal regional brain atrophy rates in 184 subjects (42% FH+, mean age 79.9) with mild cognitive impairment (MCI) enrolled in a national biomarker study. An automated image analysis method was applied to T1-weighted MR images to measure atrophy rates for 20 cortical and subcortical regions. Mixed-effects linear regression models incorporating repeated-measures to control for within-subject variation over multiple time points tested the effect of FH over a follow-up of up to 48 months. Most of the 20 regions showed significant atrophy over time. Adjusting for age and gender, subjects with a positive FH had greater atrophy of the amygdala (p atrophy rates was numerically greater in ε3 homozygotes than in E4 carriers, but this difference was not significant. FH+ subjects had numerically greater 4-year cognitive decline and conversion rates than FH- subjects but the difference was not statistically significant after adjusting for ApoE and other variables. We conclude that a positive family history of AD may influence cortical and temporal lobe atrophy in subjects with mild cognitive impairment, but it does not have a significant additional effect beyond the known effect of the E4 genotype.

  8. Genetically engineered fusion of MAP-1 and factor H domains 1-5 generates a potent dual upstream inhibitor of both the lectin and alternative complement pathways.

    Science.gov (United States)

    Nordmaj, Mie Anemone; Munthe-Fog, Lea; Hein, Estrid; Skjoedt, Mikkel-Ole; Garred, Peter

    2015-12-01

    Inhibition of the complement cascade has emerged as an option for treatment of a range of diseases. Mannose-binding lectin/ficolin/collectin-associated protein (MAP-1) is a pattern recognition molecule (PRM)-associated inhibitor of the lectin pathway. The central regulator of the alternative pathway (AP) is complement factor H (FH). Our aim was to design a dual upstream inhibitor of both human lectin and APs by fusing MAP-1 with a part of FH. There were 2 different recombinant chimeric proteins comprising full-length human MAP-1 and the first 5 N-terminal domains of human FH designed. The FH domains were orientated either in the N- or C-terminal part of MAP-1. The complement inhibition potential in human serum was assessed. Both chimeric constructs displayed the characteristics of the native molecules and bound to the PRMs with an EC50 of ∼ 2 nM. However, when added to serum diluted 1:4 in a solid-phase functional assay, only the first 5 N-terminal domains of complement FH fused to the C-terminal part of full-length MAP-1 chimeric construct were able to combine inhibition of lectin and AP activation with an half maximal inhibitory concentration of ∼ 100 and 20 nM, respectively. No effect was seen on the classical pathway. Fusion of MAP-1 with FH domains represents a novel therapeutic approach for selective targeting upstream and central complement activation at sites of inflammation.

  9. HDL abnormalities in familial hypercholesterolemia: Focus on biological functions.

    Science.gov (United States)

    Ganjali, Shiva; Momtazi, Amir Abbas; Banach, Maciej; Kovanen, Petri T; Stein, Evan A; Sahebkar, Amirhossein

    2017-07-01

    Although a selective strong elevation in the plasma level of low-density lipoprotein (LDL) cholesterol is the hallmark of familial hypercholesterolemia (FH), also other plasma lipoprotein and lipid subspecies are changed in these patients. Several studies in FH patients have pointed to the qualitative abnormalities of high-density lipoprotein (HDL) particles, including their triglyceride and sphingomyelin enrichment, reduced capacity to promote cholesterol efflux from macrophages, impaired anti-inflammatory and anti-oxidant activities, and reduced plasma levels of miRs regulating HDL-dependent cholesterol efflux from macrophage foam cells, typical of atherosclerotic lesions. Thus, accurate understanding of HDL functionality and its disturbances in FH may serve a better estimation of the prognosis and also provide additional clues when searching for novel therapeutic choices in this disease. In spite of such a potential promise, there has been no prior comprehensive review focusing on indices of HDL function in FH patients. In the present review, we aim to fulfill this gap by identifying measures of HDL function that are impaired in FH, and by providing a concise summary on the impact of different lipid-modifying therapies on HDL functionality in FH. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Shiga toxin activates complement and binds factor H: evidence for an active role of complement in hemolytic uremic syndrome.

    Science.gov (United States)

    Orth, Dorothea; Khan, Abdul Basit; Naim, Asma; Grif, Katharina; Brockmeyer, Jens; Karch, Helge; Joannidis, Michael; Clark, Simon J; Day, Anthony J; Fidanzi, Sonja; Stoiber, Heribert; Dierich, Manfred P; Zimmerhackl, Lothar B; Würzner, Reinhard

    2009-05-15

    Infections with enterohemorrhagic Escherichia coli (EHEC) are a major cause of hemolytic uremic syndrome (HUS). Shiga toxins (Stxs), especially Stx2, are believed to represent major virulence factors of EHEC, contributing to HUS pathogenesis. Beside EHEC-associated HUS, there are hereditary atypical forms of HUS, which are mostly caused by mutations of complement regulators. The aim of the present study was to investigate whether or not complement is also involved in the pathogenesis of EHEC-induced typical HUS, by being activated either directly or indirectly by involvement of its inhibitors. Purified Stx2 markedly activated complement via the alternative pathway and was found to bind to factor H (FH), however, only when it was active. No apparent cleavage or destruction of FH was visible, and cofactor activity in fluid phase was unaffected, but clearly delayed for surface-attached FH, where it is essential for host cell protection. Binding studies using FH constructs revealed that Stx2 binds to short consensus repeats (SCRs) 6-8 and SCRs18-20, but not to SCRs16-17, i.e., to regions involved in the surface recognition function of FH. In conclusion, complement, and in particular FH, not only plays an important role in atypical HUS, but most probably also in EHEC-induced HUS.

  11. Addition of a novel, protective family history category allows better profiling of cardiovascular risk and atherosclerotic burden in the general population. The Asklepios Study.

    Science.gov (United States)

    Van daele, Caroline M; De Meyer, Tim; De Buyzere, Marc L; Gillebert, Thierry C; Denil, Simon L I J; Bekaert, Sofie; Chirinos, Julio A; Segers, Patrick; De Backer, Guy G; De Bacquer, Dirk; Rietzschel, Ernst R

    2013-01-01

    Whereas the importance of family history (FH) is widely recognized in cardiovascular risk assessment, its full potential could be underutilized, when applied with its current simple guidelines-based definition (cFH): presence of premature cardiovascular disease (CVD) in a first-degree relative. We tested the added value of a new, extended family history definition (eFH), also taking into account later onset of disease, second-degree relatives and number of affected relatives, on profiling cardiovascular risk and atherosclerotic burden in the general population. Longitudinal population study. Random, representative population sample from Erpe-Mere and Nieuwerkerken (Belgium, primary care). 2524 male/female volunteers, aged 35-55 years, free from overt CVD. Subjects were extensively phenotyped including presence of atherosclerosis (ultrasound) and a newly developed FH questionnaire (4 generations). Compared to cFH, eFH was superior in predicting an adverse risk profile (glycemic state, elevated blood pressure, lipid abnormalities, presence of metabolic syndrome components) and presence of atherosclerosis (all age & sex-adjusted pprofiling cardiovascular risk and atherosclerotic burden in the general population. There remain clear opportunities to refine and increase the performance and informational content of this simple, readily-available inexpensive tool.

  12. [Expert consensus on the detection and clinical management of familial hypercholesterolemia].

    Science.gov (United States)

    Masana, Lluís; Civeira, Fernando; Pedro-Botet, Juan; de Castro, Isabel; Pocoví, Miguel; Plana, Núria; Mateo-Gallego, Rocío; Jarauta, Estíbaliz; Pedragosa, Àngels

    2013-01-01

    Familial hypercholesterolemia (FH) is one of the most common and severe genetic diseases, causing disabilities and premature death to those who suffer it. Lipid-lowering therapy substantially improves the prognosis of FH patients and, therefore, appropriate pharmacological treatment is of the utmost importance. The Spanish Society of Arteriosclerosis (SEA) has always been a pioneer in the diagnosis and treatment of FH. Since its inception, FH has been one of the main areas of clinical and scientific interest, mainly for Lipids Units of the SEA, where most patients with this pathology are referred in Spain. This document arises from the willingness of our society to update the scientific knowledge on this subject and to provide physicians with clear clinical guidelines regarding diagnosis and treatment of FH. These guidelines can be summarized in two main aspects: early diagnosis of the disease and a rapid normalization of LDLcholesterol. In the coming years, health providers should accomplish that the majority of patients with FH are aware of their diagnosis and that adequate treatment is provided. Copyright © 2013 Elsevier España, S.L. and SEA. All rights reserved.

  13. Effectiveness of Geoelectrical Resistivity Surveys for the Detection of a Debris Flow Causative Water Conducting Zone at KM 9, Gap-Fraser’s Hill Road (FT 148, Fraser’s Hill, Pahang, Malaysia

    Directory of Open Access Journals (Sweden)

    Mohamad Anuri Ghazali

    2013-01-01

    Full Text Available This study reports the findings of resistivity surveys which were conducted at the initiation area of debris flow at KM 9, Fraser’s Hill Gap road (FT148. The study involves three slope parallel survey lines and two lines perpendicular to the slope face. The parallel lines are FH01, FH02, and FH03, while the lines FH04 and FH05 are perpendicular. A granite body was detected at the central part of the east line and is nearest to the ground surface along FH02. The existence of low resistivity zones within the granite body is interpreted as highly fractured, water conducting zones. These zones are continuous as they have been detected in both the east-west as well as the north-south lines. The residual soil layer is relatively thin at zones where weathered granite dominates the slope face of the failure mass. The weak layer is relatively thick with an estimated thickness of 80 m and water flow occurs at the base of it. The high water flow recorded from the horizontal drains further supports the possible existence of these highly fractured, water conducting zones located within the granite. The shallow fractured granite is virtually “floating” above the water saturated zone and therefore is considered unstable.

  14. Amine-synthesizing enzyme N-substituted formamide deformylase: Screening, purification, characterization, and gene cloning

    OpenAIRE

    Fukatsu, Hiroshi; Hashimoto, Yoshiteru; Goda, Masahiko; Higashibata, Hiroki; Kobayashi, Michihiko

    2004-01-01

    N-substituted formamide was produced through the hydration of an isonitrile by isonitrile hydratase in the isonitrile metabolism. The former compound was further degraded by a microorganism, strain F164, which was isolated from soil through an acclimatization culture. The N-substituted formamide-degrading microorganism was identified as Arthrobacter pascens. The microbial degradation was found to proceed through an enzymatic reaction, the N-substituted formamide being hydrolyzed to yield the ...

  15. 3-Methylglutaconic aciduria—lessons from 50 genes and 977 patients

    DEFF Research Database (Denmark)

    Wortmann, Saskia B; Kluijtmans, Leo A J; Rodenburg, Richard J;

    2013-01-01

    Elevated urinary excretion of 3-methylglutaconic acid is considered rare in patients suspected of a metabolic disorder. In 3-methylglutaconyl-CoA hydratase deficiency (mutations in AUH), it derives from leucine degradation. In all other disorders with 3-methylglutaconic aciduria the origin...... with 3-methylglutaconic aciduria (e.g. organic acidurias, urea cycle disorders, haematological and neuromuscular disorders). In the patient cohort with genetically proven mitochondrial disorders 11 % presented 3-methylglutaconic aciduria. It was more frequently seen in ATPase related disorders...

  16. Reactions of Cg10062, a cis-3-Chloroacrylic Acid Dehalogenase Homologue, with Acetylene and Allene Substrates: Evidence for a Hydration-Dependent Decarboxylation.

    Science.gov (United States)

    Huddleston, Jamison P; Johnson, William H; Schroeder, Gottfried K; Whitman, Christian P

    2015-05-19

    Cg10062 is a cis-3-chloroacrylic acid dehalogenase (cis-CaaD) homologue from Corynebacterium glutamicum with an unknown function and an uninformative genomic context. It shares 53% pairwise sequence similarity with cis-CaaD including the six active site amino acids (Pro-1, His-28, Arg-70, Arg-73, Tyr-103, and Glu-114) that are critical for cis-CaaD activity. However, Cg10062 is a poor cis-CaaD: it lacks catalytic efficiency and isomer specificity. Two acetylene compounds (propiolate and 2-butynoate) and an allene compound, 2,3-butadienoate, were investigated as potential substrates. Cg10062 functions as a hydratase/decarboxylase using propiolate as well as the cis-3-chloro- and 3-bromoacrylates, generating mixtures of malonate semialdehyde and acetaldehyde. The two activities occur sequentially at the active site using the initial substrate. With 2,3-butadienoate and 2-butynoate, Cg10062 functions as a hydratase and converts both to acetoacetate. Mutations of the proposed water-activating residues (E114Q, E114D, and Y103F) have a range of consequences from a reduction in wild type activity to a switch of activities (i.e., hydratase into a hydratase/decarboxylase or vice versa). The intermediates for the hydration and decarboxylation products can be trapped as covalent adducts to Pro-1 when NaCNBH3 is incubated with the E114D mutant and 2,3-butadienoate or 2-butynoate, and the Y103F mutant and 2-butynoate. Three mechanisms are presented to explain these findings. One mechanism involves the direct attack of water on the substrate, whereas the other two mechanisms use covalent catalysis in which a covalent bond forms between Pro-1 and the hydration product or the substrate. The strengths and weaknesses of the mechanisms and the implications for Cg10062 function are discussed.

  17. Treatment-Induced Autophagy Associated with Tumor Dormancy and Relapse

    Science.gov (United States)

    2015-07-01

    Gene, 245, 193–201. 375. Owen, O.E. et al. (2002) The key role of anaplerosis and cataplerosis for citric acid cycle function. J. Biol. Chem., 277...nearly every enzyme in glycolysis, in the tricarboxylic acid cycle , in the urea cycle , in gluconeogenesis and in fatty acid and glycogen metabolism...the tricarboxylic acid cycle , such as fumarate hydratase, succinate dehydrogenase and isocitrate dehydrogenase, play crucial roles in oxidative

  18. Formation, stability, and solubility of metal oxide nanoparticles: Surface entropy, enthalpy, and free energy of ferrihydrite

    Science.gov (United States)

    Hiemstra, Tjisse

    2015-06-01

    Ferrihydrite (Fh) is an excellent model for understanding nanoparticle behavior in general. Moreover, Fh is one of the most important Fe (hydr) oxides in nature. Fh particles can be extremely small leading to a very high reactive surface area that changes its chemical potential, strongly affecting the solubility, nucleation, and stability. These characteristics can be coupled to the interfacial Gibbs free energy, being γ = 0.186 ± 0.01 J m-2 for Fh. The surface free energy has a relatively large contribution of surface entropy (-TSsurf = +0.079 ± 0.01 J m-2). The surface entropy is primarily related to the formation of surface groups by chemisorption of water (-17.1 J mol-1 K-1), for Fh equivalent with +0.064 ± 0.002 J m-2 at a surface loading NH2O = 12.6 μmol m-2. The entropy contribution of physisorbed water has been estimated by analyzing, as model, the surface enthalpy, entropy, and Gibbs free energy of the principal interfaces of H2O, i.e. ice-water-gas. It is about 20% of the contribution of chemisorbed water. The surface enthalpy of Fh is exceptionally low (Hsurf = +0.107 ± 0.01 J m-2), which can be explained by surface depletion (SD) of relatively unstable Fe polyhedra, or similarly, by additional surface loading of the non-depleted mineral core with specific Fe polyhedra for stabilization. The experimental enthalpy of Fh formation varies linearly with the surface area and correctly predicts the enthalpy value for the mineral core (-405.2 ± 1.2 kJ mol FeO3/2), being similar to the literature value for Fh as virtual bulk material (-406.7 ± 1.5 kJ mol FeO3/2) obtained with MO/DFT computations. The thermochemical quantities of the mineral core and surface are essentially the same for the entire range of Fh samples, in line with the SD model. The solubility of Fh suspensions as a whole may differ from the behavior of individual particles due to polydispersity. For 2-line Fh, the overall solubility is log Kso ∼ -38.5 ± 0.1 and for prolongedly aged 6

  19. Acetylene as fast food: Implications for development of life on anoxic primordial earth and in the outer solar system

    Science.gov (United States)

    Oremland, R.S.; Voytek, M.A.

    2008-01-01

    Acetylene occurs, by photolysis of methane, in the atmospheres of jovian planets and Titan. In contrast, acetylene is only a trace component of Earth's current atmosphere. Nonetheless, a methane-rich atmosphere has been hypothesized for early Earth; this atmosphere would also have been rich in acetylene. This poses a paradox, because acetylene is a potent inhibitor of many key anaerobic microbial processes, including methanogenesis, anaerobic methane oxidation, nitrogen fixation, and hydrogen oxidation. Fermentation of acetylene was discovered 25 years ago, and Pelobacter acetylenicus was shown to grow on acetylene by virtue of acetylene hydratase, which results in the formation of acetaldehyde. Acetaldehyde subsequently dismutates to ethanol and acetate (plus some hydrogen). However, acetylene hydratase is specific for acetylene and does not react with any analogous compounds. We hypothesize that microbes with acetylene hydratase played a key role in the evolution of Earth's early biosphere by exploiting an available source of carbon from the atmosphere and in so doing formed protective niches that allowed for other microbial processes to flourish. Furthermore, the presence of acetylene in the atmosphere of a planet or planetoid could possibly represent evidence for an extraterrestrial anaerobic ecosystem. ?? Mary Ann Liebert, Inc.

  20. Isolation, identification and characterization of Bacillus subtilis ZJB-063, a versatile nitrile-converting bacterium.

    Science.gov (United States)

    Zheng, Yu-Guo; Chen, Jing; Liu, Zhi-Qiang; Wu, Ming-Huo; Xing, Liang-Ying; Shen, Yin-Chu

    2008-01-01

    Strain ZJB-063, a versatile nitrile-amide-degrading strain, was newly isolated from soil in this study. Based on morphology, physiological tests, Biolog and the 16S rDNA sequence, strain ZJB-063 was identified as Bacillus subtilis. ZJB-063 exhibited nitrilase activity without addition of inducers, indicating that the nitrilase in B. subtilis ZJB-063 is constitutive. Interestingly, the strain exhibited nitrile hydratase and amidase activity with the addition of epsilon-caprolactam. Moreover, the substrate spectrum altered with the alteration of enzyme systems due to the addition of epsilon-caprolactam. The constitutive nitrilase was highly specific for arylacetonitriles, while the nitrile hydratase/amidase in B. subtilis ZJB-063 could not only hydrolyze arylacetonitriles but also other nitriles including some aliphatic nitriles and heterocyclic nitriles. Despite comparatively low activity, the amidase of hydratase/amidase system was effective in converting amides to acids. The versatility of this strain in the hydrolysis of various nitriles and amides makes it a potential biocatalyst in organic synthesis.