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Sample records for adh null mutations

  1. DNA sequence analysis of X-ray induced Adh null mutations in Drosophila melanogaster

    SciTech Connect

    Mahmoud, J.; Fossett, N.G.; Arbour-Reily, P.; McDaniel, M.; Tucker, A.; Chang, S.H.; Lee, W.R. )

    1991-01-01

    The mutational spectrum for 28 X-ray induced mutations and 2 spontaneous mutations, previously determined by genetic and cytogenetic methods, consisted of 20 multilocus deficiencies (19 induced and 1 spontaneous) and 10 intragenic mutations (9 induced and 1 spontaneous). One of the X-ray induced intragenic mutations was lost, and another was determined to be a recombinant with the allele used in the recovery scheme. The DNA sequence of two X-ray induced intragenic mutations has been published. This paper reports the results of DNA sequence analysis of the remaining intragenic mutations and a summary of the X-ray induced mutational spectrum. The combination of DNA sequence analysis with genetic complementation analysis shows a continuous distribution in size of deletions rather than two different types of mutations consisting of deletions and point mutations'. Sequencing is shown to be essential for detecting intragenic deletions. Of particular importance for future studies is the observation that all of the intragenic deletions consist of a direct repeat adjacent to the breakpoint with one of the repeats deleted.

  2. Increased Variation in Adh Enzyme Activity in Drosophila Mutation-Accumulation Experiment Is Not Due to Transposable Elements at the Adh Structural Gene

    PubMed Central

    Aquadro, C. F.; Tachida, H.; Langley, C. H.; Harada, K.; Mukai, T.

    1990-01-01

    We present here a molecular analysis of the region surrounding the structural gene encoding alcohol dehydrogenase (Adh) in 47 lines of Drosophila melanogaster that have each accumulated mutations for 300 generations. While these lines show a significant increase in variation of alcohol dehydrogenase enzyme activity compared to control lines, we found no restriction map variation in a 13-kb region including the complete Adh structural gene and roughly 5 kb of both 5' and 3' sequences. Thus, the rapid accumulation of ADH activity variation after 28,200 allele generations does not appear to have been due to the mobilization of transposable elements into or out of the Adh structural gene region. PMID:1963870

  3. Progranulin null mutations in both sporadic and familial frontotemporal dementia.

    PubMed

    Le Ber, Isabelle; van der Zee, Julie; Hannequin, Didier; Gijselinck, Ilse; Campion, Dominique; Puel, Michèle; Laquerrière, Annie; De Pooter, Tim; Camuzat, Agnès; Van den Broeck, Marleen; Dubois, Bruno; Sellal, François; Lacomblez, Lucette; Vercelletto, Martine; Thomas-Antérion, Catherine; Michel, Bernard-François; Golfier, Véronique; Didic, Mira; Salachas, François; Duyckaerts, Charles; Cruts, Marc; Verpillat, Patrice; Van Broeckhoven, Christine; Brice, Alexis

    2007-09-01

    Frontotemporal dementia (FTD) is the second most frequent type of neurodegenerative dementias. Mutations in the progranulin gene (GRN, PGRN) were recently identified in FTDU-17, an FTD subtype characterized by ubiquitin-immunoreactive inclusions and linkage to chromosome 17q21. We looked for PGRN mutations in a large series of 210 FTD patients (52 familial, 158 sporadic) to accurately evaluate the frequency of PGRN mutations in both sporadic and familial FTD, and FTD with associated motoneuron disease (FTD-MND), as well as to study the clinical phenotype of patients with a PGRN mutation. We identified nine novel PGRN null mutations in 10 index patients. The relative frequency of PGRN null mutations in FTD was 4.8% (10/210) and 12.8% (5/39) in pure familial forms. Interestingly, 5/158 (3.2%) apparently sporadic FTD patients carried a PGRN mutation, suggesting the possibility of de novo mutations or incomplete penetrance. In contrast, none of the 43 patients with FTD-MND had PGRN mutations, supporting that FTDU-17 and FTD-MND are genetically distinct. The clinical phenotype of PGRN mutation carriers was particular because of the wide range in onset age and the frequent occurrence of early apraxia (50%), visual hallucinations (30%), and parkinsonism (30%) during the course of the disease. This study supports that PGRN null mutations represent a more frequent cause of FTD than MAPT mutations (4.8% vs. 2.9%) but are not responsible for FTD-MND. It also demonstrates that half of the patients with a PGRN mutation in our series had no apparent family history of dementia. Taking this into account, genetic testing should be now considered more systematically, even in patients without obvious familial history of FTD. PMID:17436289

  4. Mechanisms for dominance: Adh heterodimer formation in heterozygotes between ENU or x-ray induced null alleles and normal alleles in drosophila melanogaster

    SciTech Connect

    Jiang, J.C.; Lee, W.R.; Chang, S.H.; Silverman, H. )

    1992-01-01

    To study mechanisms for dominance of phenotype, eight ENU- and four x-ray-induced mutations at the alcohol dehydrogenase (Adh) locus were analyzed for partial dominance in their interaction with normal alleles. All ENU and one of the x-ray mutations were single base substitutions; the other three x-ray mutations were 9-21 base deletions. All but one of the 12 mutant alleles were selected for this study because they produced detectable mutant polypeptides, but seven of the 11 producing a peptide could not form dimers with the normal peptide and the enzyme activity of heterozygotes was about half that of normal homozygotes. Four mutations formed dimers with a decreased catalytic efficiency and two of these were near the limit of detectability; these two also inhibited the formation of normal homodimers. The mutant alleles therefore show multiple mechanisms leading to partial enzyme expression in heterozygotes and a wide range of dominance ranging from almost complete recessive to nearly dominant. All amino acid changes in mutant peptides that form dimers are located between amino acids 182 and 194, so this region is not critical for dimerization. It may, however, be an important surface domain for catalyzation. 34 refs., 8 figs., 2 tabs.

  5. Targeting the Ataxia Telangiectasia Mutated-null phenotype in chronic lymphocytic leukemia with pro-oxidants

    PubMed Central

    Agathanggelou, Angelo; Weston, Victoria J.; Perry, Tracey; Davies, Nicholas J.; Skowronska, Anna; Payne, Daniel T.; Fossey, John S.; Oldreive, Ceri E.; Wei, Wenbin; Pratt, Guy; Parry, Helen; Oscier, David; Coles, Steve J.; Hole, Paul S.; Darley, Richard L.; McMahon, Michael; Hayes, John D.; Moss, Paul; Stewart, Grant S.; Taylor, A. Malcolm R.; Stankovic, Tatjana

    2015-01-01

    Inactivation of the Ataxia Telangiectasia Mutated gene in chronic lymphocytic leukemia results in resistance to p53-dependent apoptosis and inferior responses to treatment with DNA damaging agents. Hence, p53-independent strategies are required to target Ataxia Telangiectasia Mutated-deficient chronic lymphocytic leukemia. As Ataxia Telangiectasia Mutated has been implicated in redox homeostasis, we investigated the effect of the Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia genotype on cellular responses to oxidative stress with a view to therapeutic targeting. We found that in comparison to Ataxia Telangiectasia Mutated-wild type chronic lymphocytic leukemia, pro-oxidant treatment of Ataxia Telangiectasia Mutated-null cells led to reduced binding of NF-E2 p45-related factor-2 to antioxidant response elements and thus decreased expression of target genes. Furthermore, Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia cells contained lower levels of antioxidants and elevated mitochondrial reactive oxygen species. Consequently, Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia, but not tumors with 11q deletion or TP53 mutations, exhibited differentially increased sensitivity to pro-oxidants both in vitro and in vivo. We found that cell death was mediated by a p53- and caspase-independent mechanism associated with apoptosis inducing factor activity. Together, these data suggest that defective redox-homeostasis represents an attractive therapeutic target for Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia. PMID:25840602

  6. Null Mutations in LTBP2 Cause Primary Congenital Glaucoma

    PubMed Central

    Ali, Manir; McKibbin, Martin; Booth, Adam; Parry, David A.; Jain, Payal; Riazuddin, S. Amer; Hejtmancik, J. Fielding; Khan, Shaheen N.; Firasat, Sabika; Shires, Mike; Gilmour, David F.; Towns, Katherine; Murphy, Anna-Louise; Azmanov, Dimitar; Tournev, Ivailo; Cherninkova, Sylvia; Jafri, Hussain; Raashid, Yasmin; Toomes, Carmel; Craig, Jamie; Mackey, David A.; Kalaydjieva, Luba; Riazuddin, Sheikh; Inglehearn, Chris F.

    2009-01-01

    Primary congenital glaucoma (PCG) is an autosomal-recessive condition characterized by high intraocular pressure (IOP), usually within the first year of life, which potentially could lead to optic nerve damage, globe enlargement, and permanent loss of vision. To date, PCG has been linked to three loci: 2p21 (GLC3A), for which the responsible gene is CYP1B1, and 1p36 (GLC3B) and 14q24 (GLC3C), for which the genes remain to be identified. Here we report that null mutations in LTBP2 cause PCG in four consanguineous families from Pakistan and in patients of Gypsy ethnicity. LTBP2 maps to chromosome 14q24.3 but is around 1.3 Mb proximal to the documented GLC3C locus. Therefore, it remains to be determined whether LTBP2 is the GLC3C gene or whether a second adjacent gene is also implicated in PCG. LTBP2 is the largest member of the latent transforming growth factor (TGF)-beta binding protein family, which are extracellular matrix proteins with multidomain structure. It has homology to fibrillins and may have roles in cell adhesion and as a structural component of microfibrils. We confirmed localization of LTBP2 in the anterior segment of the eye, at the ciliary body, and particularly the ciliary process. These findings reveal that LTBP2 is essential for normal development of the anterior chamber of the eye, where it may have a structural role in maintaining ciliary muscle tone. PMID:19361779

  7. Exome sequencing identified null mutations in LOXL3 associated with early-onset high myopia

    PubMed Central

    Li, Jiali; Gao, Bei; Xiao, Xueshan; Li, Shiqiang; Jia, Xiaoyun; Sun, Wenmin; Guo, Xiangming

    2016-01-01

    Purpose To identify null mutations in novel genes associated with early-onset high myopia using whole exome sequencing. Methods Null mutations, including homozygous and compound heterozygous truncations, were selected from whole exome sequencing data for 298 probands with early-onset high myopia. These data were compared with those of 507 probands with other forms of eye diseases. Null mutations specific to early-onset high myopia were considered potential candidates. Candidate mutations were confirmed with Sanger sequencing and were subsequently evaluated in available family members and 480 healthy controls. Results A homozygous frameshift mutation (c.39dup; p.L14Afs*21) and a compound heterozygous frameshift mutation (c.39dup; p.L14Afs*21 and c.594delG; p.Q199Kfs*35) in LOXL3 were separately identified in two of the 298 probands with early-onset high myopia. These mutations were confirmed with Sanger sequencing and were not detected in 1,974 alleles of the controls from the same region (507 individuals with other conditions and 480 healthy control individuals). These two probands were singleton cases, and their parents had only heterozygous mutations. A homozygous missense mutation in LOXL3 was recently reported in a consanguineous family with Stickler syndrome. Conclusions Our results suggest that null mutations in LOXL3 are likely associated with autosomal recessive early-onset high myopia. LOXL3 is a potential candidate gene for high myopia, but this possibility should be confirmed in additional studies. LOXL3 null mutations in human beings are not lethal, providing a phenotype contrary to that in mice. PMID:26957899

  8. Shuttle mutagenesis of Neisseria gonorrhoeae: pilin null mutations lower DNA transformation competence.

    PubMed Central

    Seifert, H S; Ajioka, R S; Paruchuri, D; Heffron, F; So, M

    1990-01-01

    The method of shuttle mutagenesis has been extended to Neisseria gonorrhoeae. We have constructed a defective mini-Tn3 derivative that encodes chloramphenicol resistance in both N. gonorrhoeae and Escherichia coli and selected for mutations in the chloramphenicol resistance gene that express higher levels of antibiotic resistance in N. gonorrhoeae. Isogenic N. gonorrhoeae strains that differ only in pilin expression were constructed and used to test the effect of pilin null mutations on DNA transformation competence. PMID:2152910

  9. Gene Coexpression Analyses Differentiate Networks Associated with Diverse Cancers Harboring TP53 Missense or Null Mutations

    PubMed Central

    Oros Klein, Kathleen; Oualkacha, Karim; Lafond, Marie-Hélène; Bhatnagar, Sahir; Tonin, Patricia N.; Greenwood, Celia M. T.

    2016-01-01

    In a variety of solid cancers, missense mutations in the well-established TP53 tumor suppressor gene may lead to the presence of a partially-functioning protein molecule, whereas mutations affecting the protein encoding reading frame, often referred to as null mutations, result in the absence of p53 protein. Both types of mutations have been observed in the same cancer type. As the resulting tumor biology may be quite different between these two groups, we used RNA-sequencing data from The Cancer Genome Atlas (TCGA) from four different cancers with poor prognosis, namely ovarian, breast, lung and skin cancers, to compare the patterns of coexpression of genes in tumors grouped according to their TP53 missense or null mutation status. We used Weighted Gene Coexpression Network analysis (WGCNA) and a new test statistic built on differences between groups in the measures of gene connectivity. For each cancer, our analysis identified a set of genes showing differential coexpression patterns between the TP53 missense- and null mutation-carrying groups that was robust to the choice of the tuning parameter in WGCNA. After comparing these sets of genes across the four cancers, one gene (KIR3DL2) consistently showed differential coexpression patterns between the null and missense groups. KIR3DL2 is known to play an important role in regulating the immune response, which is consistent with our observation that this gene's strongly-correlated partners implicated many immune-related pathways. Examining mutation-type-related changes in correlations between sets of genes may provide new insight into tumor biology. PMID:27536319

  10. Minimum Variance Distortionless Response Beamformer with Enhanced Nulling Level Control via Dynamic Mutated Artificial Immune System

    PubMed Central

    Kiong, Tiong Sieh; Salem, S. Balasem; Paw, Johnny Koh Siaw; Sankar, K. Prajindra

    2014-01-01

    In smart antenna applications, the adaptive beamforming technique is used to cancel interfering signals (placing nulls) and produce or steer a strong beam toward the target signal according to the calculated weight vectors. Minimum variance distortionless response (MVDR) beamforming is capable of determining the weight vectors for beam steering; however, its nulling level on the interference sources remains unsatisfactory. Beamforming can be considered as an optimization problem, such that optimal weight vector should be obtained through computation. Hence, in this paper, a new dynamic mutated artificial immune system (DM-AIS) is proposed to enhance MVDR beamforming for controlling the null steering of interference and increase the signal to interference noise ratio (SINR) for wanted signals. PMID:25003136

  11. Identification of a G‐Protein Subunit‐α11 Gain‐of‐Function Mutation, Val340Met, in a Family With Autosomal Dominant Hypocalcemia Type 2 (ADH2)

    PubMed Central

    Piret, Sian E; Gorvin, Caroline M; Pagnamenta, Alistair T; Howles, Sarah A; Cranston, Treena; Rust, Nigel; Nesbit, M Andrew; Glaser, Ben; Taylor, Jenny C; Buchs, Andreas E; Hannan, Fadil M

    2016-01-01

    ABSTRACT Autosomal dominant hypocalcemia (ADH) is characterized by hypocalcemia, inappropriately low serum parathyroid hormone concentrations and hypercalciuria. ADH is genetically heterogeneous with ADH type 1 (ADH1), the predominant form, being caused by germline gain‐of‐function mutations of the G‐protein coupled calcium‐sensing receptor (CaSR), and ADH2 caused by germline gain‐of‐function mutations of G‐protein subunit α‐11 (Gα11). To date Gα11 mutations causing ADH2 have been reported in only five probands. We investigated a multigenerational nonconsanguineous family, from Iran, with ADH and keratoconus which are not known to be associated, for causative mutations by whole‐exome sequencing in two individuals with hypoparathyroidism, of whom one also had keratoconus, followed by cosegregation analysis of variants. This identified a novel heterozygous germline Val340Met Gα11 mutation in both individuals, and this was also present in the other two relatives with hypocalcemia that were tested. Three‐dimensional modeling revealed the Val340Met mutation to likely alter the conformation of the C‐terminal α5 helix, which may affect G‐protein coupled receptor binding and G‐protein activation. In vitro functional expression of wild‐type (Val340) and mutant (Met340) Gα11 proteins in HEK293 cells stably expressing the CaSR, demonstrated that the intracellular calcium responses following stimulation with extracellular calcium, of the mutant Met340 Gα11 led to a leftward shift of the concentration‐response curve with a significantly (p < 0.0001) reduced mean half‐maximal concentration (EC50) value of 2.44 mM (95% CI, 2.31 to 2.77 mM) when compared to the wild‐type EC50 of 3.14 mM (95% CI, 3.03 to 3.26 mM), consistent with a gain‐of‐function mutation. A novel His403Gln variant in transforming growth factor, beta‐induced (TGFBI), that may be causing keratoconus was also identified, indicating likely digenic

  12. Identification of a G-Protein Subunit-α11 Gain-of-Function Mutation, Val340Met, in a Family With Autosomal Dominant Hypocalcemia Type 2 (ADH2).

    PubMed

    Piret, Sian E; Gorvin, Caroline M; Pagnamenta, Alistair T; Howles, Sarah A; Cranston, Treena; Rust, Nigel; Nesbit, M Andrew; Glaser, Ben; Taylor, Jenny C; Buchs, Andreas E; Hannan, Fadil M; Thakker, Rajesh V

    2016-06-01

    Autosomal dominant hypocalcemia (ADH) is characterized by hypocalcemia, inappropriately low serum parathyroid hormone concentrations and hypercalciuria. ADH is genetically heterogeneous with ADH type 1 (ADH1), the predominant form, being caused by germline gain-of-function mutations of the G-protein coupled calcium-sensing receptor (CaSR), and ADH2 caused by germline gain-of-function mutations of G-protein subunit α-11 (Gα11 ). To date Gα11 mutations causing ADH2 have been reported in only five probands. We investigated a multigenerational nonconsanguineous family, from Iran, with ADH and keratoconus which are not known to be associated, for causative mutations by whole-exome sequencing in two individuals with hypoparathyroidism, of whom one also had keratoconus, followed by cosegregation analysis of variants. This identified a novel heterozygous germline Val340Met Gα11 mutation in both individuals, and this was also present in the other two relatives with hypocalcemia that were tested. Three-dimensional modeling revealed the Val340Met mutation to likely alter the conformation of the C-terminal α5 helix, which may affect G-protein coupled receptor binding and G-protein activation. In vitro functional expression of wild-type (Val340) and mutant (Met340) Gα11 proteins in HEK293 cells stably expressing the CaSR, demonstrated that the intracellular calcium responses following stimulation with extracellular calcium, of the mutant Met340 Gα11 led to a leftward shift of the concentration-response curve with a significantly (p < 0.0001) reduced mean half-maximal concentration (EC50 ) value of 2.44 mM (95% CI, 2.31 to 2.77 mM) when compared to the wild-type EC50 of 3.14 mM (95% CI, 3.03 to 3.26 mM), consistent with a gain-of-function mutation. A novel His403Gln variant in transforming growth factor, beta-induced (TGFBI), that may be causing keratoconus was also identified, indicating likely digenic inheritance of keratoconus and ADH2 in this family. In

  13. A Novel Null Homozygous Mutation Confirms CACNA2D2 as a Gene Mutated in Epileptic Encephalopathy

    PubMed Central

    Pippucci, Tommaso; Parmeggiani, Antonia; Palombo, Flavia; Maresca, Alessandra; Angius, Andrea; Crisponi, Laura; Cucca, Francesco; Liguori, Rocco; Valentino, Maria Lucia; Seri, Marco; Carelli, Valerio

    2013-01-01

    Contribution to epileptic encephalopathy (EE) of mutations in CACNA2D2, encoding α2δ-2 subunit of Voltage Dependent Calcium Channels, is unclear. To date only one CACNA2D2 mutation altering channel functionality has been identified in a single family. In the same family, a rare CELSR3 polymorphism also segregated with disease. Involvement of CACNA2D2 in EE is therefore not confirmed, while that of CELSR3 is questionable. In a patient with epilepsy, dyskinesia, cerebellar atrophy, psychomotor delay and dysmorphic features, offspring to consanguineous parents, we performed whole exome sequencing (WES) for homozygosity mapping and mutation detection. WES identified extended autozygosity on chromosome 3, containing two novel homozygous candidate mutations: c.1295delA (p.Asn432fs) in CACNA2D2 and c.G6407A (p.Gly2136Asp) in CELSR3. Gene prioritization pointed to CACNA2D2 as the most prominent candidate gene. The WES finding in CACNA2D2 resulted to be statistically significant (p = 0.032), unlike that in CELSR3. CACNA2D2 homozygous c.1295delA essentially abolished α2δ-2 expression. In summary, we identified a novel null CACNA2D2 mutation associated to a clinical phenotype strikingly similar to the Cacna2d2 null mouse model. Molecular and statistical analyses together argued in favor of a causal contribution of CACNA2D2 mutations to EE, while suggested that finding in CELSR3, although potentially damaging, is likely incidental. PMID:24358150

  14. A GLRA1 null mutation in recessive hyperekplexia challenges the functional role of glycine receptors

    SciTech Connect

    Brune, W.; Saul, M.; Becker, C.M.

    1996-05-01

    Dominant missense mutations in the human glycine receptor (GlyR) {alpha}1 subunit gene (GLRA1) give rise to hereditary hyperekplexia. These mutations impair agonist affinities and change conductance states of expressed mutant channels, resulting in a partial loss of function. In a recessive case of hyperekplexia, we found a deletion of exons 1-6 of the GLRA1 gene. Born to consanguineous parents, the affected child is homozygous for this GLRA1{sup null} allele consistent with a complete loss of gene function. The child displayed exaggerated startle responses and pronounced head-retraction jerks reflecting a disinhibition of vestigial brain-stem reflexes. In contrast, proprio- and exteroceptive inhibition of muscle activity previously correlated to glycinergic mechanisms were not affected. This case demonstrates that, in contrast to the lethal effect of a null allele in the recessive mouse mutant oscillator (Glra1{sup spd-ot}), the loss of the GlyR {alpha}1 subunit is effectively compensated in man. 38 refs.

  15. A GLRA1 null mutation in recessive hyperekplexia challenges the functional role of glycine receptors.

    PubMed Central

    Brune, W.; Weber, R. G.; Saul, B.; von Knebel Doeberitz, M.; Grond-Ginsbach, C.; Kellerman, K.; Meinck, H. M.; Becker, C. M.

    1996-01-01

    Dominant missense mutations in the human glycine receptor (GlyR) alpha 1 subunit gene (GLRA1) give rise to hereditary hyperekplexia. These mutations impair agonist affinities and change conductance states of expressed mutant channels, resulting in a partial loss of function. In a recessive case of hyperekplexia, we found a deletion of exons 1-6 of the GLRA1 gene. Born to consanguineous parents, the affected child is homozygous for this GLRA1(null) allele consistent with a complete loss of gene function. The child displayed exaggerated startle responses and pronounced head-retraction jerks reflecting a disinhibition of vestigial brain-stem reflexes. In contrast, proprio- and exteroceptive inhibition of muscle activity previously correlated to glycinergic mechanisms were not affected. This case demonstrates that, in contrast to the lethal effect of a null allele in the recessive mouse mutant oscillator (Glra1 spd-ot), the loss of the GlyR alpha 1 subunit is effectively compensated in man. Images Figure 2 Figure 3 Figure 4 Figure 5 PMID:8651283

  16. Peroxisome proliferator-activated receptor-binding protein null mutation results in defective mammary gland development.

    PubMed

    Jia, Yuzhi; Qi, Chao; Zhang, Zhongyi; Zhu, Yiwei Tony; Rao, Sambasiva M; Zhu, Yi-Jun

    2005-03-18

    A conditional null mutation of peroxisome proliferator-activated receptor-binding protein (PBP) gene was generated to understand its role in mammary gland development. PBP-deficient mammary glands exhibited retarded ductal elongation during puberty, and decreased alveolar density during pregnancy and lactation. PBP-deficient mammary glands could not produce milk to nurse pups during lactation. Both the mammary ductal elongation in response to estrogen treatment and the mammary lobuloalveolar proliferation stimulated by estrogen plus progesterone were attenuated in PBP-deficient mammary glands. The proliferation index was decreased in PBP-deficient mammary glands. PBP-deficient mammary epithelial cells expressed abundant beta-casein, whey acidic protein, and WDNM1 mRNA, indicating a relatively intact differentiated function. PBP-deficient epithelial cells were unable to form mammospheres, which were considered to be derived from mammary progenitor/stem cells. We conclude that PBP plays a pivotal role in the normal mammary gland development. PMID:15647257

  17. A functional null mutation of SCN1B in a patient with Dravet syndrome.

    PubMed

    Patino, Gustavo A; Claes, Lieve R F; Lopez-Santiago, Luis F; Slat, Emily A; Dondeti, Raja S R; Chen, Chunling; O'Malley, Heather A; Gray, Charles B B; Miyazaki, Haruko; Nukina, Nobuyuki; Oyama, Fumitaka; De Jonghe, Peter; Isom, Lori L

    2009-08-26

    Dravet syndrome (also called severe myoclonic epilepsy of infancy) is one of the most severe forms of childhood epilepsy. Most patients have heterozygous mutations in SCN1A, encoding voltage-gated sodium channel Na(v)1.1 alpha subunits. Sodium channels are modulated by beta1 subunits, encoded by SCN1B, a gene also linked to epilepsy. Here we report the first patient with Dravet syndrome associated with a recessive mutation in SCN1B (p.R125C). Biochemical characterization of p.R125C in a heterologous system demonstrated little to no cell surface expression despite normal total cellular expression. This occurred regardless of coexpression of Na(v)1.1 alpha subunits. Because the patient was homozygous for the mutation, these data suggest a functional SCN1B null phenotype. To understand the consequences of the lack of beta1 cell surface expression in vivo, hippocampal slice recordings were performed in Scn1b(-/-) versus Scn1b(+/+) mice. Scn1b(-/-) CA3 neurons fired evoked action potentials with a significantly higher peak voltage and significantly greater amplitude compared with wild type. However, in contrast to the Scn1a(+/-) model of Dravet syndrome, we found no measurable differences in sodium current density in acutely dissociated CA3 hippocampal neurons. Whereas Scn1b(-/-) mice seize spontaneously, the seizure susceptibility of Scn1b(+/-) mice was similar to wild type, suggesting that, like the parents of this patient, one functional SCN1B allele is sufficient for normal control of electrical excitability. We conclude that SCN1B p.R125C is an autosomal recessive cause of Dravet syndrome through functional gene inactivation. PMID:19710327

  18. A functional null mutation of SCN1B in a patient with Dravet Syndrome

    PubMed Central

    Patino, Gustavo A.; Claes, Lieve R.F.; Lopez-Santiago, Luis; Slat, Emily A.; Dondeti, Raja S. R.; Chen, Chunling; O'Malley, Heather A.; Gray, Charles B.B.; Miyazaki, Haruko; Nukina, Nobuyuki; Oyama, Fumitaka; Jonghe, Peter De; Isom, Lori L.

    2009-01-01

    Dravet syndrome (also called Severe Myoclonic Epilepsy of Infancy) is one of the most severe forms of childhood epilepsy. Most patients have heterozygous mutations in SCN1A, encoding voltage-gated sodium channel Nav1.1 α subunits. Sodium channels are modulated by β1 subunits, encoded by SCN1B, a gene also linked to epilepsy. Here we report the first patient with Dravet Syndrome associated with a recessive mutation in SCN1B (p.R125C). Biochemical characterization of p.R125C in a heterologous system demonstrated little to no cell surface expression despite normal total cellular expression. This occurred regardless of co-expression of Nav1.1 α subunits. Because the patient was homozygous for the mutation, these data suggest a functional SCN1B null phenotype. To understand the consequences of the lack of β1 cell surface expression in vivo, hippocampal slice recordings were performed in Scn1b−/− vs. Scn1b+/+ mice. Scn1b−/− CA3 neurons fired evoked action potentials with a significantly higher peak voltage and significantly greater amplitude compared to wildtype. However, in contrast to the Scn1a+/− model of Dravet syndrome, we found no measurable differences in sodium current density in acutely dissociated CA3 hippocampal neurons. While Scn1b−/− mice seize spontaneously, the seizure susceptibility of Scn1b+/− mice was similar to wildtype, suggesting that, like the parents of this patient, one functional SCN1B allele is sufficient for normal control of electrical excitability. We conclude that SCN1B p.R125C is an autosomal recessive cause of Dravet syndrome through functional gene inactivation. PMID:19710327

  19. Cofactor Specificity of the Bifunctional Alcohol and Aldehyde Dehydrogenase (AdhE) in Wild-Type and Mutant Clostridium thermocellum and Thermoanaerobacterium saccharolyticum

    PubMed Central

    Zheng, Tianyong; Olson, Daniel G.; Tian, Liang; Bomble, Yannick J.; Himmel, Michael E.; Lo, Jonathan; Hon, Shuen; Shaw, A. Joe; van Dijken, Johannes P.

    2015-01-01

    ABSTRACT Clostridium thermocellum and Thermoanaerobacterium saccharolyticum are thermophilic bacteria that have been engineered to produce ethanol from the cellulose and hemicellulose fractions of biomass, respectively. Although engineered strains of T. saccharolyticum produce ethanol with a yield of 90% of the theoretical maximum, engineered strains of C. thermocellum produce ethanol at lower yields (∼50% of the theoretical maximum). In the course of engineering these strains, a number of mutations have been discovered in their adhE genes, which encode both alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) enzymes. To understand the effects of these mutations, the adhE genes from six strains of C. thermocellum and T. saccharolyticum were cloned and expressed in Escherichia coli, the enzymes produced were purified by affinity chromatography, and enzyme activity was measured. In wild-type strains of both organisms, NADH was the preferred cofactor for both ALDH and ADH activities. In high-ethanol-producing (ethanologen) strains of T. saccharolyticum, both ALDH and ADH activities showed increased NADPH-linked activity. Interestingly, the AdhE protein of the ethanologenic strain of C. thermocellum has acquired high NADPH-linked ADH activity while maintaining NADH-linked ALDH and ADH activities at wild-type levels. When single amino acid mutations in AdhE that caused increased NADPH-linked ADH activity were introduced into C. thermocellum and T. saccharolyticum, ethanol production increased in both organisms. Structural analysis of the wild-type and mutant AdhE proteins was performed to provide explanations for the cofactor specificity change on a molecular level. IMPORTANCE This work describes the characterization of the AdhE enzyme from different strains of C. thermocellum and T. saccharolyticum. C. thermocellum and T. saccharolyticum are thermophilic anaerobes that have been engineered to make high yields of ethanol and can solubilize components of

  20. Null mutations in human and mouse orthologs frequently result in different phenotypes

    PubMed Central

    Liao, Ben-Yang; Zhang, Jianzhi

    2008-01-01

    One-to-one orthologous genes of relatively closely related species are widely assumed to have similar functions and cause similar phenotypes when deleted from the genome. Although this assumption is the foundation of comparative genomics and the basis for the use of model organisms to study human biology and disease, its validity is known only from anecdotes rather than from systematic examination. Comparing documented phenotypes of null mutations in humans and mice, we find that >20% of human essential genes have nonessential mouse orthologs. These changes of gene essentiality appear to be associated with adaptive evolution at the protein-sequence, but not gene-expression, level. Proteins localized to the vacuole, a cellular compartment for waste management, are highly enriched among essentiality-changing genes. It is probable that the evolution of the prolonged life history in humans required enhanced waste management for proper cellular function until the time of reproduction, which rendered these vacuole proteins essential and generated selective pressures for their improvement. If our gene sample represents the entire genome, our results would mean frequent changes of phenotypic effects of one-to-one orthologous genes even between relatively closely related species, a possibility that should be considered in comparative genomic studies and in making cross-species inferences of gene function and phenotypic effect. PMID:18458337

  1. A heterozygous putative null mutation in ROM1 without a mutation in peripherin/RDS in a family with retinitis pigmentosa

    SciTech Connect

    Sakuma, Hitoshi; Inana, G.; Murakami, Akira

    1995-05-20

    ROM1 is a 351-amino-acid, 37-kDa outer segment membrane protein of rod photoreceptors. ROM1 is related to peripherin/RDS, another outer segment membrane protein found in both rods and cones. The precise function of ROM1 or peripherin/RDS is not known, but they have been suggested to play important roles in the function and/or structure of the rod photoreceptor outer segment disks. A recent report implicated ROM1 in disease by suggesting that RP can be caused by a heterozygous null mutation in ROM1 but only in combination with another heterozygous mutation in peripherin/RDS. Screening of the ROM1 gene using polymerase chain reaction amplification, denaturing gradient gel electrophoresis, and direct DNA sequencing identified the same heterozygous putative null mutation in a family with RP.

  2. Ectopic ADH secretion

    MedlinePlus

    ... ADH. Often, there are no symptoms from a low sodium level. When symptoms do occur, they may include ... Lab tests that can confirm and help diagnose low sodium include: Comprehensive metabolic panel (includes blood sodium) Osmolality ...

  3. ADH (Antidiuretic Hormone) Test

    MedlinePlus

    ... Also known as: Vasopressin; AVP Formal name: Antidiuretic Hormone; Arginine Vasopressin Related tests: Osmolality , BUN , Creatinine , Sodium , ... should know? How is it used? The antidiuretic hormone (ADH) test is used to help detect, diagnose, ...

  4. Somatic-cell mutation induced by short exposures to cigarette smoke in urate-null, oxidative stress-sensitive Drosophila.

    PubMed

    Uchiyama, Tomoyo; Koike, Ryota; Yuma, Yoko; Okamoto, Keinosuke; Arimoto-Kobayashi, Sakae; Suzuki, Toshinori; Negishi, Tomoe

    2016-01-01

    We previously reported that a urate-null strain of Drosophila is hypersensitive to cigarette smoke (CS), and we suggested that CS induces oxidative stress in Drosophila because uric acid is a potent antioxidant. Although the carcinogenic risk of CS exposure is widely recognized; documentation of in vivo genotoxic activity of environmental CS, especially gaseous-phase CS, remains inconclusive. To date, somatic-cell mutations in Drosophila resulting from exposure to CS have not been detected via the somatic mutation and recombination test (wing spot test) with wild-type flies, a widely used Drosophila assay for the detection of somatic-cell mutation; moreover, genotoxicity has not been documented via a DNA repair test that involves DNA repair-deficient Drosophila. In this study, we used a new Drosophila strain (y v ma-l; mwh) to examine the mutagenicity induced by gaseous-phase CS; these flies are urate-null due to a mutation in ma-l, and they are heterozygous for multiple wing hair (mwh), a mutation that functions as a marker for somatic-cell mutation. In an assay with this newly developed strain, a superoxide anion-producing weed-killer, paraquat, exhibited significant mutagenicity; in contrast, paraquat was hardly mutagenic with a wild-type strain. Drosophila larvae were exposed to CS for 2, 4 or 6h, and then kept at 25°C on instant medium until adulthood. After eclosion, mutant spots, which consisted of mutant hairs on wings, were scored. The number of mutant spots increased significantly in an exposure time-dependent manner in the urate-null females (ma-l (-/-)), but not in the urate-positive females (ma-l (+/-)). In this study, we showed that short-term exposure to CS was mutagenic in this in vivo system. In addition, we obtained suggestive data regarding reactive oxygen species production in larva after CS exposure using the fluorescence probe H2DCFDA. These results suggest that oxidative damage, which might be countered by uric acid, was partly responsible

  5. Null mutations of the Dictyostelium cyclic nucleotide phosphodiesterase gene block chemotactic cell movement in developing aggregates.

    PubMed

    Sucgang, R; Weijer, C J; Siegert, F; Franke, J; Kessin, R H

    1997-12-01

    Extracellular cAMP is a critical messenger in the multicellular development of the cellular slime mold Dictyostelium discoideum. The levels of cAMP are controlled by a cyclic nucleotide phosphodiesterase (PDE) that is secreted by the cells. The PDE gene (pdsA) is controlled by three promoters that permit expression during vegetative growth, during aggregation, and in prestalk cells of the older structures. Targeted disruption of the gene aborts development, and complementation with a modified pdsA restores development. Two distinct promoters must be used for full complementation, and an inhibitory domain of the PDE must be removed. We took advantage of newly isolated PDE-null cells and the natural chimerism of the organism to ask whether the absence of PDE affected individual cell behavior. PDE-null cells aggregated with isogenic wild-type cells in chimeric mixtures, but could not move in a coordinated manner in mounds. The wild-type cells move inward toward the center of the mound, leaving many of the PDE-null cells at the periphery of the aggregate. During the later stages of development, PDE-null cells in the chimera segregate to regions which correspond to the prestalk region and the rear of the slug. Participation in the prespore/spore population returns with the restoration of a modified pdsA to the null cells. PMID:9405107

  6. Evolution of the adhE gene product of Escherichia coli from a functional reductase to a dehydrogenase. Genetic and biochemical studies of the mutant proteins.

    PubMed

    Membrillo-Hernandez, J; Echave, P; Cabiscol, E; Tamarit, J; Ros, J; Lin, E C

    2000-10-27

    The multifunctional AdhE protein of Escherichia coli (encoded by the adhE gene) physiologically catalyzes the sequential reduction of acetyl-CoA to acetaldehyde and then to ethanol under fermentative conditions. The NH(2)-terminal region of the AdhE protein is highly homologous to aldehyde:NAD(+) oxidoreductases, whereas the COOH-terminal region is homologous to a family of Fe(2+)-dependent ethanol:NAD(+) oxidoreductases. This fusion protein also functions as a pyruvate formate lyase deactivase. E. coli cannot grow aerobically on ethanol as the sole carbon and energy source because of inadequate rate of adhE transcription and the vulnerability of the AdhE protein to metal-catalyzed oxidation. In this study, we characterized 16 independent two-step mutants with acquired and improved aerobic growth ability on ethanol. The AdhE proteins in these mutants catalyzed the sequential oxidation of ethanol to acetaldehyde and to acetyl-CoA. All first stage mutants grew on ethanol with a doubling time of about 240 min. Sequence analysis of a randomly chosen mutant revealed an Ala-267 --> Thr substitution in the acetaldehyde:NAD(+) oxidoreductase domain of AdhE. All second stage mutants grew on ethanol with a doubling time of about 90 min, and all of them produced an AdhE(A267T/E568K). Purified AdhE(A267T) and AdhE(A267T/E568K) showed highly elevated acetaldehyde dehydrogenase activities. It therefore appears that when AdhE catalyzes the two sequential reactions in the counter-physiological direction, acetaldehyde dehydrogenation is the rate-limiting step. Both mutant proteins were more thermosensitive than the wild-type protein, but AdhE(A267T/E568K) was more thermal stable than AdhE(A267T). Since both mutant enzymes exhibited similar kinetic properties, the second mutation probably conferred an increased growth rate on ethanol by stabilizing AdhE(A267T). PMID:10922373

  7. Conserved enhancer and silencer elements responsible for differential Adh transcription in Drosophila cell lines.

    PubMed Central

    Ayer, S; Benyajati, C

    1990-01-01

    The distal promoter of Adh is differentially expressed in Drosophila tissue culture cell lines. After transfection with an exogenous Adh gene, there was a specific increase in distal alcohol dehydrogenase (ADH) transcripts in ADH-expressing (ADH+) cells above the levels observed in transfected ADH-nonexpressing (ADH-) cells. We used deletion mutations and a comparative transient-expression assay to identify the cis-acting elements responsible for enhanced Adh distal transcription in ADH+ cells. DNA sequences controlling high levels of distal transcription were localized to a 15-base-pair (bp) region nearly 500 bp upstream of the distal RNA start site. In addition, a 61-bp negative cis-acting element was found upstream from and adjacent to the enhancer. When this silencer element was deleted, distal transcription increased only in the ADH+ cell line. These distant upstream elements must interact with the promoter elements, the Adf-1-binding site and the TATA box, as they only influenced transcription when at least one of these two positive distal promoter elements was present. Internal deletions targeted to the Adf-1-binding site or the TATA box reduced transcription in both cell types but did not affect the transcription initiation site. Distal transcription in transfected ADH- cells appears to be controlled primarily through these promoter elements and does not involve the upstream regulatory elements. Evolutionary conservation in distantly related Drosophila species suggests the importance of these upstream elements in correct developmental and tissue-specific expression of ADH. Images PMID:1694013

  8. TP53 mutations induced by BPDE in Xpa-WT and Xpa-Null human TP53 knock-in (Hupki) mouse embryo fibroblasts

    PubMed Central

    Kucab, Jill E.; van Steeg, Harry; Luijten, Mirjam; Schmeiser, Heinz H.; White, Paul A.; Phillips, David H.; Arlt, Volker M.

    2015-01-01

    Somatic mutations in the tumour suppressor gene TP53 occur in more than 50% of human tumours; in some instances exposure to environmental carcinogens can be linked to characteristic mutational signatures. The Hupki (human TP53 knock-in) mouse embryo fibroblast (HUF) immortalization assay (HIMA) is a useful model for studying the impact of environmental carcinogens on TP53 mutagenesis. In an effort to increase the frequency of TP53-mutated clones achievable in the HIMA, we generated nucleotide excision repair (NER)-deficient HUFs by crossing the Hupki mouse with an Xpa-knockout (Xpa-Null) mouse. We hypothesized that carcinogen-induced DNA adducts would persist in the TP53 sequence of Xpa-Null HUFs leading to an increased propensity for mismatched base pairing and mutation during replication of adducted DNA. We found that Xpa-Null Hupki mice, and HUFs derived from them, were more sensitive to the environmental carcinogen benzo[a]pyrene (BaP) than their wild-type (Xpa-WT) counterparts. Following treatment with the reactive metabolite of BaP, benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE), Xpa-WT and Xpa-Null HUF cultures were subjected to the HIMA. A significant increase in TP53 mutations on the transcribed strand was detected in Xpa-Null HUFs compared to Xpa-WT HUFs, but the TP53-mutant frequency overall was not significantly different between the two genotypes. BPDE induced mutations primarily at G:C base pairs, with approximately half occurring at CpG sites, and the predominant mutation type was G:C > T:A in both Xpa-WT and Xpa-Null cells. Further, several of the TP53 mutation hotspots identified in smokers’ lung cancer were mutated by BPDE in HUFs (codons 157, 158, 245, 248, 249, 273). Therefore, the pattern and spectrum of BPDE-induced TP53 mutations in the HIMA are consistent with TP53 mutations detected in lung tumours of smokers. While Xpa-Null HUFs exhibited increased sensitivity to BPDE-induced damage on the transcribed strand, NER-deficiency did not

  9. Quantitative analysis of RNA produced by slow and fast alleles of Adh in Drosophila melanogaster.

    PubMed Central

    Laurie, C C; Stam, L F

    1988-01-01

    The alcohol dehydrogenase (ADH) locus (Adh) of Drosophila melanogaster in polymorphic on a world-wide basis for two allozymes, Fast and Slow. This study was undertaken to determine whether the well-established difference in ADH protein concentration between the allozymes is due to a difference in mRNA levels. RNA gel blot hybridization and an RNase protection assay were used to quantify ADH mRNA levels. Each method used an Adh null mutant as an internal standard. Several Slow and Fast allele pairs of different geographic origins were analyzed. The results provide strong evidence that the ADH protein concentration difference is not accounted for by RNA level. Images PMID:2455893

  10. lon incompatibility associated with mutations causing SOS induction: null uvrD alleles induce an SOS response in Escherichia coli.

    PubMed

    SaiSree, L; Reddy, M; Gowrishankar, J

    2000-06-01

    The uvrD gene in Escherichia coli encodes a 720-amino-acid 3'-5' DNA helicase which, although nonessential for viability, is required for methyl-directed mismatch repair and nucleotide excision repair and furthermore is believed to participate in recombination and DNA replication. We have shown in this study that null mutations in uvrD are incompatible with lon, the incompatibility being a consequence of the chronic induction of SOS in uvrD strains and the resultant accumulation of the cell septation inhibitor SulA (which is a normal target for degradation by Lon protease). uvrD-lon incompatibility was suppressed by sulA, lexA3(Ind(-)), or recA (Def) mutations. Other mutations, such as priA, dam, polA, and dnaQ (mutD) mutations, which lead to persistent SOS induction, were also lon incompatible. SOS induction was not observed in uvrC and mutH (or mutS) mutants defective, respectively, in excision repair and mismatch repair. Nor was uvrD-mediated SOS induction abolished by mutations in genes that affect mismatch repair (mutH), excision repair (uvrC), or recombination (recB and recF). These data suggest that SOS induction in uvrD mutants is not a consequence of defects in these three pathways. We propose that the UvrD helicase participates in DNA replication to unwind secondary structures on the lagging strand immediately behind the progressing replication fork, and that it is the absence of this function which contributes to SOS induction in uvrD strains. PMID:10809694

  11. Lethality of glnD null mutations in Azotobacter vinelandii is suppressible by prevention of glutamine synthetase adenylylation.

    PubMed

    Colnaghi, R; Rudnick, P; He, L; Green, A; Yan, D; Larson, E; Kennedy, C

    2001-05-01

    GlnD is a pivotal protein in sensing intracellular levels of fixed nitrogen and has been best studied in enteric bacteria, where it reversibly uridylylates two related proteins, PII and GlnK. The uridylylation state of these proteins determines the activities of glutamine synthetase (GS) and NtrC. Results presented here demonstrate that glnD is an essential gene in Azotobacter vinelandii. Null glnD mutations were introduced into the A. vinelandii genome, but none could be stably maintained unless a second mutation was present that resulted in unregulated activity of GS. One mutation, gln-71, occurred spontaneously to give strain MV71, which failed to uridylylate the GlnK protein. The second, created by design, was glnAY407F (MV75), altering the adenylylation site of GS. The gln-71 mutation is probably located in glnE, encoding adenylyltransferase, because introducing the Escherichia coli glnE gene into MV72, a glnD(+) derivative of MV71, restored the regulation of GS activity. GlnK-UMP is therefore apparently required for GS to be sufficiently deadenylylated in A. vinelandii for growth to occur. The DeltaglnD GS(c) isolates were Nif(-), which could be corrected by introducing a nifL mutation, confirming a role for GlnD in mediating nif gene regulation via some aspect of the NifL/NifA interaction. MV71 was unexpectedly NtrC(+), suggesting that A. vinelandii NtrC activity might be regulated differently than in enteric organisms. PMID:11320130

  12. Superoxide Dismutase (Sod-1) Null Mutants of Neurospora Crassa: Oxidative Stress Sensitivity, Spontaneous Mutation Rate and Response to Mutagens

    PubMed Central

    Chary, P.; Dillon, D.; Schroeder, A. L.; Natvig, D. O.

    1994-01-01

    Enzymatic superoxide-dismutase activity is believed to be important in defense against the toxic effects of superoxide. Although superoxide dismutases are among the best studied proteins, numerous questions remain concerning the specific biological roles of the various superoxide-dismutase types. In part, this is because the proposed damaging effects of superoxide are manifold, ranging from inactivation of certain metabolic enzymes to DNA damage. Studies with superoxide-deficient mutants have proven valuable, but surprisingly few such studies have been reported. We have constructed and characterized Neurospora crassa mutants that are null for sod-1, the gene that encodes copper-zinc superoxide dismutase. Mutant strains are sensitive to paraquat and elevated oxygen concentrations, and they exhibit an increased spontaneous mutation rate. They appear to have near wild-type sensitivities to near- and far-UV, heat shock and γ-irradiation. Unlike the equivalent Saccharomyces cerevisiae mutant and the sodA sodB double mutant of Escherichia coli, they do not exhibit aerobic auxotrophy. These results are discussed in the context of an attempt to identify consensus phenotypes among superoxide dismutase-deficient mutants. N. crassa sod-1 null mutant strains were also employed in genetic and subcellular fractionation studies. Results support the hypothesis that a single gene (sod-1), located between Fsr-12 and leu-3 on linkage group I, is responsible for most or all CuZn superoxide dismutase activity in this organism. PMID:8088518

  13. Effect of a null mutation of the oviduct-specific glycoprotein gene on mouse fertilization.

    PubMed Central

    Araki, Yoshihiko; Nohara, Makoto; Yoshida-Komiya, Hiromi; Kuramochi, Takashi; Ito, Mamoru; Hoshi, Hiroyoshi; Shinkai, Yoichi; Sendai, Yutaka

    2003-01-01

    The mammalian fertilization process takes place in a complex microenvironment within the female genital tract. A member of the chitinase protein family, oviduct-specific glycoprotein (OGP), has been identified in oviductal fluid from various mammalian species, including humans. Although OGP is widely believed to be involved in the process of mammalian fertilization, including spermatozoon function and gamete interactions, based on experimental results obtained in vitro, its physiological significance remains controversial. The present study established OGP gene-null ( ogp (-/-)) mice, and primarily characterized their reproductive properties to study the physiological function(s) of OGP. Results obtained from studies using an in vivo or in vitro system showed that the fertility of ogp (-/-) females was within normal limits. These results indicate that OGP is not essential for the process of in vivo fertilization, at least in mice. PMID:12814341

  14. Phenotypic Characterization of Mice Heterozygous for a Null Mutation of Glutamate Carboxypeptidase II

    PubMed Central

    Han, Liqun; Picker, Jonathan D.; Schaevitz, Laura R.; Tsai, Guochuan; Feng, Jiamin; Jiang, Zhichun; Chu, Hillary C.; Basu, Alo C.; Berger-Sweeney, Joanne; Coyle, Joseph T.

    2009-01-01

    Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. Disturbed glutamate signaling resulting in hypofunction of NMDA receptors has been implicated in the pathophysiology of schizophrenia. Glutamate Carboxypeptidase II (GCP II) hydrolyzes N-acetyl-alpha L-aspartyl-L-glutamate (NAAG) into glutamate and N-acetyl-aspartate (NAA). NAAG is a neuropeptide that is an NMDA receptor antagonist as well as an agonist for the metabotropic glutamate receptor-3 (mGluR3), which inhibits glutamate release. The aggregate effect of NAAG is thus to attenuate NMDA receptor activation. To manipulate the expression of GCP II, loxP sites were inserted flanking exon 1 and 2, which were excised by crossing with a Cre-expressing mouse. The mice heterozygous for this deletion showed a 50% reduction in the expression level of protein and functional activity of GCP II in brain samples. Heterozygous mutant crosses did not yield any homozygous null animals at birth or as embryos (N >200 live births and fetuses). These data are consistent with the previous report that GCP II homozygous mutant mice generated by removing exons 9 and 10 of GCP II gene were embryonically lethal and confirm our hypothesis that GCP II plays an essential role early in embryonic development. Heterozygous mice, however, developed normally to adulthood and exhibited increased locomotor activity, reduced social interaction, and a subtle cognitive deficit in working memory. PMID:19347959

  15. Phenotypic characterization of mice heterozygous for a null mutation of glutamate carboxypeptidase II.

    PubMed

    Han, Liqun; Picker, Jonathan D; Schaevitz, Laura R; Tsai, Guochuan; Feng, Jiamin; Jiang, Zhichun; Chu, Hillary C; Basu, Alo C; Berger-Sweeney, Joanne; Coyle, Joseph T

    2009-08-01

    Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. Disturbed glutamate signaling resulting in hypofunction of N-methyl-D-aspartate receptors (NMDAR) has been implicated in the pathophysiology of schizophrenia. Glutamate Carboxypeptidase II (GCP II) hydrolyzes N-acetyl-alpha L-aspartyl-L-glutamate (NAAG) into glutamate and N-acetyl-aspartate. NAAG is a neuropeptide that is an NMDAR antagonist as well as an agonist for the metabotropic glutamate receptor-3 (mGluR3), which inhibits glutamate release. The aggregate effect of NAAG is thus to attenuate NMDAR activation. To manipulate the expression of GCP II, LoxP sites were inserted flanking exons 1 and 2, which were excised by crossing with a Cre-expressing mouse. The mice heterozygous for this deletion showed a 50% reduction in the expression level of protein and functional activity of GCP II in brain samples. Heterozygous mutant crosses did not yield any homozygous null animals at birth or as embryos (N > 200 live births and fetuses). These data are consistent with the previous report that GCP II homozygous mutant mice generated by removing exons 9 and 10 of GCP II gene were embryonically lethal and confirm our hypothesis that GCP II plays an essential role early in embryonic development. Heterozygous mice, however, developed normally to adulthood and exhibited increased locomotor activity, reduced social interaction, and a subtle cognitive deficit in working memory. PMID:19347959

  16. Homozygous NOTCH3 null mutation and impaired NOTCH3 signaling in recessive early-onset arteriopathy and cavitating leukoencephalopathy

    PubMed Central

    Pippucci, Tommaso; Maresca, Alessandra; Magini, Pamela; Cenacchi, Giovanna; Donadio, Vincenzo; Palombo, Flavia; Papa, Valentina; Incensi, Alex; Gasparre, Giuseppe; Valentino, Maria Lucia; Preziuso, Carmela; Pisano, Annalinda; Ragno, Michele; Liguori, Rocco; Giordano, Carla; Tonon, Caterina; Lodi, Raffaele; Parmeggiani, Antonia; Carelli, Valerio; Seri, Marco

    2015-01-01

    Notch signaling is essential for vascular physiology. Neomorphic heterozygous mutations in NOTCH3, one of the four human NOTCH receptors, cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Hypomorphic heterozygous alleles have been occasionally described in association with a spectrum of cerebrovascular phenotypes overlapping CADASIL, but their pathogenic potential is unclear. We describe a patient with childhood-onset arteriopathy, cavitating leukoencephalopathy with cerebral white matter abnormalities presented as diffuse cavitations, multiple lacunar infarctions and disseminated microbleeds. We identified a novel homozygous c.C2898A (p.C966*) null mutation in NOTCH3 abolishing NOTCH3 expression and causing NOTCH3 signaling impairment. NOTCH3 targets acting in the regulation of arterial tone (KCNA5) or expressed in the vasculature (CDH6) were downregulated. Patient's vessels were characterized by smooth muscle degeneration as in CADASIL, but without deposition of granular osmiophilic material (GOM), the CADASIL hallmark. The heterozygous parents displayed similar but less dramatic trends in decrease in the expression of NOTCH3 and its targets, as well as in vessel degeneration. This study suggests a functional link between NOTCH3 deficiency and pathogenesis of vascular leukoencephalopathies. PMID:25870235

  17. Precise null deletion mutations of the mycothiol synthesis genes reveal their role in isoniazid and ethionamide resistance in Mycobacterium smegmatis.

    PubMed

    Xu, Xia; Vilchèze, Catherine; Av-Gay, Yossef; Gómez-Velasco, Anaximandro; Jacobs, William R

    2011-07-01

    Mycothiol (MSH; AcCys-GlcN-Ins) is the glutathione analogue for mycobacteria. Mutations in MSH biosynthetic genes have been associated with resistance to isoniazid (INH) and ethionamide (ETH) in mycobacteria, but rigorous genetic studies are lacking, and those that have been conducted have yielded different results. In this study, we constructed independent null deletion mutants for all four genes involved in the MSH biosynthesis pathway (mshA, mshB, mshC, and mshD) in Mycobacterium smegmatis and made complementing constructs in integrating plasmids. The resulting set of strains was analyzed for levels of MSH, INH resistance, and ETH resistance. The mshA and mshC single deletion mutants were devoid of MSH production and resistant to INH, whereas the mshB deletion mutant produced decreased levels of MSH yet was sensitive to INH, suggesting that MSH biosynthesis is essential for INH susceptibility in M. smegmatis. Further evidence supporting this conclusion was generated by deleting the gene encoding the MSH S-conjugate amidase (mca) from the ΔmshB null mutant. This double mutant, ΔmshB Δmca, completely abolished MSH production and was resistant to INH. The mshA, mshC, and mshB single deletion mutants were also resistant to ETH, indicating that ETH resistance is modulated by the level of MSH in M. smegmatis. Surprisingly, the mshD deletion mutant lacked MSH production but was sensitive to both INH and ETH. The drug sensitivity was likely mediated by the compensated synthesis of N-formyl-Cys-GlcN-Ins, previously demonstrated to substitute for MSH in an mshD mutant of M. smegmatis. We conclude that MSH or N-formyl-Cys-GlcN-Ins is required for susceptibility to INH or ETH in M. smegmatis. PMID:21502624

  18. Identification of a null mutation in the human dopamine D4 receptor gene

    SciTech Connect

    Noethen, M.M.; Cichon, S.; Hebebrand, J.

    1994-09-01

    Dopamine receptors belong to the family of G protein-coupled receptors. Five different dopamine receptor genes have thus far been identified. These receptors are classified into two main subfamilies: D1, which includes the D1 and D5 receptors, and D2, which includes the D2, D3, and D4 receptors. The dopamine D4 receptor is of great interest for research into neuropsychiatric disorders and psychopharmacology in light of the fact that it binds the antipsychotic medication clozapine with higher affinity than does any other dopamine receptor. In addition, among the dopamine receptors, the D4 receptor shows a uniquely high degree of genetic variation in the human population. We identified a new 13 bp deletion in exon 1 of the D4 gene. This frameshift creates a terminator codon at amino acid position 98. mRNA isolated from brain tissue of two heterozygous persons showed both alleles to be expressed. The deletion occurs with a frequency of 2% in the German population. One person was identified to be homozygous for the deletion. Interestingly, he has a normal intelligence and did not exhibit a major psychiatric disorder as defined by DSM III-R. The 13 bp deletion is the first mutation resulting in premature translation termination reported for a dopamine receptor gene so far. This mutation is a good candidate to test for potential effects on disease and/or individual response to pharmacotherapy. Association studies in patients with various psychiatric illnesses and differences in response to clozapine are underway.

  19. Delineation of Cis-Acting Sequences Required for Expression of Drosophila Mojavensis Adh-1

    PubMed Central

    Bayer, C. A.; Curtiss, S. W.; Weaver, J. A.; Sullivan, D. T.

    1992-01-01

    The control of expression of the Adh-1 gene of Drosophila mojavensis has been analyzed by transforming ADH null Drosophila melanogaster hosts with P element constructs which contain D. mojavensis Adh-1 having deletions of different extent in the 5' and 3' ends. Adh-1 expression in the D. melanogaster hosts is qualitatively similar to expression in D. mojavensis, although expression is quantitatively lower in transformants. Deletions of the 5' end indicate that information required for normal temporal and tissue expression in larvae is contained within 70 bp of the transcription start site. However, deletion constructs to -70 are deficient in ovarian nurse cell expression, whereas the additional upstream sequences present in constructs containing deletions to -257 do support expression in the ovary. Comparison of the nucleotide sequence in the -257 to -70 region of Adh-1 of four species: D. mojavensis and Drosophila arizona, which express Adh-1 in the ovary, and Drosophila mulleri and Drosophila navojoa, which do not, has led to the identification of regions of sequence similarity that correlate with ovary expression. One of these bears a striking similarity to a conserved sequence located upstream of the three heat shock genes that have constitutive ovarian expression and may be an ovarian control element. We have identified an aberrant aspect of Adh-1 expression. In transformants which carry an Adh-1 gene without a functional upstream Adh-2 gene Adh-1 expression continues into the adult stage instead of ceasing at the onset of metamorphosis. In transformants with a functional Adh-2 gene, Adh-1 expression ceases in the third larval instar stage and aberrant expression in the adult stage does not occur. PMID:1317314

  20. Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity

    PubMed Central

    Goudy, Kevin; Aydin, Didem; Barzaghi, Federica; Gambineri, Eleonora; Vignoli, Marina; Mannurita, Sara Ciullini; Doglioni, Claudio; Ponzoni, Maurilio; Cicalese, Maria Pia; Assanelli, Andrea; Tommasini, Alberto; Brigida, Immacolata; Dellepiane, Rosa Maria; Martino, Silvana; Olek, Sven; Aiuti, Alessandro; Ciceri, Fabio; Roncarolo, Maria Grazia; Bacchetta, Rosa

    2013-01-01

    Cell-surface CD25 expression is critical for maintaining immune function and homeostasis. As in few reported cases, CD25 deficiency manifests with severe autoimmune enteritis and viral infections. To dissect the underlying immunological mechanisms driving these symptoms, we analyzed the regulatory and effector T cell functions in a CD25 deficient patient harboring a novel IL2RA mutation. Pronounced lymphoproliferation, mainly of the CD8+ T cells, was detected together with an increase in T cell activation markers and elevated serum cytokines. However, Ag-specific responses were impaired in vivo and in vitro. Activated CD8+STAT5+ T cells with lytic potential infiltrated the skin, even though FOXP3+ Tregs were present and maintained a higher capacity to respond to IL-2 compared to other T-cell subsets. Thus, the complex pathogenesis of CD25 deficiency provides invaluable insight into the role of IL2/IL-2RA-dependent regulation in autoimmunity and inflammatory diseases. PMID:23416241

  1. Pyruvate dehydrogenase phosphatase 1 (PDP1) null mutation produces a lethal infantile phenotype.

    PubMed

    Cameron, J M; Maj, M; Levandovskiy, V; Barnett, C P; Blaser, S; Mackay, N; Raiman, J; Feigenbaum, A; Schulze, A; Robinson, B H

    2009-04-01

    Pyruvate dehydrogenase phosphatase deficiency has previously only been confirmed at the molecular level in two brothers and two breeds of dog with exercise intolerance. A female patient, who died at 6 months, presented with lactic acidemia in the neonatal period with serum lactate levels ranging from 2.5 to 17 mM. Failure of dichloroacetate to activate the PDH complex in skin fibroblasts was evident, but not in early passages. A homozygous c.277G > T (p.E93X) nonsense mutation in the PDP1 gene was identified in genomic DNA and immunoblotting showed a complete absence of PDP1 protein in mitochondria. Native PDHC activity could be restored by the addition of either recombinant PDP1 or PDP2. This highlights the role of PDP2, the second phosphatase isoform, in PDP1-deficient patients for the first time. We conclude that the severity of the clinical course associated with PDP1 deficiency can be quite variable depending on the exact nature of the molecular defect. PMID:19184109

  2. A null mutation in TNIK defines a novel locus for intellectual disability.

    PubMed

    Anazi, Shams; Shamseldin, Hanan E; AlNaqeb, Dhekra; Abouelhoda, Mohamed; Monies, Dorota; Salih, Mustafa A; Al-Rubeaan, Khalid; Alkuraya, Fowzan S

    2016-07-01

    Intellectual disability (ID) is one of the most common disabilities and, although many genes have been implicated in its etiology, the genetic heterogeneity of ID continues to expand. The purpose of the study was to describe a novel autosomal recessive non-syndromic ID locus. Autozygome and linkage analysis, and exome sequencing followed by RNA and protein analysis of the candidate disease gene were performed. We describe two multiplex consanguineous families with non-syndromic ID phenotype, which maps to a critical linkage locus on 3q26. Exome sequencing of the index in each family revealed the same homozygous truncating mutation in TNIK that results in complete loss of the protein. TNIK is a kinase with a well-established role in dendrite development and synaptic transmission. The phenotype we observe in human patients who lack TNIK is consistent with the previously published Tnik (-/-) phenotype in the murine model. Our data strongly implicate TNIK deficiency in the causation of ID in humans. PMID:27106596

  3. Leptin Resistance Contributes to Obesity in Mice with Null Mutation of Carcinoembryonic Antigen-related Cell Adhesion Molecule 1.

    PubMed

    Heinrich, Garrett; Russo, Lucia; Castaneda, Tamara R; Pfeiffer, Verena; Ghadieh, Hilda E; Ghanem, Simona S; Wu, Jieshen; Faulkner, Latrice D; Ergün, Süleyman; McInerney, Marcia F; Hill, Jennifer W; Najjar, Sonia M

    2016-05-20

    Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) promotes hepatic insulin clearance. Consistently, mice with null mutation of Ceacam1 (Cc1(-/-)) exhibit impaired insulin clearance with increased lipid production in liver and redistribution to white adipose tissue, leading to visceral obesity at 2 months of age. When the mutation is propagated on the C57/BL6J genetic background, total fat mass rises significantly with age, and glucose intolerance and systemic insulin resistance develop at 6 months of age. This study was carried out to determine the mechanisms underlying the marked increase in total fat mass in 6-month-old mutants. Indirect calorimetry analysis showed that Cc1(-/-) mice develop hyperphagia and a significant reduction in physical activity, in particular in the early hours of the dark cycle, during which energy expenditure is only slightly lower than in wild-type mice. They also exhibit increased triglyceride accumulation in skeletal muscle, due in part to incomplete fatty acid β-oxidation. Mechanistically, hypothalamic leptin signaling is reduced, as demonstrated by blunted STAT3 phosphorylation in coronal sections in response to an intracerebral ventricular injection of leptin. Hypothalamic fatty-acid synthase activity is also elevated in the mutants. Together, the data show that the increase in total fat mass in Cc1(-/-) mice is mainly attributed to hyperphagia and reduced spontaneous physical activity. Although the contribution of the loss of CEACAM1 from anorexigenic proopiomelanocortin neurons in the arcuate nucleus is unclear, leptin resistance and elevated hypothalamic fatty-acid synthase activity could underlie altered energy balance in these mice. PMID:27002145

  4. Sexually dimorphic effects of the Lhx7 null mutation on forebrain cholinergic function.

    PubMed

    Fragkouli, A; Stamatakis, A; Zographos, E; Pachnis, V; Stylianopoulou, F

    2006-01-01

    It has been reported recently that mice lacking both alleles of the LIM-homeobox gene Lhx7, display dramatically reduced number of forebrain cholinergic neurons. In the present study, we investigated whether the Lhx7 mutation affects male and female mice differently, given the fact that gender differences are consistently observed in forebrain cholinergic function. Our results show that in adult male as well as female Lhx7 homozygous mutants there is a dramatic loss of choline acetyltransferase immunoreactive forebrain neurons, both projection and interneurons. The reduction of forebrain choline acetyltransferase immunoreactive neurons in Lhx7 homozygous mutants is accompanied by a decrease of acetylcholinesterase histochemical staining in all forebrain cholinergic neuron target areas of both male and female homozygous mutants. Furthermore, there was an increase of M1-, but not M2-, muscarinic acetylcholine receptor binding site density in the somatosensory cortex and basal ganglia of only the female homozygous mutant mice. Such an increase can be regarded as a mechanism acting to compensate for the dramatically reduced cholinergic input, raising the possibility that the forebrain cholinergic system in female mice may be more plastic and responsive to situations of limited neurotransmitter availability. Finally, our study provides additional data for the sexual dimorphism of the forebrain cholinergic system, as female mice appear to have a lower density of M1-muscarinic acetylcholine receptors in the striatal areas of the basal ganglia and a higher density of M2-muscarinic acetylcholine receptors, in a number of cortical areas, as well as the striatal areas of the basal ganglia. PMID:16338089

  5. Null mutation of peroxisome proliferator-activated receptor-interacting protein in mammary glands causes defective mammopoiesis.

    PubMed

    Qi, Chao; Kashireddy, Papreddy; Zhu, Yiwei Tony; Rao, Sambasiva M; Zhu, Yi-Jun

    2004-08-01

    To investigate the role of nuclear receptor coactivator peroxisome proliferator-activated receptor-interacting protein (PRIP) in mammary gland development, we generated a conditional null mutation of PRIP in mammary glands. In PRIP-deficient mammary glands, the elongation of ducts during puberty was not affected, but the numbers of ductal branches were decreased, a condition that persisted long after puberty, indicating that the potential of ductal branching was impaired. During pregnancy, PRIP-deficient mammary glands exhibited decreased alveolar density. The lactating PRIP-deficient glands contained scant lobuloalveoli with many adipocytes, whereas the wild type glands were composed of virtually no adipocytes but mostly lobuloalveoli. As a result, PRIP mammary-deficient glands could not produce enough milk to nurse all the pups during lactation. The ductal branching of mammary glands in response to estrogen treatment was attenuated in PRIP mutant glands. Whereas the proliferation index was similar between wild type and PRIP-deficient glands, increased apoptosis was observed in PRIP-deficient glands. PRIP-deficient glands expressed increased amphiregulin, transforming growth factor-alpha, and betacellulin mRNA as compared with wild type glands. The differentiated function of PRIP-deficient mammary epithelial cells was largely intact, as evidenced by the expression of abundant beta-casein, whey acidic protein (WAP), and WDNM1 mRNA. We conclude that PRIP is important for normal mammary gland development. PMID:15161927

  6. Null Mutations of NT-3 and Bax Affect Trigeminal Ganglion Cell Number but Not Brainstem Barrelette Pattern Formation

    PubMed Central

    Mosconi, Tony; Arends, J.J.; Jacquin, Mark F.

    2014-01-01

    Trigeminal ganglion (TG) neurons innervate the grid-like array of whisker follicles on the face of the mouse. Central TG axons project to the trigeminal (V) brainstem nuclear complex, including the nucleus principalis (PrV), and the spinal subnucleus interpolaris (SpVi), where they innervate barrelettes that are organized in a pattern that recapitulates the whisker pattern on the face. Neurotrophin-3 (NT-3) supports a population of TG cells that supply slowly adapting mechanoreceptors in the whisker pad. We examined mice at embryonic day 17 (E17) and on the day of birth (P0) with null mutations of NT-3, Bax, a proapoptotic gene associated with naturally occurring cell death, and Bax/NT-3 double knockout mutants to determine if: 1) the number of TG cells would be reduced; 2) eliminating the Bax gene would rescue the NT-3 dependent neurons; and 3) the central projections of the rescued axons in the Bax/NT-3 double knockout mice would fail to develop the barrelette patterns in the PrV and SpVi subnuclei. In mice at E17, NT-3−/− mutants had 65% fewer TG neurons than found in age matched wild-type (WT) mice, and at P0, the number was reduced by 55% (p < 0.001 for both). Bax null mutant mice at E17 had 132% of the WT number of TG cells (p < 0.001), although the numbers returned to WT levels by P0. Bax/NT-3 double knockout mice at E17 had TG cell numbers equal to those seen in WT, but the double knockout failed to retain WT TG neuron numbers in P0 mice (39% fewer cells; p < 0.001). In all cases of reduced experimental neuron numbers, and in the E17 Bax−/− mice with supernumerary cells, the barrelette patterns in the PrV and SpVi were normal. Only a slight qualitative reduction in overall barrelette field area and clarity of barrelettes were seen. These results suggest that NT-3 is not necessary for barrelette pattern formation in the brainstem. PMID:23614607

  7. The common missense mutation D489N in TRIM32 causing limb girdle muscular dystrophy 2H leads to loss of the mutated protein in knock-in mice resulting in a Trim32-null phenotype.

    PubMed

    Kudryashova, Elena; Struyk, Arie; Mokhonova, Ekaterina; Cannon, Stephen C; Spencer, Melissa J

    2011-10-15

    Mutations in tripartite motif protein 32 (TRIM32) are responsible for several hereditary disorders that include limb girdle muscular dystrophy type 2H (LGMD2H), sarcotubular myopathy (STM) and Bardet Biedl syndrome. Most LGMD2H mutations in TRIM32 are clustered in the NHL β-propeller domain at the C-terminus and are predicted to interfere with homodimerization. To get insight into TRIM32's role in the pathogenesis of LGMD2H and to create an accurate model of disease, we have generated a knock-in mouse (T32KI) carrying the c.1465G > A (p.D489N) mutation in murine Trim32 corresponding to the human LGMD2H/STM pathogenic mutation c.1459G > A (p.D487N). Our data indicate that T32KI mice have both a myopathic and a neurogenic phenotype, very similar to the one described in the Trim32-null mice that we created previously. Analysis of Trim32 gene expression in T32KI mice revealed normal mRNA levels, but a severe reduction in mutant TRIM32 (D489N) at the protein level. Our results suggest that the D489N pathogenic mutation destabilizes the protein, leading to its degradation, and results in the same mild myopathic and neurogenic phenotype as that found in Trim32-null mice. Thus, one potential mechanism of LGMD2H might be destabilization of mutated TRIM32 protein leading to a null phenotype. PMID:21775502

  8. Synergistic effect of Tim4 and MFG-E8 null mutations on the development of autoimmunity.

    PubMed

    Miyanishi, Masanori; Segawa, Katsumori; Nagata, Shigekazu

    2012-09-01

    Phagocytes, including macrophages, recognize phosphatidylserine exposed on apoptotic cells as an "eat me" signal. Milk Fat Globule EGF Factor VIII (MFG-E8) is secreted by one subset of macrophages, whereas Tim4, a type I membrane protein, is expressed by another. These proteins bind tightly to phosphatidylserine on apoptotic cells and enhance their engulfment by macrophages. To study the contribution of these proteins to the engulfment of apoptotic cells, we established a mouse line that was deficient in the genes encoding MFG-E8 and Tim4. The null mutation of Tim4 impaired the ability of resident peritoneal macrophages, but not thioglycollate-elicited macrophages, to engulf apoptotic cells. Mice deficient in either MFG-E8 or Tim4 on the C57BL/6 background developed hardly any autoantibodies, but aged female mice deficient in both MFG-E8 and Tim4 developed autoantibodies in an age-dependent manner. Tumour necrosis factor (TNF) α is known to protect against systemic lupus erythematosus-type autoimmunity, whereas type I IFN accelerates the disease. Indeed, the administration of an anti-TNFα antibody or a reagent that stimulates the IFN-α production [2,6,10,14-tetramethylpentadecane (TMPD; also known as pristane)] enhanced the production of autoantibodies in the MFG-E8- and Tim4-double-deficient mice. These results suggest that the double deficiency of Tim4 and MFG-E8, phosphatidylserine-binding proteins, can trigger autoimmunity and that TNFα and type I IFN regulate reciprocally the development of autoimmune disease. PMID:22723547

  9. N-ethyl-N-nitrosourea-induced null mutation at the mouse Car-2 locus: an animal model for human carbonic anhydrase II deficiency syndrome.

    PubMed Central

    Lewis, S E; Erickson, R P; Barnett, L B; Venta, P J; Tashian, R E

    1988-01-01

    Electrophoretic screening of (C57BL/6J x DBA/2J)F1 progeny of male mice treated with N-ethyl-N-nitrosourea revealed a mouse that lacked the paternal carbonic anhydrase II (CA II). Breeding tests showed that this trait was heritable and due to a null mutation at the Car-2 locus on chromosome 3. Like humans with the same inherited enzyme defect, animals homozygous for the new null allele are runted and have renal tubular acidosis. However, the prominent osteopetrosis found in humans with CA II deficiency could not be detected even in very old homozygous null mice. A molecular analysis of the deficient mice shows that the mutant gene is not deleted and is transcribed. The CA II protein, which is normally expressed in most tissues, could not be detected by immunodiffusion analysis in any tissues of the CA II-deficient mice, suggesting a nonsense or a missense mutation at the Car-2 locus. Images PMID:3126501

  10. Pro- and anti-atherogenic effects of a dominant negative P465L mutation of PPARγ in apolipoprotein E-null mice

    PubMed Central

    Pendse, Avani A.; Johnson, Lance A.; Kim, Hyung-Suk; McNair, Marcus; Nipp, C. Taylor; Wilhelm, Carolyn; Maeda, Nobuyo

    2012-01-01

    Objective The dominant-negative mutation, P467L, in Peroxisome Proliferator Activated Receptor gamma (PPARγ) affects adipose tissue distribution, insulin sensitivity and blood pressure in heterozygous humans. We hypothesized that the equivalent mutation, PPARγ-P465L, in mice will worsen atherosclerosis. Methods and Results ApolipoproteinE-null mice with and without PPARγ-P465L mutation were bred in 129S6 inbred genetic background. Mild hypertension and lipodystrophy of PPARγ-P465L persisted in the apoE-null background. Glucose homeostasis was normal, but plasma adiponectin was significantly lower and resistin was higher in PPARγ-P465L mice. Plasma cholesterol and lipoprotein distribution were not different, but plasma triglycerides tended to be reduced. Surprisingly, there were no overall changes in the atherosclerotic plaque size or composition. PPARγ-P465L macrophages had a small decrease in CD-36 mRNA and a small yet significant reduction in VLDL uptake in culture. In unloaded apoE-null macrophages with PPARγ-P465L, cholesterol uptake was reduced while apoAI-mediated efflux was increased. However, when cells were cholesterol loaded in presence of acetylated LDL, no genotype difference in uptake or efflux was apparent. A reduction of VCAM1 expression in aorta suggests a relatively anti-atherogenic vascular environment in mice with PPARγ-P465L. Conclusions Small, competing pro- and anti-atherogenic effects of PPARγ-P465L mutation result in unchanged plaque development in apoE-deficient mice. PMID:22539598

  11. The anti-leukemic activity of sodium dichloroacetate in p53mutated/null cells is mediated by a p53-independent ILF3/p21 pathway

    PubMed Central

    Agnoletto, Chiara; Brunelli, Laura; Melloni, Elisabetta; Pastorelli, Roberta; Casciano, Fabio; Rimondi, Erika; Rigolin, Gian Matteo; Cuneo, Antonio; Secchiero, Paola; Zauli, Giorgio

    2015-01-01

    B-chronic lymphocytic leukemia (B-CLL) patients harboring p53 mutations are invariably refractory to therapies based on purine analogues and have limited treatment options and poor survival. Having recently demonstrated that the mitochondria-targeting small molecule sodium dichloroacetate (DCA) exhibits anti-leukemic activity in p53wild-type B-CLL cells, the aim of this study was to evaluate the effect of DCA in p53mutated B-CLL cells and in p53mutated/null leukemic cell lines. DCA exhibited comparable cytotoxicity in p53wild-type and p53mutated B-CLL patient cell cultures, as well as in p53mutated B leukemic cell lines (MAVER, MEC-1, MEC-2). At the molecular level, DCA promoted the transcriptional induction of p21 in all leukemic cell types investigated, including p53null HL-60. By using a proteomic approach, we demonstrated that DCA up-regulated the ILF3 transcription factor, which is a known regulator of p21 expression. The role of the ILF3/p21 axis in mediating the DCA anti-leukemic activity was underscored by knocking-down experiments. Indeed, transfection with ILF3 and p21 siRNAs significantly decreased both the DCA-induced p21 expression and the DCA-mediated cytotoxicity. Taken together, our results emphasize that DCA is a small molecule that merits further evaluation as a therapeutic agent also for p53mutated leukemic cells, by acting through the induction of a p53-independent pathway. PMID:25544776

  12. Ethanol-Induced Alcohol Dehydrogenase E (AdhE) Potentiates Pneumolysin in Streptococcus pneumoniae

    PubMed Central

    Luong, Truc Thanh; Kim, Eun-Hye; Bak, Jong Phil; Nguyen, Cuong Thach; Choi, Sangdun; Briles, David E.; Pyo, Suhkneung

    2014-01-01

    Alcohol impairs the host immune system, rendering the host more vulnerable to infection. Therefore, alcoholics are at increased risk of acquiring serious bacterial infections caused by Streptococcus pneumoniae, including pneumonia. Nevertheless, how alcohol affects pneumococcal virulence remains unclear. Here, we showed that the S. pneumoniae type 2 D39 strain is ethanol tolerant and that alcohol upregulates alcohol dehydrogenase E (AdhE) and potentiates pneumolysin (Ply). Hemolytic activity, colonization, and virulence of S. pneumoniae, as well as host cell myeloperoxidase activity, proinflammatory cytokine secretion, and inflammation, were significantly attenuated in adhE mutant bacteria (ΔadhE strain) compared to D39 wild-type bacteria. Therefore, AdhE might act as a pneumococcal virulence factor. Moreover, in the presence of ethanol, S. pneumoniae AdhE produced acetaldehyde and NADH, which subsequently led Rex (redox-sensing transcriptional repressor) to dissociate from the adhE promoter. An increase in AdhE level under the ethanol condition conferred an increase in Ply and H2O2 levels. Consistently, S. pneumoniae D39 caused higher cytotoxicity to RAW 264.7 cells than the ΔadhE strain under the ethanol stress condition, and ethanol-fed mice (alcoholic mice) were more susceptible to infection with the D39 wild-type bacteria than with the ΔadhE strain. Taken together, these data indicate that AdhE increases Ply under the ethanol stress condition, thus potentiating pneumococcal virulence. PMID:25312953

  13. The ADH7 Promoter of Saccharomyces cerevisiae is Vanillin-Inducible and Enables mRNA Translation Under Severe Vanillin Stress.

    PubMed

    Nguyen, Trinh T M; Iwaki, Aya; Izawa, Shingo

    2015-01-01

    Vanillin is one of the major phenolic aldehyde compounds derived from lignocellulosic biomass and acts as a potent fermentation inhibitor to repress the growth and fermentative ability of yeast. Vanillin can be reduced to its less toxic form, vanillyl alcohol, by the yeast NADPH-dependent medium chain alcohol dehydrogenases, Adh6 and Adh7. However, there is little information available regarding the regulation of their gene expression upon severe vanillin stress, which has been shown to repress the bulk translation activity in yeast cells. Therefore, in this study, we investigated expression patterns of the ADH6 and ADH7 genes in the presence of high concentrations of vanillin. We found that although both genes were transcriptionally upregulated by vanillin stress, they showed different protein expression patterns in response to vanillin. Expression of Adh6 was constitutive and gradually decreased under vanillin stress, whereas expression of Adh7 was inducible, and, importantly, occurred under severe vanillin stress. The null mutants of ADH6 or ADH7 genes were hypersensitive to vanillin and reduced vanillin less efficiently than the wild type, confirming the importance of Adh6 and Adh7 in vanillin detoxification. Additionally, we demonstrate that the ADH7 promoter is vanillin-inducible and enables effective protein synthesis even under severe vanillin stress, and it may be useful for the improvement of vanillin-tolerance and biofuel production efficiency via modification of yeast gene expression in the presence of high concentrations of vanillin. PMID:26696995

  14. The ADH7 Promoter of Saccharomyces cerevisiae is Vanillin-Inducible and Enables mRNA Translation Under Severe Vanillin Stress

    PubMed Central

    Nguyen, Trinh T. M.; Iwaki, Aya; Izawa, Shingo

    2015-01-01

    Vanillin is one of the major phenolic aldehyde compounds derived from lignocellulosic biomass and acts as a potent fermentation inhibitor to repress the growth and fermentative ability of yeast. Vanillin can be reduced to its less toxic form, vanillyl alcohol, by the yeast NADPH-dependent medium chain alcohol dehydrogenases, Adh6 and Adh7. However, there is little information available regarding the regulation of their gene expression upon severe vanillin stress, which has been shown to repress the bulk translation activity in yeast cells. Therefore, in this study, we investigated expression patterns of the ADH6 and ADH7 genes in the presence of high concentrations of vanillin. We found that although both genes were transcriptionally upregulated by vanillin stress, they showed different protein expression patterns in response to vanillin. Expression of Adh6 was constitutive and gradually decreased under vanillin stress, whereas expression of Adh7 was inducible, and, importantly, occurred under severe vanillin stress. The null mutants of ADH6 or ADH7 genes were hypersensitive to vanillin and reduced vanillin less efficiently than the wild type, confirming the importance of Adh6 and Adh7 in vanillin detoxification. Additionally, we demonstrate that the ADH7 promoter is vanillin-inducible and enables effective protein synthesis even under severe vanillin stress, and it may be useful for the improvement of vanillin-tolerance and biofuel production efficiency via modification of yeast gene expression in the presence of high concentrations of vanillin. PMID:26696995

  15. Long-term improvements in sensory inhibition with gestational choline supplementation linked to α7 nicotinic receptors through studies in Chrna7 null mutation mice.

    PubMed

    Stevens, Karen E; Choo, Kevin S; Stitzel, Jerry A; Marks, Michael J; Adams, Catherine E

    2014-03-13

    Perinatal choline supplementation has produced several benefits in rodent models, from improved learning and memory to protection from the behavioral effects of fetal alcohol exposure. We have shown that supplemented choline through gestation and lactation produces long-term improvement in deficient sensory inhibition in DBA/2 mice which models a similar deficit in schizophrenia patients. The present study extends that research by feeding normal or supplemented choline diets to DBA/2 mice carrying the null mutation for the α7 nicotinic receptor gene (Chrna7). DBA/2 mice heterozygotic for Chrna7 were bred together. Dams were placed on supplemented (5 gm/kg diet) or normal (1.1 gm/kg diet) choline at mating and remained on the specific diet until offspring weaning. Thereafter, offspring were fed standard rodent chow. Adult offspring were assessed for sensory inhibition. Brains were obtained to ascertain hippocampal α7 nicotinic receptor levels. Choline-supplemented mice heterozygotic or null-mutant for Chrna7 failed to show improvement in sensory inhibition. Only wildtype choline-supplemented mice showed improvement with the effect solely through a decrease in test amplitude. This supports the hypothesis that gestational-choline supplementation is acting through the α7 nicotinic receptor to improve sensory inhibition. Although there was a significant gene-dose-related change in hippocampal α7 receptor numbers, binding studies did not reveal any choline-dose-related change in binding in any hippocampal region, the interaction being driven by a significant genotype main effect (wildtype>heterozygote>null mutant). These data parallel a human study wherein the offspring of pregnant women receiving choline supplementation during gestation, showed better sensory inhibition than offspring of women on placebo. PMID:24462939

  16. Axonopathy in the Central Nervous System Is the Hallmark of Mice with a Novel Intragenic Null Mutation of Dystonin.

    PubMed

    Seehusen, Frauke; Kiel, Kirsten; Jottini, Stefano; Wohlsein, Peter; Habierski, Andre; Seibel, Katharina; Vogel, Tanja; Urlaub, Henning; Kollmar, Martin; Baumgärtner, Wolfgang; Teichmann, Ulrike

    2016-09-01

    Dystonia musculorum is a neurodegenerative disorder caused by a mutation in the dystonin gene. It has been described in mice and humans where it is called hereditary sensory autonomic neuropathy. Mutated mice show severe movement disorders and die at the age of 3-4 weeks. This study describes the discovery and molecular, clinical, as well as pathological characterization of a new spontaneously occurring mutation in the dystonin gene in C57BL/6N mice. The mutation represents a 40-kb intragenic deletion allele of the dystonin gene on chromosome 1 with exactly defined deletion borders. It was demonstrated by Western blot, mass spectrometry, and immunohistology that mice with a homozygous mutation were entirely devoid of the dystonin protein. Pathomorphological lesions were restricted to the brain stem and spinal cord and consisted of swollen, argyrophilic axons and dilated myelin sheaths in the white matter and, less frequently, total chromatolysis of neurons in the gray matter. Axonal damage was detected by amyloid precursor protein and nonphosphorylated neurofilament immunohistology. Axonopathy in the central nervous system (CNS) represents the hallmark of this disease. Mice with the dystonin mutation also showed suppurative inflammation in the respiratory tract, presumably due to brain stem lesion-associated food aspiration, whereas skeletal muscles showed no pathomorphological changes. This study describes a novel mutation in the dystonin gene in mice leading to axonopathy in the CNS. In further studies, this model may provide new insights into the pathogenesis of neurodegenerative diseases and may elucidate the complex interactions of dystonin with various other cellular proteins especially in the CNS. PMID:27401753

  17. Inheritance of low-frequency regulatory SNPs and a rare null mutation in exon-junction complex subunit RBM8A causes TAR

    PubMed Central

    Albers, Cornelis A; Paul, Dirk S; Schulze, Harald; Freson, Kathleen; Stephens, Jonathan C; Smethurst, Peter A; Jolley, Jennifer D; Cvejic, Ana; Kostadima, Myrto; Bertone, Paul; Breuning, Martijn H; Debili, Najet; Deloukas, Panos; Favier, Rémi; Fiedler, Janine; Hobbs, Catherine M; Huang, Ni; Hurles, Matthew E; Kiddle, Graham; Krapels, Ingrid; Nurden, Paquita; Ruivenkamp, Claudia A L; Sambrook, Jennifer G; Smith, Kenneth; Stemple, Derek L; Strauss, Gabriele; Thys, Chantal; van Geet, Christel; Newbury-Ecob, Ruth; Ouwehand, Willem H; Ghevaert, Cedric

    2012-01-01

    The exon-junction complex (EJC) performs essential RNA processing tasks1-5. Here, we describe the first human disorder, Thrombocytopenia with Absent Radii6 (TAR), caused by deficiency in one of the four EJC subunits. A compound inheritance mechanism of a rare null allele and one of two low-frequency SNPs in the regulatory regions of RBM8A, encoding the Y14 subunit of EJC, causes TAR. We found that this mechanism explained 53 of 55 cases (P<5×10−228) with the rare congenital malformation syndrome. Fifty-one of those 53 carried a previously associated7 submicroscopic deletion of 1q21.1; two carried a truncation or frameshift null mutation in RBM8A. We show that the two regulatory SNPs result in reduction of RBM8A transcription in vitro and that Y14 expression is reduced in platelets from TAR cases. Our data implicate Y14 insufficiency, and presumably EJC defect, as the cause of TAR syndrome. PMID:22366785

  18. Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome.

    PubMed

    Albers, Cornelis A; Paul, Dirk S; Schulze, Harald; Freson, Kathleen; Stephens, Jonathan C; Smethurst, Peter A; Jolley, Jennifer D; Cvejic, Ana; Kostadima, Myrto; Bertone, Paul; Breuning, Martijn H; Debili, Najet; Deloukas, Panos; Favier, Rémi; Fiedler, Janine; Hobbs, Catherine M; Huang, Ni; Hurles, Matthew E; Kiddle, Graham; Krapels, Ingrid; Nurden, Paquita; Ruivenkamp, Claudia A L; Sambrook, Jennifer G; Smith, Kenneth; Stemple, Derek L; Strauss, Gabriele; Thys, Chantal; van Geet, Chris; Newbury-Ecob, Ruth; Ouwehand, Willem H; Ghevaert, Cedric

    2012-04-01

    The exon-junction complex (EJC) performs essential RNA processing tasks. Here, we describe the first human disorder, thrombocytopenia with absent radii (TAR), caused by deficiency in one of the four EJC subunits. Compound inheritance of a rare null allele and one of two low-frequency SNPs in the regulatory regions of RBM8A, encoding the Y14 subunit of EJC, causes TAR. We found that this inheritance mechanism explained 53 of 55 cases (P < 5 × 10(-228)) of the rare congenital malformation syndrome. Of the 53 cases with this inheritance pattern, 51 carried a submicroscopic deletion of 1q21.1 that has previously been associated with TAR, and two carried a truncation or frameshift null mutation in RBM8A. We show that the two regulatory SNPs result in diminished RBM8A transcription in vitro and that Y14 expression is reduced in platelets from individuals with TAR. Our data implicate Y14 insufficiency and, presumably, an EJC defect as the cause of TAR syndrome. PMID:22366785

  19. A Novel DNA-Binding Protein Bound to the Mitochondrial Inner Membrane Restores the Null Mutation of Mitochondrial Histone Abf2p in Saccharomyces cerevisiae

    PubMed Central

    Cho, Jae Hyoung; Ha, Sang Jin; Kao, Ling Rong; Megraw, Timothy L.; Chae, Chi-Bom

    1998-01-01

    The yeast mitochondrial HMG-box protein, Abf2p, is essential for maintenance of the mitochondrial genome. To better understand the role of Abf2p in the maintenance of the mitochondrial chromosome, we have isolated a multicopy suppressor (YHM2) of the temperature-sensitive defect associated with an abf2 null mutation. The function of Yhm2p was characterized at the molecular level. Yhm2p has 314 amino acid residues, and the deduced amino acid sequence is similar to that of a family of mitochondrial carrier proteins. Yhm2p is localized in the mitochondrial inner membrane and is also associated with mitochondrial DNA in vivo. Yhm2p exhibits general DNA-binding activity in vitro. Thus, Yhm2p appears to be novel in that it is a membrane-bound DNA-binding protein. A sequence that is similar to the HMG DNA-binding domain is important for the DNA-binding activity of Yhm2p, and a mutation in this region abolishes the ability of YHM2 to suppress the temperature-sensitive defect of respiration of the abf2 null mutant. Disruption of YHM2 causes a significant growth defect in the presence of nonfermentable carbon sources such as glycerol and ethanol, and the cells have defects in respiration as determined by 2,3,5,-triphenyltetrazolium chloride staining. Yhm2p may function as a member of the protein machinery for the mitochondrial inner membrane attachment site of mitochondrial DNA during replication and segregation of mitochondrial genomes. PMID:9742088

  20. A genetic analysis of Adh1 regulation

    SciTech Connect

    Freeling, M.

    1992-01-01

    The overall goal of our research proposal is to understand the meaning of the various cis-acting sites responsible for AdH1 expression in the entire maize plant. Progress is reported in the following areas: Studies on the TATA box and analysis of revertants of the Adh1-3F1124 allele; screening for more different mutants that affect Adh1 expression differentially; studies on cis-acting sequences required for root-specific Adh1 expression; refinement of the use of the particle gun; and functional analysis of a non- glycolytic anaerobic protein.

  1. NOD/SCID IL2Rγ-null mouse xenograft model of human p53-mutated chronic lymphocytic leukemia and ATM-mutated mantle cell lymphoma using permanent cell lines.

    PubMed

    Verner, Jan; Trbusek, Martin; Chovancova, Jana; Jaskova, Zuzana; Moulis, Mojmir; Folber, Frantisek; Halouzka, Roman; Mayer, Jiri; Pospisilova, Sarka; Doubek, Michael

    2015-01-01

    Xenograft models represent a promising tool to study the pathogenesis of hematological malignancies. To establish a reliable and appropriate in vivo model of aggressive human B-cell leukemia and lymphoma we xenotransplanted four p53-mutated cell lines and one ATM-mutated cell line into immunodeficient NOD/SCID IL2Rγ-null mice. The cell lines MEC-1, SU-DHL-4, JEKO-1, REC-1, and GRANTA-519 were transplanted intraperitoneally or subcutaneously and the engraftment was investigated using immunohistochemistry and flow cytometry. We found significant differences in engraftment efficiency. MEC-1, JEKO-1 and GRANTA-519 cell lines engrafted most efficiently, while SU-DHL-4 cells did not engraft at all. MEC-1 and GRANTA-519 massively infiltrated organs and the whole intraperitoneal cavity showing very aggressive growth. In addition, GRANTA-519 cells massively migrated to the bone marrow regardless of the transplantation route. The MEC-1 and GRANTA-519 cells can be especially recommended for in vivo study of p53-mutated chronic lymphocytic leukemia and ATM-mutated mantle cell lymphoma, respectively. PMID:25827173

  2. Suppressors of ssy1 and ptr3 null mutations define novel amino acid sensor-independent genes in Saccharomyces cerevisiae.

    PubMed Central

    Forsberg, H; Hammar, M; Andréasson, C; Molinér, A; Ljungdahl, P O

    2001-01-01

    Ssy1p and Ptr3p are components of the yeast plasma membrane SPS amino acid sensor. In response to extracellular amino acids this sensor initiates metabolic signals that ultimately regulate the functional expression of several amino acid-metabolizing enzymes and amino acid permeases (AAPs). As a result of diminished leucine uptake capabilities, ssy1Delta leu2 and ptr3Delta leu2 mutant strains are unable to grow on synthetic complete medium (SC). Genes affecting the functional expression of AAPs were identified by selecting spontaneous suppressing mutations in amino acid sensor-independent (ASI) genes that restore growth on SC. The suppressors define 11 recessive (asi) complementation groups and 5 dominant (ASI) linkage groups. Strains with mutations in genes assigned to these 16 groups fall into two phenotypic classes. Mutations in the class I genes (ASI1, ASI2, ASI3, TUP1, SSN6, ASI13) derepress the transcription of AAP genes. ASI1, ASI2, and ASI3 encode novel membrane proteins, and Asi1p and Asi3p are homologous proteins that have conserved ubiquitin ligase-like RING domains at their extreme C termini. Several of the class II genes (DOA4, UBA1, BRO1, BUL1, RSP5, VPS20, VPS36) encode proteins implicated in controlling aspects of post-Golgi endosomal-vacuolar protein sorting. The results from genetic and phenotypic analysis indicate that SPS sensor-initiated signals function positively to facilitate amino acid uptake and that two independent ubiquitin-mediated processes negatively modulate amino acid uptake. PMID:11454748

  3. Characterization of the temperate bacteriophage phi adh and plasmid transduction in Lactobacillus acidophilus ADH.

    PubMed Central

    Raya, R R; Kleeman, E G; Luchansky, J B; Klaenhammer, T R

    1989-01-01

    Lactobacillus acidophilus ADH is lysogenic and harbors an inducible prophage, phi adh. Bacteriophage were detected in cell lysates induced by treatment with mitomycin C or UV light. Electron microscopy of lysates revealed phage particles with a hexagonal head (62 nm) and a long, noncontractile, flexible tail (398 nm) ending in at last five short fibers. Phage phi adh was classified within Bradley's B1 phage group and the Siphoviridae family. The phi adh genome is a linear double-stranded DNA molecule of 41.7 kilobase pairs with cohesive ends: a physical map of the phi adh genome was constructed. A prophage-cured derivative of strain ADH, designated NCK102, was isolated from cells that survived UV exposure. NCK102 did not exhibit mitomycin C-induced lysis, but broth cultures lysed upon addition of phage. Phage phi adh produced clear plaques on NCK102 in media containing 10 mM CaCl2 at pH values between 5.2 and 5.5. A relysogenized derivative (NCK103) of NCK102 was isolated that exhibited mitomycin C-induced lysis and superinfection immunity to phage phi adh. Hybridization experiments showed that the phi adh genome was present in the ADH and NCK103 chromosomes, but absent in NCK102. These results demonstrated classic lytic and lysogenic cycles of replication for the temperate phage phi adh induced from L. acidophilus ADH. Phage phi adh also mediates transduction of plasmid DNA. Transductants of strain ADH containing pC194, pGK12, pGB354, and pVA797 were detected at frequencies in the range of 3.6 x 10(-8) to 8.3 x 10(-10) per PFU. Rearrangements or deletions were not detected in these plasmids as a consequence of transduction. This is the first description of plasmid transduction in the genus Lactobacillus. Images PMID:2508554

  4. A null mutation in the first enzyme of flavonoid biosynthesis does not affect male fertility in Arabidopsis.

    PubMed Central

    Burbulis, I E; Iacobucci, M; Shirley, B W

    1996-01-01

    Flavonoids are a major class of secondary metabolites that serves a multitude of functions in higher plants, including a recently discovered role in male fertility. Surprisingly, Arabidopsis plants deficient in flavonoid biosynthesis appear to be fully fertile. Using RNA gel blot analysis and polymerase chain reaction-based assays, we have shown that a mutation at the 3' splice acceptor site in the Arabidopsis chalcone synthase gene completely disrupts synthesis of the active form of the enzyme. We also confirmed that this enzyme, which catalyzes the first step of flavonoid biosynthesis, is encoded by a single-copy gene. HPLC analysis of whole flowers and stamens was used to show that plants homozygous for the splice site mutation are completely devoid of flavonoids. This work provides compelling evidence that despite the high levels of these compounds in the pollen of most plant species, flavonoids are not universally required for fertility. The role of flavonoids in plant reproduction may therefore offer an example of convergent functional evolution in secondary metabolism. PMID:8672888

  5. Subjects with isolated GH deficiency due to a null GHRHR mutation eat proportionally more, but healthier than controls.

    PubMed

    Oliveira-Santos, Alécia A; Salvatori, Roberto; Gomes-Santos, Elenilde; Santana, João A M; Leal, Ângela C G B; Barbosa, Rita A A; Oliveira, Carla R P; Souza, Anita H O; Valença, Eugênia H O; Aguiar-Oliveira, Manuel H

    2016-02-01

    The GH/IGF-I axis has important interactions with the alimentary system and with the balance between energy intake (EI) and energy requirement (ER). Reduced EI has been described in adult-onset acquired GH deficiency (GHD). Individuals from the Brazilian Itabaianinha cohort, with isolated GHD (IGHD) due to a homozygous mutation (c.57+1G→A) in the GHRH receptor gene, are an ideal model to study the consequences of lifetime GHD. The purpose of this study is to evaluate EI and ER in this untreated IGHD cohort. Cross-sectional study of 24 adult IGHD patients and 23 controls from the same region, matched for age and gender. Estimated EI (EEI) was evaluated by dietary recall, and estimated ER (EER) by the equation of the Dietary Reference Intakes. Fat mass was assessed by DXA. Both EEI and EER were lower in IGHD than controls. However, when corrected by body weight, EEI was higher in IGHD (p = 0.005). IGHD individuals consume in percentage more proteins (p < 0.0001), less carbohydrates (p = 0.013), and equal amount of lipids in comparison to controls. The higher EEI per body weight suggests a possible increase of orexigenic mechanisms in untreated IGHD individuals, ensuring greater caloric intake, which would have adaptive advantages for small-sized individuals in environments with limited access to food. IGHD individuals seem to have a healthier dietary pattern than CO. PMID:26100788

  6. Null steering of adaptive beamforming using linear constraint minimum variance assisted by particle swarm optimization, dynamic mutated artificial immune system, and gravitational search algorithm.

    PubMed

    Darzi, Soodabeh; Kiong, Tiong Sieh; Islam, Mohammad Tariqul; Ismail, Mahamod; Kibria, Salehin; Salem, Balasem

    2014-01-01

    Linear constraint minimum variance (LCMV) is one of the adaptive beamforming techniques that is commonly applied to cancel interfering signals and steer or produce a strong beam to the desired signal through its computed weight vectors. However, weights computed by LCMV usually are not able to form the radiation beam towards the target user precisely and not good enough to reduce the interference by placing null at the interference sources. It is difficult to improve and optimize the LCMV beamforming technique through conventional empirical approach. To provide a solution to this problem, artificial intelligence (AI) technique is explored in order to enhance the LCMV beamforming ability. In this paper, particle swarm optimization (PSO), dynamic mutated artificial immune system (DM-AIS), and gravitational search algorithm (GSA) are incorporated into the existing LCMV technique in order to improve the weights of LCMV. The simulation result demonstrates that received signal to interference and noise ratio (SINR) of target user can be significantly improved by the integration of PSO, DM-AIS, and GSA in LCMV through the suppression of interference in undesired direction. Furthermore, the proposed GSA can be applied as a more effective technique in LCMV beamforming optimization as compared to the PSO technique. The algorithms were implemented using Matlab program. PMID:25147859

  7. Null Steering of Adaptive Beamforming Using Linear Constraint Minimum Variance Assisted by Particle Swarm Optimization, Dynamic Mutated Artificial Immune System, and Gravitational Search Algorithm

    PubMed Central

    Sieh Kiong, Tiong; Tariqul Islam, Mohammad; Ismail, Mahamod; Salem, Balasem

    2014-01-01

    Linear constraint minimum variance (LCMV) is one of the adaptive beamforming techniques that is commonly applied to cancel interfering signals and steer or produce a strong beam to the desired signal through its computed weight vectors. However, weights computed by LCMV usually are not able to form the radiation beam towards the target user precisely and not good enough to reduce the interference by placing null at the interference sources. It is difficult to improve and optimize the LCMV beamforming technique through conventional empirical approach. To provide a solution to this problem, artificial intelligence (AI) technique is explored in order to enhance the LCMV beamforming ability. In this paper, particle swarm optimization (PSO), dynamic mutated artificial immune system (DM-AIS), and gravitational search algorithm (GSA) are incorporated into the existing LCMV technique in order to improve the weights of LCMV. The simulation result demonstrates that received signal to interference and noise ratio (SINR) of target user can be significantly improved by the integration of PSO, DM-AIS, and GSA in LCMV through the suppression of interference in undesired direction. Furthermore, the proposed GSA can be applied as a more effective technique in LCMV beamforming optimization as compared to the PSO technique. The algorithms were implemented using Matlab program. PMID:25147859

  8. Minimal influence of G-protein null mutations on ozone-induced changes in gene expression, foliar injury, gas exchange and peroxidase activity in Arabidopsis thaliana L

    PubMed Central

    Booker, Fitzgerald; Burkey, Kent; Morgan, Patrick; Fiscus, Edwin; Jones, Alan

    2016-01-01

    Ozone (O3) uptake by plants leads to an increase in reactive oxygen species (ROS) in the intercellular space of leaves and induces signalling processes reported to involve the membrane-bound heterotrimeric G-protein complex. Therefore, potential G-protein-mediated response mechanisms to O3 were compared between Arabidopsis thaliana L. lines with null mutations in the α- and β-subunits (gpa1-4, agb1-2 and gpa1-4/agb1-2) and Col-0 wild-type plants. Plants were treated with a range of O3 concentrations (5, 125, 175 and 300 nL L−1) for 1 and 2 d in controlled environment chambers. Transcript levels of GPA1, AGB1 and RGS1 transiently increased in Col-0 exposed to 125 nL L−1 O3 compared with the 5 nL L−1 control treatment. However, silencing of α and β G-protein genes resulted in little alteration of many processes associated with O3 injury, including the induction of ROS-signalling genes, increased leaf tissue ion leakage, decreased net photosynthesis and stomatal conductance, and increased peroxidase activity, especially in the leaf apoplast. These results indicated that many responses to O3 stress at physiological levels were not detectably influenced by α and β G-proteins. PMID:21988569

  9. Calcilytic Ameliorates Abnormalities of Mutant Calcium-Sensing Receptor (CaSR) Knock-In Mice Mimicking Autosomal Dominant Hypocalcemia (ADH).

    PubMed

    Dong, Bingzi; Endo, Itsuro; Ohnishi, Yukiyo; Kondo, Takeshi; Hasegawa, Tomoka; Amizuka, Norio; Kiyonari, Hiroshi; Shioi, Go; Abe, Masahiro; Fukumoto, Seiji; Matsumoto, Toshio

    2015-11-01

    Activating mutations of calcium-sensing receptor (CaSR) cause autosomal dominant hypocalcemia (ADH). ADH patients develop hypocalcemia, hyperphosphatemia, and hypercalciuria, similar to the clinical features of hypoparathyroidism. The current treatment of ADH is similar to the other forms of hypoparathyroidism, using active vitamin D3 or parathyroid hormone (PTH). However, these treatments aggravate hypercalciuria and renal calcification. Thus, new therapeutic strategies for ADH are needed. Calcilytics are allosteric antagonists of CaSR, and may be effective for the treatment of ADH caused by activating mutations of CaSR. In order to examine the effect of calcilytic JTT-305/MK-5442 on CaSR harboring activating mutations in the extracellular and transmembrane domains in vitro, we first transfected a mutated CaSR gene into HEK cells. JTT-305/MK-5442 suppressed the hypersensitivity to extracellular Ca(2+) of HEK cells transfected with the CaSR gene with activating mutations in the extracellular and transmembrane domains. We then selected two activating mutations locating in the extracellular (C129S) and transmembrane (A843E) domains, and generated two strains of CaSR knock-in mice to build an ADH mouse model. Both mutant mice mimicked almost all the clinical features of human ADH. JTT-305/MK-5442 treatment in vivo increased urinary cAMP excretion, improved serum and urinary calcium and phosphate levels by stimulating endogenous PTH secretion, and prevented renal calcification. In contrast, PTH(1-34) treatment normalized serum calcium and phosphate but could not reduce hypercalciuria or renal calcification. CaSR knock-in mice exhibited low bone turnover due to the deficiency of PTH, and JTT-305/MK-5442 as well as PTH(1-34) increased bone turnover and bone mineral density (BMD) in these mice. These results demonstrate that calcilytics can reverse almost all the phenotypes of ADH including hypercalciuria and renal calcification, and suggest that calcilytics can become a

  10. Primary structure and functional analysis of the lysis genes of Lactobacillus gasseri bacteriophage phi adh.

    PubMed

    Henrich, B; Binishofer, B; Bläsi, U

    1995-02-01

    The lysis genes of the Lactobacillus gasseri bacteriophage phi adh were isolated by complementation of a lambda Sam mutation in Escherichia coli. Nucleotide sequencing of a 1,735-bp DNA fragment revealed two adjacent coding regions of 342 bp (hol) and 951 bp (lys) in the same reading frame which appear to belong to a common transcriptional unit. Proteins corresponding to the predicted gene products, holin (12.9 kDa) and lysin (34.7 kDa), were identified by in vitro and in vivo expression of the cloned genes. The phi adh holin is a membrane-bound protein with structural similarity to lysis proteins of other phage, known to be required for the transit of murein hydrolases through the cytoplasmic membrane. The phi adh lysin shows homology with mureinolytic enzymes encoded by the Lactobacillus bulgaricus phage mv4, the Streptococcus pneumoniae phage Cp-1, Cp-7, and Cp-9, and the Lactococcus lactis phage phi LC3. Significant homology with the N termini of known muramidases suggests that phi adh lysin acts by a similar catalytic mechanism. In E. coli, the phi adh lysin seems to be associated with the total membrane fraction, from which it can be extracted with lauryl sarcosinate. Either one of the phi adh lysis proteins provoked lysis of E. coli when expressed along with holins or lysins of phage lambda or Bacillus subtilis phage phi 29. Concomitant expression of the combined holin and lysin functions of phi adh in E. coli, however, did not result in efficient cell lysis. PMID:7836307

  11. Post-translationally Abnormal Collagens of Prolyl 3-Hydroxylase-2 Null Mice Offer a Pathobiological Mechanism for the High Myopia Linked to Human LEPREL1 Mutations*

    PubMed Central

    Hudson, David M.; Joeng, Kyu Sang; Werther, Rachel; Rajagopal, Abbhirami; Weis, MaryAnn; Lee, Brendan H.; Eyre, David R.

    2015-01-01

    Myopia, the leading cause of visual impairment worldwide, results from an increase in the axial length of the eyeball. Mutations in LEPREL1, the gene encoding prolyl 3-hydroxylase-2 (P3H2), have recently been identified in individuals with recessively inherited nonsyndromic severe myopia. P3H2 is a member of a family of genes that includes three isoenzymes of prolyl 3-hydroxylase (P3H), P3H1, P3H2, and P3H3. Fundamentally, it is understood that P3H1 is responsible for converting proline to 3-hydroxyproline. This limited additional knowledge also suggests that each isoenzyme has evolved different collagen sequence-preferred substrate specificities. In this study, differences in prolyl 3-hydroxylation were screened in eye tissues from P3h2-null (P3h2n/n) and wild-type mice to seek tissue-specific effects due the lack of P3H2 activity on post-translational collagen chemistry that could explain myopia. The mice were viable and had no gross musculoskeletal phenotypes. Tissues from sclera and cornea (type I collagen) and lens capsule (type IV collagen) were dissected from mouse eyes, and multiple sites of prolyl 3-hydroxylation were identified by mass spectrometry. The level of prolyl 3-hydroxylation at multiple substrate sites from type I collagen chains was high in sclera, similar to tendon. Almost every known site of prolyl 3-hydroxylation in types I and IV collagen from P3h2n/n mouse eye tissues was significantly under-hydroxylated compared with their wild-type littermates. We conclude that altered collagen prolyl 3-hydroxylation is caused by loss of P3H2. We hypothesize that this leads to structural abnormalities in multiple eye tissues, but particularly sclera, causing progressive myopia. PMID:25645914

  12. Isolation and Identification of Genes Activating Uas2-Dependent Adh2 Expression in Saccharomyces Cerevisiae

    PubMed Central

    Donoviel, M. S.; Young, E. T.

    1996-01-01

    Two cis-acting elements have been identified that act synergistically to regulate expression of the glucose-repressed alcohol dehydrogenase 2 (ADH2) gene. UAS1 is bound by the trans-activator Adr1p. UAS2 is thought to be the binding site for an unidentified regulatory protein. A genetic selection based on a UAS2-dependent ADH2 reporter was devised to isolate genes capable of activating UAS2-dependent transcription. One set of UAS2-dependent genes contained SPT6/CRE2/SSN20. Multicopy SPT6 caused improper expression of chromosomal ADH2. A second set of UAS2-dependent clones contained a previously uncharacterized open reading frame designated MEU1 (Multicopy Enhancer of UAS2). A frame shift mutation in MEU1 abolished its ability to activate UAS2-dependent gene expression. Multicopy MEU1 expression suppressed the constitutive ADH2 expression caused by cre2-1. Disruption of MEU1 reduced endogenous ADH2 expression about twofold but had no effect on cell viability or growth. No homologues of MEU1 were identified by low-stringency Southern hybridization of yeast genomic DNA, and no significant homologues were found in the sequence data bases. A MEU1/β-gal fusion protein was not localized to a particular region of the cell. MEU1 is linked to PPR1 on chromosome XII. PMID:8807288

  13. ADH IB Expression, but Not ADH III, Is Decreased in Human Lung Cancer

    PubMed Central

    Mutka, Sarah C.; Green, Lucia H.; Verderber, Evie L.; Richards, Jane P.; Looker, Doug L.; Chlipala, Elizabeth A.; Rosenthal, Gary J.

    2012-01-01

    Endogenous S-nitrosothiols, including S-nitrosoglutathione (GSNO), mediate nitric oxide (NO)-based signaling, inflammatory responses, and smooth muscle function. Reduced GSNO levels have been implicated in several respiratory diseases, and inhibition of GSNO reductase, (GSNOR) the primary enzyme that metabolizes GSNO, represents a novel approach to treating inflammatory lung diseases. Recently, an association between decreased GSNOR expression and human lung cancer risk was proposed in part based on immunohistochemical staining using a polyclonal GSNOR antibody. GSNOR is an isozyme of the alcohol dehydrogenase (ADH) family, and we demonstrate that the antibody used in those studies cross reacts substantially with other ADH proteins and may not be an appropriate reagent. We evaluated human lung cancer tissue arrays using monoclonal antibodies highly specific for human GSNOR with minimal cross reactivity to other ADH proteins. We verified the presence of GSNOR in ≥85% of specimens examined, and extensive analysis of these samples demonstrated no difference in GSNOR protein expression between cancerous and normal lung tissues. Additionally, GSNOR and other ADH mRNA levels were evaluated quantitatively in lung cancer cDNA arrays by qPCR. Consistent with our immunohistochemical findings, GSNOR mRNA levels were not changed in lung cancer tissues, however the expression levels of other ADH genes were decreased. ADH IB mRNA levels were reduced (>10-fold) in 65% of the lung cancer cDNA specimens. We conclude that the previously reported results showed an incorrect association of GSNOR and human lung cancer risk, and a decrease in ADH IB, rather than GSNOR, correlates with human lung cancer. PMID:23285246

  14. ADH IB expression, but not ADH III, is decreased in human lung cancer.

    PubMed

    Mutka, Sarah C; Green, Lucia H; Verderber, Evie L; Richards, Jane P; Looker, Doug L; Chlipala, Elizabeth A; Rosenthal, Gary J

    2012-01-01

    Endogenous S-nitrosothiols, including S-nitrosoglutathione (GSNO), mediate nitric oxide (NO)-based signaling, inflammatory responses, and smooth muscle function. Reduced GSNO levels have been implicated in several respiratory diseases, and inhibition of GSNO reductase, (GSNOR) the primary enzyme that metabolizes GSNO, represents a novel approach to treating inflammatory lung diseases. Recently, an association between decreased GSNOR expression and human lung cancer risk was proposed in part based on immunohistochemical staining using a polyclonal GSNOR antibody. GSNOR is an isozyme of the alcohol dehydrogenase (ADH) family, and we demonstrate that the antibody used in those studies cross reacts substantially with other ADH proteins and may not be an appropriate reagent. We evaluated human lung cancer tissue arrays using monoclonal antibodies highly specific for human GSNOR with minimal cross reactivity to other ADH proteins. We verified the presence of GSNOR in ≥85% of specimens examined, and extensive analysis of these samples demonstrated no difference in GSNOR protein expression between cancerous and normal lung tissues. Additionally, GSNOR and other ADH mRNA levels were evaluated quantitatively in lung cancer cDNA arrays by qPCR. Consistent with our immunohistochemical findings, GSNOR mRNA levels were not changed in lung cancer tissues, however the expression levels of other ADH genes were decreased. ADH IB mRNA levels were reduced (>10-fold) in 65% of the lung cancer cDNA specimens. We conclude that the previously reported results showed an incorrect association of GSNOR and human lung cancer risk, and a decrease in ADH IB, rather than GSNOR, correlates with human lung cancer. PMID:23285246

  15. The role of aldehyde/alcohol dehydrogenase (AdhE) in ethanol production from glycerol by Klebsiella pneumoniae.

    PubMed

    Oh, Baek-Rock; Hong, Won-Kyung; Heo, Sun-Yeon; Joe, Min-ho; Seo, Jeong-Woo; Kim, Chul Ho

    2013-02-01

    Transcriptome analysis of a K. pneumoniae GEM167 mutant strain derived by irradiation with gamma rays, which exhibited high-level production of ethanol from glycerol, showed that the mutant expressed AdhE at a high level. Ethanol production decreased significantly, from 8.8 to 0.5 g l(-1), when an adhE-deficient derivative of that strain was grown on glycerol. Bacterial growth was also reduced under such conditions, showing that AdhE plays a critical role in maintenance of redox balance by catalyzing ethanol production. Overexpression of AdhE enhanced ethanol production, from pure or crude glycerol, to a maximal level of 31.9 g l(-1) under fed-batch fermentation conditions; this is the highest level of ethanol production from glycerol reported to date. PMID:23296976

  16. Differential interactions of promoter elements in stress responses of the Arabidopsis Adh gene.

    PubMed Central

    Dolferus, R; Jacobs, M; Peacock, W J; Dennis, E S

    1994-01-01

    The Adh (alcohol dehydrogenase, EC 1.1.1.1.) gene from Arabidopsis thaliana (L.) Heynh. can be induced by dehydration and cold, as well as by hypoxia. A 1-kb promoter fragment (CADH: -964 to +53) is sufficient to confer the stress induction and tissue-specific developmental expression characteristics of the Adh gene to a beta-glucuronidase reporter gene. Deletion mapping of the 5' end and site-specific mutagenesis identified four regions of the promoter essential for expression under the three stress conditions. Some sequence elements are important for response to all three stress treatments, whereas others are stress specific. The most critical region essential for expression of the Arabidopsis Adh promoter under all three environmental stresses (region IV: -172 to -141) contains sequences homologous to the GT motif (-160 to -152) and the GC motif (-147 to -144) of the maize Adh1 anaerobic responsive element. Region III (-235 to -172) contains two regions shown by R.J. Ferl and B.H. Laughner ([1989] Plant Mol Biol 12: 357-366) to bind regulatory proteins; mutation of the G-box-1 region (5'-CCACGTGG-3', -216 to -209) does not affect expression under uninduced or hypoxic conditions, but significantly reduces induction by cold stress and, to a lesser extent, by dehydration stress. Mutation of the other G-box-like sequence (G-box-2: 5'-CCAAGTGG-3', -193 to -182) does not change hypoxic response and affects cold and dehydration stress only slightly. G-box-2 mutations also promote high levels of expression under uninduced conditions. Deletion of region I (-964 to -510) results in increased expression under uninduced and all stress conditions, suggesting that this region contains a repressor binding site. Region II (-510 to -384) contains a positive regulatory element and is necessary for high expression levels under all treatments. PMID:7972489

  17. Data on docking and dynamics simulation of Entamoeba histolytica EhADH (an ALIX protein) and lysobisphosphatidic acid.

    PubMed

    Castellanos-Castro, Silvia; Montaño, Sarita; Orozco, Esther

    2016-06-01

    Entamoeba histolytica is the protozoan agent responsible for human amoebiasis. Trophozoites are highly phagocytic cells and the lysobisphosphatidic acid (LBPA) is involved in endocytosis. LBPA interacts with EhADH protein (an ALIX family member) also participating in phagocytosis, as it is referred in the research article Identification of the phospholipid lysobisphosphatidic acid in the protozoan Entamoeba histolytica: an active molecule in endocytosis (Castellanos-Castro et al., 2016) [1]. To unveil the interaction site between EhADH and LBPA, here we performed molecular modeling, dynamics simulation and docking. Molecular modeling and docking predictions revealed that EhADH interacts with LBPA through the Bro1 domain, located at the N-terminus of the protein and through the adherence domain at the C-terminus. In silico mutation abolished these interactions, supporting the data obtained in molecular dynamic and docking in silico assays. PMID:27014730

  18. Data on docking and dynamics simulation of Entamoeba histolytica EhADH (an ALIX protein) and lysobisphosphatidic acid

    PubMed Central

    Castellanos-Castro, Silvia; Montaño, Sarita; Orozco, Esther

    2016-01-01

    Entamoeba histolytica is the protozoan agent responsible for human amoebiasis. Trophozoites are highly phagocytic cells and the lysobisphosphatidic acid (LBPA) is involved in endocytosis. LBPA interacts with EhADH protein (an ALIX family member) also participating in phagocytosis, as it is referred in the research article Identification of the phospholipid lysobisphosphatidic acid in the protozoan Entamoeba histolytica: an active molecule in endocytosis (Castellanos-Castro et al., 2016) [1]. To unveil the interaction site between EhADH and LBPA, here we performed molecular modeling, dynamics simulation and docking. Molecular modeling and docking predictions revealed that EhADH interacts with LBPA through the Bro1 domain, located at the N-terminus of the protein and through the adherence domain at the C-terminus. In silico mutation abolished these interactions, supporting the data obtained in molecular dynamic and docking in silico assays. PMID:27014730

  19. Locus Adh of Drosophila melanogaster under selection for delayed senescence

    SciTech Connect

    Khaustova, N.D.

    1995-05-01

    Dynamics of the Adh activity and frequencies of alleles Adh{sup F} and Adh{sup S} were analyzed under selection for delayed senescence. The experiments were performed on Drosophila melanogaster. Lines Adh{sup S}cn and Adh{sup F}vg and experimental populations cn` and vg`, selected for an increased duration of reproductive period (late oviposition) were used. Analysis of fertility, longevity, viability and resistance to starvation showed that selection for late oviposition resulted in delayed senescence of flies of the experimental populations. Genetic structure of population vg` changed considerably with regard to the Adh locus. This was confirmed by parameters of activity, thermostability, and electrophoretic mobility of the enzyme isolated from flies after 30 generations of selection. Analysis of frequencies of the Adh alleles showed that in both selected populations, which initially had different genetic composition, accumulated allele Adh{sup S}, which encodes the isozyme that is less active but more resistant to inactivation. Genetic mechanism of delayed senescence in Drosophila is assumed to involve selection at vitally important enzyme loci, including Adh. 18 refs., 2 tabs., 4 figs.

  20. Null mutation of the nicotinamide adenine dinucleotide phosphate-oxidase subunit p67phox protects the Dahl-S rat from salt-induced reductions in medullary blood flow and glomerular filtration rate.

    PubMed

    Evans, Louise C; Ryan, Robert P; Broadway, Elizabeth; Skelton, Meredith M; Kurth, Theresa; Cowley, Allen W

    2015-03-01

    Null mutations in the p67(phox) subunit of nicotinamide adenine dinucleotide phosphate-oxidase confer protection from salt sensitivity on Dahl salt-sensitive rats. Here, we track the sequential changes in medullary blood flow (MBF), glomerular filtration rate (GFR), urinary protein, and mean arterial pressure in SSp67(phox) null rats and wild-type littermates during 21 days of 4.0% NaCl high-salt (HS) diet. Optical fibers were implanted in the renal medulla and MBF was measured in conscious rats by laser Doppler flowmetry. Separate groups of rats were prepared with femoral venous catheters and GFR was measured by the transcutaneous assessment of fluorescein isothiocyanate-sinistrin disappearance curves. Mean arterial blood pressure was measured by telemetry. In wild-type rats, HS caused a rapid reduction in MBF, which was significantly lower than control values by HS day-6. Reduced MBF was associated with a progressive increase in mean arterial pressure, averaging 170±5 mm Hg by HS salt day-21. A significant reduction in GFR was evident on day-14 HS, after the onset of hypertension and reduced MBF. In contrast, HS had no significant effect on MBF in SSp67(phox) null rats and the pressor response to sodium was blunted, averaging 150±3 mm Hg on day-21 HS. GFR was maintained throughout the study and proteinuria was reduced. In summary, when p67(phox) is not functional in the salt-sensitive rats, HS does not cause reduced MBF and salt-sensitive hypertension is attenuated, and consequently renal injury is reduced and GFR is maintained. PMID:25489057

  1. A null mutation in VAMP1/synaptobrevin is associated with neurological defects and prewean mortality in the lethal-wasting mouse mutant.

    PubMed

    Nystuen, Arne M; Schwendinger, Jamie K; Sachs, Andrew J; Yang, Andy W; Haider, Neena B

    2007-01-01

    The soluble N-ethylmaleimide sensitive factor attachment receptors are a large family of membrane-associated proteins that are critical for Ca(2+)-mediated synaptic vesicle release. This family includes the VAMP, synaptosomal-associated protein, and syntaxin proteins. In this report, we describe a mutation in vesicle-associated membrane protein 1(VAMP1)/synaptobrevin in the mouse neurological mutant lethal-wasting (lew). The lethal-wasting mutant phenotype is characterized by a general lack of movement and wasting, eventually leading to death before weaning. Mutants are visibly immobile and lay on their side by postnatal day 10 (P10). Before this stage, mutants can be identified by a failure to attempt to right themselves. Affected mice die on average at P15. We used a positional cloning strategy to identify the mutation associated with this neurological phenotype. Lethal wasting had previously been linked to chromosome 6. We further narrowed the genetic disease interval and selected a small number of candidate genes for mutation screening. Genes were evaluated by quantitative reverse transcription-polymerase chain reaction (RT-PCR) to detect differences in their expression levels between control and mutant brain ribonucleic acid (RNA) samples. VAMP1 mRNA was found to be significantly downregulated in the lethal-wasting brain compared to wild-type littermates. Subsequently, a nonsense mutation was identified in the coding region of the gene. This mutation is predicted to truncate approximately half of the protein; however, Western blot analysis showed that no protein is detectable in the mutant. VAMP1 is selectively expressed in the retina and in discrete areas of the brain including the zona incerta and rostral periolivary region, although no gross histological abnormalities were observed in these tissues. Taken together, these data indicate that VAMP1 has a vital role in a subset of central nervous system tissues. PMID:17102983

  2. Effects of endogenous antidiuretic hormone (ADH) on macrophage phagocytosis

    SciTech Connect

    Fernandez-Repollet, E.; Opava-Stitzer, S.; Tiffany, S.; Schwartz, A.

    1983-07-01

    Although several studies have indicated that antidiuretic hormone (ADH) enhances the phagocytic function of the reticuloendothelial system (RES) in shock syndromes, it remains unknown what influence ADH exerts upon the individual phagocytic components of this system. The present investigation was designed to evaluate the effects of endogenous ADH on the phagocytic activity of peritoneal macrophage cells. As a phagocytic stimuli, fluorescent methacrylate microbeads were injected intraperitoneally into Brattleboro (ADH deficient) and normal Long Evans rats in the presence and absence of exogenous ADH. Peritoneal cells were harvested 19-22 hr after the administration of the microbeads and the percent phagocytosis was determined in macrophage cells using a fluorescence-activated cell sorter (FACS II). Our results indicate that the percentage of peritoneal macrophages ingesting the fluorescent methacrylate microbeads was significantly reduced in the absence of ADH (Brattleboro rats: 5.4 +/- 0.6% versus Long Evans rats: 16.8 +/- 2.3%; p less than 0.001). In addition, our data demonstrate that exogenous administration of ADH significantly enhanced macrophage phagocytosis in Brattleboro (14.7 +/- 2.2%) and normal Long Evans (49.6 +/- 4.5%) rats. These data suggest, for the first time, that endogenous ADH might play a modulatory role in the phagocytic activity of a specific component of the RES, namely, the macrophage cell.

  3. Regulation of human alcohol dehydrogenase gene ADH7: importance of an AP-1 site.

    PubMed

    Kotagiri, S; Edenberg, H J

    1998-07-01

    The structure and function of the human alcohol dehydrogenase 7 (ADH7) promoter were analyzed. A promoter fragment extending to bp -232 functioned well in H4IIE-C3, CV-1, and HeLa cells, whereas the region extending further upstream to bp -799 had no significant effect on activity. We identified cis-acting elements in the proximal 232 bp and examined their effect on promoter activity. Mutation of site A, where c-Jun bound, caused a drastic decrease in the promoter activity in H4IIE-C3 and CV-1 cells, suggesting that AP-1 plays an important role in the regulation of ADH7. Mutation of site B also caused a large drop in promoter activity in both cell lines; C/EBPalpha can bind to this site, but because the site affects activity approximately equally in CV-1 cells that lack C/EBPalpha and in H4IIE-C3 cells that contain low levels, other proteins are likely to play the major roles in vivo. Mutation of site C, where C/EBP bound and c-Jun bound weakly, had different effects in the two cell lines: in H4IIE-C3 cells, the site C mutation did not significantly increase promoter activity, whereas in CV-1 cells, which lack C/EBPalpha, it led to a doubling of activity. Surprisingly, cotransfection of the wild-type promoter with C/EBPa or C/EBPbeta led to a decrease in promoter activity, which might in part explain the lack of activity of ADH7 in adult liver. PMID:9703017

  4. The metabolic enzyme AdhE controls the virulence of Escherichia coli O157:H7

    PubMed Central

    Beckham, Katherine S H; Connolly, James P R; Ritchie, Jennifer M; Wang, Dai; Gawthorne, Jayde A; Tahoun, Amin; Gally, David L; Burgess, Karl; Burchmore, Richard J; Smith, Brian O; Beatson, Scott A; Byron, Olwyn; Wolfe, Alan J; Douce, Gillian R; Roe, Andrew J

    2014-01-01

    Classical studies have focused on the role that individual regulators play in controlling virulence gene expression. An emerging theme, however, is that bacterial metabolism also plays a key role in this process. Our previous work identified a series of proteins that were implicated in the regulation of virulence. One of these proteins was AdhE, a bi-functional acetaldehyde-CoA dehydrogenase and alcohol dehydrogenase. Deletion of its gene (adhE) resulted in elevated levels of extracellular acetate and a stark pleiotropic phenotype: strong suppression of the Type Three Secretion System (T3SS) and overexpression of non-functional flagella. Correspondingly, the adhE mutant bound poorly to host cells and was unable to swim. Furthermore, the mutant was significantly less virulent than its parent when tested in vivo, which supports the hypothesis that attachment and motility are central to the colonization process. The molecular basis by which AdhE affects virulence gene regulation was found to be multifactorial, involving acetate-stimulated transcription of flagella expression and post-transcriptional regulation of the T3SS through Hfq. Our study reveals fascinating insights into the links between bacterial physiology, the expression of virulence genes, and the underlying molecular mechanism mechanisms by which these processes are regulated. PMID:24846743

  5. Bifunctional aldehyde/alcohol dehydrogenase (ADHE) in chlorophyte algal mitochondria.

    PubMed

    Atteia, Ariane; van Lis, Robert; Mendoza-Hernández, Guillermo; Henze, Katrin; Martin, William; Riveros-Rosas, Hector; González-Halphen, Diego

    2003-09-01

    Protein profiles of mitochondria isolated from the heterotrophic chlorophyte Polytomella sp. grown on ethanol at pH 6.0 and pH 3.7 were analyzed by Blue Native and denaturing polyacrylamide gel electrophoresis. Steady-state levels of oxidative phosphorylation complexes were influenced by external pH. Levels of an abundant, soluble, mitochondrial protein of 85 kDa and its corresponding mRNA increased at pH 6.0 relative to pH 3.7. N-terminal and internal sequencing of the 85 kDa mitochondrial protein together with the corresponding cDNA identified it as a bifunctional aldehyde/alcohol dehydrogenase (ADHE) with strong similarity to homologues from eubacteria and amitochondriate protists. A mitochondrial targeting sequence of 27 amino acids precedes the N-terminus of the mature mitochondrial protein. A gene encoding an ADHE homologue was also identified in the genome of Chlamydomonas reinhardtii, a photosynthetic relative of Polytomella. ADHE reveals a complex picture of sequence similarity among homologues. The lack of ADHE from archaebacteria indicates a eubacterial origin for the eukaryotic enzyme. Among eukaryotes, ADHE has hitherto been characteristic of anaerobes since it is essential to cytosolic energy metabolism of amitochondriate protists such as Giardia intestinalis and Entamoeba histolytica. Its abundance and expression pattern suggest an important role for ADHE in mitochondrial metabolism of Polytomella under the conditions studied. The current data are compatible with the view that Polytomella ADHE could be involved either in ethanol production or assimilation, or both, depending upon environmental conditions. Presence of ADHE in an oxygen-respiring algal mitochondrion and co-expression at ambient oxygen levels with respiratory chain components is unexpected with respect to the view that eukaryotes acquired ADHE genes specifically as an adaptation to an anaerobic lifestyle. PMID:14756315

  6. Importance of genetics in fetal alcohol effects: null mutation of the nNOS gene worsens alcohol-induced cerebellar neuronal losses and behavioral deficits

    PubMed Central

    Bonthius, Daniel J.; Winters, Zachary; Karacay, Bahri; Bousquet, Samantha Larimer; Bonthius, Daniel J.

    2014-01-01

    The cerebellum is a major target of alcohol-induced damage in the developing brain. However, the cerebella of some children are much more seriously affected than others by prenatal alcohol exposure. As a consequence of in utero alcohol exposure, some children have substantial reductions in cerebellar volume and corresponding neurodevelopmental problems, including microencephaly, ataxia, and balance deficits, while other children who were exposed to similar alcohol quantities are spared. One factor that likely plays a key role in determining the impact of alcohol on the fetal cerebellum is genetics. However, no specific gene variant has yet been identified that worsens cerebellar function as a consequence of developmental alcohol exposure. Previous studies have revealed that mice carrying a homozygous mutation of the gene for neuronal nitric oxide synthase (nNOS−/− mice) have more severe acute alcohol-induced neuronal losses from the cerebellum than wild type mice. Therefore, the goals of this study were to determine whether alcohol induces more severe cerebellum-based behavioral deficits in nNOS−/− mice than in wild type mice and to determine whether these worsened behavior deficits are associated with worsened cerebellar neuronal losses. nNOS−/− mice and their wild type controls received alcohol (0.0, 2.2, or 4.4 mg/g) daily over postnatal days 4–9. In adulthood, the mice underwent behavioral testing, followed by neuronal quantification. Alcohol caused dose-related deficits in rotarod and balance beam performance in both nNOS−/− and wild type mice. However, the alcohol-induced behavioral deficits were substantially worse in the nNOS−/− mice than in wild type. Likewise, alcohol exposure led to losses of Purkinje cells and cerebellar granule cells in mice of both genotypes, but the cell losses were more severe in the nNOS−/− mice than in wild type. Behavioral performances were correlated with neuronal number in the nNOS−/− mice, but not

  7. A null mutation in the Bacillus subtilis aconitase gene causes a block in Spo0A-phosphate-dependent gene expression.

    PubMed Central

    Craig, J E; Ford, M J; Blaydon, D C; Sonenshein, A L

    1997-01-01

    The citB gene of Bacillus subtilis encodes aconitase, the enzyme of the Krebs citric acid cycle, which is responsible for the interconversion of citrate and isocitrate. A B. subtilis strain with an insertion mutation in the citB gene was devoid of aconitase activity and aconitase protein, required glutamate for growth in minimal medium, and was unable to sporulate efficiently in nutrient broth sporulation medium. Mutant cells failed to form the asymmetric septum characteristic of sporulating cells and were defective in transcription of the earliest-expressed spo genes, that is, the genes dependent on the Spo0A phosphorelay. However, this early block in sporulation was partially overcome when cells of the citB mutant were induced to sporulate by resuspension in a poor medium. Accumulation of citrate in the mutant cells or in their culture fluid may be responsible for the early block, possibly because citrate can chelate divalent cations needed for the activity of the phosphorelay. PMID:9393699

  8. Comparison of Effects of p53 Null and Gain-of-Function Mutations on Salivary Tumors in MMTV-Hras Transgenic Mice

    PubMed Central

    Jiang, Dadi; Dumur, Catherine I.; Massey, H. Davis; Ramakrishnan, Viswanathan; Subler, Mark A.; Windle, Jolene J.

    2015-01-01

    p53 is an important tumor suppressor gene which is mutated in ~50% of all human cancers. Some of these mutants appear to have acquired novel functions beyond merely losing wild-type functions. To investigate these gain-of-function effects in vivo, we generated mice of three different genotypes: MMTV-Hras/p53+/+, MMTV-Hras/p53-/-, and MMTV-Hras/p53R172H/R172H. Salivary tumors from these mice were characterized with regard to age of tumor onset, tumor growth rates, cell cycle distribution, apoptotic levels, tumor histopathology, as well as response to doxorubicin treatment. Microarray analysis was also performed to profile gene expression. The MMTV-Hras/p53-/- and MMTV-Hras/p53R172H/R172H mice displayed similar properties with regard to age of tumor onset, tumor growth rates, tumor histopathology, and response to doxorubicin, while both groups were clearly distinct from the MMTV-Hras/p53+/+ mice by these measurements. In addition, the gene expression profiles of the MMTV-Hras/p53-/- and MMTV-Hras/p53R172H/R172H tumors were tightly clustered, and clearly distinct from the profiles of the MMTV-Hras/p53+/+ tumors. Only a small group of genes showing differential expression between the MMTV-Hras/p53-/- and MMTV-Hras/p53R172H/R172H tumors, that did not appear to be regulated by wild-type p53, were identified. Taken together, these results indicate that in this MMTV-Hras-driven salivary tumor model, the major effect of the p53 R172H mutant is due to the loss of wild-type p53 function, with little or no gain-of-function effect on tumorigenesis, which may be explained by the tissue- and tumor type-specific properties of this gain-of-function mutant of p53. PMID:25695772

  9. Genetic polymorphisms of ADH1B, ADH1C and ALDH2 in Turkish alcoholics: lack of association with alcoholism and alcoholic cirrhosis

    PubMed Central

    Vatansever, Sezgin; Tekin, Fatih; Salman, Esin; Altintoprak, Ender; Coskunol, Hakan; Akarca, Ulus Salih

    2015-01-01

    No data exists regarding the alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) gene polymorphisms in Turkish alcoholic cirrhotics. We studied the polymorphisms of ADH1B, ADH1C and ALDH2 genes in alcoholic cirrhotics and compared the results with non-cirrhotic alcoholics and healthy volunteers. Overall, 237 subjects were included for the study: 156 alcoholic patients (78 cirrhotics, 78 non-cirrhotic alcoholics) and 81 healthy volunteers. Three different single-nucleotide-polymorphism genotyping methods were used. ADH1C genotyping was performed using a polymerase chain reaction-restriction fragment length polymorphism method. The identified ADH1C genotypes were named according to the presence or absence of the enzyme restriction sites. ADH1B (Arg47Hys) genotyping was performed using the allele specific primer extension method, and ALDH2 (Glu487Lys) genotyping was performed by a multiplex polymerase chain reaction using two allele-specific primer pairs. For ADH1B, the frequency of allele *1 in the cirrhotics, non-cirrhotic alcoholics and healthy volunteers was 97.4%, 94.9% and 99.4%, respectively. For ADH1C, the frequency of allele *1 in the cirrhotics, non-cirrhotic alcoholics and healthy volunteers was 47%, 36.3% and 45%, respectively. There was no statistical difference between the groups for ADH1B and ADH1C (p>0.05). All alcoholic and non-alcoholic subjects (100%) had the allele *1 for ALDH2. The obtained results for ADH1B, ADH1C, and ALDH gene polymorphisms in the present study are similar to the results of Caucasian studies. ADH1B and ADH1C genetic variations are not related to the development of alcoholism or susceptibility to alcoholic cirrhosis. ALDH2 gene has no genetic variation in the Turkish population. PMID:26042511

  10. Transcriptional control of ADH genes in the xylose-fermenting yeast Pichia stipitis

    SciTech Connect

    Cho, J.Y.; Jeffries, T.W. |

    1999-06-01

    The authors studied the expression of the genes encoding group 1 alcohol dehydrogenases (PsADH1 and PsADH2) in the xylose-fermenting yeast Pichia stipitis CBS 6054. The cells expressed PsADH1 approximately 10 times higher under oxygen-limited conditions than under fully aerobic conditions when cultivated on xylose. Transcripts of PsADH2 were not detectable under either aeration condition. The authors used a PsADH1::lacZ fusion to monitor PsADH1 expression and found that expression increased as oxygen decreased. The level of PsADH1 transcript was expressed about 10-fold in cells grown in the presence of heme under oxygen-limited conditions. Concomitantly with the induction of PsADH1, PsCYC1 expression was regressed. These results indicate that oxygen availability regulates PsADH1 expression and that regulation may be mediated by heme. The regulation of PsADH2 expression was also examined in other genetic backgrounds. Disruption of PsADH1 dramatically increased PsADH2 expression on nonfermentable carbon sources under fully aerobic conditions, indicating that the expression of PsADH2 is subject to feedback regulation under these conditions.

  11. Genetic Association and Gene-Gene Interaction Reveal Genetic Variations in ADH1B, GSTM1 and MnSOD Independently Confer Risk to Alcoholic Liver Diseases in India

    PubMed Central

    Mukhopadhyay, Indranil; Chatterjee, Ankita; Das, Kausik; Bhowmik, Pradip; Das, Soumyajit; Basu, Priyadarshi; Santra, Amal K.; Datta, Simanti; Dhali, Gopal Krishna; Chowdhury, Abhijit; Banerjee, Soma

    2016-01-01

    Genetic susceptibility is an important modifier of clinical outcome and natural history of progression in Alcoholic liver disease (ALD). While the significance of ethnicity in this evolution is very clear, subtle inter-individual genetic variant(s) might be important and thus we investigated those in an Indian population. Fourteen markers were genotyped within two alcohol metabolism genes [Alcohol dehydrogenase (ADH) gene clusters (ADH1B and ADH1C) and Aldehyde dehydrogenase (ALDH2)], one microsomal ethanol oxidizing enzyme cytochrome p450 (CYP2E1) and three oxidative stress response (OSR) genes (MnSOD, GSTT1 and GSTM1) among 490 Bengali individuals (322 ALD and 168 control) from Eastern and North-Eastern India and validation was performed in a new cohort of 150 Bengali patients including 100 ALD and 50 advanced non-alcoholic steatohepatitis (NASH). Out of 14 genetic variants, carriage of 5 genotypes (rs2066701CC in ADH1B, rs1693425TT in ADH1C, rs4880TT in MnSOD and GSTT1/GSTM1 null, p-value <0.05) were noted significantly higher among ALD patients while inter or intra group gene-gene interaction analysis revealed that addition of risk genotype of any OSR gene enhanced the possibility of ALD synergistically. Multiple logistic regression analysis showed independent association of rs2066701CC, rs4880TT and GSTM1 null genotype with ALD while lower frequencies of those genotypes in advanced NASH patients further confirmed their causal relation to ALD. Thus these findings suggest that the three variants of ADH1C, MnSOD and GSTM1 can be used to identify individuals who are at high risk to develop ALD and may be helpful in proper management of Indian alcoholics. PMID:26937962

  12. Selection variability for Arg48His in alcohol dehydrogenase ADH1B among Asian populations.

    PubMed

    Evsyukov, Alexey; Ivanov, Denis

    2013-08-01

    The variant His at codon 48 of the alcohol dehydrogenase gene (ADH1B) results in more efficient ethanol metabolism than with the "typical" codon 48Arg. In this study we introduced selection properties of Arg48His genotypes of ADH1B and estimated fitness in four ethnic-geographical clusters in Asia. Population genetics models were employed that derive observed gene frequencies from fitness relationships among genotypes, to infer the selection pattern of polymorphisms in an indirect manner. The data were analyzed using the model of "complete stationary distribution" by Wright that takes into account random genetic drift, pressure of migrations, mutations, and selection as influential factors of gene frequency. We found that the different population groups showed some variation in the types of selection for Arg48His. Han Chinese from eastern and southeastern China and the Japanese and Korean populations showed stabilizing selection, while the groups from Central Asian and Indochina showed divergent selection. However, all the groups demonstrated a strong positive selection for Arg48His. PMID:25019189

  13. Chromatin remodeling during Saccharomyces cerevisiae ADH2 gene activation.

    PubMed

    Verdone, L; Camilloni, G; Di Mauro, E; Caserta, M

    1996-05-01

    We have analyzed at both low and high resolution the distribution of nucleosomes over the Saccharomyces cerevisiae ADH2 promoter region in its chromosomal location, both under repressing (high-glucose) conditions and during derepression. Enzymatic treatments (micrococcal nuclease and restriction endonucleases) were used to probe the in vivo chromatin structure during ADH2 gene activation. Under glucose-repressed conditions, the ADH2 promoter was bound by a precise array of nucleosomes, the principal ones positioned at the RNA initiation sites (nucleosome +1), at the TATA box (nucleosome -1), and upstream of the ADR1-binding site (UAS1) (nucleosome -2). The UAS1 sequence and the adjacent UAS2 sequence constituted a nucleosome-free region. Nucleosomes -1 and +1 were destabilized soon after depletion of glucose and had become so before the appearance of ADH2 mRNA. When the transcription rate was high, nucleosomes -2 and +2 also underwent rearrangement. When spheroplasts were prepared from cells grown in minimal medium, detection of this chromatin remodeling required the addition of a small amount of glucose. Cells lacking the ADR1 protein did not display any of these chromatin modifications upon glucose depletion. Since the UAS1 sequence to which Adr1p binds is located immediately upstream of nucleosome -1, Adr1p is presumably required for destabilization of this nucleosome and for aiding the TATA-box accessibility to the transcription machinery. PMID:8628264

  14. Excess polymorphism at the Adh locus in Drosophila melanogaster.

    PubMed

    Kreitman, M E; Aguadé, M

    1986-09-01

    The evolutionary history of a region of DNA encompassing the Adh locus is studied by comparing patterns of variation in Drosophila melanogaster and its sibling species, D. simulans. An unexpectedly high level of silent polymorphism in the Adh coding region relative to the 5' and 3' flanking regions in D. melanogaster is revealed by a populational survey of restriction polymorphism using a four-cutter filter hybridization technique as well as by direct sequence comparisons. In both of these studies, a region of the Adh gene encompassing the three coding exons exhibits a frequency of polymorphism equal to that of a 4-kb 5' flanking region. In contrast, an interspecific sequence comparison shows a two-fold higher level of divergence in the 5' flanking sequence compared to the structural locus. Analysis of the patterns of variation suggest an excess of polymorphism within the D. melanogaster Adh locus, rather than lack of polymorphism in the 5' flanking region. An approach is outlined for testing neutral theory predictions about patterns of variation within and between species. This approach indicates that the observed patterns of variation are incompatible with an infinite site neutral model. PMID:3021568

  15. A human alcohol dehydrogenase gene (ADH6) encoding an additional class of isozyme.

    PubMed Central

    Yasunami, M; Chen, C S; Yoshida, A

    1991-01-01

    The human alcohol dehydrogenase (ADH; alcohol:NAD+ oxidoreductase, EC 1.1.1.1) gene family consists of five known loci (ADH1-ADH5), which have been mapped close together on chromosome 4 (4q21-25). ADH isozymes encoded by these genes are grouped in three distinct classes in terms of their enzymological properties. A moderate structural similarity is observed between the members of different classes. We isolated an additional member of the ADH gene family by means of cross-hybridization with the ADH2 (class I) cDNA probe. cDNA clones corresponding to this gene were derived from PCR-amplified libraries as well. The coding sequence of a 368-amino-acid-long open reading frame was interrupted by introns into eight exons and spanned approximately 17 kilobases on the genome. The gene contains a glucocorticoid response element at the 5' region. The transcript was detected in the stomach and liver. The deduced amino acid sequence of the open reading frame showed about 60% positional identity with known human ADHs. This extent of homology is comparable to interclass similarity in the human ADH family. Thus, the newly identified gene, which is designated ADH6, governs the synthesis of an enzyme that belongs to another class of ADHs presumably with a distinct physiological role. Images PMID:1881901

  16. ADH-PGE2 interactions in cortical collecting tubule. II. inhibition of Ca and P reabsorption.

    PubMed

    Holt, W F; Lechene, C

    1981-10-01

    In the absence of ADH, microperfused cortical collecting tubules of rabbits reabsorb calcium and phosphorus. Antidiuretic hormone (ADH) (200 microunits/ml Pitressin or synthetic arginine vasopressin) inhibits the reabsorption and may promote the secretion of calcium and phosphorus. At 5 min after incubation with ADH, there was a transitory increase in the potential difference and the reabsorption of sodium. The fluxes of calcium and phosphorus, however, showed no significant change from the control values. At 30-50 min after treatment with ADH, the reabsorption of calcium and phosphorus was inhibited and in some tubules calcium and phosphorus were secreted. The removal of vasopressin from the bath or the addition of 10(-5) M meclofenamate in vitro prevented ADH from inhibiting the reabsorption of calcium and phosphorus. Treatment of tubules with 10(-5) M prostaglandin E2 (PGE2) subsequent to incubation in a medium containing ADH and meclofenamate inhibited the reabsorption or even promoted the secretin of calcium and phosphorus, as did the prolonged incubation with ADH alone. We conclude that cortical collecting tubules reabsorb calcium and phosphorus in the absence of vasopressin and that ADH inhibits calcium and phosphorus reabsorption. Endogenous synthesis of PGE2 may mediate the inhibitory action of ADH, since meclofenamate (an inhibitor of the synthesis of prostaglandins) opposes and exogenous PGE2 mimics ADH. PMID:6947697

  17. Responses of reindeer to water loading, water restriction and ADH.

    PubMed

    Valtonen, M; Eriksson, L

    1977-07-01

    Two female reindeer were hydrated by administration of (10% of b.wt.) water into the rumen. The diuretic response was very fast and strong but the urea and electrolyte excretion were little affected. Dehydration was carried out by not giving the reindeer water for 48 h. This water deprivation caused a loss of up to 20% of their body weight. The urine osmolality did not exceed 840 mosm/kg H2O, although the plasma osmolality rose from 300 to 346 and 368 mosm/kg H2O respectively. The plasma and urine urea concentrations were elevated during dehydration, while the urine urea excretion did not increase. Urine sodium concentration did not increase. When the urine flow rate, after two days of water deprivation, decreased to half of the original, the urine Na+ concentrations, instead of increasing, went down to half of the original. So did the potassium excretion. When ADH was injected intravenously into hydrated animals a dose of 30 mU of ADH was needed to induce antidiuresis or increased excretion of potassium. The resistance to ADH and the low relative thickness of the medulla confirm the limited capacity of reindeer kidney to concentrate urine or to excrete a solute load. On the other hand, reindeer is able rapidly to excrete surplus water without affecting the electrolyte or nitrogen balance. PMID:920204

  18. Radiant Temperature Nulling Radiometer

    NASA Technical Reports Server (NTRS)

    Ryan, Robert (Inventor)

    2003-01-01

    A self-calibrating nulling radiometer for non-contact temperature measurement of an object, such as a body of water, employs a black body source as a temperature reference, an optomechanical mechanism, e.g., a chopper, to switch back and forth between measuring the temperature of the black body source and that of a test source, and an infrared detection technique. The radiometer functions by measuring radiance of both the test and the reference black body sources; adjusting the temperature of the reference black body so that its radiance is equivalent to the test source; and, measuring the temperature of the reference black body at this point using a precision contact-type temperature sensor, to determine the radiative temperature of the test source. The radiation from both sources is detected by an infrared detector that converts the detected radiation to an electrical signal that is fed with a chopper reference signal to an error signal generator, such as a synchronous detector, that creates a precision rectified signal that is approximately proportional to the difference between the temperature of the reference black body and that of the test infrared source. This error signal is then used in a feedback loop to adjust the reference black body temperature until it equals that of the test source, at which point the error signal is nulled to zero. The chopper mechanism operates at one or more Hertz allowing minimization of l/f noise. It also provides pure chopping between the black body and the test source and allows continuous measurements.

  19. In vivo roles of alcohol dehydrogenase (ADH), catalase and the microsomal ethanol oxidizing system (MEOS) in deermice

    SciTech Connect

    Takagi, T.; Alderman, J.; Lieber, C.S.

    1985-01-01

    The relative importance of ADH and MEOS for ethanol oxidation in the liver has yet to be elucidated. The discovery of a strain of deermice genetically lacking ADH (ADH-) which can consume ethanol at greater than 50% of the rates seen in deermice having ADH (ADH+) suggested a significant role for non-ADH pathways in vivo. To quantitate contributions of the various pathways, the authors examined first the ethanol oxidation rates with or without 4-methylpyrazole in isolated deermice hepatocytes. 4-Methylpyrazole significantly reduced the ethanol oxidation in both ADH+ and ADH- hepatocytes. The reduction seen in ADH- cells can be applied to correct for the effect of 4-methylpyrazole on non-ADH pathways of ADH+ deermouse hepatocytes. After correction, non-ADH pathways were found to contribute 28% of ethanol metabolism at 10 mM and 52% at 50 mM. When using a different approach namely measurement of the isotope effect, MEOS was calculated to account for 35% at low and about 70% at high blood ethanol concentrations. Thus, they found that two different complementary approaches yielded similar results, namely that non-ADH pathways play a significant role in ethanol oxidation even in the presence of ADH.

  20. A genetic analysis of Adh1 regulation. Progress report, June 1991--February 1992

    SciTech Connect

    Freeling, M.

    1992-03-01

    The overall goal of our research proposal is to understand the meaning of the various cis-acting sites responsible for AdH1 expression in the entire maize plant. Progress is reported in the following areas: Studies on the TATA box and analysis of revertants of the Adh1-3F1124 allele; screening for more different mutants that affect Adh1 expression differentially; studies on cis-acting sequences required for root-specific Adh1 expression; refinement of the use of the particle gun; and functional analysis of a non- glycolytic anaerobic protein.

  1. Effects of glucose, ethanol and acetic acid on regulation of ADH2 gene from Lachancea fermentati.

    PubMed

    Yaacob, Norhayati; Mohamad Ali, Mohd Shukuri; Salleh, Abu Bakar; Abdul Rahman, Nor Aini

    2016-01-01

    Background. Not all yeast alcohol dehydrogenase 2 (ADH2) are repressed by glucose, as reported in Saccharomyces cerevisiae. Pichia stipitis ADH2 is regulated by oxygen instead of glucose, whereas Kluyveromyces marxianus ADH2 is regulated by neither glucose nor ethanol. For this reason, ADH2 regulation of yeasts may be species dependent, leading to a different type of expression and fermentation efficiency. Lachancea fermentati is a highly efficient ethanol producer, fast-growing cells and adapted to fermentation-related stresses such as ethanol and organic acid, but the metabolic information regarding the regulation of glucose and ethanol production is still lacking. Methods. Our investigation started with the stimulation of ADH2 activity from S. cerevisiae and L. fermentati by glucose and ethanol induction in a glucose-repressed medium. The study also embarked on the retrospective analysis of ADH2 genomic and protein level through direct sequencing and sites identification. Based on the sequence generated, we demonstrated ADH2 gene expression highlighting the conserved NAD(P)-binding domain in the context of glucose fermentation and ethanol production. Results. An increase of ADH2 activity was observed in starved L. fermentati (LfeADH2) and S. cerevisiae (SceADH2) in response to 2% (w/v) glucose induction. These suggest that in the presence of glucose, ADH2 activity was activated instead of being repressed. An induction of 0.5% (v/v) ethanol also increased LfeADH2 activity, promoting ethanol resistance, whereas accumulating acetic acid at a later stage of fermentation stimulated ADH2 activity and enhanced glucose consumption rates. The lack in upper stream activating sequence (UAS) and TATA elements hindered the possibility of Adr1 binding to LfeADH2. Transcription factors such as SP1 and RAP1 observed in LfeADH2 sequence have been implicated in the regulation of many genes including ADH2. In glucose fermentation, L. fermentati exhibited a bell-shaped ADH2

  2. Effects of glucose, ethanol and acetic acid on regulation of ADH2 gene from Lachancea fermentati

    PubMed Central

    Yaacob, Norhayati; Salleh, Abu Bakar; Abdul Rahman, Nor Aini

    2016-01-01

    Background. Not all yeast alcohol dehydrogenase 2 (ADH2) are repressed by glucose, as reported in Saccharomyces cerevisiae. Pichia stipitis ADH2 is regulated by oxygen instead of glucose, whereas Kluyveromyces marxianus ADH2 is regulated by neither glucose nor ethanol. For this reason, ADH2 regulation of yeasts may be species dependent, leading to a different type of expression and fermentation efficiency. Lachancea fermentati is a highly efficient ethanol producer, fast-growing cells and adapted to fermentation-related stresses such as ethanol and organic acid, but the metabolic information regarding the regulation of glucose and ethanol production is still lacking. Methods. Our investigation started with the stimulation of ADH2 activity from S. cerevisiae and L. fermentati by glucose and ethanol induction in a glucose-repressed medium. The study also embarked on the retrospective analysis of ADH2 genomic and protein level through direct sequencing and sites identification. Based on the sequence generated, we demonstrated ADH2 gene expression highlighting the conserved NAD(P)-binding domain in the context of glucose fermentation and ethanol production. Results. An increase of ADH2 activity was observed in starved L. fermentati (LfeADH2) and S. cerevisiae (SceADH2) in response to 2% (w/v) glucose induction. These suggest that in the presence of glucose, ADH2 activity was activated instead of being repressed. An induction of 0.5% (v/v) ethanol also increased LfeADH2 activity, promoting ethanol resistance, whereas accumulating acetic acid at a later stage of fermentation stimulated ADH2 activity and enhanced glucose consumption rates. The lack in upper stream activating sequence (UAS) and TATA elements hindered the possibility of Adr1 binding to LfeADH2. Transcription factors such as SP1 and RAP1 observed in LfeADH2 sequence have been implicated in the regulation of many genes including ADH2. In glucose fermentation, L. fermentati exhibited a bell-shaped ADH2

  3. Translation initiation in Drosophila melanogaster is reduced by mutations upstream of the AUG initiator codon

    SciTech Connect

    Feng, Yue; Gunter, L.E.; Organ, E.L.; Cavener, D.R. )

    1991-04-01

    The importance to in vivo translation of sequences immediately upstream of the Drosophila alcohol dehydrogenase (Adh) start codon was examined at two developmental stages. Mutations were introduced into the Adh gene in vitro, and the mutant gene was inserted into the genome via germ line transformation. An A-to-T substitution at the [minus]3 position did not affect relative translation of ADH at the adult stage. A second mutant gene, containing five mutations in the region [minus]1 to [minus]9, was designed to completely block translation initiation. However, transformant lines bearing these mutations still exhibit detectable ADH, albeit at substantially reduced levels. The average fold reduction at the second-instar larval stage was 5.9, while at the adult stage a 12.5-fold reduction was observed.

  4. The Adh1 gene of the fungus Metarhizium anisopliae is expressed during insect colonization and required for full virulence.

    PubMed

    Callejas-Negrete, Olga Alicia; Torres-Guzmán, Juan Carlos; Padilla-Guerrero, Israel Enrique; Esquivel-Naranjo, Ulises; Padilla-Ballesteros, Maria Fernanda; García-Tapia, Adriana; Schrank, Augusto; Salazar-Solís, Eduardo; Gutiérrez-Corona, Félix; González-Hernández, Gloria Angélica

    2015-03-01

    Zymography of alcohol dehydrogenase (ADH) activity in the entomopathogenic fungus Metarhizium anisopliae grown under various conditions revealed that micro-aerobic growth was associated with increased ADH activity. The major ADH protein, AdhIp, was purified to homogeneity by affinity chromatography and has an estimated molecular weight of 41kDa and an isoelectric point (pI) of 6.4. Peptide mass fingerprint analysis allowed the identification and cloning of the gene that encodes this protein, Adh1, as annotated in the M. anisopliae genome database. AdhIp is related to the medium-chain dehydrogenase/reductase (MDR)/zinc-dependent alcohol dehydrogenase-like family and contains conserved ADH sequence motifs, such as the zinc-containing ADH signature, the FAD/NAD binding domain and amino acid residues that are conserved in most microbial ADHs. Semi-quantitative RT-PCR analysis revealed that Adh1 gene expression occurs at low levels during early Plutella xylostella infection and that the Adh1 gene was primarily expressed at larval death and as mycelia emerge from the insect cuticle before conidiation. Antisense-RNA experiments indicated that NAD(+)-dependent ADH activity was diminished by 20-75% in the transformants, and the transformants that had lower ADH activity showed allyl alcohol resistance, which indicates that reduction in ADH activity also occurs in vivo. Bioassays performed using antisense adh1 transformants, which have lower ADH activity, showed that LC50 values were two to five times higher than the wild-type, indicating that AdhIp is required for full capability of the fungus to penetrate and/or colonize the insect. PMID:25534970

  5. Designing with null flux coils

    SciTech Connect

    Davey, K.R.

    1997-09-01

    Null flux were suggested by Danby and Powell in the late 1960`s as a useful means for realizing induced lift with little drag. As an array of alternating magnets is translated past a set of null flux coils, the currents induced in these coils act to vertically center the magnets on those coils. At present, one Japanese MAGLEV system company and two American-based companies are employing either null flux or flux eliminating coils in their design for high speed magnetically levitated transportation. The principle question addressed in paper is: what is the proper choice of coil length to magnet length in a null flux system? A generic analysis in the time and frequency domain is laid out with the intent of showing the optimal design specification in terms of coil parameters.

  6. Fructophilic characteristics of Fructobacillus spp. may be due to the absence of an alcohol/acetaldehyde dehydrogenase gene (adhE).

    PubMed

    Endo, Akihito; Tanaka, Naoto; Oikawa, Yo; Okada, Sanae; Dicks, Leon

    2014-04-01

    Fructophilic strains of Leuconostoc spp. have recently been reclassified to a new genus, i.e., Fructobacillus. Members of the genus are differentiated from Leuconostoc spp. by their preference for fructose on growth, requirement of an electron acceptor for glucose metabolism, and the inability to produce ethanol from the fermentation of glucose. In the present study, enzyme activities and genes involved in ethanol production were studied, since this is the key pathway for NAD(+)/NADH cycling in heterofermentative lactic acid bacteria. Fructobacillus spp. has a weak alcohol dehydrogenase activity and has no acetaldehyde dehydrogenase activity, whereas both enzymes are active in Leuconostoc mesenteroides. The bifunctional alcohol/acetaldehyde dehydrogenase gene, adhE, was described in Leuconostoc spp., but not in Fructobacillus spp. These results suggested that, due to the deficiency of the adhE gene, the normal pathway for ethanol production is absent in Fructobacillus spp. This leads to a shortage of NAD(+), and the requirement for an electron acceptor in glucose metabolism. Fructophilic characteristics, as observed for Fructobacillus spp., are thus due to the absence of the adhE gene, and a phenotype that most likely evolved as a result of regressive evolution. PMID:24352296

  7. Mutant alcohol dehydrogenase (ADH III) presequences that affect both in vitro mitochondrial import and in vitro processing by the matrix protease.

    PubMed Central

    Mooney, D T; Pilgrim, D B; Young, E T

    1990-01-01

    Point mutations in the presequence of the mitochondrial alcohol dehydrogerase isoenzyme (ADH III) have been shown to affect either the import of the precursor protein into yeast mitochondria in vivo or its processing within the organelle. In the present work, the behavior of these mutants during in vitro import into isolated mitochondria was investigated. All point mutants tested were imported with a slower initial rate than that of the wild-type precursor. This defect was corrected when the precursors were treated with urea prior to import. Once imported, the extent of processing to the mature form of mutant precursors varied greatly and correlated well with the defects observed in vivo. This result was not affected by prior urea treatment. When matrix extracts enriched for the processing protease were used, this defect was shown to be due to failure of the protease to efficiently recognize or cleave the presequence, rather than to a lack of access to the precursor. The rate of import of two ADH III precursors bearing internal deletions in the leader sequence was similar to those of the point mutants, whereas a deletion leading to the removal of the 15 amino-terminal amino acids was poorly imported. The mature amino terminus of wild-type ADH III was determined to be Gln-25. Mutant m01 (Ser-26 to Phe), which reduced the efficiency of cleavage in vitro by 80%, was cleaved at the correct site. Images PMID:2188098

  8. Mineral exploration, Mahd adh Dhahab District, Kingdom of Saudi Arabia

    USGS Publications Warehouse

    Worl, Ronald G.

    1978-01-01

    Mahd adh Dhahab is the largest of numerous ancient gold mines scattered through the Precambrian shield of Saudi Arabia and the only one with recent production. During the period 1939-54, 765,768 fine ounces of gold and 1,002,029 ounces of silver were produced from the mines by the Saudi Arabian Mining Syndicate. Ore minerals at Mahd adh Dhahab include free gold and silver, tellurides, sphalerite, and chalcopyrite in and associated with a system of north-trending quartz veins and quartz veinlet stockworks. Pyrite is a common sulfide gangue mineral. Country rocks are a north dipping sequence of pyroclastic and transported pyroclastic rocks of the Hulayfah Group that are locally highly silicified and potassium-feldspathized. The prime target for this exploration program was a north-trending zone of quartz veins and breccias, faults, alteration, and metalization approximately 400 m wide and 1000 m long. The ancient and recent mine workings are located in the northern part of this zone. Although the quartz veins and alteration cut all lithologies, the major metalization is confined to the intersection of veins and agglomerate. Ten holes were diamond drilled to explore geochemical, geological, and geophysical targets in the area. A significant new zone of metalization was discovered 700 m south of the ancient and recent mine workings and within the same major zone of quartz veins, alteration, and faults. Metalization in this southern mineralized zone is at the intersection of the quartz veins and a distinctive and highly altered agglomerate. The total zone of vein and agglomerate intercept is potentially metalized and comprises a block of ground 40 m thick and 400 m wide along the strike of the agglomerate and projected downdip 250 m. Tonnage of this block is 17.2 million tons. The explored zone, approximately 25 percent of the potentially metalized rock, has a potential resource of 1.1 million tons containing 27 g/t gold and 73 g/t silver.

  9. Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation

    PubMed Central

    Marduel, Marie; Ouguerram, Khadija; Serre, Valérie; Bonnefont-Rousselot, Dominique; Marques-Pinheiro, Alice; Berge, Knut Erik; Devillers, Martine; Luc, Gérald; Lecerf, Jean-Michel; Tosolini, Laurent; Erlich, Danièle; Peloso, Gina M.; Stitziel, Nathan; Nitchké, Patrick; Jaïs, Jean-Philippe; Abifadel, Marianne; Kathiresan, Sekar; Leren, Trond Paul; Rabès, Jean-Pierre; Boileau, Catherine; Varret, Mathilde

    2013-01-01

    Apo E mutants are associated with type III hyperlipoproteinemia characterized by high cholesterol and triglycerides levels. Autosomal Dominant Hypercholesterolemia (ADH), due to mutations in the LDLR, APOB or PCSK9 genes, is characterized by an isolated elevation of cholesterol due to high levels of low-density lipoproteins (LDL). We now report an exceptionally large family including 14 members with ADH. Through genome wide mapping, analysis of regional/functional candidate genes and whole exome sequencing, we identified a mutation in the APOE gene, p.Leu167del previously reported associated with sea-blue histiocytosis and familial combined hyperlipidemia. We confirmed the involvement of the APOE p.Leu167del in ADH, with (1) a predicted destabilization of an alpha-helix in the binding domain; (2) a decreased apo E level in LDL; and (3) a decreased catabolism of LDL. Our results show that mutations in the APOE gene can be associated with bona fide ADH. PMID:22949395

  10. On spinors and null vectors

    NASA Astrophysics Data System (ADS)

    Budinich, Marco

    2014-03-01

    We investigate the relations between spinors and null vectors in Clifford algebra of any dimension with particular emphasis on the conditions that a spinor must satisfy to be simple (also: pure). In particular, we prove: (i) a new property for null vectors: each of them bisects spinor space into two subspaces of equal size; (ii) that simple spinors form one-dimensional subspaces of spinor space; (iii) a necessary and sufficient condition for a spinor to be simple that generalizes a theorem of Cartan and Chevalley which becomes a corollary of this result. We also show how to write down easily the most general spinor with a given associated totally null plane. This paper is dedicated to the memory of my father Paolo Budinich who passed away in November 2013 not before transferring to me his enthusiasm for simple spinors.

  11. NULL convention floating point multiplier.

    PubMed

    Albert, Anitha Juliette; Ramachandran, Seshasayanan

    2015-01-01

    Floating point multiplication is a critical part in high dynamic range and computational intensive digital signal processing applications which require high precision and low power. This paper presents the design of an IEEE 754 single precision floating point multiplier using asynchronous NULL convention logic paradigm. Rounding has not been implemented to suit high precision applications. The novelty of the research is that it is the first ever NULL convention logic multiplier, designed to perform floating point multiplication. The proposed multiplier offers substantial decrease in power consumption when compared with its synchronous version. Performance attributes of the NULL convention logic floating point multiplier, obtained from Xilinx simulation and Cadence, are compared with its equivalent synchronous implementation. PMID:25879069

  12. NULL Convention Floating Point Multiplier

    PubMed Central

    Ramachandran, Seshasayanan

    2015-01-01

    Floating point multiplication is a critical part in high dynamic range and computational intensive digital signal processing applications which require high precision and low power. This paper presents the design of an IEEE 754 single precision floating point multiplier using asynchronous NULL convention logic paradigm. Rounding has not been implemented to suit high precision applications. The novelty of the research is that it is the first ever NULL convention logic multiplier, designed to perform floating point multiplication. The proposed multiplier offers substantial decrease in power consumption when compared with its synchronous version. Performance attributes of the NULL convention logic floating point multiplier, obtained from Xilinx simulation and Cadence, are compared with its equivalent synchronous implementation. PMID:25879069

  13. Two new molecular bases for the Dombrock null phenotype.

    PubMed

    Rios, Maria; Storry, Jill R; Hue-Roye, Kim; Chung, Amy; Reid, Marion E

    2002-06-01

    Red blood cells (RBCs) with the Do(null) phenotype lack all antigens in the Dombrock blood group system, i.e. Do(a), Do(b), Gy(a), Hy and Jo(a). Sequence analysis of DNA from one proband with the Do(null) phenotype revealed a single nucleotide mutation of t to c in the donor splice site of DO (IVS1 + 2t > c), with outsplicing of exon 2. Analysis of a second proband revealed a homozygous nonsense mutation 442 C > T in exon 2 predicting a premature stop codon (Gln148 Stop). The molecular bases described in these two probands provide an explanation for the lack of Do glycoprotein on their RBCs. PMID:12028057

  14. Transient Overexpression of adh8a Increases Allyl Alcohol Toxicity in Zebrafish Embryos

    PubMed Central

    Klüver, Nils; Ortmann, Julia; Paschke, Heidrun; Renner, Patrick; Ritter, Axel P.; Scholz, Stefan

    2014-01-01

    Fish embryos are widely used as an alternative model to study toxicity in vertebrates. Due to their complexity, embryos are believed to more resemble an adult organism than in vitro cellular models. However, concerns have been raised with respect to the embryo's metabolic capacity. We recently identified allyl alcohol, an industrial chemical, to be several orders of magnitude less toxic to zebrafish embryo than to adult zebrafish (embryo LC50 = 478 mg/L vs. fish LC50 = 0.28 mg/L). Reports on mammals have indicated that allyl alcohol requires activation by alcohol dehydrogenases (Adh) to form the highly reactive and toxic metabolite acrolein, which shows similar toxicity in zebrafish embryos and adults. To identify if a limited metabolic capacity of embryos indeed can explain the low allyl alcohol sensitivity of zebrafish embryos, we compared the mRNA expression levels of Adh isoenzymes (adh5, adh8a, adh8b and adhfe1) during embryo development to that in adult fish. The greatest difference between embryo and adult fish was found for adh8a and adh8b expression. Therefore, we hypothesized that these genes might be required for allyl alcohol activation. Microinjection of adh8a, but not adh8b mRNA led to a significant increase of allyl alcohol toxicity in embryos similar to levels reported for adults (LC50 = 0.42 mg/L in adh8a mRNA-injected embryos). Furthermore, GC/MS analysis of adh8a-injected embryos indicated a significant decline of internal allyl alcohol concentrations from 0.23-58 ng/embryo to levels below the limit of detection (< 4.6 µg/L). Injection of neither adh8b nor gfp mRNA had an impact on internal allyl alcohol levels supporting that the increased allyl alcohol toxicity was mediated by an increase in its metabolization. These results underline the necessity to critically consider metabolic activation in the zebrafish embryo. As demonstrated here, mRNA injection is one useful approach to study the role of candidate enzymes involved in

  15. Transient overexpression of adh8a increases allyl alcohol toxicity in zebrafish embryos.

    PubMed

    Klüver, Nils; Ortmann, Julia; Paschke, Heidrun; Renner, Patrick; Ritter, Axel P; Scholz, Stefan

    2014-01-01

    Fish embryos are widely used as an alternative model to study toxicity in vertebrates. Due to their complexity, embryos are believed to more resemble an adult organism than in vitro cellular models. However, concerns have been raised with respect to the embryo's metabolic capacity. We recently identified allyl alcohol, an industrial chemical, to be several orders of magnitude less toxic to zebrafish embryo than to adult zebrafish (embryo LC50 = 478 mg/L vs. fish LC50 = 0.28 mg/L). Reports on mammals have indicated that allyl alcohol requires activation by alcohol dehydrogenases (Adh) to form the highly reactive and toxic metabolite acrolein, which shows similar toxicity in zebrafish embryos and adults. To identify if a limited metabolic capacity of embryos indeed can explain the low allyl alcohol sensitivity of zebrafish embryos, we compared the mRNA expression levels of Adh isoenzymes (adh5, adh8a, adh8b and adhfe1) during embryo development to that in adult fish. The greatest difference between embryo and adult fish was found for adh8a and adh8b expression. Therefore, we hypothesized that these genes might be required for allyl alcohol activation. Microinjection of adh8a, but not adh8b mRNA led to a significant increase of allyl alcohol toxicity in embryos similar to levels reported for adults (LC50 = 0.42 mg/L in adh8a mRNA-injected embryos). Furthermore, GC/MS analysis of adh8a-injected embryos indicated a significant decline of internal allyl alcohol concentrations from 0.23-58 ng/embryo to levels below the limit of detection (< 4.6 µg/L). Injection of neither adh8b nor gfp mRNA had an impact on internal allyl alcohol levels supporting that the increased allyl alcohol toxicity was mediated by an increase in its metabolization. These results underline the necessity to critically consider metabolic activation in the zebrafish embryo. As demonstrated here, mRNA injection is one useful approach to study the role of candidate enzymes involved in

  16. Influence of ADH1B polymorphism on alcohol use and its subjective effects in a Jewish population.

    PubMed

    Carr, Lucinda G; Foroud, Tatiana; Stewart, Trent; Castelluccio, Peter; Edenberg, Howard J; Li, Ting-Kai

    2002-10-01

    Class I alcohol dehydrogenases (ADHs) are the principal enzymes responsible for ethanol metabolism in humans. Genetic polymorphism at the ADH1B locus (old nomenclature ADH2) results in isozymes with quite different catalytic properties. The frequency of the ADH1B*2 allele varies among ethnic groups. ADH1B*2 is most often observed in Asian populations, and has been shown to be protective against alcoholism. The Jewish population has a higher frequency of the ADH1B*2 allele and lower rates of alcohol-related problems as compared to other Caucasian populations. Thus, it would be of interest to determine whether the ADH1B*2 allele is associated with alcohol consumption and its subjective effects in this group. Four groups of Jewish subjects (male and female college-age samples, and male and female general samples) were recruited from the same region of the United States. All subjects completed a questionnaire to delineate alcohol consumption and its subjective consequences. Genotype at the ADH1B locus was determined for each participant. ADH1B*2 allele frequencies were similar for the Jewish college-age and general population samples. Men in both the college-age and general population in the ADH1B*2 group reported more unpleasant reactions following alcohol consumption than men in the ADH1B*1 group. Men in the general population in the ADH1B*2 group drank alcohol less frequently than men who were homozygous ADH1B*1; there was a similar trend among the women. The ADH1B polymorphism is associated with unpleasant reactions after alcohol consumption, and frequency of alcohol consumption in these Jewish samples. PMID:12244546

  17. Fracture characterisation using geoelectric null-arrays

    NASA Astrophysics Data System (ADS)

    Falco, Pierik; Negro, François; Szalai, Sándor; Milnes, Ellen

    2013-06-01

    The term "geoelectric null-array" is used for direct current electrode configurations yielding a potential difference of zero above a homogeneous half-space. This paper presents a comparative study of the behaviour of three null-arrays, midpoint null-array (MAN), Wenner-γ null-array and Schlumberger null-array in response to a fracture, both in profiling and in azimuthal mode. The main objective is to determine which array(s) best localise fractures or best identify their orientation. Forward modelling of the three null-arrays revealed that the Wenner-γ and Schlumberger null-arrays localise vertical fractures the most accurately, whilst the midpoint null-array combined with the Schlumberger null-array allows accurate orientation of a fracture. Numerical analysis then served as a basis to interpret the field results. Field test measurements were carried out above a quarry in Les Breuleux (Switzerland) with the three null-arrays and classical arrays. The results were cross-validated with quarry-wall geological mapping. In real field circumstances, the Wenner-γ null-array proved to be the most efficient and accurate in localising fractures. The orientations of the fractures according to the numerical results were most efficiently determined with the midpoint null-array, whilst the Schlumberger null-array adds accuracy to the results. This study shows that geoelectrical null-arrays are more suitable than classical arrays for the characterisation of fracture geometry.

  18. Characterization of polymorphisms of genes ADH2, ADH3, ALDH2 and CYP2E1 and relationship to the alcoholism in a Colombian population

    PubMed Central

    Méndez, Claudia

    2015-01-01

    Objective: Identify and characterize polymorphisms of genes ADH2, ADH3, ALDH2 and CYP2E1 in a Colombian population residing in the city of Bogotá and determine its possible relationship to the alcoholism. Methods: ADH2, ADH3, ALDH2, and CYP2E1 genotypes a population of 148 individuals with non-problematic alcohol and 65 individuals with alcoholism were determined with TaqMan probes and PCR-RFLP. DNA was obtained from peripheral blood white cells. Results: Significant difference was found in family history of alcoholism and use of other psychoactive substances to compare alcoholics with controls. When allelic frequencies for each category (gender) were considered, frequency of A2 allele carriers in ADH2 was found higher in male patients than controls. In women, the relative frequency for c1 allele in CYP2E1 was lower in controls than alcoholics. The ALDH2 locus is monomorphic. No significant differences in allele distributions of the loci examined to compare two populations were observed, however when stratifying the same trend was found that these differences tended to be significant. Conclusions: This study allows us to conclude the positive association between family history of alcoholism and alcoholism suggesting that there is a favourable hereditary predisposition. Since substance dependence requires interaction of multiple genes, the combination of genotypes ADH2 * 2, CYP2E1 * 1 combined with genotype homozygous ALDH2 * 1 found in this study could be leading to the population to a potential risk to alcoholism. PMID:26848198

  19. ADH and ALDH polymorphisms and alcohol dependence in Mexican and Native Americans

    PubMed Central

    Ehlers, Cindy L.; Liang, Tiebing; Gizer, Ian R.

    2012-01-01

    Background Ethanol is primarily metabolized in the liver by 2 rate-limiting reactions: conversion of ethanol to acetaldehyde by alcohol dehydrogenase (ADH) and subsequent conversion of acetaldehyde to acetate by aldehyde dehydrogenase (ALDH). ADH and ALDH exist in multiple isozymes that differ in their kinetic properties. Notably, polymorphisms within the genes that encode for these isozymes vary in their allele frequencies between ethnic groups, and thus, they have been considered as candidate genes that may differentially influence risk for the development of alcohol dependence across ethnic groups. Objectives and Methods Associations between alcohol dependence and polymorphisms in ADH1B, ADH1C, and ALDH2, were compared in a community sample of Native Americans living on reservations (n=791) and Mexican Americans (n=391) living within the same county. Results Two Mexican Americans and no Native Americans possessed one ALDH2*2 allele. Presence of at least one ADH1B*2 allele was found in 7% of the Native Americans and 13% of the Mexican Americans, but was only associated with protection against alcohol dependence in the Mexican Americans. Presence of at least one ADH1B*3 allele was found in 4% if the Native Americans and 2% of the Mexican Americans, but was associated with protection against alcohol dependence only in the Native Americans. No associations between alcohol dependence and polymorphisms in ADH1C were found. Conclusions and Scientific Significance Polymorphisms in ADH1B are protective against alcoholism in these two populations; however, these findings do not explain the high prevalence of alcoholism in these populations. PMID:22931071

  20. Fast Principal-Component Analysis Reveals Convergent Evolution of ADH1B in Europe and East Asia.

    PubMed

    Galinsky, Kevin J; Bhatia, Gaurav; Loh, Po-Ru; Georgiev, Stoyan; Mukherjee, Sayan; Patterson, Nick J; Price, Alkes L

    2016-03-01

    Searching for genetic variants with unusual differentiation between subpopulations is an established approach for identifying signals of natural selection. However, existing methods generally require discrete subpopulations. We introduce a method that infers selection using principal components (PCs) by identifying variants whose differentiation along top PCs is significantly greater than the null distribution of genetic drift. To enable the application of this method to large datasets, we developed the FastPCA software, which employs recent advances in random matrix theory to accurately approximate top PCs while reducing time and memory cost from quadratic to linear in the number of individuals, a computational improvement of many orders of magnitude. We apply FastPCA to a cohort of 54,734 European Americans, identifying 5 distinct subpopulations spanning the top 4 PCs. Using the PC-based test for natural selection, we replicate previously known selected loci and identify three new genome-wide significant signals of selection, including selection in Europeans at ADH1B. The coding variant rs1229984(∗)T has previously been associated to a decreased risk of alcoholism and shown to be under selection in East Asians; we show that it is a rare example of independent evolution on two continents. We also detect selection signals at IGFBP3 and IGH, which have also previously been associated to human disease. PMID:26924531

  1. Fast Principal-Component Analysis Reveals Convergent Evolution of ADH1B in Europe and East Asia

    PubMed Central

    Galinsky, Kevin J.; Bhatia, Gaurav; Loh, Po-Ru; Georgiev, Stoyan; Mukherjee, Sayan; Patterson, Nick J.; Price, Alkes L.

    2016-01-01

    Searching for genetic variants with unusual differentiation between subpopulations is an established approach for identifying signals of natural selection. However, existing methods generally require discrete subpopulations. We introduce a method that infers selection using principal components (PCs) by identifying variants whose differentiation along top PCs is significantly greater than the null distribution of genetic drift. To enable the application of this method to large datasets, we developed the FastPCA software, which employs recent advances in random matrix theory to accurately approximate top PCs while reducing time and memory cost from quadratic to linear in the number of individuals, a computational improvement of many orders of magnitude. We apply FastPCA to a cohort of 54,734 European Americans, identifying 5 distinct subpopulations spanning the top 4 PCs. Using the PC-based test for natural selection, we replicate previously known selected loci and identify three new genome-wide significant signals of selection, including selection in Europeans at ADH1B. The coding variant rs1229984∗T has previously been associated to a decreased risk of alcoholism and shown to be under selection in East Asians; we show that it is a rare example of independent evolution on two continents. We also detect selection signals at IGFBP3 and IGH, which have also previously been associated to human disease. PMID:26924531

  2. [Changes in antidiuretic hormone (ADH) in liver cirrhosis with resistant ascites].

    PubMed

    Marenco, G; Giudici Cipriani, A; Folco, U; Colombo, P; Menardo, G; Cattana, A; Barbetti, V; Rembado, R

    1989-09-01

    The pathogenetic role of ADH in determining hyponatremia in patients with liver cirrhosis is still much debated. Osmotic stimuli are not able to inhibit secretion of ADH in refractory ascites and under such conditions the reduction in effective plasma volume has been put forward as the main cause. Twenty patients with liver cirrhosis and refractory ascites were studied before and during extraction-concentration-reinfusion (ECR) of ascitic fluid by means of Rhodiascit. ADH, renin, aldosterone, blood and urine osmolarity, plasma and urinary concentration of sodium, potassium, chlorine, and the clearance of free water were evaluated. All patients presented high renin values (15.4 +/- 11.7 ng/ml), aldosterone (341 +/- 172 ng/ml), ADH (6.3 +/- 5.2 pg/ml). During ECR, a significant drop was observed in renin (p less than 0.001), aldosterone (p less than 0.001) urinary osmolarity (p less than 0.001) and an equality significant increase in diuresis (p less than 0.001), natriuria (p less than 0.005), kaliuria (p less than 0.001) while ADH presented an irregular course: in 11 cases it remained unchanged, in 3 it fell and in 6 it presented a constant increase. To conclude, data suggest that the diminished filtrate reaching the distal tubule constitutes the greatest cause of the inability to dilute urine in many patients with cirrhosis and that ADH is a permissive rather than a primary factor. PMID:2682381

  3. Effect of ADH on rubidium transport in isolated perfused rat cortical collecting tubules

    SciTech Connect

    Schafer, J.A.; Troutman, S.L.

    1986-06-01

    Unidirectional fluxes of 86Rb+ were measured as an indicator of potassium transport in isolated rat cortical collecting tubules perfused and bathed at 38 degrees C with isotonic solutions in which Rb+ replaced K+. Under control conditions the lumen-to-bath flux (Jl----b) was significantly less than the bath-to-lumen flux (Jb----l), indicating net Rb+ secretion. Net secretion increased approximately 180% after addition of 100 microU/ml of arginine vasopressin (ADH) to the bathing solution, due to a rapid and reversible increase in Jb----l from 4.6 +/- 0.8 to 9.0 +/- 1.9 pmol X min-1 X mm-1 with no significant change in Jl----b. The ADH effect was completely inhibited by 2 mM luminal Ba2+. The average transepithelial voltage (Ve) was not significantly different from zero in the control period but became lumen negative (-5 to -10 mV) after ADH. With 10(-5) M amiloride in the lumen Ve was lumen positive (+2 to +4 mV) and was unaltered by ADH or Ba2+, yet ADH produced a significant but attentuated increase in Jb----l with no change in Jl----b. The results indicate that ADH augments net K+ secretion either by an increase in the Ba2+-sensitive conductance of the apical membrane or by an increase in the electrochemical potential driving force for net Rb+ secretion through this pathway.

  4. Role of Plasmodium vivax Duffy-binding protein 1 in invasion of Duffy-null Africans.

    PubMed

    Gunalan, Karthigayan; Lo, Eugenia; Hostetler, Jessica B; Yewhalaw, Delenasaw; Mu, Jianbing; Neafsey, Daniel E; Yan, Guiyun; Miller, Louis H

    2016-05-31

    The ability of the malaria parasite Plasmodium vivax to invade erythrocytes is dependent on the expression of the Duffy blood group antigen on erythrocytes. Consequently, Africans who are null for the Duffy antigen are not susceptible to P. vivax infections. Recently, P. vivax infections in Duffy-null Africans have been documented, raising the possibility that P. vivax, a virulent pathogen in other parts of the world, may expand malarial disease in Africa. P. vivax binds the Duffy blood group antigen through its Duffy-binding protein 1 (DBP1). To determine if mutations in DBP1 resulted in the ability of P. vivax to bind Duffy-null erythrocytes, we analyzed P. vivax parasites obtained from two Duffy-null individuals living in Ethiopia where Duffy-null and -positive Africans live side-by-side. We determined that, although the DBP1s from these parasites contained unique sequences, they failed to bind Duffy-null erythrocytes, indicating that mutations in DBP1 did not account for the ability of P. vivax to infect Duffy-null Africans. However, an unusual DNA expansion of DBP1 (three and eight copies) in the two Duffy-null P. vivax infections suggests that an expansion of DBP1 may have been selected to allow low-affinity binding to another receptor on Duffy-null erythrocytes. Indeed, we show that Salvador (Sal) I P. vivax infects Squirrel monkeys independently of DBP1 binding to Squirrel monkey erythrocytes. We conclude that P. vivax Sal I and perhaps P. vivax in Duffy-null patients may have adapted to use new ligand-receptor pairs for invasion. PMID:27190089

  5. Role of Plasmodium vivax Duffy-binding protein 1 in invasion of Duffy-null Africans

    PubMed Central

    Gunalan, Karthigayan; Lo, Eugenia; Hostetler, Jessica B.; Yewhalaw, Delenasaw; Mu, Jianbing; Neafsey, Daniel E.; Yan, Guiyun; Miller, Louis H.

    2016-01-01

    The ability of the malaria parasite Plasmodium vivax to invade erythrocytes is dependent on the expression of the Duffy blood group antigen on erythrocytes. Consequently, Africans who are null for the Duffy antigen are not susceptible to P. vivax infections. Recently, P. vivax infections in Duffy-null Africans have been documented, raising the possibility that P. vivax, a virulent pathogen in other parts of the world, may expand malarial disease in Africa. P. vivax binds the Duffy blood group antigen through its Duffy-binding protein 1 (DBP1). To determine if mutations in DBP1 resulted in the ability of P. vivax to bind Duffy-null erythrocytes, we analyzed P. vivax parasites obtained from two Duffy-null individuals living in Ethiopia where Duffy-null and -positive Africans live side-by-side. We determined that, although the DBP1s from these parasites contained unique sequences, they failed to bind Duffy-null erythrocytes, indicating that mutations in DBP1 did not account for the ability of P. vivax to infect Duffy-null Africans. However, an unusual DNA expansion of DBP1 (three and eight copies) in the two Duffy-null P. vivax infections suggests that an expansion of DBP1 may have been selected to allow low-affinity binding to another receptor on Duffy-null erythrocytes. Indeed, we show that Salvador (Sal) I P. vivax infects Squirrel monkeys independently of DBP1 binding to Squirrel monkey erythrocytes. We conclude that P. vivax Sal I and perhaps P. vivax in Duffy-null patients may have adapted to use new ligand–receptor pairs for invasion. PMID:27190089

  6. Nulling at the Keck Interferometer

    NASA Technical Reports Server (NTRS)

    Colavita, M. Mark; Serabyn, Gene; Wizinowich, Peter L.; Akeson, Rachel L.

    2006-01-01

    The nulling mode of the Keck Interferometer is being commissioned at the Mauna Kea summit. The nuller combines the two Keck telescope apertures in a split-pupil mode to both cancel the on-axis starlight and to coherently detect the residual signal. The nuller, working at 10 um, is tightly integrated with the other interferometer subsystems including the fringe and angle trackers, the delay lines and laser metrology, and the real-time control system. Since first 10 um light in August 2004, the system integration is proceeding with increasing functionality and performance, leading to demonstration of a 100:1 on-sky null in 2005. That level of performance has now been extended to observations with longer coherent integration times. An overview of the overall system is presented, with emphasis on the observing sequence, phasing system, and differences with respect to the V2 system, along with a presentation of some recent engineering data.

  7. Balloon Exoplanet Nulling Interferometer (BENI)

    NASA Technical Reports Server (NTRS)

    Lyon, Richard G.; Clampin, Mark; Woodruff, Robert A.; Vasudevan, Gopal; Ford, Holland; Petro, Larry; Herman, Jay; Rinehart, Stephen; Carpenter, Kenneth; Marzouk, Joe

    2009-01-01

    We evaluate the feasibility of using a balloon-borne nulling interferometer to detect and characterize exosolar planets and debris disks. The existing instrument consists of a 3-telescope Fizeau imaging interferometer with 3 fast steering mirrors and 3 delay lines operating at 800 Hz for closed-loop control of wavefront errors and fine pointing. A compact visible nulling interferometer is under development which when coupled to the imaging interferometer would in-principle allow deep suppression of starlight. We have conducted atmospheric simulations of the environment above 100,000 feet and believe balloons are a feasible path forward towards detection and characterization of a limited set of exoplanets and their debris disks. Herein we will discuss the BENI instrument, the balloon environment and the feasibility of such as mission.

  8. Null Arguments in German Child Language.

    ERIC Educational Resources Information Center

    Hamann, Cornelia

    1996-01-01

    Investigates the 10% to 20% null subject stage in 3-year-olds in Germany and shows that this stage, though long, is not final. Findings indicate that children in this phase use structures found neither in the state of early null subjects nor in adult German, namely, postverbal referential null subjects. Further study is proposed. (94 references)…

  9. Allosteric Modulation of the Calcium-sensing Receptor Rectifies Signaling Abnormalities Associated with G-protein α-11 Mutations Causing Hypercalcemic and Hypocalcemic Disorders*

    PubMed Central

    Babinsky, Valerie N.; Hannan, Fadil M.; Gorvin, Caroline M.; Howles, Sarah A.; Nesbit, M. Andrew; Rust, Nigel; Hanyaloglu, Aylin C.; Hu, Jianxin; Spiegel, Allen M.; Thakker, Rajesh V.

    2016-01-01

    Germline loss- and gain-of-function mutations of G-protein α-11 (Gα11), which couples the calcium-sensing receptor (CaSR) to intracellular calcium (Ca2+i) signaling, lead to familial hypocalciuric hypercalcemia type 2 (FHH2) and autosomal dominant hypocalcemia type 2 (ADH2), respectively, whereas somatic Gα11 mutations mediate uveal melanoma development by constitutively up-regulating MAPK signaling. Cinacalcet and NPS-2143 are allosteric CaSR activators and inactivators, respectively, that ameliorate signaling disturbances associated with CaSR mutations, but their potential to modulate abnormalities of the downstream Gα11 protein is unknown. This study investigated whether cinacalcet and NPS-2143 may rectify Ca2+i alterations associated with FHH2- and ADH2-causing Gα11 mutations, and evaluated the influence of germline gain-of-function Gα11 mutations on MAPK signaling by measuring ERK phosphorylation, and assessed the effect of NPS-2143 on a uveal melanoma Gα11 mutant. WT and mutant Gα11 proteins causing FHH2, ADH2 or uveal melanoma were transfected in CaSR-expressing HEK293 cells, and Ca2+i and ERK phosphorylation responses measured by flow-cytometry and Alphascreen immunoassay following exposure to extracellular Ca2+ (Ca2+o) and allosteric modulators. Cinacalcet and NPS-2143 rectified the Ca2+i responses of FHH2- and ADH2-associated Gα11 loss- and gain-of-function mutations, respectively. ADH2-causing Gα11 mutations were demonstrated not to be constitutively activating and induced ERK phosphorylation following Ca2+o stimulation only. The increased ERK phosphorylation associated with ADH2 and uveal melanoma mutants was rectified by NPS-2143. These findings demonstrate that CaSR-targeted compounds can rectify signaling disturbances caused by germline and somatic Gα11 mutations, which respectively lead to calcium disorders and tumorigenesis; and that ADH2-causing Gα11 mutations induce non-constitutive alterations in MAPK signaling. PMID:26994139

  10. ADH1A variation predisposes to personality traits and substance dependence

    PubMed Central

    Zuo, Lingjun; Gelernter, Joel; Kranzler, Henry R.; Stein, Murray B.; Zhang, Huiping; Wei, Feng; Sen, Srijan; Poling, James; Luo, Xingguang

    2010-01-01

    Background Human personality traits are strong predictors or characteristics of many psychiatric disorders including substance dependence (SD). Recently, significant associations between ADH1A and SD have been reported, which led us to investigate the impact of ADH1A variation on personality traits and risk of SD. Methods Five hundred fifty-eight subjects with SD [398 European-Americans (EAs) and 160 African-Americans (AAs)], 517 college students (384 EAs and 133 European-origin Hispanics) and 448 healthy subjects (385 EAs, 48 AAs and 15 European-origin Hispanics) participated. Personality traits were assessed in 247 subjects with SD (179 EAs and 68 AAs), all 517 college students, and 332 healthy subjects (285 EAs, 40 AAs and 7 European-origin Hispanics). The relationships between ADH1A and personality traits were comprehensively examined using stepwise multivariate analysis of covariance (MANCOVA), and then decomposed by stepwise analysis of covariance (ANCOVA). The relationship between ADH1A and SD was examined using stepwise logistic regression analysis. Admixture effects on analyses were considered. Results Overall, Agreeableness and Conscientiousness were associated with the diplotypes, haplotypes, genotypes and/or alleles of ADH1A in three of four phenotype groups including European-American SD subjects, healthy subjects, and African-American SD subjects (1.7×10-4≤p≤0.055), but not college students. Neuroticism was associated with diplotype, haplotypes and genotypes in African-American SD subjects (0.001≤p≤0.031). In addition, SD was associated with diplotypes, haplotypes, genotypes and/or alleles of ADH1A (0.008≤p≤0.060). Conclusions The present study demonstrates that the ADH1A variation may contribute to the genetic component of variation in personality traits and SD. PMID:19526455

  11. Broken chiral symmetry on a null plane

    SciTech Connect

    Beane, Silas R.

    2013-10-15

    On a null-plane (light-front), all effects of spontaneous chiral symmetry breaking are contained in the three Hamiltonians (dynamical Poincaré generators), while the vacuum state is a chiral invariant. This property is used to give a general proof of Goldstone’s theorem on a null-plane. Focusing on null-plane QCD with N degenerate flavors of light quarks, the chiral-symmetry breaking Hamiltonians are obtained, and the role of vacuum condensates is clarified. In particular, the null-plane Gell-Mann–Oakes–Renner formula is derived, and a general prescription is given for mapping all chiral-symmetry breaking QCD condensates to chiral-symmetry conserving null-plane QCD condensates. The utility of the null-plane description lies in the operator algebra that mixes the null-plane Hamiltonians and the chiral symmetry charges. It is demonstrated that in a certain non-trivial limit, the null-plane operator algebra reduces to the symmetry group SU(2N) of the constituent quark model. -- Highlights: •A proof (the first) of Goldstone’s theorem on a null-plane is given. •The puzzle of chiral-symmetry breaking condensates on a null-plane is solved. •The emergence of spin-flavor symmetries in null-plane QCD is demonstrated.

  12. TBX6 Null Variants and a Common Hypomorphic Allele in Congenital Scoliosis

    PubMed Central

    Wu, N.; Ming, X.; Xiao, J.; Wu, Z.; Chen, X.; Shinawi, M.; Shen, Y.; Yu, G.; Liu, J.; Xie, H.; Gucev, Z.S.; Liu, S.; Yang, N.; Al-Kateb, H.; Chen, J.; Zhang, Jian; Hauser, N.; Zhang, T.; Tasic, V.; Liu, P.; Su, X.; Pan, X.; Liu, C.; Wang, L.; Shen, Joseph; Shen, Jianxiong; Chen, Y.; Zhang, T.; Zhang, Jianguo; Choy, K.W.; Wang, Jun; Wang, Q.; Li, S.; Zhou, W.; Guo, J.; Wang, Y.; Zhang, C.; Zhao, H.; An, Y.; Zhao, Y.; Wang, Jiucun; Liu, Z.; Zuo, Y.; Tian, Y.; Weng, X.; Sutton, V.R.; Wang, H.; Ming, Y.; Kulkarni, S.; Zhong, T.P.; Giampietro, P.F.; Dunwoodie, S.L.; Cheung, S.W.; Zhang, X.; Jin, L.; Lupski, J.R.; Qiu, G.; Zhang, F.

    2015-01-01

    BACKGROUND Congenital scoliosis is a common type of vertebral malformation. Genetic susceptibility has been implicated in congenital scoliosis. METHODS We evaluated 161 Han Chinese persons with sporadic congenital scoliosis, 166 Han Chinese controls, and 2 pedigrees, family members of which had a 16p11.2 deletion, using comparative genomic hybridization, quantitative polymerase-chain-reaction analysis, and DNA sequencing. We carried out tests of replication using an additional series of 76 Han Chinese persons with congenital scoliosis and a multi-center series of 42 persons with 16p11.2 deletions. RESULTS We identified a total of 17 heterozygous TBX6 null mutations in the 161 persons with sporadic congenital scoliosis (11%); we did not observe any null mutations in TBX6 in 166 controls (P<3.8×10−6). These null alleles include copy-number variants (12 instances of a 16p11.2 deletion affecting TBX6) and single-nucleotide variants (1 nonsense and 4 frame-shift mutations). However, the discordant intrafamilial phenotypes of 16p11.2 deletion carriers suggest that heterozygous TBX6 null mutation is insufficient to cause congenital scoliosis. We went on to identify a common TBX6 haplotype as the second risk allele in all 17 carriers of TBX6 null mutations (P<1.1×10−6). Replication studies involving additional persons with congenital scoliosis who carried a deletion affecting TBX6 confirmed this compound inheritance model. In vitro functional assays suggested that the risk haplotype is a hypomorphic allele. Hemivertebrae are characteristic of TBX6-associated congenital scoliosis. CONCLUSIONS Compound inheritance of a rare null mutation and a hypomorphic allele of TBX6 accounted for up to 11% of congenital scoliosis cases in the series that we analyzed. PMID:25564734

  13. Neurite outgrowth resistance to rho kinase inhibitors in PC12 Adh cell.

    PubMed

    Yin, Hua; Hou, Xiaolin; Tao, Tingrui; Lv, Xiaoman; Zhang, Luyong; Duan, Weigang

    2015-05-01

    Rho kinase (ROCK) inhibitor is a promising agent for neural injury disorders, which mechanism is associated with neurite outgrowth. However, neurite outgrowth resistance occurred when PC12 Adh cell was treated with ROCK inhibitors for a longer time. PC12 Adh cells were treated with ROCK inhibitor Y27632 or NGF for different durations. Neurite outgrowth resistance occurred when PC12 Adh cell exposed to Y27632 (33 µM) for 3 or more days, but not happen when exposed to nerve growth factor (NGF, 100 ng/mL). The gene expression in the PC12 Adh cells treated with Y27632 (33 µM) or NGF (100 ng/mL) for 2 or 4 days was assayed by gene microarray, and the reliability of the results were confirmed by real-time RT-PCR. Cluster analysis proved that the gene expression profile of PC12 Adh cell treated with Y27632 for 4 days was different from that treated with Y27632 for 2 days and those treated with NGF for 2 and 4 days, respectively. Pathway analysis hinted that the neurite outgrowth resistance could be associated with up-regulation of inflammatory pathways, especially rno04610 (complement and coagulation cascades), and down-regulation of cell cycle pathways, especially rno04110. PMID:25571866

  14. Visible Nulling Coronagraph Testbed Results

    NASA Technical Reports Server (NTRS)

    Lyon, Richard G.; Clampin, Mark; Melnick, Gary; Tolls, Volker; Woodruff, Robert; Vasudevan, Gopal; Rizzo, Maxime; Thompson, Patrick

    2009-01-01

    The Extrasolar Planetary Imaging Coronagraph (EPIC) is a NASA Astrophysics Strategic Mission Concept study and a proposed NASA Discovery mission to image and characterize extrasolar giant planets in orbits with semi-major axes between 2 and 10 AU. EPIC would provide insights into the physical nature of a variety of planets in other solar systems complimenting radial velocity (RV) and astrometric planet searches. It will detect and characterize the atmospheres of planets identified by radial velocity surveys, determine orbital inclinations and masses, characterize the atmospheres around A and F stars, observed the inner spatial structure and colors of inner Spitzer selected debris disks. EPIC would be launched to heliocentric Earth trailing drift-away orbit, with a 5-year mission lifetime. The starlight suppression approach consists of a visible nulling coronagraph (VNC) that enables starlight suppression in broadband light from 480-960 nm. To demonstrate the VNC approach and advance it's technology readiness we have developed a laboratory VNC and have demonstrated white light nulling. We will discuss our ongoing VNC work and show the latest results from the VNC testbed.

  15. Exceptionally High Levels of Restriction Site Polymorphism in DNA near the Maize Adh1 Gene

    PubMed Central

    Johns, Mitrick A.; Strommer, Judith N.; Freeling, Michael

    1983-01-01

    Restriction maps have been prepared for the chromosomal region near seven biochemically and genetically distinct maize alcohol dehydrogenase-1 (Adh1) alleles using a small cDNA probe for Adh1. Five restriction sites spanning about 4 kb in and near the Adh1 transcription unit appear identical in all seven alleles. Outside this conserved region, variation in restriction site position is the rule. Six of the seven alleles are distinguishable, and the alleles appear to fall into four groups. The DNA flanking the 1S-type alleles seems to share no restriction site homology with the DNA near the 1F-type alleles. Several hypotheses are put forward to explain how such high levels of polymorphism could have arisen in a species that has been domesticated for only about 10,000 years. PMID:17246173

  16. Which alcohol use disorder criteria contribute to the association of ADH1B with alcohol dependence?

    PubMed

    Hart, Amy B; Lynch, Kevin G; Farrer, Lindsay; Gelernter, Joel; Kranzler, Henry R

    2016-07-01

    Although alcohol dependence (AD) is approximately 50% heritable, little is known about how specific genetic loci affect AD risk. In a genome-wide association study (GWAS), we identified highly significant associations between two population-specific functional variants in the alcohol dehydrogenase 1B gene (ADH1B) and AD in African-Americans (AAs; rs2066702) and European-Americans (EAs; rs1229984). In the current study, we determined which specific diagnostic criteria contributed to the observed associations of ADH1B SNPs with AD. Our analysis included both the DSM-IV and DSM-5 diagnostic systems. We also investigated the relationship of ADH1B variants to the maximum number of drinks consumed in a 24-hour period (MaxDrinks), a presumed intermediate phenotype of AD. We found that, although all criteria made strong individual contributions to the associations, the largest contributions came from those reflecting neuroadaptation: tolerance (rs2066702) and withdrawal (rs1229984). Overall, evidence for association with DSM-5 criteria was slightly stronger than for DSM-IV criteria. For rs2066702, results were similar for DSM-IV and DSM-5 criteria. However, the most significant DSM-5 criterion associated with rs1229984 was alcohol-related social/interpersonal problems. Both ADH1B variants were associated with MaxDrinks, a measure of innate tolerance, and MaxDrinks mediated the associations between ADH1B and alcohol outcomes. We replicated the findings for rs2066702 and tolerance in an independent sample of AAs. Taken together, these results suggest that variation in ADH1B affects the adaptation to heavy drinking, highlighting population-specific differences in genetic risk for AUD. They also suggest that the revisions reflected in DSM-5 AUD may enhance the utility of that diagnosis for gene finding. PMID:25828809

  17. EhADH112 Is a Bro1 Domain-Containing Protein Involved in the Entamoeba histolytica Multivesicular Bodies Pathway

    PubMed Central

    Bañuelos, Cecilia; García-Rivera, Guillermina; López-Reyes, Israel; Mendoza, Leobardo; González-Robles, Arturo; Herranz, Silvia; Vincent, Olivier; Orozco, Esther

    2012-01-01

    EhADH112 is an Entamoeba histolytica Bro1 domain-containing protein, structurally related to mammalian ALIX and yeast BRO1, both involved in the Endosomal Sorting Complexes Required for Transport (ESCRT)-mediated multivesicular bodies (MVB) biogenesis. Here, we investigated an alternative role for EhADH112 in the MVB protein trafficking pathway by overexpressing 166 amino acids of its N-terminal Bro1 domain in trophozoites. Trophozoites displayed diminished phagocytosis rates and accumulated exogenous Bro1 at cytoplasmic vesicles which aggregated into aberrant complexes at late stages of phagocytosis, probably preventing EhADH112 function. Additionally, the existence of a putative E. histolytica ESCRT-III subunit (EhVps32) presumably interacting with EhADH112, led us to perform pull-down experiments with GST-EhVps32 and [35S]-labeled EhADH112 or EhADH112 derivatives, confirming EhVps32 binding to EhADH112 through its Bro1 domain. Our overall results define EhADH112 as a novel member of ESCRT-accessory proteins transiently present at cellular surface and endosomal compartments, probably contributing to MVB formation during phagocytosis. PMID:22500103

  18. Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France.

    PubMed

    Wintjens, René; Bozon, Dominique; Belabbas, Khaldia; MBou, Félicien; Girardet, Jean-Philippe; Tounian, Patrick; Jolly, Mathilde; Boccara, Franck; Cohen, Ariel; Karsenty, Alexandra; Dubern, Béatrice; Carel, Jean-Claude; Azar-Kolakez, Ahlam; Feillet, François; Labarthe, François; Gorsky, Anne-Marie Colin; Horovitz, Alice; Tamarindi, Catherine; Kieffer, Pierre; Lienhardt, Anne; Lascols, Olivier; Di Filippo, Mathilde; Dufernez, Fabienne

    2016-03-01

    Autosomal dominant hypercholesterolemia (ADH) is a human disorder characterized phenotypically by isolated high-cholesterol levels. Mutations in the low density lipoprotein receptor (LDLR), APOB, and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes are well known to be associated with the disease. To characterize the genetic background associated with ADH in France, the three ADH-associated genes were sequenced in a cohort of 120 children and 109 adult patients. Fifty-one percent of the cohort had a possible deleterious variant in LDLR, 3.1% in APOB, and 1.7% in PCSK9. We identified 18 new variants in LDLR and 2 in PCSK9. Three LDLR variants, including two newly identified, were studied by minigene reporter assay confirming the predicted effects on splicing. Additionally, as recently an in-frame deletion in the APOE gene was found to be linked to ADH, the sequencing of this latter gene was performed in patients without a deleterious variant in the three former genes. An APOE variant was identified in three patients with isolated severe hypercholesterolemia giving a frequency of 1.3% in the cohort. Therefore, even though LDLR mutations are the major cause of ADH with a large mutation spectrum, APOE variants were found to be significantly associated with the disease. Furthermore, using structural analysis and modeling, the identified APOE sequence changes were predicted to impact protein function. PMID:26802169

  19. Parasitic interference in nulling interferometry

    NASA Astrophysics Data System (ADS)

    Matter, A.; Defrère, D.; Danchi, W. C.; Lopez, B.; Absil, O.

    2013-05-01

    Nulling interferometry aims to detect faint objects close to bright stars. Its principle is to produce a destructive interference along the line of sight so that the stellar flux is rejected, while the flux of the off-axis source can be transmitted. In practice, various instrumental perturbations can degrade the nulling performance. Any imperfection in phase, amplitude or polarization produces a spurious flux that leaks to the interferometer output and corrupts the transmitted off-axis flux. One of these instrumental perturbations is the crosstalk phenomenon, which occurs because of multiple parasitic reflections inside transmitting optics, and/or diffraction effects related to beam propagation along finite size optics. It can include a crosstalk of a beam with itself, and a mutual crosstalk between different beams. This can create a parasitic interference pattern, which degrades the intrinsic transmission map - or intensity response - of the interferometer. In this context, we describe how this instrumental effect impairs the performance of a Bracewell interferometer. A simple formalism is developed to derive the corresponding modified intensity response of the interferometer, as a function of the two parameters of interest: the crosstalk level (or contamination rate) and the phase shift between the primary and secondary - parasitic - beams. We then apply our mathematical approach to a few scientific cases, both analytically and using the GENIESIM simulation software, adapted to handle coherent crosstalk. Our results show that a coherent crosstalk level of about 1 per cent implies a 20 per cent drop of the signal-to-noise ratio at most. Careful attention should thus be paid to reduce the crosstalk level inside an interferometric instrument and ensure an instrumental stability that provides the necessary sensitivity through calibration procedures.

  20. Activity of Yeast Alcohol Dehydrogenases on Benzyl Alcohols and Benzaldehydes. Characterization of ADH1 from Saccharomyces carlsbergensis and Transition State Analysis

    PubMed Central

    Pal, Suresh; Park, Doo-Hong; Plapp, Bryce V.

    2009-01-01

    The substrate specificities of yeast alcohol dehydrogenases I and II from Saccharomyces cerevisiae (SceADH1 and SceADH2) and Saccharomyces carlsbergensis (ScbADH1) were studied. For this work, the gene for the S. carlsbergensis ADH1 was cloned, sequenced and expressed. The amino acid sequence of ScbADH1 differs at four positions as compared to SceADH1, including substitutions of two glutamine residues with glutamic acid residues, and has the same sequence as the commercial yeast enzyme, which apparently is prepared from S. carlsbergensis. The electrophoretic mobilities of ScbADH1, SceADH2 and commercial ADH are similar. The kinetics and specificities of ScbADH1 and SceADH1 acting on branched, long-chain and benzyl alcohols are very similar, but the catalytic efficiency of SceADH2 is about 10 to 100-fold higher on these substrates. A three dimensional structure of SceADH1 shows that the substrate binding pocket has Met-270, whereas SceADH2 has Leu-270, which allows larger substrates to bind. The reduction of a series of p-substituted benzaldehydes catalyzed by SceADH2 is significantly enhanced by electron-withdrawing groups, whereas the oxidation of p-substituted aromatic alcohols may be only slightly affected by the substituents. The substituent effects on catalysis generally reflect the effects on the equilibrium constant for the reaction, where electron-withdrawing substituents favor alcohol. The results are consistent with a transition state that is electronically similar to the alcohol, supporting previous results obtained with commercial yeast ADH. PMID:19022233

  1. SPINK1 gene mutations and pancreatitis in Japan.

    PubMed

    Shimosegawa, Tooru; Kume, Kiyoshi; Masamune, Atsushi

    2006-10-01

    SPINK1 can inhibit up to 20% of trypsin activity, and may constitute one major mechanism to protect the pancreas from autodigestion. In 2000, Witt et al. first recognized the association between mutations in the SPINK1 gene and chronic pancreatitis (CP), but the significance of SPINK1 gene mutation in pancreatitis and its relation to alcohol consumption remains unclear in Japan. The aim of the present paper was to clarify the incidence of SPINK1 mutations in CP patients with various etiologies in Japan and, in addition, to examine the relationship between alcohol metabolism and the polymorphisms in the key enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase-2 (ALDH2). A total of 156 patients with CP, and 165 healthy volunteers, all Japanese, were examined for the SPINK1 mutations by polymerase chain reaction-restriction fragment length polymorphism and direct sequencing. In Japan, the prevalence of [N34S; IVS1-37T > C] and [-215G > A; IVS3 + 2T > C] was significantly higher in patients with idiopathic CP (10.6% and 12.8%, respectively) than normal subjects (0.6% and 0%). The frequency of the [-215G > A; IVS3 + 2T > C] mutation in Japan was significantly higher than that reported in other populations. Concerning alcoholic CP, the [-215G > A; IVS3 + 2T > C] mutation was found in only a small number of patients (3.9%). On analysis of ADH2 and ALDH2 gene polymorphisms an association was found between ADH2*2 allele and alcoholic CP, and the ADH2*2/2*2 genotype had a tendency to increase the risk of developing pancreatic pseudocyst. In conclusion, in Japan the [-215G > A; IVS3 + 2T > C] mutation in the SPINK1 gene may form a unique genetic background for pancreatitis. PMID:16958672

  2. Optimal Beam Combiner Design for Nulling Interferometers

    NASA Astrophysics Data System (ADS)

    Guyon, Olivier; Mennesson, Bertrand; Serabyn, Eugene; Martin, Stefan

    2013-08-01

    A scheme to optimally design a beam combiner is discussed for any predetermined fixed geometry nulling interferometer aimed at detection and characterization of exoplanets with multiple telescopes or a single telescope (aperture masking). We show that considerably higher order nulls can be achieved with 1D (one-dimensional) interferometer geometries than possible with 2D (two-dimensional) geometries with the same number of apertures. Any 1D interferometer with N apertures can achieve a 2(N - 1)-order null, while the order of the deepest null for a random 2D aperture geometry interferometer is the order of the Nth term in the Taylor expansion of ei(x2+y2) around x = 0, y = 0 (2nd order null for N = 2,3 4th order null for N = 4,5,6). We also show that an optimal beam combiner for nulling interferometry relies on only 0 or π phase shifts. Examples of nulling interferometer designs are shown to illustrate these findings.

  3. Case of inappropriate ADH syndrome: hyponatremia due to polyethylene glycol bowel preparation.

    PubMed

    Ko, Sun-Hye; Lim, Chul-Hyun; Kim, Jae-Young; Kang, Seung Hun; Baeg, Myong Ki; Oh, Hyun Jin

    2014-09-14

    Colonoscopic screening has been reported to reduce deaths from colorectal cancer. Adequate bowel preparation is essential for this and safety is an important issue in choosing the methods. Polyethylene glycol (PEG) is regarded as a safe method for cleansing, especially compared with oral sodium phosphate. Here, we present a case of hyponatremia caused by the syndrome of inappropriate antidiuretic hormone (ADH) syndrome after PEG precolonoscopic cleansing resulting in generalized tonic-clonic seizures. A 62-year-old women had ingested PEG for precolonoscopic bowel cleansing. While waiting for the colonoscopy, she developed a stuporous mentality and generalized tonic-clonic seizures, which did not correlate with brain magnetic resonance imaging. Her serum sodium level was 113 mEq per liter and laboratory analyses were consistent with inappropriate ADH syndrome. Her thyroid and adrenal functions were normal. There were no malignancies, infections, respiratory disorders or central nervous disorders and she had no history of taking either diuretics or other medications, which might have caused inappropriate ADH syndrome. She was treated with 3% hypertonic saline and showed a complete neurological recovery as her sodium levels recovered. Follow-up visits showed the patient to have a normal sodium level without neurologic deficits. This case shows that inappropriate ADH syndrome can be caused by PEG preparation, which implies that physicians have to be aware of the possible side effects of this colonic cleansing approach and mindful of the possible ensuing symptoms. PMID:25232272

  4. The influence of Adh function on ethanol preference and tolerance in adult Drosophila melanogaster.

    PubMed

    Ogueta, Maite; Cibik, Osman; Eltrop, Rouven; Schneider, Andrea; Scholz, Henrike

    2010-11-01

    Preference determines behavioral choices such as choosing among food sources and mates. One preference-affecting chemical is ethanol, which guides insects to fermenting fruits or leaves. Here, we show that adult Drosophila melanogaster prefer food containing up to 5% ethanol over food without ethanol and avoid food with high levels (23%) of ethanol. Although female and male flies behaved differently at ethanol-containing food sources, there was no sexual dimorphism in the preference for food containing modest ethanol levels. We also investigated whether Drosophila preference, sensitivity and tolerance to ethanol was related to the activity of alcohol dehydrogenase (Adh), the primary ethanol-metabolizing enzyme in D. melanogaster. Impaired Adh function reduced ethanol preference in both D. melanogaster and a related species, D. sechellia. Adh-impaired flies also displayed reduced aversion to high ethanol concentrations, increased sensitivity to the effects of ethanol on postural control, and negative tolerance/sensitization (i.e., a reduction of the increased resistance to ethanol's effects that normally occurs upon repeated exposure). These data strongly indicate a linkage between ethanol-induced behavior and ethanol metabolism in adult fruit flies: Adh deficiency resulted in reduced preference to low ethanol concentrations and reduced aversion to high ones, despite recovery from ethanol being strongly impaired. PMID:20739429

  5. Meta-Analyses of ALDH2 and ADH1B with Alcohol Dependence in Asians

    ERIC Educational Resources Information Center

    Luczak, Susan E.; Glatt, Stephen J.; Wall, Tamara J.

    2006-01-01

    Meta-analyses were conducted to determine the magnitude of relationships between polymorphisms in 2 genes, ALDH2 and ADH1B, with alcohol dependence in Asians. For each gene, possession of 1 variant [asterisk]2 allele was protective against alcohol dependence, and possession of a 2nd [asterisk]2 allele did not offer significant additional…

  6. Hemodynamic and ADH responses to central blood volume shifts in cardiac-denervated humans

    NASA Technical Reports Server (NTRS)

    Convertino, V. A.; Thompson, C. A.; Benjamin, B. A.; Keil, L. C.; Savin, W. M.; Gordon, E. P.; Haskell, W. L.; Schroeder, J. S.; Sandler, H.

    1990-01-01

    Hemodynamic responses and antidiuretic hormone (ADH) were measured during body position changes designed to induce blood volume shifts in ten cardiac transplant recipients to assess the contribution of cardiac and vascular volume receptors in the control of ADH secretion. Each subject underwent 15 min of a control period in the seated posture, then assumed a lying posture for 30 min at 6 deg head down tilt (HDT) followed by 20 min of seated recovery. Venous blood samples and cardiac dimensions (echocardiography) were taken at 0 and 15 min before HDT, 5, 15, and 30 min of HDT, and 5, 15, and 30 min of seated recovery. Blood samples were analyzed for hematocrit, plasma osmolality, plasma renin activity (PRA), and ADH. Resting plasma volume (PV) was measured by Evans blue dye and percent changes in PV during posture changes were calculated from changes in hematocrit. Heart rate (HR) and blood pressure (BP) were recorded every 2 min. Results indicate that cardiac volume receptors are not the only mechanism for the control of ADH release during acute blood volume shifts in man.

  7. Evaluation of the Saccharomyces cerevisiae ADH2 promoter for protein synthesis.

    PubMed

    Lee, K Michael; DaSilva, Nancy A

    2005-04-30

    The Saccharomyces cerevisiae ADH2 promoter (P(ADH2)) is repressed several hundred-fold in the presence of glucose; transcription is initiated once the glucose in the medium is exhausted. The promoter can thus be utilized for effective regulation of recombinant gene expression in S. cerevisiae without the addition of an inducer. To evaluate this promoter in the absence of plasmid copy number and stability variations, the P(ADH2)-lacZ cassette was integrated into the yeast chromosomes. The effects of medium composition, glucose concentration and cultivation time on promoter derepression and expression level were investigated. Maximum protein activity was obtained after 48 h of growth in complex YPD medium containing 1% glucose. The widely used S. cerevisiae GAL1 and CUP1 promoters both require the addition of an inducer [galactose and copper(II) ion, respectively] before regulated genes will be expressed. The strengths of these three different promoters were compared for cells containing one copy of an integrated lacZ gene under their control. The ADH2 promoter was superior for all induction strategies investigated. PMID:15849781

  8. Effects of ADH on the apical and basolateral membranes of toad urinary bladder epithelial cells.

    PubMed

    Donaldson, P J; Leader, J P

    1993-11-01

    Short-circuited urinary bladders from Bufo marinus were supported on their apical surface by an agar mounting method and impaled with microelectrodes via their basolateral membrane. This arrangement provided stable and long-lasting impalements of epithelial cells and yielded reliable membrane potentials and voltage divider ratios (Ra/Rb), where Ra and Rb are apical and basolateral membrane resistances respectively. The membrane potential under short-circuit conditions (Vsc) was -51.4 +/- 2.2 mV (n = 59), while under open-circuit conditions apical membrane potential (Va) and basolateral membrane potential (Vb) were -31.0 +/- 2.4 and 59.5 +/- 2.4 mV, respectively. This yields a "well-shaped" potential profile across the toad urinary bladder, where Va is inversely related to the rate of transport, Isc. Antidiuretic hormone (ADH) produced a hyperpolarisation of Vsc and Vb but had no significant effect on Va. In addition, Ra/Rb was significantly increased by ADH (4.6 +/- 0.5 to 10.2 +/- 3.6). Calculation of individual membrane resistances following the addition of amiloride showed that ADH produced a parallel decrease in Ra and Rb membrane resistance, with the observed increase in Ra/Rb being due to a greater percentage decrease in Rb than in Ra. The ability of ADH to effect parallel changes in apical and basolateral membrane conductance helps to maintain a constant cellular volume despite an increase in transepithelial transport. PMID:8309781

  9. Interactions between ADH and prostaglandins in isolated erythrocyte-perfused rat kidney

    SciTech Connect

    Lieberthal, W.; Vasilevsky, M.L.; Valeri, C.R.; Levinsky, N.G.

    1987-02-01

    Interactions between antidiuretic hormone (ADH) and renal prostaglandins in the regulation of sodium reabsorption and urinary concentrating ability were studied in isolated erythrocyte-perfused rat kidneys (IEPK). In this model, hemodynamic characteristics are comparable to those found in vivo, and tubular morphology is preserved throughout the period of perfusion. (Deamino)-D-arginine vasopressin (dDAVP) markedly reduced fractional sodium excretion (FE/sub Na/) in the IEPK. After indomethacin, FE/sub Na/ fell still further. In the absence of dDAVP indomethacin had no effect on sodium excretion. dDAVP increased urine osmolality in the IEPK. When prostaglandin synthesis was blocked with indomethacin, urinary osmolality increased further. In isolated kidneys perfused without erythrocytes (IPK), dDAVP decreased FE/sub Na/ from 14.5 +/- 1.8% to 9.6 +/- 1.2%. dDAVP increased urine osmolality only modestly in the IPK and indomethacin did not increase concentrating ability further. Thus the IEPK (unlike the IPK) can excrete markedly hypertonic urine in response to ADH. ADH also enhances tubular reabsorption of sodium in the IEPK. Prostaglandins inhibit both these actions of ADH but do not directly affect sodium excretion in the absence of the hormone. Prostaglandius were measured by radioimmunoassay.

  10. Suppression of ADH during water immersion in normal man. [antidiuretic hormone

    NASA Technical Reports Server (NTRS)

    Epstein, M.; Pins, D. S.; Miller, M.

    1975-01-01

    A study was undertaken to ascertain whether diuresis induced by immersion is medicated by an inhibition of ADH. Immersion resulted in a progressive decrease in ADH excretion from 80.1 + or - 7 (SEM) to 37.3 + or - 6.3 microU/min (P less than 0.025). Cessation of immersion was associated with a marked increase in ADH from 37.3 + or - 6.3 microU/min to 176.6 + or - 72.6 microU/min during the recovery hour (P less than 0.05). Concomitant with these changes, urine osmolality decreased significantly beginning as early as the initial hour of immersion from 1044 + or - 36 to 542 + or - 66 mosmol/kg H2O during the final hour of immersion (P less than 0.001). These findings are consistent with the earlier suggestion that suppression of ADH release contributes to enhanced free water clearance in hydrated subjects undergoing immersion.

  11. Defective intestinal amino acid absorption in Ace2 null mice.

    PubMed

    Singer, Dustin; Camargo, Simone M R; Ramadan, Tamara; Schäfer, Matthias; Mariotta, Luca; Herzog, Brigitte; Huggel, Katja; Wolfer, David; Werner, Sabine; Penninger, Josef M; Verrey, François

    2012-09-15

    Mutations in the main intestinal and kidney luminal neutral amino acid transporter B(0)AT1 (Slc6a19) lead to Hartnup disorder, a condition that is characterized by neutral aminoaciduria and in some cases pellagra-like symptoms. These latter symptoms caused by low-niacin are thought to result from defective intestinal absorption of its precursor L-tryptophan. Since Ace2 is necessary for intestinal B(0)AT1 expression, we tested the impact of intestinal B(0)AT1 absence in ace2 null mice. Their weight gain following weaning was decreased, and Na(+)-dependent uptake of B(0)AT1 substrates measured in everted intestinal rings was defective. Additionally, high-affinity Na(+)-dependent transport of L-proline, presumably via SIT1 (Slc6a20), was absent, whereas glucose uptake via SGLT1 (Slc5a1) was not affected. Measurements of small intestine luminal amino acid content following gavage showed that more L-tryptophan than other B(0)AT1 substrates reach the ileum in wild-type mice, which is in line with its known lower apparent affinity. In ace2 null mice, the absorption defect was confirmed by a severalfold increase of L-tryptophan and of other neutral amino acids reaching the ileum lumen. Furthermore, plasma and muscle levels of glycine and L-tryptophan were significantly decreased in ace2 null mice, with other neutral amino acids displaying a similar trend. A low-protein/low-niacin diet challenge led to differential changes in plasma amino acid levels in both wild-type and ace2 null mice, but only in ace2 null mice to a stop in weight gain. Despite the combination of low-niacin with a low-protein diet, plasma niacin concentrations remained normal in ace2 null mice and no pellagra symptoms, such as photosensitive skin rash or ataxia, were observed. In summary, mice lacking Ace2-dependent intestinal amino acid transport display no total niacin deficiency nor clear pellagra symptoms, even under a low-protein and low-niacin diet, despite gross amino acid homeostasis alterations

  12. Nulling interferometry: symmetry requirements and experimental results

    NASA Astrophysics Data System (ADS)

    Serabyn, Eugene

    2000-07-01

    This paper provides a derivation from first principles of the stringent symmetry and stability requirements which deep stellar nulling demands, and also includes a brief status report on recent nulling results obtained with the Jet Propulsion Laboratory's fiber-coupled rotational-shearing interferometer. To date, the deepest transient nulls obtained (at red wavelengths) are 2 X 10-6 with a laser diode source, and 1.4 X 10-5 with a single- polarization thermal white-light source filtered to provide an 18% passband. In addition, both the laser and white light nulls have been stabilized to the 10-4 level. This visible wavelength laboratory nuller thus meets essentially all of the performance goals for the planned nulling experiment on board NASA's Space Interferometer Mission, with the sole exception of dual-polarization operation.

  13. Automatic null ellipsometry with an interferometer

    SciTech Connect

    Watkins, Lionel R.

    2009-11-10

    A new approach to automatic null ellipsometry is described in which the analyzer of a traditional polarizer compensator sample analyzer (PCSA) null ellipsometer is replaced with a heterodyne Michelson interferometer. One arm of this interferometer is modified such that it produces a fixed, linearly polarized reference beam, irrespective of the input polarization state. This beam is recombined interferometrically with the measurement beam and spatially separated into its p and s polarizations. The relative phase of the resulting temporal fringes is a linear function of the polarizer azimuthal angle P, and thus this component can be driven to its null position without iteration. Once at null, the azimuthal angle of the reflected, linearly polarized light is trivially determined from the relative amplitude of the fringes. Measurements made with this instrument on a native oxide film on a silicon wafer were in excellent agreement with those made with a traditional PCSA null ellipsometer.

  14. Nulling interferometry without achromatic phase shifters.

    PubMed

    Mieremet, Arjan L; Braat, Joseph J M

    2002-08-01

    In the infrared wavelength region, a typical star is approximately a million times brighter than the planet that surrounds it, which is a major problem when we attempt to detect exoplanets in a direct manner. Nulling interferometry is a technique that one can use to solve this problem by attenuating the stellar light and enhancing that of the planet. Generally, deep nulling is achieved by use of achromatic phase shifters (APSs). Unfortunately, the technology needed to build these APSs is not yet fully developed. We show that deep nulling can also be achieved by using delay lines only. We investigate the nulling depth as a function of the width of the wavelength interval and the number of telescopes. We also show that we can obtain nulling depths of less than 10(-6), which are required for exoplanet detection. Furthermore, we investigate the properties of the transmission map and make a comparison between our system and an APS system. PMID:12153105

  15. The EhADH112 recombinant polypeptide inhibits cell destruction and liver abscess formation by Entamoeba histolytica trophozoites.

    PubMed

    Martínez-López, Carolina; Orozco, Esther; Sánchez, Tomás; García-Pérez, Rosa María; Hernández-Hernández, Fidel; Rodríguez, Mario A

    2004-04-01

    The Entamoeba histolytica EhCPADH complex, formed by a cysteine proteinase (EhCP112) and an adhesin (EhADH112), is involved in adherence, phagocytosis and cytolysis. This makes this complex an attractive candidate as a vaccine against amoebiasis. Here, we produced the recombinant polypeptide EhADH243, which includes the adherence epitope detected by a monoclonal antibody against the EhCPADH complex. EhADH243 was purified, and the effect of the polypeptide on in vitro and in vivo virulence was studied. Antibodies against EhADH243 reacted with the EhCPADH complex and with the recombinant polypeptide. EhADH243 and antibodies against this polypeptide inhibited adherence, phagocytosis and destruction of cell monolayers by live trophozoites, but had little effect on cell monolayer destruction by trophozoite extracts. EhADH243 recognized a 97 kDa protein in the MDCK membrane fraction that could be a putative receptor for E. histolytica trophozoites. Hamsters immunized with EhADH243 developed humoral response against EhCPADH, and animals were partially protected from amoebic liver abscess. PMID:15009028

  16. The Adh-related gene of Drosophila melanogaster is expressed as a functional dicistronic messenger RNA: multigenic transcription in higher organisms.

    PubMed

    Brogna, S; Ashburner, M

    1997-04-15

    Essentially all eukaryotic cellular mRNAs are monocistronic, and are usually transcribed individually. Two tandemly arranged Drosophila genes, alcohol dehydrogenase (Adh) and Adh-related (Adhr), are transcribed as a dicistronic transcript. From transcripts initiated from the Adh promoter, two classes of mRNA are accumulated, one is monocistronic and encodes Adh alone, the other is dicistronic and includes the open reading frames of both Adh and Adhr. The dicistronic transcript is found in polysomes and the Adhr protein product is detected by antibody staining. We present evidence that the accumulation of the dicistronic mRNA is controlled at the level of the 3' end processing. PMID:9155028

  17. Alcohol Consumption Mediates the Relationship Between ADH1B and DSM-IV Alcohol Use Disorder and Criteria

    PubMed Central

    Kilcoyne, Bari; Shmulewitz, Dvora; Meyers, Jacquelyn L; Aharonovich, Efrat; Greenstein, Eliana; Frisch, Amos; Weizman, Abraham; Spivak, Baruch; Edenberg, Howard J; Gelernter, Joel; Hasin, Deborah S

    2014-01-01

    Objective: A single nucleotide variation in the alcohol dehydrogenase 1B (ADH1B) gene, rs1229984, produces an ADH1B enzyme with faster acetaldehyde production. This protective variant is associated with lower alcohol consumption and lower risk for alcohol use disorders (AUDs). Based on the premise that faster ADH1B kinetics decreases alcohol consumption, we formally tested if the association between ADH1B variant rs1229984 and AUDs occurs through consumption. We also tested whether the association between rs1 229984 and each of the 11 Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), AUD criteria occurs through consumption. Method: A total of 1,130 lifetime drinkers from an Israeli household sample were assessed with a structured interview and genotyped for rs1229984 (protective allele frequency = 0.28). Logistic regression evaluated the association between rs1229984 and each phenotype (AUDs, 11 individual DSM-IV criteria). For phenotypes significantly related to rs1229984, the effect through consumption was tested with logistic regression and bootstrapping. Results: ADH1B rs1229984 was significantly associated with AUDs and six criteria, with odds ratios ranging from 1.32 to 1.96. The effect through consumption was significant for these relationships, explaining 23%–74% of the total ADH1B effect. Conclusions: This is the first study to show that ADH1B rs1229984 is related to 6 of the 11 DSM-IV AUD criteria and that alcohol consumption explained a significant proportion of these associations and the association of ADH1B with AUDs. Better understanding of the relationship between ADH1B and the DSM-IV AUD criteria, including effects through consumption, will enhance our understanding of the etiologic model through which AUDs can occur. PMID:24988262

  18. Polymorphism of Alcohol Metabolizing Gene ADH3 Predisposes to Development of Alcoholic Pancreatitis in North Indian Population

    PubMed Central

    Singh, Divya; Negi, Tajwar S.; Upadhyay, Ghanshyam; Choudhuri, Gourdas

    2015-01-01

    Background and aim: Genetic factors regulating alcohol metabolism could predispose in developing alcoholic pancreatitis (ACP). Studies revealed that alcohol could be metabolized by both ways, oxidative and non-oxidative. The main oxidative pathway includes alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), and cytochrome P450 enzyme. We investigated the association of polymorphisms in these enzymes with the alcoholic pancreatitis in the north Indian population. Method: Patients with alcoholic pancreatitis (ACP; n = 72), tropical calcific pancreatitis (TCP; n = 75), alcoholic controls (AC; n = 40), and healthy controls (HC; n = 100) were included in the study. Blood samples were collected from the subjects in EDTA coated vials. DNA was extracted and genotyping for ADH3, ALDH2, and CYP2E1 was done by PCR-RFLP (polymerase chain reaction—restriction fragment length polymorphism). The products were analyzed by gel electrophoresis. Result: The frequency distribution of ADH3*1/*1 genotype was significantly higher in ACP group (59.7%) compared with TCP (38.7%), HC (42%), and AC (37.5%) and was found to be associated with increased risk of alcoholic pancreatitis. There was no statistically significant difference between the frequency distribution of ADH3*1/*1, ADH3*1/*2, and ADH3*2/*2 genotypes between TCP and HC or healthy alcoholics. ALDH2 gene was monomorphic in our population, and the frequencies for CYP2E1 intron 6 Dra I polymorphism were comparable in all the four groups. Conclusion: This study shows that carriers of ADH3*1/*1 individuals consuming alcohol are at higher risk for alcoholic pancreatitis than those with other genotypes such as ADH3*1/*2 and ADH3*2/*2. PMID:26734614

  19. Targeting FoxM1 effectively retards p53-null lymphoma and sarcoma

    PubMed Central

    Wang, Zebin; Zheng, Yu; Park, Hyun Jung; Li, Jing; Carr, Janai R.; Chen, Yi-ju; Kiefer, Megan M.; Kopanja, Dragana; Bagchi, Srilata; Tyner, Angela L.; Raychaudhuri, Pradip

    2013-01-01

    The forkhead box transcription factor FOXM1 is considered to be a promising target for cancer therapy. However, the significance of FOXM1 in tumors harboring mutation in p53, which is very common, is unclear. In this study, we investigated the efficacy of FoxM1-targeting in spontaneous p53-null tumors using genetic ablation as well as using a peptide-inhibitor of FOXM1. We show that conditional deletion of FoxM1 inhibits growth of the p53 null thymic lymphoma and sarcoma cells. In addition, deletion of FoxM1 induces apoptotic cell death of the p53 null tumors, accompanied by reduced expression of the FOXM1 target genes Survivin and Bmi1. An ARF-derived peptide that inhibits the activity of FOXM1, by targeting it to the nucleolus, also induces apoptosis in the p53 null sarcoma and lymphoma, leading to a strong inhibition of their metastatic colonization. Together, our observations suggest that FOXM1 is critical for survival and growth of the p53-null lymphoma and sarcoma, and provide proof-of-principle that FOXM1 is an effective therapeutic target for sarcoma and lymphoma carrying loss of function mutation in p53. PMID:23427295

  20. Characterization of the treefrog null allele

    SciTech Connect

    Guttman, S.I. . Dept. of Zoology)

    1990-12-01

    As part of the authors intensive year-long baseline ecological study, they characterized the degree of genetic polymorphism and heterozygosity in selected Feed Materials Production Center (FMPC) populations using electrophoretic techniques. These data are being used as an indicator of stress by comparing populations on and off the FMPC site. The current study was initiated to determine whether this GPI null allele is lethal, when homozygous, in spring peepers. Also, a sampling protocol was implemented to determine whether a linear effect occurs relative to the frequency of the null allele offsite and to determine the origination site of the null allele. 18 refs., 2 figs., 4 tabs.

  1. Abnormal Activation of BMP Signaling Causes Myopathy in Fbn2 Null Mice.

    PubMed

    Sengle, Gerhard; Carlberg, Valerie; Tufa, Sara F; Charbonneau, Noe L; Smaldone, Silvia; Carlson, Eric J; Ramirez, Francesco; Keene, Douglas R; Sakai, Lynn Y

    2015-06-01

    Fibrillins are large extracellular macromolecules that polymerize to form the backbone structure of connective tissue microfibrils. Mutations in the gene for fibrillin-1 cause the Marfan syndrome, while mutations in the gene for fibrillin-2 cause Congenital Contractural Arachnodactyly. Both are autosomal dominant disorders, and both disorders affect musculoskeletal tissues. Here we show that Fbn2 null mice (on a 129/Sv background) are born with reduced muscle mass, abnormal muscle histology, and signs of activated BMP signaling in skeletal muscle. A delay in Myosin Heavy Chain 8, a perinatal myosin, was found in Fbn2 null forelimb muscle tissue, consistent with the notion that muscle defects underlie forelimb contractures in these mice. In addition, white fat accumulated in the forelimbs during the early postnatal period. Adult Fbn2 null mice are already known to demonstrate persistent muscle weakness. Here we measured elevated creatine kinase levels in adult Fbn2 null mice, indicating ongoing cycles of muscle injury. On a C57Bl/6 background, Fbn2 null mice showed severe defects in musculature, leading to neonatal death from respiratory failure. These new findings demonstrate that loss of fibrillin-2 results in phenotypes similar to those found in congenital muscular dystrophies and that FBN2 should be considered as a candidate gene for recessive congenital muscular dystrophy. Both in vivo and in vitro evidence associated muscle abnormalities and accumulation of white fat in Fbn2 null mice with abnormally activated BMP signaling. Genetic rescue of reduced muscle mass and accumulation of white fat in Fbn2 null mice was accomplished by deleting a single allele of Bmp7. In contrast to other reports that activated BMP signaling leads to muscle hypertrophy, our findings demonstrate the exquisite sensitivity of BMP signaling to the fibrillin-2 extracellular environment during early postnatal muscle development. New evidence presented here suggests that fibrillin-2 can

  2. Premeiotic germ cell defect in seminiferous tubules of Atm-null testis

    SciTech Connect

    Takubo, Keiyo . E-mail: keiyot@gmail.com; Hirao, Atsushi; Ohmura, Masako; Azuma, Masaki; Arai, Fumio; Nagamatsu, Go; Suda, Toshio . E-mail: sudato@sc.itc.keio.ac.jp

    2006-12-29

    Lifelong spermatogenesis is maintained by coordinated sequential processes including self-renewal of stem cells, proliferation of spermatogonial cells, meiotic division, and spermiogenesis. It has been shown that ataxia telangiectasia-mutated (ATM) is required for meiotic division of the seminiferous tubules. Here, we show that, in addition to its role in meiosis, ATM has a pivotal role in premeiotic germ cell maintenance. ATM is activated in premeiotic spermatogonial cells and the Atm-null testis shows progressive degeneration. In Atm-null testicular cells, differing from bone marrow cells of Atm-null mice, reactive oxygen species-mediated p16{sup Ink4a} activation does not occur in Atm-null premeiotic germ cells, which suggests the involvement of different signaling pathways from bone marrow defects. Although Atm-null bone marrow undergoes p16{sup Ink4a}-mediated cellular senescence program, Atm-null premeiotic germ cells exhibited cell cycle arrest and apoptotic elimination of premeiotic germ cells, which is different from p16{sup Ink4a}-mediated senescence.

  3. High diversity and no significant selection signal of human ADH1B gene in Tibet

    PubMed Central

    2012-01-01

    Background ADH1B is one of the most studied human genes with many polymorphic sites. One of the single nucleotide polymorphism (SNP), rs1229984, coding for the Arg48His substitution, have been associated with many serious diseases including alcoholism and cancers of the digestive system. The derived allele, ADH1B*48His, reaches high frequency only in East Asia and Southwest Asia, and is highly associated with agriculture. Micro-evolutionary study has defined seven haplogroups for ADH1B based on seven SNPs encompassing the gene. Three of those haplogroups, H5, H6, and H7, contain the ADH1B*48His allele. H5 occurs in Southwest Asia and the other two are found in East Asia. H7 is derived from H6 by the derived allele of rs3811801. The H7 haplotype has been shown to have undergone significant positive selection in Han Chinese, Hmong, Koreans, Japanese, Khazak, Mongols, and so on. Methods In the present study, we tested whether Tibetans also showed evidence for selection by typing 23 SNPs in the region covering the ADH1B gene in 1,175 individuals from 12 Tibetan populations representing all districts of the Tibet Autonomous Region. Multiple statistics were estimated to examine the gene diversities and positive selection signals among the Tibetans and other populations in East Asia. Results The larger Tibetan populations (Qamdo, Lhasa, Nagqu, Nyingchi, Shannan, and Shigatse) comprised mostly farmers, have around 12% of H7, and 2% of H6. The smaller populations, living on hunting or recently switched to farming, have lower H7 frequencies (Tingri 9%, Gongbo 8%, Monba and Sherpa 6%). Luoba (2%) and Deng (0%) have even lower frequencies. Long-range haplotype analyses revealed very weak signals of positive selection for H7 among Tibetans. Interestingly, the haplotype diversity of H7 is higher in Tibetans than in any other populations studied, indicating a longer diversification history for that haplogroup in Tibetans. Network analysis on the long-range haplotypes revealed

  4. Null-strut calculus. II. Dynamics

    SciTech Connect

    Kheyfets, A.; LaFave, N.J.; Miller, W.A. )

    1990-06-15

    In this paper, we continue from the preceding paper to develop a fully functional Regge calculus geometrodynamic algorithm from the null-strut-calculus construction. The developments discussed include (a) the identification of the Regge calculus analogue of the constraint and evolution equations on the null-strut lattice, (b) a description of the Minkowski solid geometry for the simplicial blocks of the null-strut lattice, (c) a description of the evolution algorithm for the geometrodynamic scheme and an analysis of its consistency, and (d) a presentation of the dynamical degrees of freedom for a simplicial hypersurface and the description of an initial-value prescription. To demonstrate qualitatively this new approach to geometrodynamics, we present the most simple application of null-strut calculus that we know of---the Friedmann cosmology using the three-boundary of a 600-cell simplicial polytope to model the simplicial hypersurface.

  5. Null structure groups in eleven dimensions

    SciTech Connect

    Cariglia, Marco; Mac Conamhna, Oisin A. P.

    2006-02-15

    We classify all the structure groups which arise as subgroups of the isotropy group (Spin(7)xR{sup 8})xR, of a single null Killing spinor in 11 dimensions. We construct the spaces of spinors fixed by these groups. We determine the conditions under which structure subgroups of the maximal null structure group (Spin(7)xR{sup 8})xR may also be embedded in SU(5), and hence the conditions under which a supersymmetric spacetime admits only null, or both timelike and null, Killing spinors. We discuss how this purely algebraic material will facilitate the direct analysis of the Killing spinor equation of 11 dimensional supergravity, and the classification of supersymmetric spacetimes therein.

  6. On the Penrose inequality along null hypersurfaces

    NASA Astrophysics Data System (ADS)

    Mars, Marc; Soria, Alberto

    2016-06-01

    The null Penrose inequality, i.e. the Penrose inequality in terms of the Bondi energy, is studied by introducing a functional on surfaces and studying its properties along a null hypersurface Ω extending to past null infinity. We prove a general Penrose-type inequality which involves the limit at infinity of the Hawking energy along a specific class of geodesic foliations called Geodesic Asymptotically Bondi (GAB), which are shown to always exist. Whenever this foliation approaches large spheres, this inequality becomes the null Penrose inequality and we recover the results of Ludvigsen–Vickers (1983 J. Phys. A: Math. Gen. 16 3349–53) and Bergqvist (1997 Class. Quantum Grav. 14 2577–83). By exploiting further properties of the functional along general geodesic foliations, we introduce an approach to the null Penrose inequality called the Renormalized Area Method and find a set of two conditions which imply the validity of the null Penrose inequality. One of the conditions involves a limit at infinity and the other a restriction on the spacetime curvature along the flow. We investigate their range of applicability in two particular but interesting cases, namely the shear-free and vacuum case, where the null Penrose inequality is known to hold from the results by Sauter (2008 PhD Thesis Zürich ETH), and the case of null shells propagating in the Minkowski spacetime. Finally, a general inequality bounding the area of the quasi-local black hole in terms of an asymptotic quantity intrinsic of Ω is derived.

  7. Phase-only nulling for transmit antenna

    NASA Astrophysics Data System (ADS)

    Hussain, Moayyed A.; Yu, Kai-Bor

    1999-11-01

    This paper describes a technique for transmit antenna nulling for low-cost large sparse phased array radar system. Radar system described includes an array of elemental antennas, each with a transmit/receive (T/R) module. The T/R modules are operated at or near maximum output to achieve maximum CD-to-RF efficiency. A phase controller controls the phase shift, which are imparted by each module to its signal, to form a mainbeam and its associated sidelobes. A perturbation phase generator adds phase shifts computed, to form wide nulls in the sidelobe structure. The nulls are achieved at very minimal loss of gain, in the order of fraction of a dB. The speed of obtaining these nulls in real time allows a rapid steering of these nulls in a hostile environment. The thinned aperture allow designing a light weigh mobile system. In radar context, these nulls may be placed on a source of ground clutter, a set of jammers or a set of undesirable radio sources.

  8. Polymorphisms in Alcohol Metabolism Genes ADH1B and ALDH2, Alcohol Consumption and Colorectal Cancer

    PubMed Central

    Crous-Bou, Marta; Rennert, Gad; Cuadras, Daniel; Salazar, Ramon; Cordero, David; Saltz Rennert, Hedy; Lejbkowicz, Flavio; Kopelovich, Levy; Monroe Lipkin, Steven; Bernard Gruber, Stephen; Moreno, Victor

    2013-01-01

    Background Colorectal cancer (CRC) is a leading cause of cancer death worldwide. Epidemiological risk factors for CRC included alcohol intake, which is mainly metabolized to acetaldehyde by alcohol dehydrogenase and further oxidized to acetate by aldehyde dehydrogenase; consequently, the role of genes in the alcohol metabolism pathways is of particular interest. The aim of this study is to analyze the association between SNPs in ADH1B and ALDH2 genes and CRC risk, and also the main effect of alcohol consumption on CRC risk in the study population. Methodology/Principal Findings SNPs from ADH1B and ALDH2 genes, included in alcohol metabolism pathway, were genotyped in 1694 CRC cases and 1851 matched controls from the Molecular Epidemiology of Colorectal Cancer study. Information on clinicopathological characteristics, lifestyle and dietary habits were also obtained. Logistic regression and association analysis were conducted. A positive association between alcohol consumption and CRC risk was observed in male participants from the Molecular Epidemiology of Colorectal Cancer study (MECC) study (OR = 1.47; 95%CI = 1.18-1.81). Moreover, the SNPs rs1229984 in ADH1B gene was found to be associated with CRC risk: under the recessive model, the OR was 1.75 for A/A genotype (95%CI = 1.21-2.52; p-value = 0.0025). A path analysis based on structural equation modeling showed a direct effect of ADH1B gene polymorphisms on colorectal carcinogenesis and also an indirect effect mediated through alcohol consumption. Conclusions/Significance Genetic polymorphisms in the alcohol metabolism pathways have a potential role in colorectal carcinogenesis, probably due to the differences in the ethanol metabolism and acetaldehyde oxidation of these enzyme variants. PMID:24282520

  9. DRYAD and ADH: Further comments on explaining age-related differences in memory.

    PubMed

    Naveh-Benjamin, Moshe; Smyth, Andrea C

    2016-02-01

    Recently, Smyth and Naveh-Benjamin (2016) questioned some of the main assumptions/hypotheses of DRYAD (or density of representations yields age-related deficits), a global-deficit model of aging and memory judgments (Benjamin, 2010; Benjamin et al., 2012). Smyth and Naveh-Benjamin (2016) provided empirical evidence that seems incompatible with DRYAD, but that fits the associative deficit hypothesis (ADH; Naveh-Benjamin, 2000), 1 specific-deficit theoretical view. In response, Aaron Benjamin (2016) offered a discussion of the complementary strengths and weaknesses of the DRYAD and the ADH, and the potential ways they might work together. We agree with many of his comments, but are not convinced that DRYAD is able to explain basic replicable empirical evidence of the type mentioned in Smyth and Naveh-Benjamin (2016). We discuss the reasons why we are not fully convinced by the demonstration of DRYAD's simulation of results presented in Benjamin (2016) and then present an implementation of ADH in a computationally based age-related impaired neuromodulation approach that was shown to simulate the basic empirical results of age-related associative memory deficits. We also discuss the issues of parsimony of theories and the appropriate type of representation, in the context of global versus specific deficits theoretical views. Finally, we show that the ADH's take on the distinction between items and associations has been adopted by some global computational models of memory. We believe that considerations of the above issues and others raised by Benjamin (2016) can lead to fruitful discussions that will benefit both theory development and existing knowledge of aging and memory. PMID:26866588

  10. APOL1 Null Alleles from a Rural Village in India Do Not Correlate with Glomerulosclerosis

    PubMed Central

    Johnstone, Duncan B.; Shegokar, Vijay; Nihalani, Deepak; Rathore, Yogendra Singh; Mallik, Leena; Ashish; Zare, Vasant; Ikizler, H. Omer; Powar, Rajaram; Holzman, Lawrence B.

    2012-01-01

    Background Among African-Americans, genome wide association revealed a strong correlation between the G1 and G2 alleles of APOL1 (apolipoproteinL1, also called trypanolytic factor) and kidney diseases including focal and segmental glomerulosclerosis, HIV-associated nephropathy and hypertensive nephrosclerosis. In the prevailing hypothesis, heterozygous APOL1 G1 and G2 alleles increase resistance against Trypanosoma that cause African sleeping sickness, resulting in positive selection of these alleles, but when homozygous the G1 and G2 alleles predispose to glomerulosclerosis. While efforts are underway to screen patients for G1 and G2 alleles and to better understand “APOL1 glomerulopathy,” no data prove that these APOL1 sequence variants cause glomerulosclerosis. G1 and G2 correlate best with glomerulosclerosis as recessive alleles, which suggests a loss of function mutation for which proof of causality is commonly tested with homozygous null alleles. This test cannot be performed in rodents as the APOL gene cluster evolved only in primates. However, there is a homozygous APOL1 null human being who lives in a village in rural India. This individual and his family offer a unique opportunity to test causality between APOL1 null alleles and glomerulosclerosis. Methods and Findings We obtained clinical data, blood and urine from this APOL1 null patient and 50 related villagers. Based on measurements of blood pressure, BUN, creatinine, albuminuria, genotyping and immunoblotting, this APOL1 null individual does not have glomerulosclerosis, nor do his relatives who carry APOL1 null alleles. Conclusions This small study cannot provide definitive conclusions but the absence of glomerulosclerosis in this unique population is consistent with the possibility that African-American glomerulosclerosis is caused, not by loss of APOL1 function, but by other mechanisms including a subtle gain of function or by the “genetic hitchhiking” of deleterious mutations in a gene

  11. The Relationship between CmADHs and the Diversity of Volatile Organic Compounds of Three Aroma Types of Melon (Cucumis melo).

    PubMed

    Chen, Hao; Cao, Songxiao; Jin, Yazhong; Tang, Yufan; Qi, Hongyan

    2016-01-01

    Alcohol dehydrogenase (ADH) plays an important role in aroma volatile compounds synthesis of plants. In this paper, we tried to explore the relationship between CmADHs and the volatile organic compounds (VOCs) in oriental melon. Three different aroma types of melon were used as materials. The principle component analysis of three types of melon fruit was conducted. We also measured the CmADHs expression level and enzymatic activities of ADH and alcohol acyl-transferase (AAT) on different stages of fruit ripening. An incubation experiment was carried out to investigate the effect of substrates and inhibitor (4-MP, 4-methylpyrazole) on CmADHs expression, ADH activity, and the main compounds of oriental melon. The results illustrated that ethyl acetate, hexyl acetate (E,Z)-3,6-nonadien-1-ol and 2-ethyl-2hexen-1-ol were the four principal volatile compounds of these three types of melon. AAT activity was increasing with fruit ripening, and the AAT activity in CH were the highest, whereas ADH activity peaked on 32 DAP, 2 days before maturation, and the ADH activity in CB and CG were higher than that in CH. The expression pattern of 11 CmADH genes from 24 to 36 day after pollination (DAP) was found to vary in three melon varieties. CmADH4 was only expressed in CG and the expression levels of CmADH3 and CmADH12 in CH and CB were much higher than that in CG, and they both peaked 2 days before fruit ripening. Ethanol and 4-MP decreased the reductase activity of ADH, the expression of most CmADHs and ethyl acetate or hexyl acetate contents of CB, except for 0.1 mM 4-MP, while aldehyde improved the two acetate ester contents. In addition, we found a positive correlation between the expression of CmADH3 and CmADH12 and the key volatile compound of CB. The relationship between CmADHs and VOCs synthesis of oriental melon was discussed. PMID:27445845

  12. The Relationship between CmADHs and the Diversity of Volatile Organic Compounds of Three Aroma Types of Melon (Cucumis melo)

    PubMed Central

    Chen, Hao; Cao, Songxiao; Jin, Yazhong; Tang, Yufan; Qi, Hongyan

    2016-01-01

    Alcohol dehydrogenase (ADH) plays an important role in aroma volatile compounds synthesis of plants. In this paper, we tried to explore the relationship between CmADHs and the volatile organic compounds (VOCs) in oriental melon. Three different aroma types of melon were used as materials. The principle component analysis of three types of melon fruit was conducted. We also measured the CmADHs expression level and enzymatic activities of ADH and alcohol acyl-transferase (AAT) on different stages of fruit ripening. An incubation experiment was carried out to investigate the effect of substrates and inhibitor (4-MP, 4-methylpyrazole) on CmADHs expression, ADH activity, and the main compounds of oriental melon. The results illustrated that ethyl acetate, hexyl acetate (E,Z)-3,6-nonadien-1-ol and 2-ethyl-2hexen-1-ol were the four principal volatile compounds of these three types of melon. AAT activity was increasing with fruit ripening, and the AAT activity in CH were the highest, whereas ADH activity peaked on 32 DAP, 2 days before maturation, and the ADH activity in CB and CG were higher than that in CH. The expression pattern of 11 CmADH genes from 24 to 36 day after pollination (DAP) was found to vary in three melon varieties. CmADH4 was only expressed in CG and the expression levels of CmADH3 and CmADH12 in CH and CB were much higher than that in CG, and they both peaked 2 days before fruit ripening. Ethanol and 4-MP decreased the reductase activity of ADH, the expression of most CmADHs and ethyl acetate or hexyl acetate contents of CB, except for 0.1 mM 4-MP, while aldehyde improved the two acetate ester contents. In addition, we found a positive correlation between the expression of CmADH3 and CmADH12 and the key volatile compound of CB. The relationship between CmADHs and VOCs synthesis of oriental melon was discussed. PMID:27445845

  13. Proof of the quantum null energy condition

    NASA Astrophysics Data System (ADS)

    Bousso, Raphael; Fisher, Zachary; Koeller, Jason; Leichenauer, Stefan; Wall, Aron C.

    2016-01-01

    We prove the quantum null energy condition (QNEC), a lower bound on the stress tensor in terms of the second variation in a null direction of the entropy of a region. The QNEC arose previously as a consequence of the quantum focusing conjecture, a proposal about quantum gravity. The QNEC itself does not involve gravity, so a proof within quantum field theory is possible. Our proof is somewhat nontrivial, suggesting that there may be alternative formulations of quantum field theory that make the QNEC more manifest. Our proof applies to free and super-renormalizable bosonic field theories, and to any points that lie on stationary null surfaces. An example is Minkowski space, where any point p and null vector ka define a null plane N (a Rindler horizon). Given any codimension-2 surface Σ that contains p and lies on N , one can consider the von Neumann entropy Sout of the quantum state restricted to one side of Σ . A second variation Sout'' can be defined by deforming Σ along N , in a small neighborhood of p with area A . The QNEC states that ⟨Tk k(p )⟩≥ℏ/2 π lim A →0 Sout''/A .

  14. Three-dimensional null point reconnection regimes

    SciTech Connect

    Priest, E. R.; Pontin, D. I.

    2009-12-15

    Recent advances in theory and computational experiments have shown the need to refine the previous categorization of magnetic reconnection at three-dimensional null points--points at which the magnetic field vanishes. We propose here a division into three different types, depending on the nature of the flow near the spine and fan of the null. The spine is an isolated field line which approaches the null (or recedes from it), while the fan is a surface of field lines which recede from it (or approach it). So-called torsional spine reconnection occurs when field lines in the vicinity of the fan rotate, with current becoming concentrated along the spine so that nearby field lines undergo rotational slippage. In torsional fan reconnection field lines near the spine rotate and create a current that is concentrated in the fan with a rotational flux mismatch and rotational slippage. In both of these regimes, the spine and fan are perpendicular and there is no flux transfer across spine or fan. The third regime, called spine-fan reconnection, is the most common in practice and combines elements of the previous spine and fan models. In this case, in response to a generic shearing motion, the null point collapses to form a current sheet that is focused at the null itself, in a sheet that locally spans both the spine and fan. In this regime the spine and fan are no longer perpendicular and there is flux transfer across both of them.

  15. Two roads to the null energy condition

    NASA Astrophysics Data System (ADS)

    Parikh, Maulik

    2015-11-01

    The null energy condition has sweeping consequences in general relativity. I argue here that it has been misunderstood as a property exclusively of matter, when in fact it arises only in a theory of both matter and gravity. I then derive an equivalent geometric formulation of the null energy condition from worldsheet string theory, where it arises beautifully as simple Einstein’s equations in two dimensions. But further, I show that this condition also has a thermodynamic origin, following from a local version of the second law of thermodynamics, applied to gravitational entropy. Thus, far from being an incidental property of matter, the validity of the null energy condition hints at the deep dual origins of gravity.

  16. Spontaneous Skin Ulceration and Defective T Cell Function in CD18 Null Mice

    PubMed Central

    Scharffetter-Kochanek, Karin; Lu, Huifang; Norman, Keith; van Nood, Nicole; Munoz, Flor; Grabbe, Stephan; McArthur, Mark; Lorenzo, Isabel; Kaplan, Sheldon; Ley, Klaus; Wayne Smith, C.; Montgomery, Charles A.; Rich, Susan; Beaudet, Arthur L.

    1998-01-01

    A null mutation was prepared in the mouse for CD18, the β2 subunit of leukocyte integrins. Homozygous CD18 null mice develop chronic dermatitis with extensive facial and submandibular erosions. The phenotype includes elevated neutrophil counts, increased immunoglobulin levels, lymphadenopathy, splenomegaly, and abundant plasma cells in skin, lymph nodes, gut, and kidney. Very few neutrophils were found in spontaneously occurring skin lesions or with an induced toxic dermatitis. Intravital microscopy in CD18 null mice revealed a lack of firm neutrophil attachment to venules in the cremaster muscle in response to N-formyl- methionyl-leucyl-phenylalanine. A severe defect in T cell proliferation was found in the CD18 null mice when T cell receptors were stimulated either by staphylococcal enterotoxin A or by major histocompatibility complex alloantigens demonstrating a greater role of CD11/CD18 integrins in T cell responses than previously documented. The null mice are useful for delineating the functions of CD18 in vivo. PMID:9653089

  17. Spontaneous skin ulceration and defective T cell function in CD18 null mice.

    PubMed

    Scharffetter-Kochanek, K; Lu, H; Norman, K; van Nood, N; Munoz, F; Grabbe, S; McArthur, M; Lorenzo, I; Kaplan, S; Ley, K; Smith, C W; Montgomery, C A; Rich, S; Beaudet, A L

    1998-07-01

    A null mutation was prepared in the mouse for CD18, the beta2 subunit of leukocyte integrins. Homozygous CD18 null mice develop chronic dermatitis with extensive facial and submandibular erosions. The phenotype includes elevated neutrophil counts, increased immunoglobulin levels, lymphadenopathy, splenomegaly, and abundant plasma cells in skin, lymph nodes, gut, and kidney. Very few neutrophils were found in spontaneously occurring skin lesions or with an induced toxic dermatitis. Intravital microscopy in CD18 null mice revealed a lack of firm neutrophil attachment to venules in the cremaster muscle in response to N-formyl- methionyl-leucyl-phenylalanine. A severe defect in T cell proliferation was found in the CD18 null mice when T cell receptors were stimulated either by staphylococcal enterotoxin A or by major histocompatibility complex alloantigens demonstrating a greater role of CD11/CD18 integrins in T cell responses than previously documented. The null mice are useful for delineating the functions of CD18 in vivo. PMID:9653089

  18. Null surfaces in static space-times

    NASA Astrophysics Data System (ADS)

    Vollick, Dan N.

    2015-07-01

    In this paper I consider surfaces in a space-time with a Killing vector ξ α that is time-like and hypersurface-orthogonal on one side of the surface. The Killing vector may be either time-like or space-like on the other side of the surface. It has been argued that the surface is null if ξ α ξ α → 0 as the surface is approached from the static region. This implies that, in a coordinate system adapted to ξ, surfaces with g tt = 0 are null. In spherically symmetric space-times the condition g rr = 0 instead of g tt = 0 is sometimes used to locate null surfaces. In this paper I examine the arguments that lead to these two different criteria and show that both arguments are incorrect. A surface ξ = const has a normal vector whose norm is proportional to ξ α ξ α . This lead to the conclusion that surfaces with ξ α ξ α = 0 are null. However, the proportionality factor generally diverges when g tt = 0, leading to a different condition for the norm to be null. In static spherically symmetric space-times this condition gives g rr = 0, not g tt = 0. The problem with the condition g rr = 0 is that the coordinate system is singular on the surface. One can either use a nonsingular coordinate system or examine the induced metric on the surface to determine if it is null. By using these approaches it is shown that the correct criteria is g tt = 0. I also examine the condition required for the surface to be nonsingular.

  19. Childhood adversity moderates the effect of ADH1B on risk for alcohol-related phenotypes in Jewish Israeli drinkers.

    PubMed

    Meyers, Jacquelyn L; Shmulewitz, Dvora; Wall, Melanie M; Keyes, Katherine M; Aharonovich, Efrat; Spivak, Baruch; Weizman, Abraham; Frisch, Amos; Edenberg, Howard J; Gelernter, Joel; Grant, Bridget F; Hasin, Deborah

    2015-01-01

    Childhood adversity and genetic variant ADH1B-rs1229984 have each been shown to influence heavy alcohol consumption and disorders. However, little is known about how these factors jointly influence these outcomes. We assessed the main and additive interactive effects of childhood adversity (abuse, neglect and parental divorce) and the ADH1B-rs1229984 on the quantitative phenotypes 'maximum drinks in a day' (Maxdrinks) and DSM-Alcohol Use Disorder (AUD) severity, adjusting for demographic variables, in an Israeli sample of adult household residents (n = 1143) evaluated between 2007 and 2009. Childhood adversity and absence of the protective ADH1B-rs1229984 A allele were associated with greater mean Maxdrinks (mean differences: 1.50; 1.13, respectively) and AUD severity (mean ratios: 0.71; 0.27, respectively). In addition, childhood adversity moderated the ADH1B-rs1229984 effect on Maxdrinks (P < 0.01) and AUD severity (P < 0.05), in that there was a stronger effect of ADH1B-rs1229984 genotype on Maxdrinks and AUD severity among those who had experienced childhood adversity compared with those who had not. ADH1B-rs1229984 impacts alcohol metabolism. Therefore, among those at risk for greater consumption, e.g. those who experienced childhood adversity, ADH1B-rs1229984 appears to have a stronger effect on alcohol consumption and consequently on risk for AUD symptom severity. Evidence for the interaction of genetic vulnerability and early life adversity on alcohol-related phenotypes provides further insight into the complex relationships between genetic and environmental risk factors. PMID:24164917

  20. Childhood adversity moderates the effect of ADH1B on risk for alcohol-related phenotypes in Jewish Israeli drinkers

    PubMed Central

    Meyers, Jacquelyn L.; Shmulewitz, Dvora; Wall, Melanie M.; Keyes, Katherine M.; Aharonovich, Efrat; Spivak, Baruch; Weizman, Abraham; Frisch, Amos; Edenberg, Howard J.; Gelernter, Joel; Grant, Bridget F.; Hasin, Deborah

    2013-01-01

    Childhood adversity and genetic variant ADH1B-rs1229984 have each been shown to influence heavy alcohol consumption and disorders. However, little is known about how these factors jointly influence these outcomes. We assessed the main and additive interactive effects of childhood adversity (abuse, neglect, parental divorce) and the ADH1B-rs1229984 on the quantitative phenotypes “maximum drinks in a day” (Maxdrinks) and DSM-Alcohol Use Disorder (AUD) severity, adjusting for demographic variables, in an Israeli sample of adult household residents (n=1,143) evaluated between 2007–2009. Childhood adversity and absence of the protective ADH1B-rs1229984 A allele were associated with greater mean Maxdrinks [Mean Differences: 1.50; 1.13 respectively] and AUD severity [Mean Ratios: 0.71; 0.27 respectively]). In addition, childhood adversity moderated the ADH1B-rs1229984 effect on Maxdrinks (p<0.01) and AUD severity (p<0.05), in that there was a stronger effect of ADH1B-rs1229984 genotype on Maxdrinks and AUD severity among those who had experienced childhood adversity compared to those who had not. ADH1B-rs1229984 impacts alcohol metabolism. Therefore, among those at risk for greater consumption, e.g., those who experienced childhood adversity, ADH1B-rs1229984 appears to have a stronger effect on alcohol consumption and consequently on risk for AUD symptom severity. Evidence for the interaction of genetic vulnerability and early life adversity on alcohol-related phenotypes provides further insight into the complex relationships between genetic and environmental risk factors. PMID:24164917

  1. Characterization of the treefrog null allele, 1991

    SciTech Connect

    Guttman, S.I.

    1992-04-01

    Spring peeper (Hyla crucifer) tadpoles collected from the waste storage area during the Biological and Ecological Site Characterization of the Feed Materials Production Center (FEMP) in 1986 and 1987 appeared to be unique. A null (inactive) allele was found at the glucose phosphate isomerase enzyme locus in significant frequencies (approximately 20%) each year; this allele did not appear to occur in the offsite sample collected approximately 15km from the FEMP. Null alleles at this locus have not been reported in other amphibian populations; when they have been found in other organisms they have invariably been lethal in the homozygous condition.

  2. Null-strut calculus. I. Kinematics

    SciTech Connect

    Kheyfets, A.; LaFave, N.J.; Miller, W.A. )

    1990-06-15

    This paper describes the kinematics of null-strut calculus---a 3+1 Regge calculus approach to general relativity. We show how to model the geometry of spacetime with simplicial spacelike three-geometries (TET's) linked to earlier'' and later'' momentumlike lattice surfaces (TET{sup *}) entirely by light rays or null struts.'' These three-layered lattice spacetime geometries are defined and analyzed using combinatorial formulas for the structure of polytopes. The following paper in this series describes how these three-layered spacetime lattices are used to model spacetimes in full conformity with Einstein's theory of gravity.

  3. Null-broadening in a waveguide.

    PubMed

    Kim, J S; Hodgkiss, W S; Kuperman, W A; Song, H C

    2002-07-01

    Null-broadening, introduced in plane wave beamforming, is extended to an ocean waveguide in the context of matched field processing. The method is based on the minimum variance processor with white noise constraint and the distribution of fictitious sources using the theory of waveguide invariants. The proposed method is demonstrated in simulation as well as with data collected during the SWellEx-96 experiment. As another application, it is shown that the width of a null can be controlled in an adaptive time reversal mirror with a source-receive array. PMID:12141344

  4. Molecular characterization of an atl null mutant of Staphylococcus aureus.

    PubMed

    Takahashi, Junko; Komatsuzawa, Hitoshi; Yamada, Sakuo; Nishida, Tetsuya; Labischinski, Harald; Fujiwara, Tamaki; Ohara, Masaru; Yamagishi, Jun-ichi; Sugai, Motoyuki

    2002-01-01

    atl is a gene encoding a bifunctional peptidoglycan hydrolase of Staphylococcus aureus. The gene product of atl is a 138 kDa protein that has an amidase domain and a glucosaminidase domain, and undergoes processing to generate two major peptidoglycan hydrolases, a 51 kDa glucosaminidase and a 62 kDa amidase in culture supernatant. An atl null mutant was isolated by allelic replacement and characterized. The mutant grew in clusters and sedimented when grown in broth culture. Analysis of peptidoglycan prepared from the wild type and the mutant revealed that there were no differences in muropeptide composition or in glycan chain length distribution. On the other hand, the atl mutation resulted in pleiotropic effects on cell surface nature. The mutant cells showed complete inhibition of metabolic turnover of cell wall peptidoglycan and revealed a rough outer cell wall surface. The mutation also decreased the amount of protein non-covalently bound to the cell surface and altered the protein profile, but did not affect proteins covalently associated with the cell wall. Lysis of growing cells treated with otherwise lytic concentration of penicillin G was completely inhibited in the mutant, but that of non-growing cells was not affected by the mutation. The atl mutation did not significantly affect the ability of S. aureus to provoke an acute infection when inoculated intraperitoneally in a mouse sepsis model. These results further support the supposition that atl gene products are involved in cell separation, cell wall turnover and penicillin-induced lysis of the cells. PMID:12437027

  5. Biosynthetic burden and plasmid burden limit expression of chromosomally integrated heterologous genes (pdc, adhB) in Escherichia coli

    SciTech Connect

    Martinez, A.; York, S.W.; Yomano, L.P.; Pineda, V.L.; Davis, F.C.; Shelton, J.C.; Ingram, L.O.

    1999-10-01

    Previous studies have shown an unexpectedly high nutrient requirement for efficient ethanol production by ethanologenic recombinants of Escherichia coli B such as LY01 which contain chromosomally integrated Zymomonas mobilis genes (pdc, adhB) encoding the ethanol pathway. The basis for this requirement has been identified as a media-dependent effect on the expression of the Z. mobilis genes rather than a nutritional limitation. Ethanol production was substantially increased without additional nutrients simply by increasing the level of pyruvate decarboxylase activity. This was accomplished by adding a multicopy plasmid containing pdc alone (but not adhB alone) to strain LY01, and by adding multicopy plasmids which express pdc and adhB from strong promoters. New strong promoters were isolated from random fragments of Z. mobilis DNA and characterized but were not used to construct integrated biocatalysts. These promoters contained regions resembling recognition sites for 3 different E. coli sigma factors: {sigma}{sup 70}, {sigma}{sup 38}, and {sigma}{sup 28}. The most effective plasmid-based promoters for fermentation were recognized by multiple sigma factors, expressed both pdc and adhB at high levels, and produced ethanol efficiently while allowing up to 80% reduction in complex nutrients as compared to LY01. The ability to utilize multiple sigma factors may be advantageous to maintain the high levels of PDC and ADH needed for efficient ethanol production throughout batch fermentation.

  6. Cloning of the Arabidopsis and Rice Formaldehyde Dehydrogenase Genes: Implications for the Origin of Plant Adh Enzymes

    PubMed Central

    Dolferus, R.; Osterman, J. C.; Peacock, W. J.; Dennis, E. S.

    1997-01-01

    This article reports the cloning of the genes encoding the Arabidopsis and rice class III ADH enzymes, members of the alcohol dehydrogenase or medium chain reductase/dehydrogenase superfamily of proteins with glutathione-dependent formaldehyde dehydrogenase activity (GSH-FDH). Both genes contain eight introns in exactly the same positions, and these positions are conserved in plant ethanol-active Adh genes (class P). These data provide further evidence that plant class P genes have evolved from class III genes by gene duplication and acquisition of new substrate specificities. The position of introns and similarities in the nucleic acid and amino acid sequences of the different classes of ADH enzymes in plants and humans suggest that plant and animal class III enzymes diverged before they duplicated to give rise to plant and animal ethanol-active ADH enzymes. Plant class P ADH enzymes have gained substrate specificities and evolved promoters with different expression properties, in keeping with their metabolic function as part of the alcohol fermentation pathway. PMID:9215914

  7. Role of cardiac volume receptors in the control of ADH release during acute simulated weightlessness in man

    NASA Technical Reports Server (NTRS)

    Convertino, V. A.; Benjamin, B. A.; Keil, L. C.; Sandler, H.

    1984-01-01

    Hemodynamic responses and antidiuretic hormone (ADH) were measured during body position changes, designed to induce central blood volume shifts in ten cardiac and one heart-lung transplant recipients, to assess the contribution of cardiac volume receptors in the control of ADH release during the initial acute phase of exposure to weightlessness. Each subject underwent 15 min of a sitting-control period (C) followed by 30 min of 6 deg headdown tilt (T) and 30 min of resumed sitting (S). Venous blood samples and cardiac dimensions were taken at 0 and 15 min of C; 5, 15, and 30 min of T; and 5, 15, and 30 min of S. Blood samples were analyzed for hematocrit, plasma osmolality, plasma renin activity (PRA), and ADH. Heart rate and blood pressure were recorded every two min. Plasma osmolality was not altered by posture changes. Mean left ventricular end-diastolic volume increased (P less than 0.05) from 90 ml in C to 106 ml in T and returned to 87 ml in S. Plasma ADH was reduced by 20 percent (P less than 0.05) with T, and returned to control levels with S. These responses were similar in six normal cardiac-innervated control subjects. These data may suggest that cardiac volume receptors are not the primary mechanism for the control of ADH release during acute central volume shifts in man.

  8. Polarization nulling interferometry for exoplanet detection.

    PubMed

    Spronck, Julien; Pereira, Silvania F; Braat, Joseph J M

    2006-04-01

    We introduce a new concept of nulling interferometer without any achromatic device, using polarization properties of light. This type of interferometer should enable a high rejection ratio in a theoretically unlimited spectral band. We analyze several consequences of the proposed design, notably, the possibility of fast internal modulation. PMID:19516397

  9. A Philosophical Critique of Null Hypothesis Testing.

    ERIC Educational Resources Information Center

    Orey III, Michael A.; And Others

    1989-01-01

    An attempt is made to clarify the philosophical foundations of the debate over research methodology appropriate for psychology in particular and the utility of null hypothesis testing in general. The article also relates the debate to education and suggests that the debate is far from settled. (IAH)

  10. Inhibition of alcohol dehydrogenase after 2-propanol exposure in different geographic races of Drosophila mojavensis: lack of evidence for selection at the Adh-2 locus.

    PubMed

    Pfeiler, Edward; Reed, Laura K; Markow, Therese A

    2005-03-15

    High frequencies of the fast allele of alcohol dehydrogenase-2 (Adh-2F) are found in populations of Drosophila mojavensis that inhabit the Baja California peninsula (race BII) whereas the slow allele (Adh-2S) predominates at most other localities within the species' geographic range. Race BII flies utilize necrotic tissue of pitaya agria cactus (Stenocereus gummosus) which contains high levels of 2-propanol, whereas flies from most other localities utilize different cactus hosts in which 2-propanol levels are low. To test if 2-propanol acts as a selective force on Adh-2 genotype, or whether some other yet undetermined genetic factor is responsible, mature males of D. mojavensis lines derived from the Grand Canyon (race A) and Santa Catalina Island (race C), each with individuals homozygous for Adh-2F and Adh-2S, were exposed to 2-propanol for 24 h and ADH-2 specific activity was then determined on each genotype. Flies from five other localities homozygous for either the fast or slow allele also were examined. Results for all reported races of D. mojavensis were obtained. 2-propanol exposure inhibited ADH-2 specific activity in both genotypes from all localities, but inhibition was significantly less in two populations of race BII flies homozygous for Adh-2F. When F/F and S/S genotypes in flies from the same locality were compared, both genotypes showed high 2-propanol inhibition that was not statistically different, indicating that the F/F genotype alone does not provide a benefit against the inhibitory effects of 2-propanol. ADH-1 activity in female ovaries was inhibited less by 2-propanol than ADH-2. These results do not support the hypothesis that 2-propanol acts as a selective factor favoring the Adh-2F allele. PMID:15726639

  11. Decrease in Leaf Sucrose Synthesis Leads to Increased Leaf Starch Turnover and Decreased RuBP-limited Photosynthesis But Not Rubisco-limited Photosynthesis in Arabidopsis Null Mutants of SPSA1

    Technology Transfer Automated Retrieval System (TEKTRAN)

    SPS (Sucrose phosphate synthase) isoforms from dicots cluster into families A, B and C. In this study, we investigated the individual effect of null mutations of each of the four SPS genes in Arabidopsis (spsa1, spsa2, spsb and spsc) on photosynthesis and carbon partitioning. Null mutants spsa1 and ...

  12. Improvement of tolerance of Saccharomyces cerevisiae to hot-compressed water-treated cellulose by expression of ADH1.

    PubMed

    Jayakody, Lahiru N; Horie, Kenta; Hayashi, Nobuyuki; Kitagaki, Hiroshi

    2012-04-01

    Hot-compressed water treatment of cellulose and hemicellulose for subsequent bioethanol production is a novel, economically feasible, and nonhazardous method for recovering sugars. However, the hot-compressed water-treated cellulose and hemicellulose inhibit subsequent ethanol fermentation by the yeast Saccharomyces cerevisiae. To overcome this problem, we engineered a yeast strain with improved tolerance to hot-compressed water-treated cellulose. We first determined that glycolaldehyde has a greater inhibitory effect than 5-HMF and furfural and a combinational effect with them. On the basis of the hypothesis that the reduction of glycolaldehyde to ethylene glycol should detoxify glycolaldehyde, we developed a strain overexpressing the alcohol dehydrogenase gene ADH1. The ADH1-overexpressing strain exhibits an improved fermentation profile in a glycolaldehyde-containing medium. The conversion ratio of glycolaldehyde to ethylene glycol is 30 ± 1.9% when the control strain is used; this ratio increases to 77 ± 3.6% in the case of the ADH1-overexpressing strain. A glycolaldehyde treatment and the overexpression of ADH1 cause changes in the fermentation products so as to balance the metabolic carbon flux and the redox status. Finally, the ADH1-overexpressing strain shows a statistically significantly improved fermentation profile in a hot-compressed water-treated cellulose-containing medium. The conversion ratio of glycolaldehyde to ethylene glycol is 33 ± 0.85% when the control strain is used but increases to 72 ± 1.7% in the case of the ADH1-overexpressing strain. These results show that the reduction of glycolaldehyde to ethylene glycol is a promising strategy to decrease the toxicity of hot-compressed water-treated cellulose. This is the first report on the improvement of yeast tolerance to hot-compressed water-treated cellulose and glycolaldehyde. PMID:22311646

  13. Dynamically Coupled Food-web and Hydrodynamic Modeling with ADH-CASM

    NASA Astrophysics Data System (ADS)

    Piercy, C.; Swannack, T. M.

    2012-12-01

    Oysters and freshwater mussels are "ecological engineers," modifying the local water quality by filtering zooplankton and other suspended particulate matter from the water column and flow hydraulics by impinging on the near-bed flow environment. The success of sessile, benthic invertebrates such as oysters depends on environmental factors including but not limited to temperature, salinity, and flow regime. Typically food-web and other types of ecological models use flow and water quality data as direct input without regard to the feedback between the ecosystem and the physical environment. The USACE-ERDC has developed a coupled hydrodynamic-ecological modeling approach that dynamically couples a 2-D hydrodynamic and constituent transport model, Adaptive Hydraulics (ADH), with a bioenergetics food-web model, the Comprehensive Aquatics Systems Model (CASM), which captures the dynamic feedback between aquatic ecological systems and the environment. We present modeling results from restored oyster reefs in the Great Wicomico River on the western shore of the Chesapeake Bay, which quantify ecosystem services such as the influence of the benthic ecosystem on water quality. Preliminary results indicate that while the influence of oyster reefs on bulk flow dynamics is limited due to the localized influence of oyster reefs, large reefs and the associated benthic ecosystem can create measurable changes in the concentrations of nitrogen, phosphorus, and carbon in the areas around reefs. We also present a sensitivity analysis to quantify the relative sensitivity of the coupled ADH-CASM model to both hydrodynamic and ecological parameter choice.

  14. Alcohol dehydrogenase gene ADH3 activates glucose alcoholic fermentation in genetically engineered Dekkera bruxellensis yeast.

    PubMed

    Schifferdecker, Anna Judith; Siurkus, Juozas; Andersen, Mikael Rørdam; Joerck-Ramberg, Dorte; Ling, Zhihao; Zhou, Nerve; Blevins, James E; Sibirny, Andriy A; Piškur, Jure; Ishchuk, Olena P

    2016-04-01

    Dekkera bruxellensis is a non-conventional Crabtree-positive yeast with a good ethanol production capability. Compared to Saccharomyces cerevisiae, its tolerance to acidic pH and its utilization of alternative carbon sources make it a promising organism for producing biofuel. In this study, we developed an auxotrophic transformation system and an expression vector, which enabled the manipulation of D. bruxellensis, thereby improving its fermentative performance. Its gene ADH3, coding for alcohol dehydrogenase, was cloned and overexpressed under the control of the strong and constitutive promoter TEF1. Our recombinant D. bruxellensis strain displayed 1.4 and 1.7 times faster specific glucose consumption rate during aerobic and anaerobic glucose fermentations, respectively; it yielded 1.2 times and 1.5 times more ethanol than did the parental strain under aerobic and anaerobic conditions, respectively. The overexpression of ADH3 in D. bruxellensis also reduced the inhibition of fermentation by anaerobiosis, the "Custer effect". Thus, the fermentative capacity of D. bruxellensis could be further improved by metabolic engineering. PMID:26743658

  15. Optical isopropanol biosensor using NADH-dependent secondary alcohol dehydrogenase (S-ADH).

    PubMed

    Chien, Po-Jen; Ye, Ming; Suzuki, Takuma; Toma, Koji; Arakawa, Takahiro; Iwasaki, Yasuhiko; Mitsubayashi, Kohji

    2016-10-01

    Isopropanol (IPA) is an important solvent used in industrial activity often found in hospitals as antiseptic alcohol rub. Also, IPA may have the potential to be a biomarker of diabetic ketoacidosis. In this study, an optical biosensor using NADH-dependent secondary alcohol dehydrogenase (S-ADH) for IPA measurement was constructed and evaluated. An ultraviolet light emitting diode (UV-LED, λ=340nm) was employed as the excitation light to excite nicotinamide adenine dinucleotide (NADH). A photomultiplier tube (PMT) was connected to a two-way branch optical fiber for measuring the fluorescence emitted from the NADH. S-ADH was immobilized on the membrane to catalyze IPA to acetone and reduce NAD(+) to be NADH. This IPA biosensor shows highly sensitivity and selectivity, the calibration range is from 500 nmol L(-1) to 1mmolL(-1). The optimization of buffer pH, temperature, and the enzyme-immobilized method were also evaluated. The detection of IPA in nail related cosmetic using our IPA biosensor was also carried out. The results showed that large amounts of IPA were used in these kinds of cosmetics. This IPA biosensor comes with the advantages of rapid reaction, good reproducibility, and wide dynamic range, and is also expected to use for clinical IPA detections in serum or other medical and health related applications. PMID:27474326

  16. Analysis and in situ mapping of the Adh locus in species of the willistoni group of Drosophila.

    PubMed

    Rohde, C; Abdelhay, E; Pinto Júnior, H; Schrank, A; Valente, V L

    1995-01-01

    The Adh locus was mapped by in situ hybridization with the heterologous biotinylated probe SAC-PAT to the salivary chromosomes of seven species of the willistoni group of Drosophila. Hybridization signals were obtained mainly at a single site to the right arm of chromosome II in six species, but in Drosophila nebulosa two sites hybridized with the same consistency. Southern blot analysis Eco RI-digested genomic DNA of the seven species revealed high molecular weight bands shared by three species, plus the appropriately sized fragment expected, suggesting the presence of Adh pseudogenes in those species. PMID:7671636

  17. Current progress on TPFI nulling architectures at Jet Propulsion Laboratory

    NASA Technical Reports Server (NTRS)

    Gappinger, Robert O.; Wallace, J. Kent; Bartos, Randall D.; Macdonald, Daniel R.; Brown, Kenneth A.

    2005-01-01

    Infrared interferometric nulling is a promising technology for exoplanet detection. Nulling research for the Terrestrial Planet Finder Interferometer has been exploring a variety of interferometer architectures at the Jet Propulsion Laboratory (JPL).

  18. Perturbative gauge theory at null infinity

    NASA Astrophysics Data System (ADS)

    Adamo, Tim; Casali, Eduardo

    2015-06-01

    We describe a theory living on the null conformal boundary I of four-dimensional Minkowski space, the states of which include the radiative modes of Yang-Mills theory. The action of a Kac-Moody symmetry algebra on the correlators of these states leads to a Ward identity for asymptotic "large" gauge transformations which is equivalent to the soft gluon theorem. The subleading soft gluon behavior is also obtained from a Ward identity for charges acting as vector fields on the sphere of null generators of I . Correlation functions of the Yang-Mills states are shown to produce the full classical S-matrix of Yang-Mills theory. The model contains additional states arising from nonunitary gravitational degrees of freedom, indicating a relationship with the twistor string of Berkovits and Witten.

  19. Adaptive Nulling for the Terrestrial Planet Finder Interferometer

    NASA Technical Reports Server (NTRS)

    Peters, Robert D.; Lay, Oliver P.; Jeganathan, Muthu; Hirai, Akiko

    2006-01-01

    A description of adaptive nulling for Terrestrial Planet Finder Interferometer (TPFI) is presented. The topics include: 1) Nulling in TPF-I; 2) Why Do Adaptive Nulling; 3) Parallel High-Order Compensator Design; 4) Phase and Amplitude Control; 5) Development Activates; 6) Requirements; 7) Simplified Experimental Setup; 8) Intensity Correction; and 9) Intensity Dispersion Stability. A short summary is also given on adaptive nulling for the TPFI.

  20. Starlight Nulling Technology at the Jet Propulsion Laboratory

    NASA Technical Reports Server (NTRS)

    Martin, Stefan

    2007-01-01

    The current interests in extra-solar planet detection and space-based and ground-based interferometry for astronomical observations has led to the development of a number of nulling instrument designs at the Jet Propulsion Laboratory (JPL) and elsewhere. This paper summarizes briefly JPL's efforts in nulling interferometry to date and consists of illustrations of some key nulling activities. Basic layouts of nulling testbeds are described and key applications discussed.

  1. Optimized Null Model for Protein Structure Networks

    PubMed Central

    Lappe, Michael; Pržulj, Nataša

    2009-01-01

    Much attention has recently been given to the statistical significance of topological features observed in biological networks. Here, we consider residue interaction graphs (RIGs) as network representations of protein structures with residues as nodes and inter-residue interactions as edges. Degree-preserving randomized models have been widely used for this purpose in biomolecular networks. However, such a single summary statistic of a network may not be detailed enough to capture the complex topological characteristics of protein structures and their network counterparts. Here, we investigate a variety of topological properties of RIGs to find a well fitting network null model for them. The RIGs are derived from a structurally diverse protein data set at various distance cut-offs and for different groups of interacting atoms. We compare the network structure of RIGs to several random graph models. We show that 3-dimensional geometric random graphs, that model spatial relationships between objects, provide the best fit to RIGs. We investigate the relationship between the strength of the fit and various protein structural features. We show that the fit depends on protein size, structural class, and thermostability, but not on quaternary structure. We apply our model to the identification of significantly over-represented structural building blocks, i.e., network motifs, in protein structure networks. As expected, choosing geometric graphs as a null model results in the most specific identification of motifs. Our geometric random graph model may facilitate further graph-based studies of protein conformation space and have important implications for protein structure comparison and prediction. The choice of a well-fitting null model is crucial for finding structural motifs that play an important role in protein folding, stability and function. To our knowledge, this is the first study that addresses the challenge of finding an optimized null model for RIGs, by

  2. Null conformal Killing-Yano tensors and Birkhoff theorem

    NASA Astrophysics Data System (ADS)

    Ferrando, Joan Josep; Sáez, Juan Antonio

    2016-04-01

    We study the space-times admitting a null conformal Killing-Yano tensor whose divergence defines a Killing vector. We analyze the similarities and differences with the recently studied non null case (Ferrando and Sáez in Gen Relativ Gravit 47:1911, 2015). The results by Barnes concerning the Birkhoff theorem for the case of null orbits are analyzed and generalized.

  3. Deficient and Null Variants of SERPINA1 Are Proteotoxic in a Caenorhabditis elegans Model of α1-Antitrypsin Deficiency

    PubMed Central

    King, Dale E.; Silverman, Richard M.; Miedel, Mark T.; Luke, Cliff J.; Perlmutter, David H.; Silverman, Gary A.; Pak, Stephen C.

    2015-01-01

    α1-antitrypsin deficiency (ATD) predisposes patients to both loss-of-function (emphysema) and gain-of-function (liver cirrhosis) phenotypes depending on the type of mutation. Although the Z mutation (ATZ) is the most prevalent cause of ATD, >120 mutant alleles have been identified. In general, these mutations are classified as deficient (<20% normal plasma levels) or null (<1% normal levels) alleles. The deficient alleles, like ATZ, misfold in the ER where they accumulate as toxic monomers, oligomers and aggregates. Thus, deficient alleles may predispose to both gain- and loss-of-function phenotypes. Null variants, if translated, typically yield truncated proteins that are efficiently degraded after being transiently retained in the ER. Clinically, null alleles are only associated with the loss-of-function phenotype. We recently developed a C. elegans model of ATD in order to further elucidate the mechanisms of proteotoxicity (gain-of-function phenotype) induced by the aggregation-prone deficient allele, ATZ. The goal of this study was to use this C. elegans model to determine whether different types of deficient and null alleles, which differentially affect polymerization and secretion rates, correlated to any extent with proteotoxicity. Animals expressing the deficient alleles, Mmalton, Siiyama and S (ATS), showed overall toxicity comparable to that observed in patients. Interestingly, Siiyama expressing animals had smaller intracellular inclusions than ATZ yet appeared to have a greater negative effect on animal fitness. Surprisingly, the null mutants, although efficiently degraded, showed a relatively mild gain-of-function proteotoxic phenotype. However, since null variant proteins are degraded differently and do not appear to accumulate, their mechanism of proteotoxicity is likely to be different to that of polymerizing, deficient mutants. Taken together, these studies showed that C. elegans is an inexpensive tool to assess the proteotoxicity of different AT

  4. Loss of BRCA1-A Complex Function in RAP80 Null Tumor Cells

    PubMed Central

    Cho, Kathleen; Yu, Xiaochun

    2012-01-01

    Receptor Associated Protein 80 (RAP80) is a subunit of the BRCA1-A complex and targets BRCA1 to DNA damage sites in response to DNA double strand breaks. Since mutations of BRCA1 are associated with familial ovarian cancers, we screened 26 ovarian cancer-derived cell lines for RAP80 mutations and found that TOV-21G cells harbor a RAP80 mutation (c.1107G >A). This mutation generates a stop codon at Trp369, which deletes the partial AIR region and the C-terminal zinc fingers of RAP80. Interestingly, both the mutant and wild type alleles of RAP80 lose their expression due to promoter hypermethylation, suggesting that TOV-21G is a RAP80-null cell line. In these cells, not only is the BRCA1-A complex disrupted, but the relocation of the remaining subunits in the BRCA1-A complex including BRCA1, CCDC98, NBA1, BRCC36 and BRE is significantly suppressed. Moreover, TOV-21G cells are hypersensitive to ionizing radiation, which is due to the compromised DNA damage repair capacity in these cells. Reconstitution of TOV-21G cells with wild type RAP80 rescues these cellular defects in response to DNA damage. Thus, our results demonstrate that RAP80 is a scaffold protein in the BRCA1-A complex. Identification of TOV-21G as a RAP80 null tumor cell line will be very useful for the study of the molecular mechanism in DNA damage response. PMID:22792303

  5. The first mecp2-null zebrafish model shows altered motor behaviors

    PubMed Central

    Pietri, Thomas; Roman, Angel-Carlos; Guyon, Nicolas; Romano, Sebastián A.; Washbourne, Philip; Moens, Cecilia B.; de Polavieja, Gonzalo G.; Sumbre, Germán

    2013-01-01

    Rett syndrome (RTT) is an X-linked neurodevelopmental disorder and one of the most common causes of mental retardation in affected girls. Other symptoms include a rapid regression of motor and cognitive skills after an apparently early normal development. Sporadic mutations in the transcription factor MECP2 has been shown to be present in more than 90% of the patients and several models of MeCP2-deficient mice have been created to understand the role of this gene. These models have pointed toward alterations in the maintenance of the central nervous system rather than its development, in line with the late onset of the disease in humans. However, the exact functions of MeCP2 remain difficult to delineate and the animal models have yielded contradictory results. Here, we present the first mecp2-null allele mutation zebrafish model. Surprisingly and in contrast to MeCP2-null mouse models, mecp2-null zebrafish are viable and fertile. They present nonetheless clear behavioral alterations during their early development, including spontaneous and sensory-evoked motor anomalies, as well as defective thigmotaxis. PMID:23874272

  6. Toroidally symmetric plasma vortex at tokamak divertor null point

    NASA Astrophysics Data System (ADS)

    Umansky, M. V.; Ryutov, D. D.

    2016-03-01

    Reduced MHD equations are used for studying toroidally symmetric plasma dynamics near the divertor null point. Numerical solution of these equations exhibits a plasma vortex localized at the null point with the time-evolution defined by interplay of the curvature drive, magnetic restoring force, and dissipation. Convective motion is easier to achieve for a second-order null (snowflake) divertor than for a regular x-point configuration, and the size of the convection zone in a snowflake configuration grows with plasma pressure at the null point. The trends in simulations are consistent with tokamak experiments which indicate the presence of enhanced transport at the null point.

  7. CHRONIC FEEDING ALCOHOL-CONTAINING DIETS VIA TOTAL ENTERAL NUTRITION INDUCES ALCOHOL DEHYDROGENASE (ADH) AND INSULIN RESISTANCE

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Induction of Class 1 ADH occurs in rats fed alcohol chronically, and we have reported that C/EBPs and SREBP-1 are important signaling factors in this process. Chronic alcohol intake in humans can result in alcohol-induced diabetes. We have studied insulin signaling pathways in adult male Sprague-D...

  8. Unexpected properties of NADP-dependent secondary alcohol dehydrogenase (ADH-1) in Trichomonas vaginalis and other microaerophilic parasites.

    PubMed

    Leitsch, David; Williams, Catrin F; Lloyd, David; Duchêne, Michael

    2013-07-01

    Our previous observation that NADP-dependent secondary alcohol dehydrogenase (ADH-1) is down-regulated in metronidazole-resistant Trichomonas vaginalis isolates prompted us to further characterise the enzyme. In addition to its canonical enzyme activity as a secondary alcohol dehydrogenase, a pronounced, so far unknown, background NADPH-oxidising activity in absence of any added substrate was observed when the recombinant enzyme or T. vaginalis extract were used. This activity was strongly enhanced at low oxygen concentrations. Unexpectedly, all functions of ADH-1 were efficiently inhibited by coenzyme A which is a cofactor of a number of key enzymes in T. vaginalis metabolism, i.e. pyruvate:ferredoxin oxidoreductase (PFOR). These observations could be extended to Entamoeba histolytica and Tritrichomonas foetus, both of which have a homologue of ADH-1, but not to Giardia lamblia which lacks an NADP-dependent secondary alcohol dehydrogenase. Although we could not identify the substrate of the observed background activity, we propose that ADH-1 functions as a major sink for NADPH in microaerophilic parasites at low oxygen tension. PMID:23578856

  9. Magnetic Null Points in Kinetic Simulations of Space Plasmas

    NASA Astrophysics Data System (ADS)

    Olshevsky, Vyacheslav; Deca, Jan; Divin, Andrey; Peng, Ivy Bo; Markidis, Stefano; Innocenti, Maria Elena; Cazzola, Emanuele; Lapenta, Giovanni

    2016-03-01

    We present a systematic attempt to study magnetic null points and the associated magnetic energy conversion in kinetic particle-in-cell simulations of various plasma configurations. We address three-dimensional simulations performed with the semi-implicit kinetic electromagnetic code iPic3D in different setups: variations of a Harris current sheet, dipolar and quadrupolar magnetospheres interacting with the solar wind, and a relaxing turbulent configuration with multiple null points. Spiral nulls are more likely created in space plasmas: in all our simulations except lunar magnetic anomaly (LMA) and quadrupolar mini-magnetosphere the number of spiral nulls prevails over the number of radial nulls by a factor of 3-9. We show that often magnetic nulls do not indicate the regions of intensive energy dissipation. Energy dissipation events caused by topological bifurcations at radial nulls are rather rare and short-lived. The so-called X-lines formed by the radial nulls in the Harris current sheet and LMA simulations are rather stable and do not exhibit any energy dissipation. Energy dissipation is more powerful in the vicinity of spiral nulls enclosed by magnetic flux ropes with strong currents at their axes (their cross sections resemble 2D magnetic islands). These null lines reminiscent of Z-pinches efficiently dissipate magnetic energy due to secondary instabilities such as the two-stream or kinking instability, accompanied by changes in magnetic topology. Current enhancements accompanied by spiral nulls may signal magnetic energy conversion sites in the observational data.

  10. System and Method for Null-Lens Wavefront Sensing

    NASA Technical Reports Server (NTRS)

    Hill, Peter C. (Inventor); Thompson, Patrick L. (Inventor); Aronstein, David L. (Inventor); Bolcar, Matthew R. (Inventor); Smith, Jeffrey S. (Inventor)

    2015-01-01

    A method of measuring aberrations in a null-lens including assembly and alignment aberrations. The null-lens may be used for measuring aberrations in an aspheric optic with the null-lens. Light propagates from the aspheric optic location through the null-lens, while sweeping a detector through the null-lens focal plane. Image data being is collected at locations about said focal plane. Light is simulated propagating to the collection locations for each collected image. Null-lens aberrations may extracted, e.g., applying image-based wavefront-sensing to collected images and simulation results. The null-lens aberrations improve accuracy in measuring aspheric optic aberrations.

  11. Interaction of vitamin A supplementation level with ADH1C genotype on intramuscular fat in beef steers.

    PubMed

    Krone, K G; Ward, A K; Madder, K M; Hendrick, S; McKinnon, J J; Buchanan, F C

    2016-03-01

    Previously, the single nucleotide polymorphism in alcohol dehydrogenase (ADH1C c.-64T>C) was shown to have an association with intramuscular fat (IMF) in the longissimus thoracis (LT) muscle when vitamin A was limited in finishing rations of beef steers. The purpose of this study was to determine the optimum vitamin A supplementation level, in combination with ADH1C genotype, to increase IMF of the LT muscle. In total, 45 TT genotype, 45 CT and 27 CC Black Angus crossbred steers were backgrounded on a commercial ration containing 3360 IU vitamin A/kg dry matter (DM). During finishing, the steers were randomly assigned to one of three vitamin A treatments at 25%, 50% and 75% of the National Research Council recommendation of 2200 IU/kg DM. Treatments were administered via an oral bolus. Carcass quality was evaluated and a sample from the LT muscle was collected for analysis of IMF. A treatment×genotype interaction (P=0.04) was observed for IMF; TT steers on the 75% treatment had higher IMF relative to CT and CC steers on the same treatment. Western blot analysis showed that TT steers had higher (P=0.02) ADH1C protein expression in hepatic tissue. Previously, TT steers exhibited increased IMF when fed limited vitamin A. In the current study, the lack of variation in IMF between treatments and genotypes at the lower vitamin A treatment levels was likely due to the majority of the steers grading Canada AAA (USDA Choice). However, the western blot data supports that TT steers are expected to have higher IMF deposition, due to an increased production of ADH1C. The interaction between ADH1C genotype and vitamin A supplementation level has the potential for use in marker-assisted management programs to target niche markets based on increased marbling. PMID:26511067

  12. Displacing Unpredictable Nulls in Antenna Radiation Patterns

    NASA Technical Reports Server (NTRS)

    Lux, James; Schaefer, Mark

    2005-01-01

    A method of maintaining radio communication despite the emergence of unpredictable fades and nulls in the radiation pattern of an antenna has been proposed. The method was originally intended to be applied in the design and operation of a radio antenna aboard a robotic exploratory vehicle on a remote planet during communication with a spacecraft in orbit around the planet. The method could also be applied in similar terrestrial situations for example, radio communication between two ground vehicles or between a ground vehicle and an aircraft or spacecraft. The method is conceptually simple, is readily adaptable to diverse situations, and can be implemented without adding greatly to the weight, cost, power demand, or complexity of a system to which it may be applied. The unpredictable fades and nulls in an antenna radiation pattern arise because of electromagnetic interactions between the antenna and other objects within the near field of the antenna (basically, objects within a distance of a few wavelengths). These objects can include general vehicle components, masts, robotic arms, other antennas, the ground, and nearby terrain features. Figure 1 presents representative plots of signal strength versus time during a typical pass of a spacecraft or aircraft through the far field of such an antenna, showing typical nulls and fades caused by nearby objects. The traditional approach to ensuring reliability of communication in the presence of deep fades calls for increasing the effective transmitter power and/or reducing the receiver noise figure at the affected ground vehicle, possibly in combination with appropriate redesign of the equipment at the spacecraft or aircraft end of the communication link. These solutions can be expensive and/or risky and, depending on the application, can add significantly to weight, cost, and power demand. The proposed method entails none of these disadvantages.

  13. Null generation using discs on a reflector

    NASA Astrophysics Data System (ADS)

    Rudisill, M. D.

    1984-12-01

    It has been shown possible experimentally to produce nulls in the pattern of a prime focus reflector antenna using discs mounted on the dish. A model of this antenna system is developed to evaluate optimal configurations and ideal performance. Aperture integration is the method of analysis used. Discs' effects are modeled as a phase shift on the aperture. No secondary effects, such as diffraction, are considered. Based on the model developed, guidelines are presented for antenna design. A computer code was written to implement the model and a prediction of antenna the system's performance is presented.

  14. Null Energy Condition in Dynamic Wormholes

    SciTech Connect

    Hochberg, D.; Visser, M.

    1998-07-01

    We extend previous proofs that violations of the null energy condition are a generic and universal feature of traversable wormholes to completely nonsymmetric time-dependent wormholes. We show that the analysis can be phrased purely in terms of local geometry at and near the wormhole throat, and we do not have to make any technical assumptions about asymptotic flatness or other global properties. A key aspect of the analysis is the demonstration that time-dependent wormholes have {ital two} throats, one for each direction through the wormhole, and that the two throats coalesce only for the case of a static wormhole. {copyright} {ital 1998} {ital The American Physical Society}

  15. Polyhedra in spacetime from null vectors

    NASA Astrophysics Data System (ADS)

    Neiman, Yasha

    2014-01-01

    We consider convex spacelike polyhedra oriented in the Minkowski space. These are the classical analogues of spinfoam intertwiners. We point out a parametrization of these shapes using null face normals, with no constraints or redundancies. Our construction is dimension-independent. In 3+1d, it provides the spacetime picture behind a well-known property of the loop quantum gravity intertwiner space in spinor form, namely that the closure constraint is always satisfied after some SL(2, C) rotation. As a simple application of our variables, we incorporate them in a 4-simplex action that reproduces the large-spin behavior of the Barrett-Crane vertex amplitude.

  16. CvADH1, a member of short-chain alcohol dehydrogenase family, is inducible by gibberellin and sucrose in developing watermelon seeds.

    PubMed

    Kim, Joonyul; Kang, Hong-Gyu; Jun, Sung-Hoon; Lee, Jinwon; Yim, Jieun; An, Gynheung

    2003-01-01

    To understand the molecular mechanisms that control seed formation, we selected a seed-preferential gene (CvADH1) from the ESTs of developing watermelon seeds. RNA blot analysis and in situ localization showed that CvADH1 was preferentially expressed in the nucellar tissue. The CvADH1 protein shared about 50% homology with short-chain alcohol dehydrogenase including ABA2 in Arabidopsis thaliana, stem secoisolariciresinol dehydrogenase in Forsythia intermedia, and 3beta-hydroxysterol dehydrogenase in Digitalis lanata. We investigated gene-expression levels in seeds from both normally pollinated fruits and those made parthenocarpic via N-(2-chloro-4-pyridyl)-N'-phenylurea treatment, the latter of which lack zygotic tissues. Whereas the transcripts of CvADH1 rapidly started to accumulate from about the pre-heart stage in normal seeds, they were not detectable in the parthenocarpic seeds. Treating the parthenogenic fruit with GA(3) strongly induced gene expression, up to the level accumulated in pollinated seeds. These results suggest that the CvADH1 gene is induced in maternal tissues by signals made in the zygotic tissues, and that gibberellin might be one of those signals. We also observed that CvADH1 expression was induced by sucrose in the parthenocarpic seeds. Therefore, we propose that the CvADH1 gene is inducible by gibberellin, and that sucrose plays an important role in the maternal tissues of watermelon during early seed development. PMID:12552151

  17. Association and ancestry analysis of sequence variants in ADH and ALDH using alcohol-related phenotypes in a Native American community sample

    PubMed Central

    Peng, Qian; Gizer, Ian R.; Libiger, Ondrej; Bizon, Chris; Wilhelmsen, Kirk C.; Schork, Nicholas J.; Ehlers, Cindy L.

    2015-01-01

    Higher rates of alcohol use and other drug-dependence have been observed in some Native American populations relative to other ethnic groups in the U.S. Previous studies have shown that alcohol dehydrogenase (ADH) genes and aldehyde dehydrogenase (ALDH) genes may affect the risk of development of alcohol dependence, and that polymorphisms within these genes may differentially affect risk for the disorder depending on the ethnic group evaluated. We evaluated variations in the ADH and ALDH genes in a large study investigating risk factors for substance use in a Native American population. We assessed ancestry admixture and tested for associations between alcohol-related phenotypes in the genomic regions around the ADH1-7 and ALDH2 and ALDH1A1 genes. Seventy-two (72) ADH variants showed significant evidence of association with a severity level of alcohol drinking-related dependence symptoms phenotype. These significant variants spanned across the entire 7 ADH gene cluster regions. Two significant associations, one in ADH and one in ALDH2, were observed with alcohol dependence diagnosis. Seventeen (17) variants showed significant association with the largest number of alcohol drinks ingested during any 24-hour period. Variants in or near ADH7 were significantly negatively associated with alcohol-related phenotypes, suggesting a potential protective effect of this gene. In addition, our results suggested that a higher degree of Native American ancestry is associated with higher frequencies of potential risk variants and lower frequencies of potential protective variants for alcohol dependence phenotypes. PMID:25270064

  18. Improvement of Ethanol Production in Saccharomyces cerevisiae by High-Efficient Disruption of the ADH2 Gene Using a Novel Recombinant TALEN Vector.

    PubMed

    Ye, Wei; Zhang, Weimin; Liu, Taomei; Tan, Guohui; Li, Haohua; Huang, Zilei

    2016-01-01

    Bioethanol is becoming increasingly important in energy supply and economic development. However, the low yield of bioethanol and the insufficiency of high-efficient genetic manipulation approaches limit its application. In this study, a novel transcription activator-like effector nuclease (TALEN) vector containing the left and right arms of TALEN was electroporated into Saccharomyces cerevisiae strain As2.4 to sequence the alcohol dehydrogenase gene ADH2 and the hygromycin-resistant gene hyg. Western blot analysis using anti-FLAG monoclonal antibody proved the successful expression of TALE proteins in As2.4 strains. qPCR and sequencing demonstrated the accurate knockout of the 17 bp target gene with 80% efficiency. The TALEN vector and ADH2 PCR product were electroporated into ΔADH2 to complement the ADH2 gene (ADH2 (+) As2.4). LC-MS and GC were employed to detect ethanol yields in the native As2.4, ΔADH2 As2.4, and ADH2 (+) As2.4 strains. Results showed that ethanol production was improved by 52.4 ± 5.3% through the disruption of ADH2 in As2.4. The bioethanol yield of ADH2 (+) As2.4 was nearly the same as that of native As2.4. This study is the first to report on the disruption of a target gene in S. cerevisiae by employing Fast TALEN technology to improve bioethanol yield. This work provides a novel approach for the disruption of a target gene in S. cerevisiae with high efficiency and specificity, thereby promoting the improvement of bioethanol production in S. cerevisiae by metabolic engineering. PMID:27462304

  19. Improvement of Ethanol Production in Saccharomyces cerevisiae by High-Efficient Disruption of the ADH2 Gene Using a Novel Recombinant TALEN Vector

    PubMed Central

    Ye, Wei; Zhang, Weimin; Liu, Taomei; Tan, Guohui; Li, Haohua; Huang, Zilei

    2016-01-01

    Bioethanol is becoming increasingly important in energy supply and economic development. However, the low yield of bioethanol and the insufficiency of high-efficient genetic manipulation approaches limit its application. In this study, a novel transcription activator-like effector nuclease (TALEN) vector containing the left and right arms of TALEN was electroporated into Saccharomyces cerevisiae strain As2.4 to sequence the alcohol dehydrogenase gene ADH2 and the hygromycin-resistant gene hyg. Western blot analysis using anti-FLAG monoclonal antibody proved the successful expression of TALE proteins in As2.4 strains. qPCR and sequencing demonstrated the accurate knockout of the 17 bp target gene with 80% efficiency. The TALEN vector and ADH2 PCR product were electroporated into ΔADH2 to complement the ADH2 gene (ADH2+ As2.4). LC–MS and GC were employed to detect ethanol yields in the native As2.4, ΔADH2 As2.4, and ADH2+ As2.4 strains. Results showed that ethanol production was improved by 52.4 ± 5.3% through the disruption of ADH2 in As2.4. The bioethanol yield of ADH2+ As2.4 was nearly the same as that of native As2.4. This study is the first to report on the disruption of a target gene in S. cerevisiae by employing Fast TALEN technology to improve bioethanol yield. This work provides a novel approach for the disruption of a target gene in S. cerevisiae with high efficiency and specificity, thereby promoting the improvement of bioethanol production in S. cerevisiae by metabolic engineering. PMID:27462304

  20. What's My Substrate? Computational Function Assignment of Candida parapsilosis ADH5 by Genome Database Search, Virtual Screening, and QM/MM Calculations.

    PubMed

    Dhoke, Gaurao V; Ensari, Yunus; Davari, Mehdi D; Ruff, Anna Joëlle; Schwaneberg, Ulrich; Bocola, Marco

    2016-07-25

    Zinc-dependent medium chain reductase from Candida parapsilosis can be used in the reduction of carbonyl compounds to pharmacologically important chiral secondary alcohols. To date, the nomenclature of cpADH5 is differing (CPCR2/RCR/SADH) in the literature, and its natural substrate is not known. In this study, we utilized a substrate docking based virtual screening method combined with KEGG, MetaCyc pathway, and Candida genome databases search for the discovery of natural substrates of cpADH5. The virtual screening of 7834 carbonyl compounds from the ZINC database provided 94 aldehydes or methyl/ethyl ketones as putative carbonyl substrates. Out of which, 52 carbonyl substrates of cpADH5 with catalytically active docking pose were identified by employing mechanism based substrate docking protocol. Comparison of the virtual screening results with KEGG, MetaCyc database search, and Candida genome pathway analysis suggest that cpADH5 might be involved in the Ehrlich pathway (reduction of fusel aldehydes in leucine, isoleucine, and valine degradation). Our QM/MM calculations and experimental activity measurements affirmed that butyraldehyde substrates are the potential natural substrates of cpADH5, suggesting a carbonyl reductase role for this enzyme in butyraldehyde reduction in aliphatic amino acid degradation pathways. Phylogenetic tree analysis of known ADHs from Candida albicans shows that cpADH5 is close to caADH5. We therefore propose, according to the experimental substrate identification and sequence similarity, the common name butyraldehyde dehydrogenase cpADH5 for Candida parapsilosis CPCR2/RCR/SADH. PMID:27387009

  1. A Nulling Coronagraph for TPF-C

    NASA Technical Reports Server (NTRS)

    Shao, Michael; Levine, Bruce Martin; Wallace, James Kent; Orton, Glenn S.; Schmidtlin, Edouard; Lane, Benjamin F.; Seager, Sara; Tolls, Volker; Lyon, Richard G.; Samuele, Rocco; Tenerelli, Domenick J.; Woodruff, Robert; Ge, Jian

    2006-01-01

    The nulling coronagraph is one of 5 instrument concepts selected by NASA for study for potential use in the TPF-C mission. This concept for extreme starlight suppression has two major components, a nulling interferometer to suppress the starlight to 10(sup -10) per airy spot within 2 (lamda)/D of the star, and a calibration interferometer to measure the residual scattered starlight. The ability to work at 2 (lamda)/D dramatically improves the science throughput of a space based coronagraph like TPF-C. The calibration interferometer is an equally important part of the starlight suppression system. It measures the measures the wavefront of the scattered starlight with very high SNR, to 0.05nm in less than 5 minutes on a 5mag star. In addition, the post coronagraph wavefront sensor will be used to measure the residual scattered light after the coronagraph and subtract it in post processing to 12x10(sup -11) to enable detection of an Earthlike planet with a SNR of 510.

  2. KLF1-null neonates display hydrops fetalis and a deranged erythroid transcriptome

    PubMed Central

    Magor, Graham W.; Tallack, Michael R.; Gillinder, Kevin R.; Bell, Charles C.; McCallum, Naomi; Williams, Bronwyn

    2015-01-01

    We describe a case of severe neonatal anemia with kernicterus caused by compound heterozygosity for null mutations in KLF1, each inherited from asymptomatic parents. One of the mutations is novel. This is the first described case of a KLF1-null human. The phenotype of severe nonspherocytic hemolytic anemia, jaundice, hepatosplenomegaly, and marked erythroblastosis is more severe than that present in congenital dyserythropoietic anemia type IV as a result of dominant mutations in the second zinc-finger of KLF1. There was a very high level of HbF expression into childhood (>70%), consistent with a key role for KLF1 in human hemoglobin switching. We performed RNA-seq on circulating erythroblasts and found that human KLF1 acts like mouse Klf1 to coordinate expression of many genes required to build a red cell including those encoding globins, cytoskeletal components, AHSP, heme synthesis enzymes, cell-cycle regulators, and blood group antigens. We identify novel KLF1 target genes including KIF23 and KIF11 which are required for proper cytokinesis. We also identify new roles for KLF1 in autophagy, global transcriptional control, and RNA splicing. We suggest loss of KLF1 should be considered in otherwise unexplained cases of severe neonatal NSHA or hydrops fetalis. PMID:25724378

  3. Off-Axis Nulling Transfer Function Measurement: A First Assessment

    NASA Technical Reports Server (NTRS)

    Vedova, G. Dalla; Menut, J.-L.; Millour, F.; Petrov, R.; Cassaing, F.; Danchi, W. C.; Jacquinod, S.; Lhome, E.; Lopez, B.; Lozi, J.; Marcotto, A.; Parisot, J.; Reess, J.-M.

    2013-01-01

    We want to study a polychromatic inverse problem method with nulling interferometers to obtain information on the structures of the exozodiacal light. For this reason, during the first semester of 2013, thanks to the support of the consortium PERSEE, we launched a campaign of laboratory measurements with the nulling interferometric test bench PERSEE, operating with 9 spectral channels between J and K bands. Our objective is to characterise the transfer function, i.e. the map of the null as a function of wavelength for an off-axis source, the null being optimised on the central source or on the source photocenter. We were able to reach on-axis null depths better than 10(exp -4). This work is part of a broader project aiming at creating a simulator of a nulling interferometer in which typical noises of a real instrument are introduced. We present here our first results.

  4. Findings from a Three Year Survey of Coronal Null Points

    NASA Astrophysics Data System (ADS)

    Freed, Michael; Longcope, Dana; McKenzie, David Eugene

    2014-06-01

    We report the findings from a comprehensive coronal magnetic null point survey created by Potential Field Source Surface (PFSS) modeling & Solar Dynamic Observatory/Atmospheric Imaging Assembly (SDO/AIA) observations. Locations of magnetic null points in the corona were predicted from the PFSS model from Carrington Rotation 2098 to 2139 and manually compared to contrast enhanced SDO/AIA images in 171 angstroms. Statistical results will be presented that illustrate the characteristics associated with the observed and predicted null points. These characteristics include the radial & latitudinal distribution; eigenvalues associated with null point structure; and the effect spine orientation has on observability.

  5. Nulling Infrared Radiometer for Measuring Temperature

    NASA Technical Reports Server (NTRS)

    Ryan, Robert

    2003-01-01

    A nulling, self-calibrating infrared radiometer is being developed for use in noncontact measurement of temperature in any of a variety of industrial and scientific applications. This instrument is expected to be especially well-suited to measurement of ambient or near-ambient temperature and, even more specifically, for measuring the surface temperature of a natural body of water. Although this radiometer would utilize the long-wavelength infrared (LWIR) portion of the spectrum (wavelengths of 8 to 12 m), its basic principle of operation could also be applied to other spectral bands (corresponding to other temperature ranges) in which the atmosphere is transparent and in which design requirements for sensitivity and temperature-measurement accuracy could be satisfied.

  6. String spectra near some null cosmological singularities

    SciTech Connect

    Madhu, Kallingalthodi; Narayan, K.

    2009-06-15

    We construct cosmological spacetimes with null Kasner-like singularities as purely gravitational solutions with no other background fields turned on. These can be recast as anisotropic plane-wave spacetimes by coordinate transformations. We analyze string quantization to find the spectrum of string modes in these backgrounds. The classical string modes can be solved for exactly in these time-dependent backgrounds, which enables a detailed study of the near-singularity string spectrum, (time-dependent) oscillator masses, and wave functions. We find that for low-lying string modes (finite oscillation number), the classical near-singularity string mode functions are nondivergent for various families of singularities. Furthermore, for any infinitesimal regularization of the vicinity of the singularity, we find a tower of string modes of ultrahigh oscillation number which propagate essentially freely in the background. The resulting picture suggests that string interactions are non-negligible near the singularity.

  7. Exoplanet detection using a nulling interferometer.

    PubMed

    Cagigal, M; Canales, V

    2001-07-01

    The detection of extra solar planets is a topic of growing interest, which stretches current technology and knowledge to their limits. Indirect measurement confirms the existence of a considerable number. However, direct imaging is the only way to obtain information about the nature of these planets and to detect Earth-like planets, which could support life. The main problem for direct imaging is that planets are associated with a much brighter source of light. Here, we propose the use of the nulling interferometer along with a photon counting technique called Dark Speckle. Using a simple model the behavior of the technique is predicted. The signal-to-noise ratio estimated confirms that it is a promising way to detect faint objects. PMID:19421271

  8. Technology Advancement of the Visible Nulling Coronagraph

    NASA Technical Reports Server (NTRS)

    Lyon, Richard G.; Clampin, Mark; Petrone, Peter; Thompson, Patrick; Bolcar, Matt; Madison, Timothy; Woodruff, Robert; Noecker, Charley; Kendrick, Steve

    2010-01-01

    The critical high contrast imaging technology for the Extrasolar Planetary Imaging Coronagraph (EPIC) mission concept is the visible nulling coronagraph (VNC). EPIC would be capable of imaging jovian planets, dust/debris disks, and potentially super-Earths and contribute to answering how bright the debris disks are for candidate stars. The contrast requirement for EPIC is 10(exp 9) contrast at 125 milli-arseconds inner working angle. To advance the VNC technology NASA/Goddard Space Flight Center, in collaboration with Lockheed-Martin, previously developed a vacuum VNC testbed, and achieved narrowband and broadband suppression of the core of the Airy disk. Recently our group was awarded a NASA Technology Development for Exoplanet Missions to achieve two milestones: (i) 10(exp 8) contrast in narrowband light, and, (ii) 10(ecp 9) contrast in broader band light; one milestone per year, and both at 2 Lambda/D inner working angle. These will be achieved with our 2nd generation testbed known as the visible nulling testbed (VNT). It contains a MEMS based hex-packed segmented deformable mirror known as the multiple mirror array (MMA) and coherent fiber bundle, i.e. a spatial filter array (SFA). The MMA is in one interferometric arm and works to set the wavefront differences between the arms to zero. Each of the MMA segments is optically mapped to a single mode fiber of the SFA, and the SFA passively cleans the sub-aperture wavefront error leaving only piston, tip and tilt error to be controlled. The piston degree of freedom on each segment is used to correct the wavefront errors, while the tip/tilt is used to simultaneously correct the amplitude errors. Thus the VNT controls both amplitude and wavefront errors with a single MMA in closed-loop in a vacuum tank at approx.20 Hz. Herein we will discuss our ongoing progress with the VNT.

  9. Competing interests in a lung cancer with metastasis to the pituitary gland: syndrome of inappropriate ADH secretion versus diabetes insipidus

    PubMed Central

    Gulsin, Gaurav Singh; Jacobs, Madeleine Louisa Bryson; Gohil, Shailesh; Thomas, Adam; Levy, Miles

    2016-01-01

    Metastases to the pituitary gland are rare; cancers that most commonly metastasize to the pituitary are breast and lung cancers. No specific computed tomography or magnetic resonance imaging features reliably distinguish primary pituitary masses from metastases. A combination of a detailed clinical assessment together with specialist endocrine and neuroradiology support is essential to make the rare diagnosis of a pituitary metastasis. We present the case of a man with metastatic lung cancer, initially presenting as hypopituitarism. Subtle features in the history, together with neuroimaging findings atypical for pituitary adenomas, provided clues that the diagnosis was one of the pituitary metastases. Treatment of diabetes insipidus (DI) with replacement antidiuretic hormone (ADH) was complicated by extreme difficulties in achieving a satisfactory sodium and water balance. This was the result of coexistent DI and syndrome of inappropriate ADH secretion perpetuated by the patient's primary lung cancer, a phenomenon not previously described in the literature. PMID:27274855

  10. Competing interests in a lung cancer with metastasis to the pituitary gland: syndrome of inappropriate ADH secretion versus diabetes insipidus.

    PubMed

    Gulsin, Gaurav Singh; Jacobs, Madeleine Louisa Bryson; Gohil, Shailesh; Thomas, Adam; Levy, Miles

    2016-01-01

    Metastases to the pituitary gland are rare; cancers that most commonly metastasize to the pituitary are breast and lung cancers. No specific computed tomography or magnetic resonance imaging features reliably distinguish primary pituitary masses from metastases. A combination of a detailed clinical assessment together with specialist endocrine and neuroradiology support is essential to make the rare diagnosis of a pituitary metastasis. We present the case of a man with metastatic lung cancer, initially presenting as hypopituitarism. Subtle features in the history, together with neuroimaging findings atypical for pituitary adenomas, provided clues that the diagnosis was one of the pituitary metastases. Treatment of diabetes insipidus (DI) with replacement antidiuretic hormone (ADH) was complicated by extreme difficulties in achieving a satisfactory sodium and water balance. This was the result of coexistent DI and syndrome of inappropriate ADH secretion perpetuated by the patient's primary lung cancer, a phenomenon not previously described in the literature. PMID:27274855

  11. Proof of the averaged null energy condition in a classical curved spacetime using a null-projected quantum inequality

    NASA Astrophysics Data System (ADS)

    Kontou, Eleni-Alexandra; Olum, Ken D.

    2015-12-01

    Quantum inequalities are constraints on how negative the weighted average of the renormalized stress-energy tensor of a quantum field can be. A null-projected quantum inequality can be used to prove the averaged null energy condition, which would then rule out exotic phenomena such as wormholes and time machines. In this work we derive such an inequality for a massless minimally coupled scalar field, working to first order of the Riemann tensor and its derivatives. We then use this inequality to prove the averaged null energy condition on achronal geodesics in a curved background that obeys the null convergence condition.

  12. Stereoselective hydroxylation by CYP2C19 and oxidation by ADH4 in the in vitro metabolism of tivantinib.

    PubMed

    Nishiya, Yumi; Nakai, Daisuke; Urasaki, Yoko; Takakusa, Hideo; Ohsuki, Satoru; Iwano, Yuji; Yasukochi, Takanori; Takayama, Tomoko; Bazyo, Shohei; Oza, Chikahiro; Kurihara, Atsushi; Savage, Ronald E; Izumi, Takashi

    2016-11-01

    1. In prior studies, it has been shown that tivantinib is extensively metabolized in humans to many oxidative metabolites and glucuronides. In order to identify the responsible enzymes, we investigated the in vitro metabolism of tivantinib and its four major circulating metabolites. 2. The primary isoforms involved in the elimination of tivantinib were CYP2C19 and CYP3A4/5. CYP2C19 showed catalytic activity for the formation of M5 (hydroxylated metabolite), but not for M4 (a stereoisomer of M5), whereas CYP3A4/5 catalyzed the formation of both metabolites. For the elimination of M4, M5 and M8 (keto-metabolite), CYP3A4/5 was the major cytochrome P450 isoform and UGT1A9 was mainly involved in the glucuronidation of M4 and M5. 3. ADH4 was identified as one of the major alcohol dehydrogenase isoforms contributing to the formation of M6 (sequential keto-metabolite of M4 and M5) and M8. The substrate preference of ADH for M4, and not M5, was observed in the formation of M6. 4. In conclusion, CYP2C19, CYP3A4/5, UGT1A9 and ADH4 were the primary drug metabolizing enzymes involved in the in vitro metabolism of tivantinib and its metabolites. The stereoselective hydroxylation by CYP2C19 and substrate stereoselectivity of ADH4-catalyzed oxidation in the in vitro metabolism of tivantinib was discovered. PMID:26899628

  13. Alcohol dehydrogenase 1C (ADH1C) gene polymorphism and alcoholic liver cirrhosis risk: a meta analysis

    PubMed Central

    He, Lei; Deng, Tao; Luo, He-Sheng

    2015-01-01

    The association between alcohol dehydrogenase 1C (ADH1C) gene polymorphism and alcoholic liver cirrhosis (ALC) has been analyzed in several studies, but results have been conflicting. In this study, a meta-analysis was performed to assess the associations between the ADH1C polymorphism and risk of ALC. Relevant studies were identified using PubMed, Web of Science, CNKI and Wanfang databases up to January 10, 2015. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the association using the fixed or random effect model. A total of 16 case-control studies, including 1375 cases and 1802 controls, were included. Overall, no significant association between the ADH1C polymorphism and ALC risk was found (dominant model: OR=0.87, 95% CI: 0.62-1.23; recessive model: OR=1.30, 95% CI: 0.84-1.99; *1/*2 vs. *1/*1: OR=0.87, 95% CI: 0.63-1.21; *2/*2 vs. *1/*1: OR=1.10, 95% CI: 0.71-1.70). In the subgroup analysis by ethnicity, we observed a significant association in Asian descent (*1/*2 vs. *1/*1: OR=1.63, 95% CI: 1.07-2.49), while a decreased risk was found among Caucasians (dominant model: OR=0.81, 95% CI: 0.66-0.99; *1/*2 vs. *1/*1: OR=0.76, 95% CI: 0.61-0.95). This meta-analysis demonstrated that the ADH1C polymorphism might increase the risk of ALC in Asians, while it may be a protective factor for ALC among Caucasians. PMID:26379912

  14. Human TSC2-null fibroblast-like cells induce hair follicle neogenesis and hamartoma morphogenesis.

    PubMed

    Li, Shaowei; Thangapazham, Rajesh L; Wang, Ji-An; Rajesh, Sangeetha; Kao, Tzu-Cheg; Sperling, Leonard; Moss, Joel; Darling, Thomas N

    2011-01-01

    Hamartomas are composed of cells native to an organ but abnormal in number, arrangement or maturity. In the tuberous sclerosis complex (TSC), hamartomas develop in multiple organs because of mutations in TSC1 or TSC2. Here we show that TSC2-null fibroblast-like cells grown from human TSC skin hamartomas induced normal human keratinocytes to form hair follicles and stimulated hamartomatous changes. Follicles were complete with sebaceous glands, hair shafts and inner and outer root sheaths. TSC2-null cells surrounding the hair bulb expressed markers of the dermal sheath and dermal papilla. Tumour xenografts recapitulated characteristics of TSC skin hamartomas with increased mammalian target of the rapamycin complex 1 (mTORC1) activity, angiogenesis, mononuclear phagocytes and epidermal proliferation. Treatment with an mTORC1 inhibitor normalized these parameters and reduced the number of tumour cells. These studies indicate that TSC2-null cells are the inciting cells for TSC skin hamartomas, and suggest that studies on hamartomas will provide insights into tissue morphogenesis and regeneration. PMID:21407201

  15. Altered Ca2+ homeostasis in the skeletal muscle of DJ – 1 null mice

    PubMed Central

    Shtifman, Alexander; Zhong, Nan; Lopez, Jose R.; Shen, Jie; Xu, Jin

    2009-01-01

    Loss-of-function mutations in DJ – 1 are associated with early-onset of Parkinson’s disease. Although DJ – 1 is ubiquitously expressed, the functional pathways affected by it remain unresolved. Here we demonstrate an involvement of DJ – 1 in the regulation of Ca2+ homeostasis in mouse skeletal muscle. Using enzymatically dissociated flexor digitorum brevis muscle fibers from wild-type (wt) and DJ – 1 null mice, we examined the effects of DJ – 1 protein on resting, cytoplasmic [Ca2+] ([Ca2+]i) and depolarization-evoked Ca2+ release in the mouse skeletal muscle. The loss of DJ – 1 resulted in a more than two-fold increase in resting [Ca2+]i. While there was no alteration in the resting membrane potential, there was a significant decrease in depolarization-evoked Ca2+ release from the sarcoplasmic reticulum in the DJ – 1 null muscle cells. Consistent with the role of DJ – 1 in oxidative stress regulation and mitochondrial functional maintenance, treatments of DJ – 1 null muscle cells with resveratrol, a mitochondrial activator, or glutathione, a potent antioxidant, reversed the effects of the loss of DJ – 1 on Ca2+ homeostasis. These results provide evidence of DJ – 1’s association with Ca2+ regulatory pathways in mouse skeletal muscle, and suggest the potential benefit of resveratrol to functionally compensate for the loss of DJ – 1. PMID:19683835

  16. Adh enhances Actinobacillus pleuropneumoniae pathogenicity by binding to OR5M11 and activating p38 which induces apoptosis of PAMs and IL-8 release

    PubMed Central

    Wang, Lei; Qin, Wanhai; Zhang, Jing; Bao, Chuntong; Zhang, Hu; Che, Yanyi; Sun, Changjiang; Gu, Jingmin; Feng, Xin; Du, Chongtao; Han, Wenyu; Richard, Paul Langford; Lei, Liancheng

    2016-01-01

    Members of the Trimeric Autotransporter Adhesin (TAA) family play a crucial role in the adhesion of Gram-negative pathogens to host cells, but the immunopathogenesis of TAAs remains unknown. Our previous studies demonstrated that Adh from Actinobacillus pleuropneumoniae (A. pleuropneumoniae) is required for full bacterial pathogenicity. Alveolar macrophages are the first line of defense against respiratory infections. This study compared the interactions between porcine alveolar macrophages (PAMs) and wild-type A. pleuropneumoniae (5b WT) or an Adh-deletion strain (5b ΔAdh) via gene microarray, immunoprecipitation and other technologies. We found that Adh was shown to interact with the PAMs membrane protein OR5M11, an olfactory receptor, resulting in the high-level secretion of IL-8 by activation of p38 MAPK signaling pathway. Subsequently, PAMs apoptosis via the activation of the Fax and Bax signaling pathways was observed, followed by activation of caspases 8, 9, and 3. The immunological pathogenic roles of Adh were also confirmed in both murine and piglets infectious models in vivo. These results identify a novel immunological strategy for TAAs to boost the pathogenicity of A. pleuropneumoniae. Together, these datas reveal the high versatility of the Adh protein as a virulence factor and provide novel insight into the immunological pathogenic role of TAAs. PMID:27046446

  17. Effect of organic solvents on the activity and stability of halophilic alcohol dehydrogenase (ADH2) from Haloferax volcanii.

    PubMed

    Alsafadi, Diya; Paradisi, Francesca

    2013-01-01

    The effect of various organic solvents on the catalytic activity, stability and substrate specificity of alchohol dehydrogenase from Haloferax volcanii (HvADH2) was evaluated. The HvADH2 showed remarkable stability and catalysed the reaction in aqueous-organic medium containing dimethyl sulfoxide (DMSO) and methanol (MeOH). Tetrahydrofuran and acetonitrile were also investigated and adversely affected the stability of the enzyme. High concentration of salt, essential to maintain the enzymatic activity and structural integrity of the halophilic enzyme under standard conditions may be partially replaced by DMSO and MeOH. The presence of organic solvents did not induce gross changes in substrate specificity. DMSO offered a protective effect for the stability of the enzyme at nonoptimal pHs such as 6 and 10. Salt and solvent effects on the HvADH2 conformation and folding were examined through fluorescence spectroscopy. The fluorescence findings were consistent with the activity and stability results and corroborated the denaturing properties of some solvents. The intrinsic tolerance of this enzyme to organic solvent makes it highly attractive to industry. PMID:23179592

  18. (Mutagenic effect of tritium on DNA of Drosophila melanogaster)

    SciTech Connect

    Not Available

    1991-01-01

    A series of Adh mutants induced in Drosophila by X-rays were compared to Adh mutants induced by tritiated water. Sequence analysis of 8 intragenic null mutations suggest a double strand break might occur, consistent with our linear dose response curve. Additional data are required before we accept this model; it is hoped experiments with {sup 60}Co will yield more intragenic deletions. Our current research project involves genetic and molecular analysis of {sup 3}H beta induced Adh null mutations. All 23 mutations induced at the Adh locus have been multilocus deletions. This is in contrast to results seen with X-ray induction of mutation; as a consequence, the emphasis of our molecular analysis has switched from sequencing intragenic mutations to developing methods for sequencing the break points of deletions. This will permit us to determine if our model of deletion formation is applicable outside the structural gene. 13 refs., 8 figs., 5 tabs.

  19. Ore controls at the Mahd adh Dhahab gold mine, Kingdom of Saudi Arabia

    USGS Publications Warehouse

    Worl, Ronald G.

    1978-01-01

    Mahd adh Dhahab is the largest of numerous ancient gold mines scattered through the Precambrian shield of Saudi Arabia and the only one with recent production. Free gold and silver, tellurides, pyrite, galena, sphalerite, and chalcopyrite are in and associated with quartz veins and quartz veinlet stockworks. Country rocks consist of a sequence of pyroclastic and transported pyroclastic rocks of the Halaban Group that are locally highly silicified and potassium-feldspathized. Two known ore zones occur in a north-trending zone of quartz veins and breccias, faults, alteration, and metallization approximately 400 m wide and 1,000 m long. The ancient and recent workings are located in the northern part of this zone, and a significant new discovery, the southern mineralized zone, is in the southern part. A potential resource of 1.1 million tons of 27 g/t Au and 73 g/t Ag ore is contained in the southern mineralized zone. Geologic setting of ore bodies is similar in both zones. Significant mineralization occurs only within altered and fractured agglomerate directly beneath a cap of fine-grained tuff and sedimentary rock where the layered rocks are cut by metalliferous quartz veins. Ore was localized by four interacting controls; depth, an impervious cap, metalliferous quartz veins and a receptive host rock.

  20. Steric vs. electronic effects in the Lactobacillus brevis ADH-catalyzed bioreduction of ketones.

    PubMed

    Rodríguez, Cristina; Borzęcka, Wioleta; Sattler, Johann H; Kroutil, Wolfgang; Lavandera, Iván; Gotor, Vicente

    2014-01-28

    Lactobacillus brevis ADH (LBADH) is an alcohol dehydrogenase that is commonly employed to reduce alkyl or aryl ketones usually bearing a methyl, an ethyl or a chloromethyl as a small ketone substituent to the corresponding (R)-alcohols. Herein we have tested a series of 24 acetophenone derivatives differing in their size and electronic properties for their reduction employing LBADH. After plotting the relative activity against the measured substrate volumes we observed that apart from the substrate size other effects must be responsible for the activity obtained. Compared to acetophenone (100% relative activity), other small substrates such as propiophenone, α,α,α-trifluoroacetophenone, α-hydroxyacetophenone, and benzoylacetonitrile had relative activities lower than 30%, while medium-sized ketones such as α-bromo-, α,α-dichloro-, and α,α-dibromoacetophenone presented relative activities between 70% and 550%. Moreover, the comparison between the enzymatic activity and the obtained final conversions using an excess or just 2.5 equiv. of the hydrogen donor 2-propanol, denoted again deviations between them. These data supported that these hydrogen transfer (HT) transformations are mainly thermodynamically controlled. For instance, bulky α-halogenated derivatives could be quantitatively reduced by LBADH even employing 2.5 equiv. of 2-propanol independently of their kinetic values. Finally, we found good correlations between the IR absorption band of the carbonyl groups and the degrees of conversion obtained in these HT processes, making this simple method a convenient tool to predict the success of these transformations. PMID:24302226

  1. Tightness of stability bounds by null space property

    NASA Astrophysics Data System (ADS)

    Chen, Xuemei; Wang, Rongrong

    2015-08-01

    The null space property (NSP) and the restricted isometry property (RIP) are two properties which have received considerable attention in the compressed sensing literature. It is known that the null space property guarantees a less than ideal stability result. In this paper, we show that this bound is actually tight by specific construction, which implies a fundamental difference between NSP and RIP.

  2. Visual and Plastic Arts in Teaching Literacy: Null Curricula?

    ERIC Educational Resources Information Center

    Wakeland, Robin Gay

    2010-01-01

    Visual and plastic arts in contemporary literacy instruction equal null curricula. Studies show that painting and sculpture facilitate teaching reading and writing (literacy), yet such pedagogy has not been formally adopted into USA curriculum. An example of null curriculum can be found in late 19th - early 20th century education the USA…

  3. Survey of Coronal Null Points with SDO/AIA & WSO

    NASA Astrophysics Data System (ADS)

    Freed, Michael; McKenzie, D. E.; Longcope, D.

    2013-07-01

    Magnetic fields in the corona can be approximated by using PFSS (Potential Field Source Surface) model in conjunction with magnetogram measurements of the photosphere. This approach is incorporated here to find locations of magnetic null points in the solar corona. Observations from WSO (Wilcox Solar Observatory) provide the necessary harmonic coefficients for a PFSS model. We located all magnetic null points in the PFSS model going back to Carrington Rotation 2098. The time and location where they cross the West limb is compared to high resolution observations made by SDO/AIA. Variations in predicted and observed null point locations, and estimates of the duration of each null, will be examined. This work will provide a catalog of coronal nulls observed by SDO that can be examined further for interesting dynamical behavior or variations in neighboring plasma.

  4. The Visible Nulling Coronagraph--Architecture Definition and Technology Development

    NASA Technical Reports Server (NTRS)

    Shao, Michael; Levine, B. Martin; Wallace, J. Kent; Liu, Duncan T.; Schmidtlin, Edouard; Serabyn, Eugene; Mennesson, Bertrand; Green, Joseph J.; Aguayo, Francisco; Fregoso, S. Felipe; Lane, Benjamin F.; Samuele, Rocco; Tuttle, Carl

    2005-01-01

    This paper describes the advantages of visible direct detection and spectroscopy of Earth-like extrasolar planets using a nulling coronagraph instrument behind a moderately sized single aperture space telescope. Our concept synthesizes a nulling interferometer by shearing the telescope pupil, with the resultant producing a deep null. We describe nulling configurations that also include methods to mitigate stellar leakage, such as spatial filtering by a coherent array of single mode fibers, and post-starlight suppression wavefront sensing and control. With diffraction limited telescope optics and similar quality components in the optical train (lambda/20), suppression of the starlight to 1e-10 is readily achievable. We describe key features of the architecture and analysis, present latest results of laboratory measurements demonstrating achievable null depth and component development, and discuss future key technical milestones.

  5. Null hypersurfaces in generalized Robertson-Walker spacetimes

    NASA Astrophysics Data System (ADS)

    Navarro, Matias; Palmas, Oscar; Solis, Didier A.

    2016-08-01

    We study the geometry of null hypersurfaces M in generalized Robertson-Walker spacetimes. First we characterize such null hypersurfaces as graphs of generalized eikonal functions over the fiber and use this characterization to show that such hypersurfaces are parallel if and only if their fibers are also parallel. We further use this technique to construct several examples of null hypersurfaces in both de Sitter and anti de Sitter spaces. Then we characterize all the totally umbilical null hypersurfaces M in a Lorentzian space form (viewed as a quadric in a semi-Euclidean ambient space) as intersections of the space form with a hyperplane. Finally we study the totally umbilical spacelike hypersurfaces of null hypersurfaces in space forms and characterize them as planar sections of M.

  6. Frequency of null allele of Human Leukocyte Antigen-G (HLA-G) locus in subjects to recurrent miscarriage

    PubMed Central

    Alizadeh, Nazila; Mosaferi, Elnaz; Farzadi, Laya; Majidi, Jafar; Monfaredan, Amir; Yousefi, Bahman; Baradaran, Behzad

    2016-01-01

    Background: Human leukocyte antigen-G (HLA-G) is a non-classical class I molecule highly expressed by extravillous cytotrophoblast cells. Due to a single base pair deletion, its function can be compensated by other isoforms. Investigating the frequency of null allele in Recurrent Miscarriage (RM) subjects could be useful in understanding the relationship between frequency of this allele and RM in a given population. Objective: This study aimed to determine the frequency of HLA-G*0105N null allele and its potential association with down-regulation of HLA-G in subjects with RM. Materials and Methods: Western blotting was used to assess the level of HLA-G protein expression. For investigating the frequency of HLA-G*0105N null allele in RM subjects, PCR-RFLP method was used. Exon 3 of HLA-G gene was amplified by polymerase chain reaction (PCR). Subsequently, PpuM-1 enzyme was employed to digest the PCR products and fragments were analyzed using gel electrophoresis. Results: Digestion using restriction enzyme showed the presence of heterozygous HLA-G*0105N null allele in 10% of the test population. Western blotting results confirmed the decrease in expression of HLA-G in the placental tissue of subjects with RM compared to subjects who could give normal birth. Conclusion: The frequency of heterozygous HLA-G*0105N null allele was high to some extent in subjects with RM. The mutation rate in subjects suggested that there is a significant association between RM and frequency of mutations in this allele. PMID:27525330

  7. Wormholes minimally violating the null energy condition

    SciTech Connect

    Bouhmadi-López, Mariam; Lobo, Francisco S N; Martín-Moruno, Prado E-mail: fslobo@fc.ul.pt

    2014-11-01

    We consider novel wormhole solutions supported by a matter content that minimally violates the null energy condition. More specifically, we consider an equation of state in which the sum of the energy density and radial pressure is proportional to a constant with a value smaller than that of the inverse area characterising the system, i.e., the area of the wormhole mouth. This approach is motivated by a recently proposed cosmological event, denoted {sup t}he little sibling of the big rip{sup ,} where the Hubble rate and the scale factor blow up but the cosmic derivative of the Hubble rate does not [1]. By using the cut-and-paste approach, we match interior spherically symmetric wormhole solutions to an exterior Schwarzschild geometry, and analyse the stability of the thin-shell to linearized spherically symmetric perturbations around static solutions, by choosing suitable properties for the exotic material residing on the junction interface radius. Furthermore, we also consider an inhomogeneous generalization of the equation of state considered above and analyse the respective stability regions. In particular, we obtain a specific wormhole solution with an asymptotic behaviour corresponding to a global monopole.

  8. The curious case of null warped space

    NASA Astrophysics Data System (ADS)

    Anninos, Dionysios; Compère, Geoffrey; de Buyl, Sophie; Detournay, Stéphane; Guica, Monica

    2010-11-01

    We initiate a comprehensive study of a set of solutions of topologically massive gravity known as null warped anti-de Sitter spacetimes. These are pp-wave extensions of three-dimensional anti-de Sitter space. We first perform a careful analysis of the linearized stability of black holes in these spacetimes. We find two qualitatively different types of solutions to the linearized equations of motion: the first set has an exponential time dependence, the second — a polynomial time dependence. The solutions polynomial in time induce severe pathologies and moreover survive at the non-linear level. In order to make sense of these geometries, it is thus crucial to impose appropriate boundary conditions. We argue that there exists a consistent set of boundary conditions that allows us to reject the above pathological modes from the physical spectrum. The asymptotic symmetry group associated to these boundary conditions consists of a centrally-extended Virasoro algebra. Using this central charge we can account for the entropy of the black holes via Cardy's formula. Finally, we note that the black hole spectrum is chiral and prove a Birkoff theorem showing that there are no other stationary axisymmetric black holes with the specified asymptotics. We extend most of the analysis to a larger family of pp-wave black holes which are related to Schrödinger spacetimes with critical exponent z.

  9. A Null Model for Pearson Coexpression Networks

    PubMed Central

    Gobbi, Andrea; Jurman, Giuseppe

    2015-01-01

    Gene coexpression networks inferred by correlation from high-throughput profiling such as microarray data represent simple but effective structures for discovering and interpreting linear gene relationships. In recent years, several approaches have been proposed to tackle the problem of deciding when the resulting correlation values are statistically significant. This is most crucial when the number of samples is small, yielding a non-negligible chance that even high correlation values are due to random effects. Here we introduce a novel hard thresholding solution based on the assumption that a coexpression network inferred by randomly generated data is expected to be empty. The threshold is theoretically derived by means of an analytic approach and, as a deterministic independent null model, it depends only on the dimensions of the starting data matrix, with assumptions on the skewness of the data distribution compatible with the structure of gene expression levels data. We show, on synthetic and array datasets, that the proposed threshold is effective in eliminating all false positive links, with an offsetting cost in terms of false negative detected edges. PMID:26030917

  10. Mutation of Tyr-218 to Phe in Thermoanaerobacter ethanolicus secondary alcohol dehydrogenase: effects on bioelectronic interface performance.

    PubMed

    Hassler, Brian L; Dennis, Megan; Laivenieks, Maris; Zeikus, J Gregory; Worden, Robert M

    2007-10-01

    Bioelectronic interfaces that facilitate electron transfer between the electrode and a dehydrogenase enzyme have potential applications in biosensors, biocatalytic reactors, and biological fuel cells. The secondary alcohol dehydrogenase (2 degrees ADH) from Thermoanaerobacter ethanolicus is especially well suited for the development of such bioelectronic interfaces because of its thermostability and facile production and purification. However, the natural cofactor for the enzyme, beta-nicotinamide adenine dinucleotide phosphate (NADP+), is more expensive and less stable than beta-nicotinamide adenine dinucleotide (NAD+). PCR-based, site-directed mutagenesis was performed on 2 degrees ADH in an attempt to adjust the cofactor specificity toward NAD+ by mutating Tyr218 to Phe (Y218F 2 degrees ADH). This mutation increased the Km(app) for NADP+ 200-fold while decreasing the Km(app) for NAD+ 2.5-fold. The mutant enzyme was incorporated into a bioelectronic interface that established electrical communication between the enzyme, the NAD+, the electron mediator toluidine blue O (TBO), and a gold electrode. Cyclic voltammetry, impedance spectroscopy, gas chromatography, mass spectrometry, constant potential amperometry, and chronoamperometry were used to characterize the mutant and wild-type enzyme incorporated in the bioelectronic interface. The Y218F 2 degrees ADH exhibited a fourfold increase in the turnover ratio compared to the wild type in the presence of NAD+. The electrochemical and kinetic measurements support the prediction that the Rossmann fold of the enzyme binds to the phosphate moiety of the cofactor. During the 45 min of continuous operation, NAD+ was electrically recycled 6.7 x 10(4) times, suggesting that the Y218F 2 degrees ADH-modified bioelectronic interface is stable. PMID:18025592

  11. GST M1-T1 null Allele Frequency Patterns in Geographically Assorted Human Populations: A Phylogenetic Approach

    PubMed Central

    Ramasamy, Thirumurugan; Ayyavoo, Jayachitra

    2015-01-01

    Genetic diversity in drug metabolism and disposition is mainly considered as the outcome of the inter-individual genetic variation in polymorphism of drug-xenobiotic metabolizing enzyme (XME). Among the XMEs, glutathione-S-transferases (GST) gene loci are an important candidate for the investigation of diversity in allele frequency, as the deletion mutations in GST M1 and T1 genotypes are associated with various cancers and genetic disorders of all major Population Affiliations (PAs). Therefore, the present population based phylogenetic study was focused to uncover the frequency distribution pattern in GST M1 and T1 null genotypes among 45 Geographically Assorted Human Populations (GAHPs). The frequency distribution pattern for GST M1 and T1 null alleles have been detected in this study using the data derived from literatures representing 44 populations affiliated to Africa, Asia, Europe, South America and the genome of PA from Gujarat, a region in western India. Allele frequency counting for Gujarat PA and scattered plot analysis for geographical distribution among the PAs were performed in SPSS-21. The GST M1 and GST T1 null allele frequencies patterns of the PAs were computed in Seqboot, Gendist program of Phylip software package (3.69 versions) and Unweighted Pair Group method with Arithmetic Mean in Mega-6 software. Allele frequencies from South African Xhosa tribe, East African Zimbabwe, East African Ethiopia, North African Egypt, Caucasian, South Asian Afghanistan and South Indian Andhra Pradesh have been identified as the probable seven patterns among the 45 GAHPs investigated in this study for GST M1-T1 null genotypes. The patternized null allele frequencies demonstrated in this study for the first time addresses the missing link in GST M1-T1 null allele frequencies among GAHPs. PMID:25867025

  12. Abnormal neuronal patterning occurs during early postnatal brain development of Scn1b-null mice and precedes hyperexcitability.

    PubMed

    Brackenbury, William J; Yuan, Yukun; O'Malley, Heather A; Parent, Jack M; Isom, Lori L

    2013-01-15

    Voltage-gated Na(+) channel (VGSC) β1 subunits, encoded by SCN1B, are multifunctional channel modulators and cell adhesion molecules (CAMs). Mutations in SCN1B are associated with the genetic epilepsy with febrile seizures plus (GEFS+) spectrum disorders in humans, and Scn1b-null mice display severe spontaneous seizures and ataxia from postnatal day (P)10. The goal of this study was to determine changes in neuronal pathfinding during early postnatal brain development of Scn1b-null mice to test the hypothesis that these CAM-mediated roles of Scn1b may contribute to the development of hyperexcitability. c-Fos, a protein induced in response to seizure activity, was up-regulated in the Scn1b-null brain at P16 but not at P5. Consistent with this, epileptiform activity was observed in hippocampal and cortical slices prepared from the P16 but not from the P5-P7 Scn1b-null brain. On the basis of these results, we investigated neuronal pathfinding at P5. We observed disrupted fasciculation of parallel fibers in the P5 null cerebellum. Further, P5 null mice showed reduced neuron density in the dentate gyrus granule cell layer, increased proliferation of granule cell precursors in the hilus, and defective axonal extension and misorientation of somata and processes of inhibitory neurons in the dentate gyrus and CA1. Thus, Scn1b is critical for neuronal proliferation, migration, and pathfinding during the critical postnatal period of brain development. We propose that defective neuronal proliferation, migration, and pathfinding in response to Scn1b deletion may contribute to the development of hyperexcitability. PMID:23277545

  13. GST M1-T1 null allele frequency patterns in geographically assorted human populations: a phylogenetic approach.

    PubMed

    Kasthurinaidu, Senthilkumar Pitchalu; Ramasamy, Thirumurugan; Ayyavoo, Jayachitra; Dave, Dhvani Kirtikumar; Adroja, Divya Anantray

    2015-01-01

    Genetic diversity in drug metabolism and disposition is mainly considered as the outcome of the inter-individual genetic variation in polymorphism of drug-xenobiotic metabolizing enzyme (XME). Among the XMEs, glutathione-S-transferases (GST) gene loci are an important candidate for the investigation of diversity in allele frequency, as the deletion mutations in GST M1 and T1 genotypes are associated with various cancers and genetic disorders of all major Population Affiliations (PAs). Therefore, the present population based phylogenetic study was focused to uncover the frequency distribution pattern in GST M1 and T1 null genotypes among 45 Geographically Assorted Human Populations (GAHPs). The frequency distribution pattern for GST M1 and T1 null alleles have been detected in this study using the data derived from literatures representing 44 populations affiliated to Africa, Asia, Europe, South America and the genome of PA from Gujarat, a region in western India. Allele frequency counting for Gujarat PA and scattered plot analysis for geographical distribution among the PAs were performed in SPSS-21. The GST M1 and GST T1 null allele frequencies patterns of the PAs were computed in Seqboot, Gendist program of Phylip software package (3.69 versions) and Unweighted Pair Group method with Arithmetic Mean in Mega-6 software. Allele frequencies from South African Xhosa tribe, East African Zimbabwe, East African Ethiopia, North African Egypt, Caucasian, South Asian Afghanistan and South Indian Andhra Pradesh have been identified as the probable seven patterns among the 45 GAHPs investigated in this study for GST M1-T1 null genotypes. The patternized null allele frequencies demonstrated in this study for the first time addresses the missing link in GST M1-T1 null allele frequencies among GAHPs. PMID:25867025

  14. Nonsense mutations in the alcohol dehydrogenase gene of Drosophila melanogaster correlate with an abnormal 3' end processing of the corresponding pre-mRNA.

    PubMed Central

    Brogna, S

    1999-01-01

    From bacteria to mammals, mutations that generate premature termination codons have been shown to result in the reduction in the abundance of the corresponding mRNA. In mammalian cells, more often than not, the reduction happens while the RNA is still associated with the nucleus. Here, it is reported that mutations in the alcohol dehydrogenase gene (Adh) of Drosophila melanogaster that generate premature termination codons lead to reduced levels of cytoplasmic and nuclear mRNA. Unexpectedly, it has been found that the poly(A) tails of Adh mRNAs and pre-mRNAs that carry a premature termination codon are longer than in the wild-type transcript. The more 5' terminal the mutation is, the longer is the poly(A) tail of the transcript. These findings suggest that the integrity of the coding region may be required for accurate mRNA 3' end processing. PMID:10199572

  15. Biogeochemical sampling in the Mahd Adh Dhahab District, Kingdom of Saudi Arabia

    USGS Publications Warehouse

    Ebens, Richard J.; Shacklette, Hansford T.; Worl, Ronald G.

    1983-01-01

    A biogeochemical reconnaissance of the Mahd adh Dhahab district, Kingdom of Saudi Arabia, confirms the ability of deep-rooted Acacia trees to reflect bedrock concentrations of some trace elements. The analytical values for lead, zinc, selenium, and cadmium in ash of tree branches are significantly higher in samples from areas of known mineralization (13 sites) than in samples from areas of no known mineralization (12 sites). Geometric mean concentrations of these elements in the two areas (mineralized; nonmineralized), quoted as parts per million in ash, are lead (122; 28), zinc (713; 443), selenium (1.2; 0.6), and cadmium (1.4; 0.5). The range of molybdenum values in ash from the two areas is similar, but a cluster of four sites in an area classified as nonmineralized corresponds to an area where the U.S. Geological Survey reported anomalous molybdenum values in rock in 1965. Results for other elements were either equivocal (mercury, tellurium, silver) or showed no correspondence to the two areas. Mean values for barium, manganese, potassium, and sodium are significantly higher in areas of no known mineralization, but we conclude that this reflects a difference in country rock major-element chemistry rather than the effect of ore-forming processes. The pattern of trace-metal values in Acacia ash is present whether the sampled tree grows on bedrock, on talus, or on residual or modern alluvium. This fact suggests that the trace-element chemistry of the trees reflects bedrock geochemistry and implies that Acacia biogeochemistry could be applied as a prospecting tool in areas where bedrock is not well exposed.

  16. Nurses’ perceptions of medication adherence in schizophrenia: results of the ADHES cross-sectional questionnaire survey

    PubMed Central

    Emsley, Robin; Alptekin, Koksal; Azorin, Jean-Michel; Cañas, Fernando; Dubois, Vincent; Gorwood, Philip; Haddad, Peter M.; Naber, Dieter; Olivares, José Manuel; Papageorgiou, Georgios; Roca, Miguel; Thomas, Pierre; Hargarter, Ludger; Schreiner, Andreas

    2015-01-01

    Objectives: Poor adherence to antipsychotic treatment is a widespread problem within schizophrenia therapy with serious consequences including increased risks of relapse and rehospitalization. Mounting evidence supports the key roles that nurses play in monitoring patient progress and facilitating long-term treatment adherence. The Adherencia Terapéutica en la Esquizofrenia (ADHES) nurses’ survey was designed to assess the opinions of nurses on the causes and management of partial/nonadherence to antipsychotic medication. Methods: A questionnaire-based cross-sectional survey of 4120 nurses from Europe, the Middle East and Africa. Interpretation of results was based on a descriptive comparison of responses. Results: Nurses perceived 54% of patients seen in the preceding month to be partially/nonadherent to treatment. Most nurses (90%) reported some level of experience with administration of long-acting injectable (LAI) antipsychotics, with 24% of nurses administering >10 injections per month. The majority (85%) of nurses surveyed believed that improving adherence would improve patient outcomes. Nearly half (49%) reported that most of their patients depend on a family member or other nonprofessional carer to remind them to take their medication as prescribed. A similar proportion of nurses (43%) reported that most of their patients relied on a professional to remind them to take medication. Most nurses (92%) felt that ensuring continuous medication with LAI antipsychotics would yield long-term benefits for patients, but their opinion was that over a third of patients were unaware of LAI antipsychotic treatments. In a series of forced options, the strategy used most often by respondents (89%) to promote medication adherence was to build trusting relationships with patients while listening to and interpreting their needs and concerns. Respondents also rated this as the most effective strategy that they used (48%). Conclusion: Nurses are highly aware of adherence

  17. Functional consequences of stably expressing a mutant calsequestrin (CASQ2D307H) in the CASQ2 null background

    PubMed Central

    Kalyanasundaram, Anuradha; Viatchenko-Karpinski, Serge; Belevych, Andriy E.; Lacombe, Veronique A.; Hwang, Hyun Seok; Knollmann, Björn C.; Gyorke, Sandor

    2012-01-01

    The role of calsequestrin (CASQ2) in cardiac sarcoplasmic reticulum (SR) calcium (Ca2+) transport has gained significant attention since point mutations in CASQ2 were reported to cause ventricular arrhythmia. In the present study, we have critically evaluated the functional consequences of expressing the CASQ2D307H mutant protein in the CASQ2 null mouse. We recently reported that the mutant CASQ2D307H protein can be stably expressed in CASQ2 null hearts, and it targets appropriately to the junctional SR (Kalyanasundaram A, Bal NC, Franzini-Armstrong C, Knollmann BC, Periasamy M. J Biol Chem 285: 3076–3083, 2010). In this study, we found that introduction of CASQ2D307H protein in the CASQ2 null background partially restored triadin 1 levels, which were decreased in the CASQ2 null mice. Despite twofold expression (relative to wild-type CASQ2), the mutant protein failed to increase SR Ca2+ load. We also found that the Ca2+ transient decays slower in the CASQ2 null and CASQ2D307H cells. CASQ2D307H myocytes, when rhythmically paced and challenged with isoproterenol, exhibit spontaneous Ca2+ waves similar to CASQ2 null myocytes; however, the stability of Ca2+ cycling was increased in the CASQ2D307H myocytes. In the presence of isoproterenol, Ca2+-transient amplitude in CASQ2D307H myocytes was significantly decreased, possibly indicating an inherent defect in Ca2+ buffering capacity and release from the mutant CASQ2 at high Ca2+ concentrations. We also observed polymorphic ventricular tachycardia in the CASQ2D307H mice, although lesser than in the CASQ2 null mice. These data suggest that CASQ2D307H point mutation may affect Ca2+ buffering capacity and Ca2+ release. We propose that poor interaction between CASQ2D307H and triadin 1 could affect ryanodine receptor 2 stability, thereby increasing susceptibility to delayed afterdepolarizations and triggered arrhythmic activity. PMID:21984545

  18. Null fields in the outer Jovian magnetosphere: ULYSSES observations

    NASA Astrophysics Data System (ADS)

    Haynes, P. L.; Balogh, A.; Dougherty, M. K.; Southwood, D. J.; Fazakerley, A.

    1994-03-01

    This paper reports on a magnetic field phenomenon, hereafter referred to as null fields, which were discovered during the inbound pass of the recent flyby of Jupiter by the Ulysses spacecraft. These null fields which were observed in the outer dayside magnetosphere are characterised by brief but sharp decreases of the field magnitude to values less than 1 nT. The nulls are distinguished from the current sheet signatures characteristic of the middle magnetosphere by the fact that the field does not reverse across the event. A field configuration is suggested that accounts for the observed features of the events.

  19. Molecular basis for the CAT-2 null phenotype in maize

    SciTech Connect

    Bethards, L.A.; Scandalios, J.G.

    1988-01-01

    Previous reports have described several maize lines whose developmental patterns of catalase gene expression vary from the typical maize line, W64A. Among these variants are the lines A16 and A338, both found to be null for the CAT-2 protein. Identification of a third CAT-2 null line, designated A340, is described. RNA blots and S1 nuclease protection analysis, using (/sup 32/P)-labeled dCTP, indicate that all three CAT-2 null lines produce a similarly shortened Cat2 transcript. The molecular basis for this aberrant Cat2 transcript is discussed.

  20. Taurodontism, variations in tooth number, and misshapened crowns in Wnt10a null mice and human kindreds

    PubMed Central

    Yang, Jie; Wang, Shih-Kai; Choi, Murim; Reid, Bryan M; Hu, Yuanyuan; Lee, Yuan-Ling; Herzog, Curtis R; Kim-Berman, Hera; Lee, Moses; Benke, Paul J; Kent Lloyd, K C; Simmer, James P; Hu, Jan C-C

    2015-01-01

    WNT10A is a signaling molecule involved in tooth development, and WNT10A defects are associated with tooth agenesis. We characterized Wnt10a null mice generated by the knockout mouse project (KOMP) and six families with WNT10A mutations, including a novel p.Arg104Cys defect, in the absence of EDA,EDAR, or EDARADD variations. Wnt10a null mice exhibited supernumerary mandibular fourth molars, and smaller molars with abnormal cusp patterning and root taurodontism. Wnt10a−/− incisors showed distinctive apical–lingual wedge-shaped defects. These findings spurred us to closely examine the dental phenotypes of our WNT10A families. WNT10A heterozygotes exhibited molar root taurodontism and mild tooth agenesis (with incomplete penetrance) in their permanent dentitions. Individuals with two defective WNT10A alleles showed severe tooth agenesis and had fewer cusps on their molars. The misshapened molar crowns and roots were consistent with the Wnt10a null phenotype and were not previously associated with WNT10A defects. The missing teeth contrasted with the presence of supplemental teeth in the Wnt10a null mice and demonstrated mammalian species differences in the roles of Wnt signaling in early tooth development. We conclude that molar crown and root dysmorphologies are caused by WNT10A defects and that the severity of the tooth agenesis correlates with the number of defective WNT10A alleles. PMID:25629078

  1. Molecular analysis of UAS(E), a cis element containing stress response elements responsible for ethanol induction of the KlADH4 gene of Kluyveromyces lactis.

    PubMed

    Mazzoni, C; Santori, F; Saliola, M; Falcone, C

    2000-01-01

    KlADH4 is a gene of Kluyveromyces lactis encoding a mitochondrial alcohol dehydrogenase activity, which is specifically induced by ethanol and insensitive to glucose repression. In this work, we report the molecular analysis of UAS(E), an element of the KlADH4 promoter which is essential for the induction of KlADH4 in the presence of ethanol. UAS(E) contains five stress response elements (STREs), which have been found in many genes of Saccharomyces cerevisiae involved in the response of cells to conditions of stress. Whereas KlADH4 is not responsive to stress conditions, the STREs present in UAS(E) seem to play a key role in the induction of the gene by ethanol, a situation that has not been observed in the related yeast S. cerevisiae. Gel retardation experiments showed that STREs in the KlADH4 promoter can bind factor(s) under non-inducing conditions. Moreover, we observed that the RAP1 binding site present in UAS(E) binds KlRap1p. PMID:10724480

  2. A boundary term for the gravitational action with null boundaries

    NASA Astrophysics Data System (ADS)

    Parattu, Krishnamohan; Chakraborty, Sumanta; Majhi, Bibhas Ranjan; Padmanabhan, T.

    2016-07-01

    Constructing a well-posed variational principle is a non-trivial issue in general relativity. For spacelike and timelike boundaries, one knows that the addition of the Gibbons-Hawking-York (GHY) counter-term will make the variational principle well-defined. This result, however, does not directly generalize to null boundaries on which the 3-metric becomes degenerate. In this work, we address the following question: What is the counter-term that may be added on a null boundary to make the variational principle well-defined? We propose the boundary integral of 2 √{-g} ( Θ +κ ) as an appropriate counter-term for a null boundary. We also conduct a preliminary analysis of the variations of the metric on the null boundary and conclude that isolating the degrees of freedom that may be fixed for a well-posed variational principle requires a deeper investigation.

  3. A null-steering viewpoint of interferometric SAR

    SciTech Connect

    BICKEL,DOUGLAS L.

    2000-05-02

    Interferometric synthetic aperture radar (IFSAR) extends the two-dimensional imaging capability of traditional synthetic aperture radar to three-dimensions by using an aperture in the elevation plane to estimate the 3-D structure of the target. The operation of this additional aperture can be viewed from a null-steering point of view, rather than the traditional phase determination point of view. Knowing that IFSAR can be viewed from the null-steering perspective allows one to take advantage of the mathematical foundation developed for null-steering arrays. In addition, in some problems of interest in IFSAR the null-steering perspective provides better intuition and suggests alternative solutions. One example is the problem of estimating building height where layover is present.

  4. Radiant Temperature Nulling Radiometer and Polarization Enhanced Thermal Radiometer

    NASA Technical Reports Server (NTRS)

    Bailey, John

    2002-01-01

    The two radiometers profiled in this viegraph presentation, the Radiant Temperature Nulling Radiometer and the Polarization Enhanced Thermal Radiometer, were developed for the calibration of remote sensing equipment. This presentation profiles the theory and components of each type of radiometer.

  5. Another Nulling Hall-Effect Current-Measuring Circuit

    NASA Technical Reports Server (NTRS)

    Thibodeau, Phillip E.; Sullender, Craig C.

    1993-01-01

    Lightweight, low-power circuit provides noncontact measurement of alternating or direct current of many ampheres in main conductor. Advantages of circuit over other nulling Hall-effect current-measuring circuits is stability and accuracy increased by putting both analog-to-digital and digital-to-analog converters in nulling feedback loop. Converters and rest of circuit designed for operation at sampling rate of 100 kHz, but rate changed to alter time or frequency response of circuit.

  6. Antimultipath communication by injecting tone into null in signal spectrum

    NASA Technical Reports Server (NTRS)

    Davarian, Faramaz (Inventor)

    1987-01-01

    A transmitter for digital radio communication creates a null by balanced encoding of data modulated on an RF carrier, and inserts a calibration tone within the null. This is accomplished by having the calibration tone coincide in phase and frequency with the transmitted radio frequency output, for coherent demodulation of data at the receiver where the tone calibration signal is extracted and used for multipath fading compensation.

  7. Experimental Progress and Results of a Visible Nulling Coronagraph

    NASA Technical Reports Server (NTRS)

    Samuele, Rocco; Wallace, J. Kent; Schmidtlin, Edouard; Shao, Mike; Levine, B. Martin; Fregoso, Santos

    2007-01-01

    The crux of visible exoplanet detection is overcoming significant star-planet contrast ratios on the order of 10(exp -7) to 10(exp -10)-at very small angular separations. We are developing an interferometric nulling coronagraph designed to achieve a 10(exp -6) contrast ratio at a working science bandpass of 20% visible light. Achieving large, broadband suppression requires a pseudo-achromatic phase flip, while maintaining a strict error budget. Recent results from our nulling interferometer testbed yield contrast ratios at the 1.05x10(exp -6) level, with a 15% visible bandpass. This result is at 65% of our final bandpass requirement, although limitations of our current configuration make major hardware changes essential to broadening the bandpass. We make the argument that broadening the bandpass should not necessarily adversely affect the null depth until beyond the 20% visible light level. Using the same setup we are able to reach monochromatic null depths of 1.11x10(exp -7) (?= 638 nm)averaged over three seconds. This paper will describe our experimental approach for achieving deep broadband nulls, as well as error considerations and limitations, and the most recent results for our nulling coronagraph testbed.

  8. Context-specific protection of TGFα null mice from osteoarthritis

    PubMed Central

    Usmani, Shirine E.; Ulici, Veronica; Pest, Michael A.; Hill, Tracy L.; Welch, Ian D.; Beier, Frank

    2016-01-01

    Transforming growth factor alpha (TGFα) is a growth factor involved in osteoarthritis (OA). TGFα induces an OA-like phenotype in articular chondrocytes, by inhibiting matrix synthesis and promoting catabolic factor expression. To better understand TGFα’s potential as a therapeutic target, we employed two in vivo OA models: (1) post-traumatic and (2) aging related OA. Ten-week old and six-month old male Tgfa null mice and their heterozygous (control) littermates underwent destabilization of the medial meniscus (DMM) surgery. Disease progression was assessed histologically using the Osteoarthritis Research Society International (OARSI) scoring system. As well, spontaneous disease progression was analyzed in eighteen-month-old Tgfa null and heterozygous mice. Ten-week old Tgfa null mice were protected from OA progression at both seven and fourteen weeks post-surgery. No protection was seen however in six-month old null mice after DMM surgery, and no differences were observed between genotypes in the aging model. Thus, young Tgfa null mice are protected from OA progression in the DMM model, while older mice are not. In addition, Tgfa null mice are equally susceptible to spontaneous OA development during aging. Thus, TGFα might be a valuable therapeutic target in some post-traumatic forms of OA, however its role in idiopathic disease is less clear. PMID:27457421

  9. Context-specific protection of TGFα null mice from osteoarthritis.

    PubMed

    Usmani, Shirine E; Ulici, Veronica; Pest, Michael A; Hill, Tracy L; Welch, Ian D; Beier, Frank

    2016-01-01

    Transforming growth factor alpha (TGFα) is a growth factor involved in osteoarthritis (OA). TGFα induces an OA-like phenotype in articular chondrocytes, by inhibiting matrix synthesis and promoting catabolic factor expression. To better understand TGFα's potential as a therapeutic target, we employed two in vivo OA models: (1) post-traumatic and (2) aging related OA. Ten-week old and six-month old male Tgfa null mice and their heterozygous (control) littermates underwent destabilization of the medial meniscus (DMM) surgery. Disease progression was assessed histologically using the Osteoarthritis Research Society International (OARSI) scoring system. As well, spontaneous disease progression was analyzed in eighteen-month-old Tgfa null and heterozygous mice. Ten-week old Tgfa null mice were protected from OA progression at both seven and fourteen weeks post-surgery. No protection was seen however in six-month old null mice after DMM surgery, and no differences were observed between genotypes in the aging model. Thus, young Tgfa null mice are protected from OA progression in the DMM model, while older mice are not. In addition, Tgfa null mice are equally susceptible to spontaneous OA development during aging. Thus, TGFα might be a valuable therapeutic target in some post-traumatic forms of OA, however its role in idiopathic disease is less clear. PMID:27457421

  10. Measurement Via Optical Near-Nulling and Subaperture Stitching

    NASA Technical Reports Server (NTRS)

    Forbes, Greg; De Vries, Gary; Murphy, Paul; Brophy, Chris

    2012-01-01

    A subaperture stitching interferometer system provides near-nulling of a subaperture wavefront reflected from an object of interest over a portion of a surface of the object. A variable optical element located in the radiation path adjustably provides near-nulling to facilitate stitching of subaperture interferograms, creating an interferogram representative of the entire surface of interest. This enables testing of aspheric surfaces without null optics customized for each surface prescription. The surface shapes of objects such as lenses and other precision components are often measured with interferometry. However, interferometers have a limited capture range, and thus the test wavefront cannot be too different from the reference or the interference cannot be analyzed. Furthermore, the performance of the interferometer is usually best when the test and reference wavefronts are nearly identical (referred to as a null condition). Thus, it is necessary when performing such measurements to correct for known variations in shape to ensure that unintended variations are within the capture range of the interferometer and accurately measured. This invention is a system for nearnulling within a subaperture stitching interferometer, although in principle, the concept can be employed by wavefront measuring gauges other than interferometers. The system employs a light source for providing coherent radiation of a subaperture extent. An object of interest is placed to modify the radiation (e.g., to reflect or pass the radiation), and a variable optical element is located to interact with, and nearly null, the affected radiation. A detector or imaging device is situated to obtain interference patterns in the modified radiation. Multiple subaperture interferograms are taken and are stitched, or joined, to provide an interferogram representative of the entire surface of the object of interest. The primary aspect of the invention is the use of adjustable corrective optics in the

  11. lagC-null and gbf-null cells define key steps in the morphogenesis of Dictyostelium mounds.

    PubMed

    Sukumaran, S; Brown, J M; Firtel, R A; McNally, J G

    1998-08-01

    The transition to multicellularity is a key feature of the Dictyostelium life cycle, and two genes, gbf and lagC, are known to play pivotal roles in regulating this developmental switch. lagC-null and gbf-null cells fail to induce cell-type-specific genes ordinarily expressed during multicellular development. The null mutants also share a similar morphological phenotype: mutant cells repeatedly aggregate to form a loose mound, disperse, and reform a mound, rather than proceeding to form a tip. To characterize defects in morphogenesis in these mutants, we examined cell motion in the mutant mounds. In analogy with the failed transition in gene expression, we found that lagC-null and gbf-null mounds failed to make a morphogenetic transition from random to rotational motion normally observed in the parent strain. One reason for this was the inability of the mutant mounds to establish a single, dominant signaling-wave center. This defect of lagC-null or gbf-null cells could be overcome by the addition of adenosine, which alters cAMP signaling, but then even in the presence of apparently normal signaling waves, cell motility was still aberrant. This motility defect, as well as the signaling-wave defect, could be overcome in lagC-null cells by overexpression of GBF, suggesting that lagC is dispensable if GBF protein levels are high enough. This set of morphogenetic defects that we have observed helps define key steps in mound morphogenesis. These include the establishment of a dominant signaling-wave center and the capacity of cells to move directionally within the cell mass in response to guidance cues. PMID:9698452

  12. Reduction of aberrant NF-κB signalling ameliorates Rett syndrome phenotypes in Mecp2-null mice

    PubMed Central

    Kishi, Noriyuki; MacDonald, Jessica L.; Ye, Julia; Molyneaux, Bradley J.; Azim, Eiman; Macklis, Jeffrey D.

    2016-01-01

    Mutations in the transcriptional regulator Mecp2 cause the severe X-linked neurodevelopmental disorder Rett syndrome (RTT). In this study, we investigate genes that function downstream of MeCP2 in cerebral cortex circuitry, and identify upregulation of Irak1, a central component of the NF-κB pathway. We show that overexpression of Irak1 mimics the reduced dendritic complexity of Mecp2-null cortical callosal projection neurons (CPN), and that NF-κB signalling is upregulated in the cortex with Mecp2 loss-of-function. Strikingly, we find that genetically reducing NF-κB signalling in Mecp2-null mice not only ameliorates CPN dendritic complexity but also substantially extends their normally shortened lifespan, indicating broader roles for NF-κB signalling in RTT pathogenesis. These results provide new insight into both the fundamental neurobiology of RTT, and potential therapeutic strategies via NF-κB pathway modulation. PMID:26821816

  13. Reduction of aberrant NF-κB signalling ameliorates Rett syndrome phenotypes in Mecp2-null mice.

    PubMed

    Kishi, Noriyuki; MacDonald, Jessica L; Ye, Julia; Molyneaux, Bradley J; Azim, Eiman; Macklis, Jeffrey D

    2016-01-01

    Mutations in the transcriptional regulator Mecp2 cause the severe X-linked neurodevelopmental disorder Rett syndrome (RTT). In this study, we investigate genes that function downstream of MeCP2 in cerebral cortex circuitry, and identify upregulation of Irak1, a central component of the NF-κB pathway. We show that overexpression of Irak1 mimics the reduced dendritic complexity of Mecp2-null cortical callosal projection neurons (CPN), and that NF-κB signalling is upregulated in the cortex with Mecp2 loss-of-function. Strikingly, we find that genetically reducing NF-κB signalling in Mecp2-null mice not only ameliorates CPN dendritic complexity but also substantially extends their normally shortened lifespan, indicating broader roles for NF-κB signalling in RTT pathogenesis. These results provide new insight into both the fundamental neurobiology of RTT, and potential therapeutic strategies via NF-κB pathway modulation. PMID:26821816

  14. Isolation of MECP2-null Rett Syndrome patient hiPS cells and isogenic controls through X-chromosome inactivation

    PubMed Central

    Cheung, Aaron Y.L.; Horvath, Lindsay M.; Grafodatskaya, Daria; Pasceri, Peter; Weksberg, Rosanna; Hotta, Akitsu; Carrel, Laura; Ellis, James

    2011-01-01

    Rett syndrome (RTT) is a neurodevelopmental autism spectrum disorder that affects girls due primarily to mutations in the gene encoding methyl-CpG binding protein 2 (MECP2). The majority of RTT patients carry missense and nonsense mutations leading to a hypomorphic MECP2, while null mutations leading to the complete absence of a functional protein are rare. MECP2 is an X-linked gene subject to random X-chromosome inactivation resulting in mosaic expression of mutant MECP2. The lack of human brain tissue motivates the need for alternative human cellular models to study RTT. Here we report the characterization of a MECP2 mutation in a classic female RTT patient involving rearrangements that remove exons 3 and 4 creating a functionally null mutation. To generate human neuron models of RTT, we isolated human induced pluripotent stem (hiPS) cells from RTT patient fibroblasts. RTT-hiPS cells retained the MECP2 mutation, are pluripotent and fully reprogrammed, and retained an inactive X-chromosome in a nonrandom pattern. Taking advantage of the latter characteristic, we obtained a pair of isogenic wild-type and mutant MECP2 expressing RTT-hiPS cell lines that retained this MECP2 expression pattern upon differentiation into neurons. Phenotypic analysis of mutant RTT-hiPS cell-derived neurons demonstrated a reduction in soma size compared with the isogenic control RTT-hiPS cell-derived neurons from the same RTT patient. Analysis of isogenic control and mutant hiPS cell-derived neurons represents a promising source for understanding the pathogenesis of RTT and the role of MECP2 in human neurons. PMID:21372149

  15. Characterization of the Saccharomyces cerevisiae YMR318C (ADH6) gene product as a broad specificity NADPH-dependent alcohol dehydrogenase: relevance in aldehyde reduction.

    PubMed Central

    Larroy, Carol; Fernández, M Rosario; González, Eva; Parés, Xavier; Biosca, Josep A

    2002-01-01

    YMR318C represents an open reading frame from Saccharomyces cerevisiae with unknown function. It possesses a conserved sequence motif, the zinc-containing alcohol dehydrogenase (ADH) signature, specific to the medium-chain zinc-containing ADHs. In the present study, the YMR318C gene product has been purified to homogeneity from overexpressing yeast cells, and found to be a homodimeric ADH, composed of 40 kDa subunits and with a pI of 5.0-5.4. The enzyme was strictly specific for NADPH and was active with a wide variety of substrates, including aliphatic (linear and branched-chain) and aromatic primary alcohols and aldehydes. Aldehydes were processed with a 50-fold higher catalytic efficiency than that for the corresponding alcohols. The highest k(cat)/K(m) values were found with pentanal>veratraldehyde > hexanal > 3-methylbutanal >cinnamaldehyde. Taking into consideration the substrate specificity and sequence characteristics of the YMR318C gene product, we have proposed this gene to be called ADH6. The disruption of ADH6 was not lethal for the yeast under laboratory conditions. Although S. cerevisiae is considered a non lignin-degrading organism, the catalytic activity of ADHVI can direct veratraldehyde and anisaldehyde, arising from the oxidation of lignocellulose by fungal lignin peroxidases, to the lignin biodegradation pathway. ADHVI is the only S. cerevisiae enzyme able to significantly reduce veratraldehyde in vivo, and its overexpression allowed yeast to grow under toxic concentrations of this aldehyde. The enzyme may also be involved in the synthesis of fusel alcohols. To our knowledge this is the first NADPH-dependent medium-chain ADH to be characterized in S. cerevisiae. PMID:11742541

  16. Aldehyde dehydrogenase 2 (ALDH2) and alcohol dehydrogenase 1B (ADH1B) polymorphisms exacerbate bladder cancer risk associated with alcohol drinking: gene-environment interaction.

    PubMed

    Masaoka, Hiroyuki; Ito, Hidemi; Soga, Norihito; Hosono, Satoyo; Oze, Isao; Watanabe, Miki; Tanaka, Hideo; Yokomizo, Akira; Hayashi, Norio; Eto, Masatoshi; Matsuo, Keitaro

    2016-06-01

    Although a range of chemical exposures (cigarette smoking and occupational exposure) are recognized risk factors for the development of bladder cancer (BCa), many epidemiological studies have demonstrated that alcohol drinking is not associated with BCa risk. Aldehyde dehydrogenase 2 (ALDH2; rs671, Glu504Lys) and alcohol dehydrogenase 1B (ADH1B; rs1229984, His47Arg) polymorphisms impact the accumulation of acetaldehyde, resulting in an increased risk of various cancers. To date, however, no studies evaluating the association between BCa risk and alcohol drinking have considered these polymorphisms. Here, we conducted a matched case-control study to investigate whether ALDH2 and ADH1B polymorphisms influence BCa risk associated with alcohol drinking. Cases were 74 BCa patients and controls were 740 first-visit outpatients without cancer at Aichi Cancer Center Hospital between January 2001 and December 2005. Odds ratio (OR), 95% confidence interval (CI) and gene-environment interaction were assessed by conditional logistic regression analysis with adjustment for potential confounders. Results showed that ALDH2 Glu/Lys was associated with a significantly increased risk of BCa compared with Glu/Glu (OR 2.03, 95% CI 1.14-3.62, P = 0.017). In contrast, ALDH2 Glu/Lys showed no increase in risk among the stratum of never drinkers compared with Glu/Glu, indicating a gene-environment interaction. ADH1B His/Arg had an OR of 1.98 (1.20-3.24, P = 0.007) compared with His/His. ADH1B Arg+ showed a similar OR and 95% CI. Individuals with ALDH2 Glu/Lys and ADH1B Arg+ had the highest risk of BCa compared with ALDH2 Glu/Glu and ADH1B His/His [OR 4.00 (1.81-8.87), P = 0.001]. PMID:26992901

  17. The effect of Clostridium perfringens type C strain CN3685 and its isogenic beta toxin null mutant in goats.

    PubMed

    Garcia, J P; Beingesser, J; Fisher, D J; Sayeed, S; McClane, B A; Posthaus, H; Uzal, F A

    2012-06-15

    Clostridium perfringens type C is an important cause of enteritis and/or enterocolitis in several animal species, including pigs, sheep, goats, horses and humans. The disease is a classic enterotoxemia and the enteric lesions and associated systemic effects are thought to be caused primarily by beta toxin (CPB), one of two typing toxins produced by C. perfringens type C. This has been demonstrated recently by fulfilling molecular Koch's postulates in rabbits and mice. We present here an experimental study to fulfill these postulates in goats, a natural host of C. perfringens type C disease. Nine healthy male or female Anglo Nubian goat kids were inoculated with the virulent C. perfringens type C wild-type strain CN3685, an isogenic CPB null mutant or a strain where the cpb null mutation had been reversed. Three goats inoculated with the wild-type strain presented abdominal pain, hemorrhagic diarrhea, necrotizing enterocolitis, pulmonary edema, hydropericardium and death within 24h of inoculation. Two goats inoculated with the CPB null mutant and two goats inoculated with sterile culture media (negative controls) remained clinically healthy during 24h after inoculation and no gross or histological abnormalities were observed in the tissues of any of them. Reversal of the null mutation to partially restore CPB production also increased virulence; 2 goats inoculated with this reversed mutant presented clinical and pathological changes similar to those observed in goats inoculated with the wild-type strain, except that spontaneous death was not observed. These results indicate that CPB is required for C. perfringens type C to induce disease in goats, supporting a key role for this toxin in natural C. perfringens type C disease pathogenesis. PMID:22296994

  18. The effect of Clostridium perfringens type C strain CN3685 and its isogenic beta toxin null mutant in goats

    PubMed Central

    Garcia, J. P.; Beingesser, J.; Fisher, D. J.; Sayeed, S.; McClane, B. A.; Posthaus, H.; Uzal, F. A.

    2012-01-01

    Clostridium perfringens type C is an important cause of enteritis and/or enterocolitis in several animal species, including pigs, sheep, goats, horses and humans. The disease is a classic enterotoxemia and the enteric lesions and associated systemic effects are thought to be caused primarily by beta toxin (CPB), one of two typing toxins produced by C. perfringens type C. This has been demonstrated recently by fulfilling molecular Koch’s postulates in rabbits and mice. We present here an experimental study to fulfill these postulates in goats, a natural host of C. perfringens type C disease. Nine healthy male or female Anglo Nubian goat kids were inoculated with the virulent C. perfringens type C wild-type strain CN3685, an isogenic CPB null mutant or a strain where the cpb null mutation had been reversed. Three goats inoculated with the wild-type strain presented abdominal pain, hemorrhagic diarrhea, necrotizing enterocolitis, pulmonary edema, hydropericardium and death within 24 h of inoculation. Two goats inoculated with the CPB null mutant and two goats inoculated with sterile culture media (negative controls) remained clinically healthy during 24 h after inoculation and no gross or histological abnormalities were observed in the tissues of any of them. Reversal of the null mutation to partially restore CPB production also increased virulence; 2 goats inoculated with this reversed mutant presented clinical and pathological changes similar to those observed in goats inoculated with the wild-type strain, except that spontaneous death was not observed. These results indicate that CPB is required for C. perfringens type C to induce disease in goats, supporting a key role for this toxin in natural C. perfringens type C disease pathogenesis. PMID:22296994

  19. Comprehensive Analysis of the 16p11.2 Deletion and Null Cntnap2 Mouse Models of Autism Spectrum Disorder.

    PubMed

    Brunner, Daniela; Kabitzke, Patricia; He, Dansha; Cox, Kimberly; Thiede, Lucinda; Hanania, Taleen; Sabath, Emily; Alexandrov, Vadim; Saxe, Michael; Peles, Elior; Mills, Alea; Spooren, Will; Ghosh, Anirvan; Feliciano, Pamela; Benedetti, Marta; Luo Clayton, Alice; Biemans, Barbara

    2015-01-01

    Autism spectrum disorder comprises several neurodevelopmental conditions presenting symptoms in social communication and restricted, repetitive behaviors. A major roadblock for drug development for autism is the lack of robust behavioral signatures predictive of clinical efficacy. To address this issue, we further characterized, in a uniform and rigorous way, mouse models of autism that are of interest because of their construct validity and wide availability to the scientific community. We implemented a broad behavioral battery that included but was not restricted to core autism domains, with the goal of identifying robust, reliable phenotypes amenable for further testing. Here we describe comprehensive findings from two known mouse models of autism, obtained at different developmental stages, using a systematic behavioral test battery combining standard tests as well as novel, quantitative, computer-vision based systems. The first mouse model recapitulates a deletion in human chromosome 16p11.2, found in 1% of individuals with autism. The second mouse model harbors homozygous null mutations in Cntnap2, associated with autism and Pitt-Hopkins-like syndrome. Consistent with previous results, 16p11.2 heterozygous null mice, also known as Del(7Slx1b-Sept1)4Aam weighed less than wild type littermates displayed hyperactivity and no social deficits. Cntnap2 homozygous null mice were also hyperactive, froze less during testing, showed a mild gait phenotype and deficits in the three-chamber social preference test, although less robust than previously published. In the open field test with exposure to urine of an estrous female, however, the Cntnap2 null mice showed reduced vocalizations. In addition, Cntnap2 null mice performed slightly better in a cognitive procedural learning test. Although finding and replicating robust behavioral phenotypes in animal models is a challenging task, such functional readouts remain important in the development of therapeutics and we

  20. Comprehensive Analysis of the 16p11.2 Deletion and Null Cntnap2 Mouse Models of Autism Spectrum Disorder

    PubMed Central

    He, Dansha; Cox, Kimberly; Thiede, Lucinda; Hanania, Taleen; Sabath, Emily; Alexandrov, Vadim; Saxe, Michael; Peles, Elior; Mills, Alea; Spooren, Will; Ghosh, Anirvan; Feliciano, Pamela; Benedetti, Marta; Luo Clayton, Alice; Biemans, Barbara

    2015-01-01

    Autism spectrum disorder comprises several neurodevelopmental conditions presenting symptoms in social communication and restricted, repetitive behaviors. A major roadblock for drug development for autism is the lack of robust behavioral signatures predictive of clinical efficacy. To address this issue, we further characterized, in a uniform and rigorous way, mouse models of autism that are of interest because of their construct validity and wide availability to the scientific community. We implemented a broad behavioral battery that included but was not restricted to core autism domains, with the goal of identifying robust, reliable phenotypes amenable for further testing. Here we describe comprehensive findings from two known mouse models of autism, obtained at different developmental stages, using a systematic behavioral test battery combining standard tests as well as novel, quantitative, computer-vision based systems. The first mouse model recapitulates a deletion in human chromosome 16p11.2, found in 1% of individuals with autism. The second mouse model harbors homozygous null mutations in Cntnap2, associated with autism and Pitt-Hopkins-like syndrome. Consistent with previous results, 16p11.2 heterozygous null mice, also known as Del(7Slx1b-Sept1)4Aam weighed less than wild type littermates displayed hyperactivity and no social deficits. Cntnap2 homozygous null mice were also hyperactive, froze less during testing, showed a mild gait phenotype and deficits in the three-chamber social preference test, although less robust than previously published. In the open field test with exposure to urine of an estrous female, however, the Cntnap2 null mice showed reduced vocalizations. In addition, Cntnap2 null mice performed slightly better in a cognitive procedural learning test. Although finding and replicating robust behavioral phenotypes in animal models is a challenging task, such functional readouts remain important in the development of therapeutics and we

  1. DNA-histone interactions are sufficient to position a single nucleosome juxtaposing Drosophila Adh adult enhancer and distal promoter.

    PubMed Central

    Jackson, J R; Benyajati, C

    1993-01-01

    The alcohol dehydrogenase gene (Adh) of Drosophila melanogaster is transcribed from two tandem promoters in distinct developmental and tissue-specific patterns. Both promoters are regulated by separate upstream enhancer regions. In its wild-type context the adult enhancer specifically stimulates only the distal promoter, approximately 400 bp downstream, and not the proximal promoter, which is approximately 700 bp further downstream. Genomic footprinting and micrococcal nuclease analyses have revealed a specifically positioned nucleosome between the distal promoter and adult enhancer. In vitro reconstitution of this nucleosome demonstrated that DNA-core histone interactions alone are sufficient to position the nucleosome. Based on this observation and sequence periodicities in the underlying DNA, the mechanism of positioning appears to involve specific DNA structural features (ie flexibility or curvature). We have observed this nucleosome positioned early during development, before tissue differentiation, and before non-histone protein-DNA interactions are established at the distal promoter or adult enhancer. This nucleosome positioning element in the Adh regulatory region could be involved in establishing a specific tertiary nucleoprotein structure that facilitates specific cis-element accessibility and/or distal promoter-adult enhancer interactions. Images PMID:8451195

  2. Expression in fibroblasts and in live animals of Entamoeba histolytica polypeptides EhCP112 and EhADH112.

    PubMed

    Madriz, Xochil; Martínez, Máximo B; Rodríguez, Mario A; Sierra, Gustavo; Martínez-López, Carolina; Riverón, Ana M; Flores, Leopoldo; Orozco, Esther

    2004-05-01

    EhCPADH is an immunogenic, heterodimeric protein that is formed by EhCP112 (cysteine protease) and EhADH112 (adhesin), polypeptides involved in Entamoeba histolytica's cytopathic effect, target-cell adherence and phagocytosis. The EhCPADH complex is located in the plasma membrane and cytoplasmic vacuoles. Here, the independent expression of EhCP112 and EhADH112 in fibroblasts and hamsters was analysed. Also investigated was the immunological response in animals independently inoculated with plasmid pcDNA-Ehcp112, which carries the complete cysteine protease-encoding gene, or with plasmid pcDNA-Ehadh112, which carries the C terminus of the adhesin-encoding gene, or with a mixture of both. Both proteins were expressed in the plasma membranes of the transfected fibroblasts. EhCP112 was toxic for the mammalian cells. Proteins were also independently expressed in hamsters after inoculation with the plasmids. Their expression was indirectly evaluated by the presence of antibodies in the inoculated animals. Remarkably, co-immunization of the animals with the two DNA plasmids resulted in an earlier and higher anti-E. histolytica IgG induction than immunization with separate plasmids. In contrast, the cellular immune response was not noticeably improved by the plasmid mixture. Interestingly, protection against liver abscesses was detected only in animals that received the plasmid mixture and no protection was observed in hamsters independently inoculated with plasmid pcDNA-Ehcp112 or pcDNA-Ehadh112. PMID:15133088

  3. Loss of locus coeruleus neurons and reduced startle in parkin null mice

    PubMed Central

    von Coelln, Rainer; Thomas, Bobby; Savitt, Joseph M.; Lim, Kah Leong; Sasaki, Masayuki; Hess, Ellen J.; Dawson, Valina L.; Dawson, Ted M.

    2004-01-01

    Parkinson's disease (PD) is the most common neurodegenerative movement disorder and is characterized pathologically by degeneration of catecholaminergic neurons of the substantia nigra pars compacta and locus coeruleus, among other regions. Autosomal-recessive juvenile Parkinsonism (ARJP) is caused by mutations in the PARK2 gene coding for parkin and constitutes the most common familial form of PD. The majority of ARJP-associated parkin mutations are thought to be loss of function-mutations; however, the pathogenesis of ARJP remains poorly understood. Here, we report the generation of parkin null mice by targeted deletion of parkin exon 7. These mice show a loss of catecholaminergic neurons in the locus coeruleus and an accompanying loss of norepinephrine in discrete regions of the central nervous system. Moreover, there is a dramatic reduction of the norepinephrine-dependent startle response. The nigrostriatal dopaminergic system does not show any impairment. This mouse model will help gain a better understanding of parkin function and the mechanisms underlying parkin-associated PD. PMID:15249681

  4. Disturbance of cardiac gene expression and cardiomyocyte structure predisposes Mecp2-null mice to arrhythmias

    PubMed Central

    Hara, Munetsugu; Takahashi, Tomoyuki; Mitsumasu, Chiaki; Igata, Sachiyo; Takano, Makoto; Minami, Tomoko; Yasukawa, Hideo; Okayama, Satoko; Nakamura, Keiichiro; Okabe, Yasunori; Tanaka, Eiichiro; Takemura, Genzou; Kosai, Ken-ichiro; Yamashita, Yushiro; Matsuishi, Toyojiro

    2015-01-01

    Methyl-CpG-binding protein 2 (MeCP2) is an epigenetic regulator of gene expression that is essential for normal brain development. Mutations in MeCP2 lead to disrupted neuronal function and can cause Rett syndrome (RTT), a neurodevelopmental disorder. Previous studies reported cardiac dysfunction, including arrhythmias in both RTT patients and animal models of RTT. In addition, recent studies indicate that MeCP2 may be involved in cardiac development and dysfunction, but its role in the developing and adult heart remains unknown. In this study, we found that Mecp2-null ESCs could differentiate into cardiomyocytes, but the development and further differentiation of cardiovascular progenitors were significantly affected in MeCP2 deficiency. In addition, we revealed that loss of MeCP2 led to dysregulation of endogenous cardiac genes and myocardial structural alterations, although Mecp2-null mice did not exhibit obvious cardiac functional abnormalities. Furthermore, we detected methylation of the CpG islands in the Tbx5 locus, and showed that MeCP2 could target these sequences. Taken together, these results suggest that MeCP2 is an important regulator of the gene-expression program responsible for maintaining normal cardiac development and cardiomyocyte structure. PMID:26073556

  5. Mechanisms of Functional Hypoconnectivity in the Medial Prefrontal Cortex of Mecp2 Null Mice.

    PubMed

    Sceniak, Michael P; Lang, Min; Enomoto, Addison C; James Howell, C; Hermes, Douglas J; Katz, David M

    2016-05-01

    Frontal cortical dysfunction is thought to contribute to cognitive and behavioral features of autism spectrum disorders; however, underlying mechanisms are poorly understood. The present study sought to define how loss ofMecp2, the gene mutated in Rett syndrome (RTT), disrupts function in the murine medial prefrontal cortex (mPFC) using acute brain slices and behavioral testing. Compared with wildtype, pyramidal neurons in theMecp2null mPFC exhibit significant reductions in excitatory postsynaptic currents, the duration of excitatory UP-states, evoked population activity, and the ratio of NMDA:AMPA currents, as well as an increase in the relative fraction of NR2B currents. These functional changes are associated with reductions in the density of excitatory dendritic spines, the ratio of vesicular glutamate to GABA transporters and GluN1 expression. In contrast to recent reports on circuit defects in other brain regions, we observed no effect ofMecp2loss on inhibitory synaptic currents or expression of the inhibitory marker parvalbumin. Consistent with mPFC hypofunction,Mecp2nulls exhibit respiratory dysregulation in response to behavioral arousal. Our data highlight functional hypoconnectivity in the mPFC as a potential substrate for behavioral disruption in RTT and other disorders associated with reduced expression ofMecp2in frontal cortical regions. PMID:25662825

  6. Disturbance of cardiac gene expression and cardiomyocyte structure predisposes Mecp2-null mice to arrhythmias.

    PubMed

    Hara, Munetsugu; Takahashi, Tomoyuki; Mitsumasu, Chiaki; Igata, Sachiyo; Takano, Makoto; Minami, Tomoko; Yasukawa, Hideo; Okayama, Satoko; Nakamura, Keiichiro; Okabe, Yasunori; Tanaka, Eiichiro; Takemura, Genzou; Kosai, Ken-ichiro; Yamashita, Yushiro; Matsuishi, Toyojiro

    2015-01-01

    Methyl-CpG-binding protein 2 (MeCP2) is an epigenetic regulator of gene expression that is essential for normal brain development. Mutations in MeCP2 lead to disrupted neuronal function and can cause Rett syndrome (RTT), a neurodevelopmental disorder. Previous studies reported cardiac dysfunction, including arrhythmias in both RTT patients and animal models of RTT. In addition, recent studies indicate that MeCP2 may be involved in cardiac development and dysfunction, but its role in the developing and adult heart remains unknown. In this study, we found that Mecp2-null ESCs could differentiate into cardiomyocytes, but the development and further differentiation of cardiovascular progenitors were significantly affected in MeCP2 deficiency. In addition, we revealed that loss of MeCP2 led to dysregulation of endogenous cardiac genes and myocardial structural alterations, although Mecp2-null mice did not exhibit obvious cardiac functional abnormalities. Furthermore, we detected methylation of the CpG islands in the Tbx5 locus, and showed that MeCP2 could target these sequences. Taken together, these results suggest that MeCP2 is an important regulator of the gene-expression program responsible for maintaining normal cardiac development and cardiomyocyte structure. PMID:26073556

  7. Interferometric nulling of four channels with integrated optics.

    PubMed

    Errmann, Ronny; Minardi, Stefano; Labadie, Lucas; Muthusubramanian, Balaji; Dreisow, Felix; Nolte, Stefan; Pertsch, Thomas

    2015-08-20

    Nulling interferometry has been identified as a competitive technique for the detection of extrasolar planets. In its basic form, the technique consists of combining out-of-phase a single pair of telescopes to effectively null the light of a bright star and reveal the dim glow of the companion. However, in order to mitigate the effect of the stellar leaks through the interferometer, a broad angular central null is required. The hierarchical combination of several pairs of telescopes can accomplish this task. We have manufactured and tested with monochromatic light an integrated optics component, which combines a linear array of four telescopes in the nulling mode envisaged by Angel and Woolf [Astroph. J.475, 373-379 (1997).10.1086/apj.1997.475.issue-1ASJOAB0004-637X]. By simulating in the laboratory the motion of a star in the sky, we could measure the expected angular transmission of the four-telescope nuller. Moreover, the tests have demonstrated a broad nulling scaling as the fourth power of the baseline delay. PMID:26368784

  8. Achromatic phase shifts utilizing dielectric plates for nulling interferometery

    NASA Astrophysics Data System (ADS)

    Morgan, R. M.; Burge, J. M.

    1998-12-01

    Schemes for detecting planets around other stars using interferometery have been developed which rely on a half wave phase delay to shift the central constructive fringe of an interferometer to a deep, destructive null fringe. To achieve the sensitivity and spectroscopy desired for exo-planets observations, such a null must be achromatic over a broad spectral region. One method for creating such a half wave phase delay achromatically involves the use of pairs of dielectric, plane parallel plates, analogous to the use of two types of glass in an achromatic lens. An analysis of the technique is presented with solutions using single plates to achieve null fringes to a cancellation of 10 exp -4 in the visible, near infrared, and mid infrared for null. Solutions using two matched materials show that nulls to a depth of 10 exp -6 are achievable in 2 um bands in the 7-17 um regime, or to a depth of 10 exp -5 over the entire 7-17 um band. Experimental results using a single plate of BK7 in the visible spectrum verify the technique.

  9. Do Null Subjects (mis-)Trigger Pro-drop Grammars?

    PubMed

    Frazier, Lyn

    2015-12-01

    Native speakers of English regularly hear sentences without overt subjects. Nevertheless, they maintain a [−pro] grammar that requires sentences to have an overt subject. It is proposed that listeners of English recognize that speakers reduce predictable material and thus attribute null subjects to this process, rather than changing their grammars to a [−pro] setting. Mack et al. (J Memory Lang 67(1):211-223, 2012) showed that sentences with noise covering the subject are analyzed as having null subjects more often with a first person pronoun and with a present tense--properties correlated with more predictable referents--compared to a third person pronoun and past tense. However, those results might in principle have been due to reporting null subjects for verbs that often occur with null subjects. An experiment is reported here in which comparable results are found for sentences containing nonsense verbs. Participants preferred a null subject more often for first person present tense sentences than for third person past tense sentences. The results are as expected if participants are responding to predictability, the likelihood of reduction, rather than to lexical statistics. The results are argued to be important in removing a class of mis-triggering examples from the language acquisition problem. PMID:25086703

  10. Ballooning modes localized near the null point of a divertor

    SciTech Connect

    Farmer, W. A.

    2014-04-15

    The stability of ballooning modes localized to the null point in both the standard and snowflake divertors is considered. Ideal magnetohydrodynamics is used. A series expansion of the flux function is performed in the vicinity of the null point with the lowest, non-vanishing term retained for each divertor configuration. The energy principle is used with a trial function to determine a sufficient instability threshold. It is shown that this threshold depends on the orientation of the flux surfaces with respect to the major radius with a critical angle appearing due to the convergence of the field lines away from the null point. When the angle the major radius forms with respect to the flux surfaces exceeds this critical angle, the system is stabilized. Further, the scaling of the instability threshold with the aspect ratio and the ratio of the scrape-off-layer width to the major radius is shown. It is concluded that ballooning modes are not a likely candidate for driving convection in the vicinity of the null for parameters relevant to existing machines. However, the results place a lower bound on the width of the heat flux in the private flux region. To explain convective mixing in the vicinity of the null point, new consideration should be given to an axisymmetric mixing mode [W. A. Farmer and D. D. Ryutov, Phys. Plasmas 20, 092117 (2013)] as a possible candidate to explain current experimental results.

  11. Visible Nulling Coronagraphy Testbed Development for Exoplanet Detection

    NASA Technical Reports Server (NTRS)

    Lyon, Richard G.; Clampin, Mark; Woodruff, Robert A.; Vasudevan, Gopal; Thompson, Patrick; Chen, Andrew; Petrone, Peter; Booth, Andrew; Madison, Timothy; Bolcar, Matthew; Noecker, M. Charley; Kendrick, Stephen; Melnick, Gary; Tolls, Volker

    2010-01-01

    Three of the recently completed NASA Astrophysics Strategic Mission Concept (ASMC) studies addressed the feasibility of using a Visible Nulling Coronagraph (VNC) as the prime instrument for exoplanet science. The VNC approach is one of the few approaches that works with filled, segmented and sparse or diluted aperture telescope systems and thus spans the space of potential ASMC exoplanet missions. NASA/Goddard Space Flight Center (GSFC) has a well-established effort to develop VNC technologies and has developed an incremental sequence of VNC testbeds to advance the this approach and the technologies associated with it. Herein we report on the continued development of the vacuum Visible Nulling Coronagraph testbed (VNT). The VNT is an ultra-stable vibration isolated testbed that operates under high bandwidth closed-loop control within a vacuum chamber. It will be used to achieve an incremental sequence of three visible light nulling milestones of sequentially higher contrasts of 10(exp 8) , 10(exp 9) and 10(exp 10) at an inner working angle of 2*lambda/D and ultimately culminate in spectrally broadband (>20%) high contrast imaging. Each of the milestones, one per year, is traceable to one or more of the ASMC studies. The VNT uses a modified Mach-Zehnder nulling interferometer, modified with a modified "W" configuration to accommodate a hex-packed MEMS based deformable mirror, a coherent fiber bundle and achromatic phase shifters. Discussed will be the optical configuration laboratory results, critical technologies and the null sensing and control approach.

  12. Behavioral disturbances in estrogen-related receptor alpha-null mice.

    PubMed

    Cui, Huxing; Lu, Yuan; Khan, Michael Z; Anderson, Rachel M; McDaniel, Latisha; Wilson, Hannah E; Yin, Terry C; Radley, Jason J; Pieper, Andrew A; Lutter, Michael

    2015-04-21

    Eating disorders, such as anorexia nervosa and bulimia nervosa, are common and severe mental illnesses of unknown etiology. Recently, we identified a rare missense mutation in the transcription factor estrogen-related receptor alpha (ESRRA) that is associated with the development of eating disorders. However, little is known about ESRRA function in the brain. Here, we report that Esrra is expressed in the mouse brain and demonstrate that Esrra levels are regulated by energy reserves. Esrra-null female mice display a reduced operant response to a high-fat diet, compulsivity/behavioral rigidity, and social deficits. Selective Esrra knockdown in the prefrontal and orbitofrontal cortices of adult female mice recapitulates reduced operant response and increased compulsivity, respectively. These results indicate that Esrra deficiency in the mouse brain impairs behavioral responses in multiple functional domains. PMID:25865889

  13. Behavioral Disturbances in Estrogen-Related Receptor alpha-Null Mice

    PubMed Central

    Cui, Huxing; Lu, Yuan; Khan, Michael Z.; Anderson, Rachel M.; McDaniel, Latisha; Wilson, Hannah E.; Yin, Terry C.; Radley, Jason J.; Pieper, Andrew A.; Lutter, Michael

    2015-01-01

    SUMMARY Eating disorders, such as anorexia nervosa and bulimia nervosa, are common and severe mental illnesses of unknown etiology. Recently, we identified a rare missense mutation in the transcription factor estrogen-related receptor alpha (ESRRA) that is associated with the development of eating disorders. However, little is known about ESRRA function in the brain. Here, we report that Esrra is expressed in the mouse brain and demonstrate that Esrra levels are regulated by energy reserves. Esrra-null female mice display a reduced operant response to a high-fat diet, compulsivity/behavioral rigidity, and social deficits. Selective Esrra knockdown in the prefrontal and orbitofrontal cortices of adult female mice recapitulates reduced operant response and increased compulsivity, respectively. These results indicate that Esrra deficiency in the mouse brain impairs behavioral responses in multiple functional domains. PMID:25865889

  14. Mice with an NaV1.4 sodium channel null allele have latent myasthenia, without susceptibility to periodic paralysis.

    PubMed

    Wu, Fenfen; Mi, Wentao; Fu, Yu; Struyk, Arie; Cannon, Stephen C

    2016-06-01

    Over 60 mutations of SCN4A encoding the NaV1.4 sodium channel of skeletal muscle have been identified in patients with myotonia, periodic paralysis, myasthenia, or congenital myopathy. Most mutations are missense with gain-of-function defects that cause susceptibility to myotonia or periodic paralysis. Loss-of-function from enhanced inactivation or null alleles is rare and has been associated with myasthenia and congenital myopathy, while a mix of loss and gain of function changes has an uncertain relation to hypokalaemic periodic paralysis. To better define the functional consequences for a loss-of-function, we generated NaV1.4 null mice by deletion of exon 12. Heterozygous null mice have latent myasthenia and a right shift of the force-stimulus relation, without evidence of periodic paralysis. Sodium current density was half that of wild-type muscle and no compensation by retained expression of the foetal NaV1.5 isoform was detected. Mice null for NaV1.4 did not survive beyond the second postnatal day. This mouse model shows remarkable preservation of muscle function and viability for haploinsufficiency of NaV1.4, as has been reported in humans, with a propensity for pseudo-myasthenia caused by a marginal Na(+) current density to support sustained high-frequency action potentials in muscle. PMID:27048647

  15. Clinical Manifestations of Highly Prevalent Corticosteroid-Binding Globulin Mutations in a Village in Southern Italy

    PubMed Central

    Bernardi, Livia; Smirne, Nicoletta; Maletta, Raffaele; Tomaino, Carmine; Costanzo, Angela; Gallo, Maura; Lewis, John G.; Geracitano, Silvana; Grasso, Maria Beatrice; Potenza, Giuseppe; Monteleone, Cosimo; Brancati, Giacomino; Ho, Jui T.; Torpy, David J.; Bruni, Amalia C.

    2011-01-01

    Context: Corticosteroid-binding globulin (CBG) is the binding protein for cortisol. Rare kindreds with CBG mutations reducing CBG levels or altering binding affinity have been described, along with clinical manifestations encompassing fatigue, chronic pain, and hypotension. The largest kindred, exhibiting two mutations (null and Lyon) were Australian immigrants from Italy. Objective: Our objective was to determine the prevalence of the null/Lyon mutations in the village where the original null/Lyon family emigrated and compare subjects with and without CBG mutations, without previous knowledge of their mutation status. Design, Setting, and Participants: We conducted a survey field study that included 495 adult residents. Main Outcomes: We assessed clinical history, CBG mutation analysis, plasma CBG, salivary cortisol, body mass index, waist circumference, blood pressure, and the Krupp fatigue scale. Results: Eighteen of 495 participants (3.6%, seven males and 11 females) had one of two function-altering CBG mutations. All were heterozygous for the null (n = 6) or Lyon mutations (n = 12). Of 12 Lyon participants (four males and eight females), eight (two males and six females) had chronic widespread pain and five osteoarthritis with associated pain (one male and four females). Of six null participants (three males and three females), three (one male and two females) had chronic pain and four osteoarthritis with associated pain (two males and two females). Conclusions: A high combined prevalence (3.6%) of these two CBG mutations was detected. The presence of either mutation conferred a propensity to chronic pain. In other communities, individuals with the same genetic background complain more of fatigue than pain, suggesting an environmental effect on the phenotype. These findings, combined with animal CBG gene knockout and human CBG single-nucleotide polymorphism haplotype studies, suggest that CBG influences the endocrine and neurobehavioral response to stress

  16. Double null hamiltonian dynamics and the gravitational degrees of freedom

    NASA Astrophysics Data System (ADS)

    Vickers, J. A.

    2011-12-01

    In this paper we review the Hamiltonian description of General Relativity using a double null foliation. We start by looking at the 2+2 version of geometrodynamics and show the role of the conformal 2-structure of the 2-metric in encoding (through the shear) the 2 gravitational degrees of freedom. In the second part of the paper we consider instead a canonical analysis of a double null 2+2 Hamiltonian description of General Relativity in terms of self-dual 2-forms and the associated SO(3) connection variables. The algebra of first class constraints is obtained and forms a Lie algebra that consists of two constraints that generate diffeomorphisms in the two surface, a constraint that generates diffeomorphisms along the null generators and a constraint that generates self-dual spin and boost transformations.

  17. sirt1-null mice develop an autoimmune-like condition

    SciTech Connect

    Sequeira, Jedon; Boily, Gino; Bazinet, Stephanie; Saliba, Sarah; He Xiaohong; Jardine, Karen; Kennedy, Christopher; Staines, William; Rousseaux, Colin; Mueller, Rudi; McBurney, Michael W.

    2008-10-01

    The sirt1 gene encodes a protein deacetylase with a broad spectrum of reported substrates. Mice carrying null alleles for sirt1 are viable on outbred genetic backgrounds so we have examined them in detail to identify the biological processes that are dependent on SIRT1. Sera from adult sirt1-null mice contain antibodies that react with nuclear antigens and immune complexes become deposited in the livers and kidneys of these animals. Some of the sirt1-null animals develop a disease resembling diabetes insipidus when they approach 2 years of age although the relationship to the autoimmunity remains unclear. We interpret these observations as consistent with a role for SIRT1 in sustaining normal immune function and in this way delaying the onset of autoimmune disease.

  18. On the geometry of null hypersurfaces in Minkowski space

    NASA Astrophysics Data System (ADS)

    Navarro, Matias; Palmas, Oscar; Solis, Didier A.

    2014-01-01

    The present work is divided into three parts. First we study the null hypersurfaces of the Minkowski space R1n+2, classifying all rotation null hypersurfaces in R1n+2. In the second part we start our analysis of the submanifold geometry of the null hypersurfaces. In the particular case of the (n+1)-dimensional light cone, we characterize its totally umbilical spacelike hypersurfaces, show the existence of non-totally umbilical ones and give a uniqueness result for the minimal spacelike rotation surfaces in the 3-dimensional light cone. In the third and final part we consider an isolated umbilical point on a spacelike surface immersed in the 3-dimensional light cone of R14 and obtain the differential equation of the principal configuration associated to this point, showing that every classical generic Darbouxian principal configuration appears in this context.

  19. Null but not void: considerations for hypothesis testing.

    PubMed

    Shaw, Pamela A; Proschan, Michael A

    2013-01-30

    Standard statistical theory teaches us that once the null and alternative hypotheses have been defined for a parameter, the choice of the statistical test is clear. Standard theory does not teach us how to choose the null or alternative hypothesis appropriate to the scientific question of interest. Neither does it tell us that in some cases, depending on which alternatives are realistic, we may want to define our null hypothesis differently. Problems in statistical practice are frequently not as pristinely summarized as the classic theory in our textbooks. In this article, we present examples in statistical hypothesis testing in which seemingly simple choices are in fact rich with nuance that, when given full consideration, make the choice of the right hypothesis test much less straightforward. Published 2012. This article is a US Government work and is in the public domain in the USA. PMID:22807023

  20. Unicorns do exist: a tutorial on "proving" the null hypothesis.

    PubMed

    Streiner, David L

    2003-12-01

    Introductory statistics classes teach us that we can never prove the null hypothesis; all we can do is reject or fail to reject it. However, there are times when it is necessary to try to prove the nonexistence of a difference between groups. This most often happens within the context of comparing a new treatment against an established one and showing that the new intervention is not inferior to the standard. This article first outlines the logic of "noninferiority" testing by differentiating between the null hypothesis (that which we are trying to nullify) and the "nill" hypothesis (there is no difference), reversing the role of the null and alternate hypotheses, and defining an interval within which groups are said to be equivalent. We then work through an example and show how to calculate sample sizes for noninferiority studies. PMID:14733457

  1. Fully achromatic nulling interferometer (FANI) for high SNR exoplanet characterization

    NASA Astrophysics Data System (ADS)

    Hénault, François

    2015-09-01

    Space-borne nulling interferometers have long been considered as the best option for searching and characterizing extrasolar planets located in the habitable zone of their parent stars. Solutions for achieving deep starlight extinction are now numerous and well demonstrated. However they essentially aim at realizing an achromatic central null in order to extinguish the star. In this communication is described a major improvement of the technique, where the achromatization process is extended to the entire fringe pattern. Therefore higher Signal-to-noise ratios (SNR) and appreciable simplification of the detection system should result. The basic principle of this Fully achromatic nulling interferometer (FANI) consists in inserting dispersive elements along the arms of the interferometer. Herein this principle is explained and illustrated by a preliminary optical system design. The typical achievable performance and limitations are discussed and some initial tolerance requirements are also provided.

  2. Statefinder hierarchy: An extended null diagnostic for concordance cosmology

    SciTech Connect

    Arabsalmani, Maryam; Sahni, Varun

    2011-02-15

    We show how higher derivatives of the expansion factor can be developed into a null diagnostic for concordance cosmology ({Lambda}CDM). It is well known that the Statefinder - the third derivative of the expansion factor written in dimensionless form, a{sup (3)}/aH{sup 3}, equals unity for {Lambda}CDM. We generalize this result and demonstrate that the hierarchy, a{sup (n)}/aH{sup n}, can be converted to a form that stays pegged at unity in concordance cosmology. This remarkable property of the Statefinder hierarchy enables it to be used as an extended null diagnostic for the cosmological constant. The Statefinder hierarchy combined with the growth rate of matter perturbations defines a composite null diagnostic which can distinguish evolving dark energy from {Lambda}CDM.

  3. KRAS Mutation

    PubMed Central

    Franklin, Wilbur A.; Haney, Jerry; Sugita, Michio; Bemis, Lynne; Jimeno, Antonio; Messersmith, Wells A.

    2010-01-01

    Treatment of colon carcinoma with the anti-epidermal growth factor receptor antibody Cetuximab is reported to be ineffective in KRAS-mutant tumors. Mutation testing techniques have therefore become an urgent concern. We have compared three methods for detecting KRAS mutations in 59 cases of colon carcinoma: 1) high resolution melting, 2) the amplification refractory mutation system using a bifunctional self-probing primer (ARMS/Scorpion, ARMS/S), and 3) direct sequencing. We also evaluated the effects of the methods of sectioning and coring of paraffin blocks to obtain tumor DNA on assay sensitivity and specificity. The most sensitive and specific combination of block sampling and mutational analysis was ARMS/S performed on DNA derived from 1-mm paraffin cores. This combination of tissue sampling and testing method detected KRAS mutations in 46% of colon tumors. Four samples were positive by ARMS/S, but initially negative by direct sequencing. Cloned DNA samples were retested by direct sequencing, and in all four cases KRAS mutations were identified in the DNA. In six cases, high resolution melting abnormalities could not be confirmed as specific mutations either by ARMS/S or direct sequencing. We conclude that coring of the paraffin blocks and testing by ARMS/S is a sensitive, specific, and efficient method for KRAS testing. PMID:20007845

  4. Magnetoacoustic Waves in Stratified Atmospheres with a Magnetic Null Point

    NASA Astrophysics Data System (ADS)

    Tarr, Lucas A.; Linton, Mark; Leake, James E.

    2016-05-01

    Magnetic fields strongly modify the propagation of MHD waves from the photosphere to the low corona, as can be shown exactly for the most simple case of a uniform magnetic field and isothermally stratrified atmosphere. For slightly more realistic scenarios, where both the atmospheric parameters and the magnetic field vary spatially, the linear MHD equations typically cannot be solved analytically. We use the Lagrangian Remap code--a nonlinear, shock-capturing MHD code--to study the propagation of initially acoustic wavepackets through a model 2D atmosphere that includes a gravitationally stratified chromosphere, transition region, and low corona. The magnetic field is formed by three photospheric concentrations and includes a single magnetic null point, resulting in an inhomogeneous system with a magnetic dome topology. A portion of an introduced wavepacket will refract toward the null due to the varying Alfven speed. Waves incident on the equipartition contour surrounding the null, where the sound and Alfven speeds coincide, partially transmit, reflect, and mode convert between branches of the local dispersion relation. Outward propagating slow modes generated during conversion become strongly concentrated along the set of field lines passing near the null. Acoustic energy is beamed back downwards towards each photospheric foot point, and upwards along one separatrix that exits the top of the numerical domain. Changes in the dominant restoring force for the wavepacket, between the Lorentz and pressure gradient forces, lead to a buildup of current density along topologically important features of the system (the null point and its four separatrices) and can drive reconnection at the null point itself. Ohmic dissipation of the currents locally heats the plasma. We find that the amount of current accumulation depends on where the centroid of a wavepacket initial crosses the photosphere, but does not simply coincide with regions of open versus closed magnetic field or

  5. Retention of crab larvae in a coastal null zone

    NASA Astrophysics Data System (ADS)

    Tilburg, Charles E.; Dittel, Ana I.; Epifanio, Charles E.

    2007-05-01

    Alongshelf transport in the southern Middle Atlantic Bight is forced by buoyancy-driven currents originating in three large estuaries along the bight. These currents are strongest in the coastal ocean near the southern terminus of each estuary, while the analogous region on the northern side is characterized by weak subtidal flow. We used a combination of field observations and numerical modeling to test the hypothesis that these regions of weak subtidal flow are coastal null zones that serve as retention areas for larvae. The field study consisted of a four-day, shipboard investigation of the distribution of blue crab larvae ( Callinectes sapidus) near the mouth of Delaware Bay (˜39°N, 75°W) in late summer, 2004. Hydrographic surveys of the study site were conducted with a hull-mounted, surface-measuring system. Results showed a sharp boundary between the null zone and the buoyancy-driven current to the south. Blue crab larvae were collected in surface plankton tows along a 30-km transect that encompassed these two areas. Stations with higher densities of larvae were clustered in the null zone during both ebb and flood tides. A numerical model was used to examine the physical mechanisms responsible for the observed distribution. Model results agreed with the field survey and showed that simulated larvae are aggregated in the null zone. The simulations also demonstrated that larvae spawned within the null zone have a much greater probability of settling in juvenile nursery habitat within the bay. The close agreement between field and model results provides consistent support for the hypothesis that coastal null zones associated with the buoyancy-driven circulation of large estuaries may allow retention of larvae in the vicinity of the natal spawning population.

  6. Preliminary mineralogic, fluid inclusion, and stable isotope study of the Mahd adh Dhahab gold mine, Kingdom of Saudi Arabia

    USGS Publications Warehouse

    Rye, Robert O.; Hall, W.E.; Cunningham, C.G.; Czamanske, G.K.; Afifi, A.M.; Stacey, J.S.

    1983-01-01

    The Mahd adh Dhahab mine, located about 280 km northeast of Jiddah, Kingdom of Saudi Arabia, has yielded more than 2 million ounces of gold from periodic production during the past 3,000 years. A new orebody on the southern side of the ancient workings, known as the South orebody, is being developed by Gold Fields-Mahd adh Dhahab Limited. A suite of samples was collected from the newly exposed orebody for preliminary mineralogic, stable isotope, fluid inclusion, and geochemical studies. The Mahd adh Dhahab deposit is in the carapace of a Proterozoic epizonal rhyolite stock that domed pyroclastic and metasedimentary rocks of the Proterozoic Halaban group. Ore of gold, silver, copper, zinc, tellurium, and lead is associated with north-trending, steeply dipping quartz veins in a zone 1,000 m long and 400 m wide. The veins include an assemblage of quartz-chlorite-pyrite-hematite-chalcopyrite-sphalerite-precious metals, which is similar to the mineral assemblage at the epithermal deposit at Creede, Colorado. The primary ore contains abundant chalcopyrite, sphalerite, and pyrite in addition to a complex precious metal assemblage. Gold and silver occur principally as minute grains of telluride minerals disseminated in quartz-chlorite-hematite and as inclusions in chalcopyrite and sphalerite. Telluride minerals include petzite, hessite, and sylvanite. Free gold is present but not abundant. All of the vein-quartz samples contained abundant, minute inclusions of both low-density, vapor-rich fluids and liquid-rich fluids. Primary fluid inclusions yielded homogenization temperatures of from 110? to 238? C. Preliminary light-stable isotope studies of the sulfide minerals and quartz showed that all of the d34S values are between 1.2 and 6.3 per mil, which is a typical range for hydrothermal sulfide minerals that derive their sulfur from an igneous source. The data-suggest that the sulfide sulfur isotope geochemistry was controlled by exchange with la large sulfur isotope

  7. Adaptive Nulling for the Terrestrial Planet Finder Interferometer

    NASA Technical Reports Server (NTRS)

    Jeganathan, Muthu; Hirai, Akiko; Lay, Oliver P.; Peters, Robert D.

    2006-01-01

    Deep, stable starlight nulls are needed for the direct detection of Earth-like planets and require careful control of the intensity and phases of the beams that are being combined. We are testing a novel compensator based on a deformable mirror to correct the intensity and phase at each wavelength and polarization across the nulling bandwidth. We have successfully demonstrated intensity and phase control using a deformable mirror across a 100nm wide band in the near-IR, and are in the process of conducting experiments in the mid-IR wavelengths. This paper covers the current results and in the mid-IR.

  8. Null geodesics in a magnetically charged stringy black hole spacetime

    NASA Astrophysics Data System (ADS)

    Kuniyal, Ravi Shankar; Uniyal, Rashmi; Nandan, Hemwati; Purohit, K. D.

    2016-04-01

    We study the null geodesics of a four-dimensional magnetic charged black hole spacetime arising in string theory. The behaviour of effective potential in view of the different values of black hole parameters are analysed in the equatorial plane. The possible orbits for null geodesics are also discussed in view of the different values of the impact parameter. We have also calculated the frequency shift of photons in this spacetime. The results are compared to those obtained for the electrically charged stringy black hole spacetime and the Schwarzschild black hole spacetime in general relativity.

  9. Subjective Response to Alcohol and ADH Polymorphisms in a Select Sample of Young Adult Male East Indians and Africans in Trinidad and Tobago

    PubMed Central

    Montane Jaime, Lazara Karelia; Shafe, Samuel; Liang, Tiebing; Wills, Derek N; Berg, Greta I; Ehlers, Cindy L

    2014-01-01

    Objective: Level of response to alcohol has been associated with risk of alcohol dependence in a number of ethnic groups. In the present study, subjective and objective responses to alcohol were evaluated in Indo-Trinidadians (Indo-T) and Afro-Trinidadians (Afro-T). Associations of alcohol dehydrogenase polymorphisms with response to alcohol, using the Subjective High Assessment Scale (SHAS), and breath alcohol concentrations (BrAC) were tested. Method: Regular male drinkers without alcohol dependence (n = 112) ages 18–25 years participated in alcohol challenge sessions consisting of placebo and two doses of alcohol (target BrAC: 0 g/dl for placebo, .04 g/dl low dose, and .08 g/dl high dose) and genotyped for variants in ADH1B*3 and ADH1C*2. Results: Indo-T had significantly higher BrAC, pulse rates, and cortisol levels when compared with Afro-T but did not have significantly higher SHAS values. Higher responses on the SHAS items muddle/confused and nauseated were significantly associated with the presence of at least one ADH1B*3 allele following the high dose of alcohol in Afro-T. Indo-T with at least one ADH1C*2 allele displayed significantly different Drug × Time interactions for the SHAS item effects of alcohol at the low dose and for the SHAS items clumsy, muddle/confused, effects of alcohol, floating, drunk, and total at the high dose from Indo-T with two ADH1C*1 alleles. Conclusions: This is the first study that has investigated individual sensitivity to alcohol in a Caribbean population and in people of East Indian descent. Indo-T with at least one ADH1C*2 allele may be at higher risk for heavy drinking by feeling less of the effects of alcohol, including nausea. In Afro-T, having at least one ADH1B*3 allele appears to exert a protective effect by enhancing the unpleasant effects of alcohol, such as nausea and confusion. PMID:25208201

  10. Suppressors of Recb Mutations in Salmonella Typhimurium

    PubMed Central

    Benson, N. R.; Roth, J.

    1994-01-01

    Using a screen that directly assesses transductional proficiency, we have isolated suppressors of recB mutations in Salmonella typhimurium. The alleles of sbcB reported here are phenotypically distinct from those isolated in Escherichia coli in that they restore recombination proficiency (Rec(+)), resistance to ultraviolet light (UV(R)), and mitomycin C resistance (MC(R)) in the absence of an accompanying sbcCD mutation. In addition the sbcB alleles reported here are co-dominant to sbcB(+). We have also isolated insertion and deletion mutants of the sbcB locus. These null mutations suppress only the UV(S) phenotype of recB mutants. We have also isolated sbcCD mutations, which map near proC. These sbcCD mutations increase the viability, recombination proficiency and MC(R) of both the transductional recombination suppressors (sbcB1 & sbcB6) and the sbcB null mutations. S. typhimurium recB sbcB1 sbcCD8 strains are 15-fold more recombination proficient than wild-type strains. The increase in transductants in these strains is accompanied by a loss of abortive transductants suggesting that these fragments are accessible to the mutant recombination apparatus. Using tandem duplications, we have constructed sbcB merodiploids and found that, in a recB mutant sbcCD(+) genetic background, the sbcB(+) allele is dominant to sbcB1 for transductional recombination but co-dominant for UV(R) and MC(R). However, in a recB sbcCD8 genetic background, the sbcB1 mutation is co-dominant to sbcB(+) for all phenotypes. Our results lead us to suggest that the SbcB and SbcCD proteins have roles in RecBCD-dependent recombination. PMID:8001778

  11. The Joint Effects of ADH1B Variants and Childhood Adversity on Alcohol-Related Phenotypes in African-American and European-American Women and Men

    PubMed Central

    Sartor, Carolyn E.; Wang, Zuoheng; Xu, Ke; Kranzler, Henry R.; Gelernter, Joel

    2015-01-01

    Background The ADH1B gene has consistently been implicated in problem drinking, but rarely incorporated into gene by environment investigations of alcohol phenotypes. This study examined the joint effects of variation in ADH1B and childhood adversity – a well-documented risk factor for alcohol problems and moderator of genetic liability to psychiatric outcomes – on maximum drinks consumed in a 24-hour period (maxdrinks) and alcohol use disorder (AUD) symptoms. Methods Data were drawn from 2,617 African-American (AA) and 1,436 European-American (EA) participants (42% female) in a multisite genetic study of substance dependence. We tested the most significant ADH1B SNPs for alcohol dependence from a genomewide association study with this sample, ADH1B-rs1229984 (Arg48His) and ADH1B-rs2066702 (Arg370Cys), in EA and AA subsamples, respectively. Results Ordinal regression analyses conducted separately by sex and population revealed significant main effects for childhood adversity both for alcohol phenotypes in AA women and men and for maxdrinks in EA women. A significant rs1229984 by childhood adversity interaction was observed for AUD symptoms in EA men. Unexposed His-allele carriers reported a mean of 3.6 AUD criteria, but adversity-exposed His-allele carriers endorsed approximately the same number (6.3) as those without the protective allele (6.3 and 7.0 for adversity-exposed and adversity-unexposed groups, respectively). Conclusions Results suggest that under conditions of childhood adversity, the His allele does not exert its protective effects in EA men (OR=0.57, CI:0.32–1.01; p=0.056). Findings highlight the robust risk effect conferred by childhood adversity and the importance of considering population and sex in genetically informative investigations of its association with alcohol outcomes. PMID:25410943

  12. A Phylogenetic Analysis of the Genus Fragaria (Strawberry) Using Intron-Containing Sequence from the ADH-1 Gene

    PubMed Central

    DiMeglio, Laura M.; Yu, Hongrun; Davis, Thomas M.

    2014-01-01

    The genus Fragaria encompasses species at ploidy levels ranging from diploid to decaploid. The cultivated strawberry, Fragaria×ananassa, and its two immediate progenitors, F. chiloensis and F. virginiana, are octoploids. To elucidate the ancestries of these octoploid species, we performed a phylogenetic analysis using intron-containing sequences of the nuclear ADH-1 gene from 39 germplasm accessions representing nineteen Fragaria species and one outgroup species, Dasiphora fruticosa. All trees from Maximum Parsimony and Maximum Likelihood analyses showed two major clades, Clade A and Clade B. Each of the sampled octoploids contributed alleles to both major clades. All octoploid-derived alleles in Clade A clustered with alleles of diploid F. vesca, with the exception of one octoploid allele that clustered with the alleles of diploid F. mandshurica. All octoploid-derived alleles in clade B clustered with the alleles of only one diploid species, F. iinumae. When gaps encoded as binary characters were included in the Maximum Parsimony analysis, tree resolution was improved with the addition of six nodes, and the bootstrap support was generally higher, rising above the 50% threshold for an additional nine branches. These results, coupled with the congruence of the sequence data and the coded gap data, validate and encourage the employment of sequence sets containing gaps for phylogenetic analysis. Our phylogenetic conclusions, based upon sequence data from the ADH-1 gene located on F. vesca linkage group II, complement and generally agree with those obtained from analyses of protein-encoding genes GBSSI-2 and DHAR located on F. vesca linkage groups V and VII, respectively, but differ from a previous study that utilized rDNA sequences and did not detect the ancestral role of F. iinumae. PMID:25078607

  13. Toll-Like Receptor 4 Mutant and Null Mice Retain Morphine-Induced Tolerance, Hyperalgesia, and Physical Dependence

    PubMed Central

    Mattioli, Theresa Alexandra; Leduc-Pessah, Heather; Skelhorne-Gross, Graham; Nicol, Christopher J. B.; Milne, Brian; Trang, Tuan; Cahill, Catherine M.

    2014-01-01

    The innate immune system modulates opioid-induced effects within the central nervous system and one target that has received considerable attention is the toll-like receptor 4 (TLR4). Here, we examined the contribution of TLR4 in the development of morphine tolerance, hyperalgesia, and physical dependence in two inbred mouse strains: C3H/HeJ mice which have a dominant negative point mutation in the Tlr4 gene rendering the receptor non-functional, and B10ScNJ mice which are TLR4 null mutants. We found that neither acute antinociceptive response to a single dose of morphine, nor the development of analgesic tolerance to repeated morphine treatment, was affected by TLR4 genotype. Likewise, opioid induced hyperalgesia and opioid physical dependence (assessed by naloxone precipitated withdrawal) were not altered in TLR4 mutant or null mice. We also examined the behavioural consequence of two stereoisomers of naloxone: (−) naloxone, an opioid receptor antagonist, and (+) naloxone, a purported antagonist of TLR4. Both stereoisomers of naloxone suppressed opioid induced hyperalgesia in wild-type control, TLR4 mutant, and TLR4 null mice. Collectively, our data suggest that TLR4 is not required for opioid-induced analgesic tolerance, hyperalgesia, or physical dependence. PMID:24824631

  14. Testing the null hypothesis: the forgotten legacy of Karl Popper?

    PubMed

    Wilkinson, Mick

    2013-01-01

    Testing of the null hypothesis is a fundamental aspect of the scientific method and has its basis in the falsification theory of Karl Popper. Null hypothesis testing makes use of deductive reasoning to ensure that the truth of conclusions is irrefutable. In contrast, attempting to demonstrate the new facts on the basis of testing the experimental or research hypothesis makes use of inductive reasoning and is prone to the problem of the Uniformity of Nature assumption described by David Hume in the eighteenth century. Despite this issue and the well documented solution provided by Popper's falsification theory, the majority of publications are still written such that they suggest the research hypothesis is being tested. This is contrary to accepted scientific convention and possibly highlights a poor understanding of the application of conventional significance-based data analysis approaches. Our work should remain driven by conjecture and attempted falsification such that it is always the null hypothesis that is tested. The write up of our studies should make it clear that we are indeed testing the null hypothesis and conforming to the established and accepted philosophical conventions of the scientific method. PMID:23249368

  15. Circumpulsar Asteroids: Inferences from Nulling Statistics and High Energy Correlations

    NASA Astrophysics Data System (ADS)

    Shannon, Ryan; Cordes, J. M.

    2006-12-01

    We have proposed that some classes of radio pulsar variability are associated with the entry of neutral asteroidal material into the pulsar magnetosphere. The region surrounding neutron stars is polluted with supernova fall-back material, which collapses and condenses into an asteroid-bearing disk that is stable for millions of years. Over time, collisional and radiative processes cause the asteroids to migrate inward until they are heated to the point of ionization. For older and cooler pulsars, asteroids ionize within the large magnetospheres and inject a sufficient amount of charged particles to alter the electrodynamics of the gap regions and modulate emission processes. This extrinsic model unifies many observed phenomena of variability that occur on time scales that are disparate with the much shorter time scales associated with pulsars and their magnetospheres. One such type of variability is nulling, in which certain pulsars exhibit episodes of quiescence that for some objects may be as short as a few pulse periods, but, for others, is longer than days. Here, in the context of this model, we examine the nulling phenomenon. We analyze the relationship between in-falling material and the statistics of nulling. In addition, as motivation for further high energy observations, we consider the relationship between the nulling and other magnetospheric processes.

  16. Modified sympathetic nerve regulation in AKAP5-null mice.

    PubMed

    Han, Chong; Tomita, Hirofumi; Ohba, Takayoshi; Nishizaki, Kimitaka; Ogata, Yoshiki; Matsuzaki, Yasushi; Sawamura, Daisuke; Yanagisawa, Teruyuki; Osanai, Tomohiro; Imaizumi, Tadaatsu; Matsubara, Atsushi; Adachi, Takeshi; Ono, Kyoichi; Okumura, Ken; Murakami, Manabu

    2016-01-22

    Genetic analyses have revealed an important association between A-kinase anchoring proteins (AKAPs) and the intracellular calcium modulating system. AKAP5, also known as AKAP79/150, is an anchoring protein between PKA and voltage-dependent calcium channels, ryanodine receptor-2, phospholamban and other molecules. The aim of the present study was to elucidate the physiological importance of AKAP5 in the creation of cardiac rhythm using AKAP5-null mice. ECG analysis showed a normal sinus rhythm and a decreased responsiveness to isoproterenol in AKAP5-null mice compared with wild-type mice. Analysis of heart rate variability revealed that the R-R interval was unstable in AKAP5-null mutants and that the low-frequency components had decreased, indicating that the tonus of the sympathetic nervous system was affected. Furthermore, the atrium of the AKAP5-null mice showed a decreased positive inotropic response to isoproterenol, indicating the involvement of AKAP5 in a PKA-dependent pathway. Thus, our present study revealed that AKAP5 plays a significant role in the regulation of sympathetic nerve activities. PMID:26713362

  17. Reassessing the Null-Subject Parameter in Second Language Acquisition.

    ERIC Educational Resources Information Center

    Lantolf, James P.

    A study is presented that examines the null-subject parameter (NSP) and that seeks to attain the following objectives: (1) to assess the validity of the implicational hierarchy for the NSP, especially as proposed by Liceras (1989); and (2) to determine if there is any evidence to support the theory of the Weaker Logical Problem of Acquisition…

  18. Self-Nulling Beam Combiner Using No External Phase Inverter

    NASA Technical Reports Server (NTRS)

    Bloemhof, Eric E.

    2010-01-01

    A self-nulling beam combiner is proposed that completely eliminates the phase inversion subsystem from the nulling interferometer, and instead uses the intrinsic phase shifts in the beam splitters. Simplifying the flight instrument in this way will be a valuable enhancement of mission reliability. The tighter tolerances on R = T (R being reflection and T being transmission coefficients) required by the self-nulling configuration actually impose no new constraints on the architecture, as two adaptive nullers must be situated between beam splitters to correct small errors in the coatings. The new feature is exploiting the natural phase shifts in beam combiners to achieve the 180 phase inversion necessary for nulling. The advantage over prior art is that an entire subsystem, the field-flipping optics, can be eliminated. For ultimate simplicity in the flight instrument, one might fabricate coatings to very high tolerances and dispense with the adaptive nullers altogether, with all their moving parts, along with the field flipper subsystem. A single adaptive nuller upstream of the beam combiner may be required to correct beam train errors (systematic noise), but in some circumstances phase chopping reduces these errors substantially, and there may be ways to further reduce the chop residuals. Though such coatings are beyond the current state of the art, the mechanical simplicity and robustness of a flight system without field flipper or adaptive nullers would perhaps justify considerable effort on coating fabrication.

  19. Traversable wormholes: Minimum violation of the null energy condition revisited

    SciTech Connect

    Zaslavskii, O. B.

    2007-08-15

    It was argued in literature that traversable wormholes can exist with an arbitrarily small violation of null energy conditions. I show that if the amount of exotic material near the wormhole throat tends to zero, either this leads to a horn instead of a wormhole or the throat approaches the horizon in such a way that infinitely large stresses develop on the throat.

  20. Proliferation, differentiation and apoptosis in connexin43-null osteoblasts

    NASA Technical Reports Server (NTRS)

    Furlan, F.; Lecanda, F.; Screen, J.; Civitelli, R.

    2001-01-01

    Osteoblasts are highly coupled by gap junctions formed primarily by connexin43 (Cx43). We have shown that interference with Cx43 expression or function disrupts transcriptional regulation of osteoblast genes, and that deletion of Cx43 in the mouse causes skeletal malformations, delayed mineralization, and osteoblast dysfunction. Here, we studied the mechanisms by which genetic deficiency of Cx43 alters osteoblast development. While cell proliferation rates were similar in osteoblastic cells derived from calvaria of Cx43-null and wild type mice, camptothecin-induced apoptosis was 3-fold higher in mutant compared to wild type osteoblasts. When grown in mineralizing medium, Cx43-null cells were able to produce mineralized matrix but it took one week longer to reach the same mineralization levels as in normal cells. Likewise, expression of alkaline phosphatase activity per cell--a marker of osteoblast differentiation--was maximal only 2 weeks later in Cx43-null relative to wild-type cells. These observations suggest that Cx43 is important for a normal and timely development of the osteoblastic phenotype. Delayed differentiation and increase programmed cell death may explain the skeletal phenotype of Cx43-null mice.

  1. Do Null Subjects (Mis-)Trigger Pro-Drop Grammars?

    ERIC Educational Resources Information Center

    Frazier, Lyn

    2015-01-01

    Native speakers of English regularly hear sentences without overt subjects. Nevertheless, they maintain a [[superscript -]pro] grammar that requires sentences to have an overt subject. It is proposed that listeners of English recognize that speakers reduce predictable material and thus attribute null subjects to this process, rather than changing…

  2. White-Light Nulling Interferometers for Detecting Planets

    NASA Technical Reports Server (NTRS)

    Mennesson, Bertrand; Serabyn, Eugene; Shao, Michael; Levine, Bruce

    2004-01-01

    A report proposes the development of a white-light nulling interferometer to be used in conjunction with a singleaperture astronomical telescope that would be operated in outer space. When such a telescope is aimed at a given star, the interferometer would suppress the light of that star while passing enough light from planets (if any) orbiting the star, to enable imaging or spectroscopic examination of the planets. In a nulling interferometer, according to the proposal, scattered light would be suppressed by spatial filtering in an array of single-mode optical fibers rather than by requiring optical surfaces to be accurate within 1/4,000 wavelength as in a coronagraph or an apodized telescope. As a result, angstrom-level precision would be needed in only the small nulling combiner, and not in large, meter-sized optics. The nulling interferometer could work as an independent instrument in space or in conjunction with a coronagraphic system to detect planets outside our solar system.

  3. Null Objects in Second Language Acquisition: Grammatical vs. Performance Models

    ERIC Educational Resources Information Center

    Zyzik, Eve C.

    2008-01-01

    Null direct objects provide a favourable testing ground for grammatical and performance models of argument omission. This article examines both types of models in order to determine which gives a more plausible account of the second language data. The data were collected from second language (L2) learners of Spanish by means of four oral…

  4. Null Lens Assembly for X-Ray Mirror Segments

    NASA Technical Reports Server (NTRS)

    Robinson, David W.

    2011-01-01

    A document discusses a null lens assembly that allows laser interferometry of 60 deg. slumped glass mirror segments used in x-ray mirrors. The assembly consists of four lenses in precise alignment to each other, with incorporated piezoelectric nanometer stepping actuators to position the lenses in six degrees of freedom for positioning relative to each other.

  5. Progress in broadband infrared nulling technology for TPF

    NASA Technical Reports Server (NTRS)

    Wallace, J. Kent; Brown, Ken; Bartos, Randall; Gappinger, Robert; Loya, Frank; Macdonald, Dan; Moser, Steve; Negron, John

    2005-01-01

    TPF-I has set for itself a host of challenging technical milestones along its path to demonstrating the feasibility of infrared nulling for planet detection Progress in each of these areas of technical development will be reviewed as well as progress in meeting the overarching technical milestones.

  6. Null point of discrimination in crustacean polarisation vision.

    PubMed

    How, Martin J; Christy, John; Roberts, Nicholas W; Marshall, N Justin

    2014-07-15

    The polarisation of light is used by many species of cephalopods and crustaceans to discriminate objects or to communicate. Most visual systems with this ability, such as that of the fiddler crab, include receptors with photopigments that are oriented horizontally and vertically relative to the outside world. Photoreceptors in such an orthogonal array are maximally sensitive to polarised light with the same fixed e-vector orientation. Using opponent neural connections, this two-channel system may produce a single value of polarisation contrast and, consequently, it may suffer from null points of discrimination. Stomatopod crustaceans use a different system for polarisation vision, comprising at least four types of polarisation-sensitive photoreceptor arranged at 0, 45, 90 and 135 deg relative to each other, in conjunction with extensive rotational eye movements. This anatomical arrangement should not suffer from equivalent null points of discrimination. To test whether these two systems were vulnerable to null points, we presented the fiddler crab Uca heteropleura and the stomatopod Haptosquilla trispinosa with polarised looming stimuli on a modified LCD monitor. The fiddler crab was less sensitive to differences in the degree of polarised light when the e-vector was at -45 deg than when the e-vector was horizontal. In comparison, stomatopods showed no difference in sensitivity between the two stimulus types. The results suggest that fiddler crabs suffer from a null point of sensitivity, while stomatopods do not. PMID:24737768

  7. A G protein alpha null mutation confers prolificacy potential in maize.

    PubMed

    Urano, Daisuke; Jackson, David; Jones, Alan M

    2015-08-01

    Plasticity in plant development is controlled by environmental signals through largely unknown signalling networks. Signalling coupled by the heterotrimeric G protein complex underlies various developmental pathways in plants. The morphology of two plastic developmental pathways, root system architecture and female inflorescence formation, was quantitatively assessed in a mutant compact plant 2 (ct2) lacking the alpha subunit of the heterotrimeric G protein complex in maize. The ct2 mutant partially compensated for a reduced shoot height by increased total leaf number, and had far more ears, even in the presence of pollination signals. The maize heterotrimeric G protein complex is important in some plastic developmental traits in maize. In particular, the maize Gα subunit is required to dampen the overproduction of female inflorescences. PMID:25948706

  8. A G protein alpha null mutation confers prolificacy potential in maize

    PubMed Central

    Urano, Daisuke; Jackson, David; Jones, Alan M.

    2015-01-01

    Plasticity in plant development is controlled by environmental signals through largely unknown signalling networks. Signalling coupled by the heterotrimeric G protein complex underlies various developmental pathways in plants. The morphology of two plastic developmental pathways, root system architecture and female inflorescence formation, was quantitatively assessed in a mutant compact plant 2 (ct2) lacking the alpha subunit of the heterotrimeric G protein complex in maize. The ct2 mutant partially compensated for a reduced shoot height by increased total leaf number, and had far more ears, even in the presence of pollination signals. The maize heterotrimeric G protein complex is important in some plastic developmental traits in maize. In particular, the maize Gα subunit is required to dampen the overproduction of female inflorescences. PMID:25948706

  9. A TAP1 null mutation leads to an enlarged olfactory bulb and supernumerary, ectopic olfactory glomeruli

    PubMed Central

    Salcedo, Ernesto; Cruz, Nicole M.; Ly, Xuan; Welander, Beth A.; Hanson, Kyle; Kronberg, Eugene; Restrepo, Diego

    2013-01-01

    Major histocompatibility class I (MHCI) molecules are well known for their immunological role in mediating tissue graft rejection. Recently, these molecules were discovered to be expressed in distinct neuronal subclasses, dispelling the long-held tenet that the uninjured brain is immune-privileged. Here, we show that MHCI molecules are expressed in the main olfactory bulb (MOB) of adult animals. Furthermore, we find that mice with diminished levels of MHCI expression have enlarged MOBs containing an increased number of small, morphologically abnormal and ectopically located P2 glomeruli. These findings suggest that MHCI molecules may play an important role in the proper formation of glomeruli in the bulb. PMID:23697805

  10. The appearance, motion, and disappearance of three-dimensional magnetic null points

    SciTech Connect

    Murphy, Nicholas A.; Parnell, Clare E.; Haynes, Andrew L.

    2015-10-15

    While theoretical models and simulations of magnetic reconnection often assume symmetry such that the magnetic null point when present is co-located with a flow stagnation point, the introduction of asymmetry typically leads to non-ideal flows across the null point. To understand this behavior, we present exact expressions for the motion of three-dimensional linear null points. The most general expression shows that linear null points move in the direction along which the magnetic field and its time derivative are antiparallel. Null point motion in resistive magnetohydrodynamics results from advection by the bulk plasma flow and resistive diffusion of the magnetic field, which allows non-ideal flows across topological boundaries. Null point motion is described intrinsically by parameters evaluated locally; however, global dynamics help set the local conditions at the null point. During a bifurcation of a degenerate null point into a null-null pair or the reverse, the instantaneous velocity of separation or convergence of the null-null pair will typically be infinite along the null space of the Jacobian matrix of the magnetic field, but with finite components in the directions orthogonal to the null space. Not all bifurcating null-null pairs are connected by a separator. Furthermore, except under special circumstances, there will not exist a straight line separator connecting a bifurcating null-null pair. The motion of separators cannot be described using solely local parameters because the identification of a particular field line as a separator may change as a result of non-ideal behavior elsewhere along the field line.

  11. Thermodynamical interpretation of the geometrical variables associated with null surfaces

    NASA Astrophysics Data System (ADS)

    Chakraborty, Sumanta; Padmanabhan, T.

    2015-11-01

    The emergent gravity paradigm interprets gravitational field equations as describing the thermodynamic limit of the underlying statistical mechanics of microscopic degrees of freedom of the spacetime. The connection is established by attributing a heat density T s to the null surfaces where T is the appropriate Davies-Unruh temperature and s is the entropy density. The field equations can be obtained from a thermodynamic variational principle which extremizes the total heat density of all null surfaces. The explicit form of s determines the nature of the theory. We explore the consequences of this paradigm for an arbitrary null surface and highlight the thermodynamic significance of various geometrical quantities. In particular, we show that (a) a conserved current, associated with the time development vector in a natural fashion, has direct thermodynamic interpretation in all Lanczos-Lovelock models of gravity; (b) one can generalize the notion of gravitational momentum, introduced in T. Padmanabhan, [arXiv:1506.03814] to all Lanczos-Lovelock models of gravity such that the conservation of the total momentum leads to the relevant field equations; (c) the thermodynamic variational principle which leads to the field equations of gravity can also be expressed in terms of the gravitational momentum in all Lanczos-Lovelock models; and (d) three different projections of gravitational momentum related to an arbitrary null surface in the spacetime lead to three different equations, all of which have thermodynamic interpretation. The first one reduces to a Navier-Stokes equation for the transverse drift velocity. The second can be written as a thermodynamic identity T d S =d E +P d V . The third describes the time evolution of the null surface in terms of suitably defined surface and bulk degrees of freedom. The implications are discussed.

  12. Phenotypic rescue by a bovine transgene in a Cu/Zn superoxide dismutase-null mutant of Drosophila melanogaster

    SciTech Connect

    Reveillaud, I.; Kongpachith, A.; Fleming, J.E.

    1994-02-01

    Null mutants for Cu/Zn superoxide dismutase (CuZnSOD) in Drosophila melanogaster are male sterile, have a greatly reduced adult life span, and are hypersensitive to paraquat. We have introduced a synthetic bovine CuZnSOD transgene under the transcriptional control of the D. melanogaster 5C actin promoter into a CuZnSOD-null mutant of D. melanogaster. This was carried out by P-element-mediated transformation of the Drosophila-bovine CuZnSOD transgene into a CuZnSOD{sup +} recipient strain followed by genetic crossing of the transgene into a strain carrying the CuZnSOD-null mutation, cSOD{sup n108}. The resulting transformants express bovine CuZnSOD exclusively to about 30% of normal Drosophila CuZnSOD levels. Expression of the Drosophila-bovine CuZnSOD transgene in the CuZnSOD-null mutant rescues male fertility and resistance to paraquat to apparently normal levels. However, adult life span is restored to only 30% of normal, and resistance to hyperoxia is 90% of that found in control flies. This striking differential restoration of pleiotropic phenotypes could be the result of a threshold of CuZnSOD expression necessary for normal male fertility and resistance to the toxicity of paraquat or hyperoxia which is lower than the threshold required to sustain a normal adult life span. Alternatively, the differential rescue of fertility, resistance to active oxygen, and life span might indicate different cell-specific transcriptional requirements for these functions which are normally provided by the control elements of the native CuZnSOD gene but are only partly compensated for by the transcriptional control elements of the actin 5C promoter. 29 refs., 5 figs., 1 tab.

  13. Impaired Lymphocytes Development and Xenotransplantation of Gastrointestinal Tumor Cells in Prkdc-Null SCID Zebrafish Model.

    PubMed

    Jung, In Hye; Chung, Yong-Yoon; Jung, Dawoon E; Kim, Young Jin; Kim, Do Hee; Kim, Kyung-Sik; Park, Seung Woo

    2016-08-01

    Severe combined immunodeficiency (SCID) mice have widely been used as hosts for human tumor cell xenograft study. This animal model, however, is labor intensive. As zebrafish is largely emerging as a promising model system for studying human diseases including cancer, developing efficient immunocompromised strains for tumor xenograft study are also demanded in zebrafish. Here, we have created the Prkdc-null SCID zebrafish model which provides the stable immune-deficient background required for xenotransplantation of tumor cell. In this study, the two transcription activator-like effector nucleases that specifically target the exon3 of the zebrafish Prkdc gene were used to induce a frame shift mutation, causing a complete knockout of the gene function. The SCID zebrafish showed susceptibility to spontaneous infection, a well-known phenotype found in the SCID mutation. Further characterization revealed that the SCID zebrafish contained no functional T and B lymphocytes which reflected the phenotypes identified in the mice SCID model. Intraperitoneal injection of human cancer cells into the adult SCID zebrafish clearly showed tumor cell growth forming into a solid mass. Our present data show the suitability of using the SCID zebrafish strain for xenotransplantation experiments, and in vivo monitoring of the tumor cell growth in the zebrafish demonstrates use of the animal model as a new platform of tumor xenograft study. PMID:27566103

  14. Null fluids: A new viewpoint of Galilean fluids

    NASA Astrophysics Data System (ADS)

    Banerjee, Nabamita; Dutta, Suvankar; Jain, Akash

    2016-05-01

    In this article, we study a Galilean fluid with a conserved U (1 ) current up to anomalies. We construct a relativistic system, which we call a null fluid and show that it is in one-to-one correspondence with a Galilean fluid living in one lower dimension. The correspondence is based on light cone reduction, which is known to reduce the Poincaré symmetry of a theory to Galilean in one lower dimension. We show that the proposed null fluid and the corresponding Galilean fluid have exactly same symmetries, thermodynamics, constitutive relations, and equilibrium partition to all orders in the derivative expansion. We also devise a mechanism to introduce U (1 ) anomaly in even dimensional Galilean theories using light cone reduction, and study its effect on the constitutive relations of a Galilean fluid.

  15. Time travel in transformation optics: Metamaterials with closed null geodesics

    NASA Astrophysics Data System (ADS)

    Boston, S. Reece

    2015-06-01

    We apply the methods of transformation optics to theoretical descriptions of spacetimes that support closed null geodesic curves. The metric used is based on frame dragging spacetimes, such as the van Stockum dust or the Kerr black hole. Through transformation optics, this metric is analogous to a material that in theory should allow for communication between past and future. Presented herein is a derivation and description of the spacetime and the resulting permeability, permittivity, and magnetoelectric couplings that a material would need in order for light in the material to follow closed null geodesics. We also address the paradoxical implications of such a material and demonstrate why such a material would not actually result in a violation of causality. A full derivation of the Plebanski equations is also included.

  16. Modifications of the Schwarzschild null geodesics in effective field theories

    SciTech Connect

    Ahmadi, N.

    2009-12-15

    In this paper the dynamics of Schwarzschild null geodesics in the context of low-energy effective field theories incorporating some interactions violating the equivalence principle is examined. Nonperturbed geodesics are expressed in terms of a convenient set of constants called orbital elements. The modifications introduced by the effective interactions are treated as small perturbations, then the method of variation of parameters is employed to find the evolution of the orbital elements for the true worldlines. We next focus our discussion on the geometry of nondispersive photon orbits and highlight the importance of different orbital elements in long-term change of the orbit. This calculation shows that nondispersive forces acting on null geodesics drive a secular growth of the positional elements. As an application of our results we examine the evolution of mean orbital elements in the semiclassical theory of quantum gravitational optics and show that the averaged correction terms are within the range of the uncertainty principle.

  17. Advances in corneal topography measurements with conical null-screens

    NASA Astrophysics Data System (ADS)

    Campos-García, Manuel; Cossio-Guerrero, Cesar; Huerta-Carranza, Oliver; Moreno-Oliva, Víctor I.

    2015-09-01

    In this work we report the design of a null-screen for corneal topography. To avoid the difficulties in the alignment of the test system due to the face contour (eyebrows, nose, or eyelids), we design a conical null-screen with a novel radial points distribution drawn on it in such a way that its image, which is formed by reflection on the test surface, becomes an exact array of circular spots if the surface is perfect. Additionally, an algorithm to compute the sagittal and meridional radii of curvature for the corneal surface is presented. The sagittal radius is obtained from the surface normal, and the meridional radius is calculated from a function fitted to the derivative of the sagittal curvature by using the surfacenormals raw data. Experimental results for the testing a calibration spherical surface are shown. Also, we perform some corneal topography measurements.

  18. Holographic proof of the quantum null energy condition

    NASA Astrophysics Data System (ADS)

    Koeller, Jason; Leichenauer, Stefan

    2016-07-01

    We use holography to prove the quantum null energy condition (QNEC) at leading order in large N for CFTs and relevant deformations of CFTs in Minkowski space which have Einstein gravity duals. Given any codimension-two surface Σ which is locally stationary under a null deformation in the direction k at the point p , the QNEC is a lower bound on the energy-momentum tensor at p in terms of the second variation of the entropy to one side of Σ : ⟨Tk k⟩≥S''/2 π √{h } . In a CFT, conformal transformations of this inequality give results which apply when Σ is not locally stationary. The QNEC was proven previously for free theories, and taken together with our result this provides strong evidence that the QNEC is a true statement about quantum field theory in general.

  19. A phenotypic null hypothesis for the genetics of personality.

    PubMed

    Turkheimer, Eric; Pettersson, Erik; Horn, Erin E

    2014-01-01

    We review the genetically informed literature on the genetics of personality. Over the past century, quantitative genetic studies, using identical and fraternal twins, have demonstrated that differences in human personality are substantially heritable. We focus on more contemporary questions to which that basic observation has led. We examine whether differences in the heritability of personality are replicable across different traits, samples, and studies; how the heritability of personality relates to its reliability; and how behavior genetics can be employed in studies of validity, and we discuss the stability of personality in genetic and environmental variance. The appropriate null hypothesis in behavior genetics is not that genetic or environmental influence on personality is zero. Instead, we offer a phenotypic null hypothesis, which states that genetic variance is not an independent mechanism of individual differences in personality but rather a reflection of processes that are best conceptualized at the phenotypic level. PMID:24050184

  20. Higher-dimensional evolving wormholes satisfying the null energy condition

    NASA Astrophysics Data System (ADS)

    Zangeneh, Mahdi Kord; Lobo, Francisco S. N.; Riazi, Nematollah

    2014-07-01

    In this work, we consider the possibility of expanding wormholes in higher dimensions, which is an important ingredient of modern theories of fundamental physics. An important motivation is that nontrivial topological objects such as microscopic wormholes may have been enlarged to macroscopic sizes in an expanding inflationary cosmological background. Since the Ricci scalar is only a function of time in standard cosmological models, we use this property as a simplifying assumption. More specifically, we consider a particular class of wormhole solutions corresponding to the choice of a spatially homogeneous Ricci scalar. The possibility of obtaining solutions with normal and exotic matter is explored and we find a variety of solutions including those in four dimensions that satisfy the null energy condition in specific time intervals. In particular, for five dimensions, we find solutions that satisfy the null energy condition throughout the respective evolution.

  1. Axon and muscle spindle hyperplasia in the myostatin null mouse

    PubMed Central

    Elashry, Mohamed I; Otto, Anthony; Matsakas, Antonios; El-Morsy, Salah E; Jones, Lisa; Anderson, Bethan; Patel, Ketan

    2011-01-01

    Germline deletion of the myostatin gene results in hyperplasia and hypertrophy of the tension-generating (extrafusal) fibres in skeletal muscle. As this gene is expressed predominantly in myogenic tissues it offers an excellent model with which to investigate the quantitative relationship between muscle and axonal development. Here we show that skeletal muscle hyperplasia in myostatin null mouse is accompanied by an increase in nerve fibres in major nerves of both the fore- and hindlimbs. We show that axons within these nerves undergo hypertrophy. Furthermore, we provide evidence that the age-related neural atrophic process is delayed in the absence of myostatin. Finally, we show that skeletal muscle hyperplasia in the myostatin null mouse is accompanied by an increase in the number of muscle spindles (also called stretch receptors or proprioceptors). However, our work demonstrates that the mechanisms regulating intrafusal fibre hyperplasia and hypertrophy differ from those that control the aetiology of extrafusal fibres. PMID:21208206

  2. Quantization of black hole entropy from unstable circular null geodesics

    NASA Astrophysics Data System (ADS)

    Wei, Shao-Wen; Liu, Yu-Xiao; Fu, Chun-E.

    2016-04-01

    The quasinormal mode frequencies can be understood from the massless particles trapped at the unstable circular null geodesics and slowly leaking out to infinity. Based on this viewpoint, in this paper, we semiclassically construct the entropy spectrum of the static and stationary black holes from the null geodesics. The result shows that the spacing of the entropy spectrum only depends on the property of the black hole in the eikonal limit. Moreover, for a black hole far from the extremal case, the spacing is found to be smaller than 2πħ for any dimension, which is very different from the result of the previous work by using the usual quasinormal mode frequencies.

  3. Exact Null Controllability of a Nonlinear Thermoelastic Contact Problem

    SciTech Connect

    Sivergina, Irina F. Polis, Michael P.

    2005-01-15

    We study the controllability properties of a nonlinear parabolic system that models the temperature evolution of a one-dimensional thermoelastic rod that may come into contact with a rigid obstacle. Basically the system dynamics is described by a one-dimensional nonlocal heat equation with a nonlinear and nonlocal boundary condition of Newmann type.We focus on the control problem and treat the case when the control is distributed over the whole space domain. In this case the system is proved to be exactly null controllable provided the parameters of the system are smooth.The proof is based on changing the control variable and using Aubin's Compactness Lemma to obtain an invariant set for the linearized controllability map. Then, by proving that the found solution is sufficiently smooth, we get the null controllability for the original system.

  4. Differential expression of pancreatic protein and chemosensing receptor mRNAs in NKCC1-null intestine

    PubMed Central

    Bradford, Emily M; Vairamani, Kanimozhi; Shull, Gary E

    2016-01-01

    AIM: To investigate the intestinal functions of the NKCC1 Na+-K+-2Cl cotransporter (SLC12a2 gene), differential mRNA expression changes in NKCC1-null intestine were analyzed. METHODS: Microarray analysis of mRNA from intestines of adult wild-type mice and gene-targeted NKCC1-null mice (n = 6 of each genotype) was performed to identify patterns of differential gene expression changes. Differential expression patterns were further examined by Gene Ontology analysis using the online Gorilla program, and expression changes of selected genes were verified using northern blot analysis and quantitative real time-polymerase chain reaction. Histological staining and immunofluorescence were performed to identify cell types in which upregulated pancreatic digestive enzymes were expressed. RESULTS: Genes typically associated with pancreatic function were upregulated. These included lipase, amylase, elastase, and serine proteases indicative of pancreatic exocrine function, as well as insulin and regenerating islet genes, representative of endocrine function. Northern blot analysis and immunohistochemistry showed that differential expression of exocrine pancreas mRNAs was specific to the duodenum and localized to a subset of goblet cells. In addition, a major pattern of changes involving differential expression of olfactory receptors that function in chemical sensing, as well as other chemosensing G-protein coupled receptors, was observed. These changes in chemosensory receptor expression may be related to the failure of intestinal function and dependency on parenteral nutrition observed in humans with SLC12a2 mutations. CONCLUSION: The results suggest that loss of NKCC1 affects not only secretion, but also goblet cell function and chemosensing of intestinal contents via G-protein coupled chemosensory receptors. PMID:26909237

  5. Uniqueness of Kerr space-time near null infinity

    SciTech Connect

    Wu Xiaoning; Bai Shan

    2008-12-15

    We reexpress the Kerr metric in standard Bondi-Sachs coordinates near null infinity I{sup +}. Using the uniqueness result of the characteristic initial value problem, we prove the Kerr metric is the only asymptotically flat, stationary, axially symmetric, type-D solution of the vacuum Einstein equation. The Taylor series of Kerr space-time is expressed in terms of Bondi-Sachs coordinates, and the Newman-Penrose constants have been calculated.

  6. Nulling Hall-Effect Current-Measuring Circuit

    NASA Technical Reports Server (NTRS)

    Sullender, Craig C.; Vazquez, Juan M.; Berru, Robert I.

    1993-01-01

    Circuit measures electrical current via combination of Hall-effect-sensing and magnetic-field-nulling techniques. Known current generated by feedback circuit adjusted until it causes cancellation or near cancellation of magnetic field produced in toroidal ferrite core by current measured. Remaining magnetic field measured by Hall-effect sensor. Circuit puts out analog signal and digital signal proportional to current measured. Accuracy of measurement does not depend on linearity of sensing components.

  7. The Phenotype of a Germline Mutation in PIGA: The Gene Somatically Mutated in Paroxysmal Nocturnal Hemoglobinuria

    PubMed Central

    Johnston, Jennifer J.; Gropman, Andrea L.; Sapp, Julie C.; Teer, Jamie K.; Martin, Jodie M.; Liu, Cyndi F.; Yuan, Xuan; Ye, Zhaohui; Cheng, Linzhao; Brodsky, Robert A.; Biesecker, Leslie G.

    2012-01-01

    Phosphatidylinositol glycan class A (PIGA) is involved in the first step of glycosylphosphatidylinositol (GPI) biosynthesis. Many proteins, including CD55 and CD59, are anchored to the cell by GPI. Loss of CD55 and CD59 on erythrocytes causes complement-mediated lysis in paroxysmal nocturnal hemoglobinuria (PNH), a disease that manifests after clonal expansion of hematopoietic cells with somatic PIGA mutations. Although somatic PIGA mutations have been identified in many PNH patients, it has been proposed that germline mutations are lethal. We report a family with an X-linked lethal disorder involving cleft palate, neonatal seizures, contractures, central nervous system (CNS) structural malformations, and other anomalies. An X chromosome exome next-generation sequencing screen identified a single nonsense PIGA mutation, c.1234C>T, which predicts p.Arg412∗. This variant segregated with disease and carrier status in the family, is similar to mutations known to cause PNH as a result of PIGA dysfunction, and was absent in 409 controls. PIGA-null mutations are thought to be embryonic lethal, suggesting that p.Arg412∗ PIGA has residual function. Transfection of a mutant p.Arg412∗ PIGA construct into PIGA-null cells showed partial restoration of GPI-anchored proteins. The genetic data show that the c.1234C>T (p.Arg412∗) mutation is present in an affected child, is linked to the affected chromosome in this family, is rare in the population, and results in reduced, but not absent, biosynthesis of GPI anchors. We conclude that c.1234C>T in PIGA results in the lethal X-linked phenotype recognized in the reported family. PMID:22305531

  8. RELN Mutations in Autism Spectrum Disorder

    PubMed Central

    Lammert, Dawn B.; Howell, Brian W.

    2016-01-01

    RELN encodes a large, secreted glycoprotein integral to proper neuronal positioning during development and regulation of synaptic function postnatally. Rare, homozygous, null mutations lead to lissencephaly with cerebellar hypoplasia (LCH), accompanied by developmental delay and epilepsy. Until recently, little was known about the frequency or consequences of heterozygous mutations. Several lines of evidence from multiple studies now implicate heterozygous mutations in RELN in autism spectrum disorders (ASD). RELN maps to the AUTS1 locus on 7q22, and at this time over 40 distinct mutations have been identified that would alter the protein sequence, four of which are de novo. The RELN mutations that are most clearly consequential are those that are predicted to inactivate the signaling function of the encoded protein and those that fall in a highly conserved RXR motif found at the core of the 16 Reelin subrepeats. Despite the growing evidence of RELN dysfunction in ASD, it appears that these mutations in isolation are insufficient and that secondary genetic or environmental factors are likely required for a diagnosis. PMID:27064498

  9. Non-null annular subaperture stitching interferometry for aspheric test

    NASA Astrophysics Data System (ADS)

    Zhang, Lei; Liu, Dong; Shi, Tu; Yang, Yongying; Chong, Shiyao; Miao, Liang; Huang, Wei; Shen, Yibing; Bai, Jian

    2015-10-01

    A non-null annular subaperture stitching interferometry (NASSI), combining the subaperture stitching idea and non-null test method, is proposed for steep aspheric testing. Compared with standard annular subaperture stitching interferometry (ASSI), a partial null lens (PNL) is employed as an alternative to the transmission sphere, to generate different aspherical wavefronts as the references. The coverage subaperture number would thus be reduced greatly for the better performance of aspherical wavefronts in matching the local slope of aspheric surfaces. Instead of various mathematical stitching algorithms, a simultaneous reverse optimizing reconstruction (SROR) method based on system modeling and ray tracing is proposed for full aperture figure error reconstruction. All the subaperture measurements are simulated simultaneously with a multi-configuration model in a ray-tracing program, including the interferometric system modeling and subaperture misalignments modeling. With the multi-configuration model, full aperture figure error would be extracted in form of Zernike polynomials from subapertures wavefront data by the SROR method. This method concurrently accomplishes subaperture retrace error and misalignment correction, requiring neither complex mathematical algorithms nor subaperture overlaps. A numerical simulation exhibits the comparison of the performance of the NASSI and standard ASSI, which demonstrates the high accuracy of the NASSI in testing steep aspheric. Experimental results of NASSI are shown to be in good agreement with that of Zygo® VerifireTM Asphere interferometer.

  10. Adult sulfatide null mice maintain an increased number of oligodendrocytes

    PubMed Central

    Shroff, S; Pomicter, AD; Fox, MA; Henderson, SC; Dupree, JL

    2015-01-01

    The galactolipids galactocerebroside and sulfatide have been implicated in oligodendrocyte development and myelin formation. Much of the evidence for these galactolipid functions has been derived from antibody and chemical perturbation of cultured oligodendrocytes. Recently, we have observed abundant, unstable myelin and an increased number of oligodendrocytes in mice incapable of synthesizing the myelin galactolipids galactocerebroside and sulfatide. We have also reported that mice lacking sulfatide but that synthesize normal levels of galactocerebroside generate myelin with unstable paranodes while Hirahara et al. (2004) have shown an enhanced population of oligodendrocytes in the forebrain, medulla and cerebellum in immature sulfatide null mice. Here, we demonstrate that an increase in the number of oligodendrocytes in sulfatide null mice is not transient but is maintained through, at least, 7 months of age. Moreover, we demonstrate that the enhanced oligodendrocyte population results from, at least in part, increased cell survival. Finally, sulfatide null oligodendrocytes exhibit decreased morphological complexity, a feature which may relate to increased oligodendrocyte survival. PMID:19224580

  11. High-power, null-type, inverted pendulum thrust stand.

    PubMed

    Xu, Kunning G; Walker, Mitchell L R

    2009-05-01

    This article presents the theory and operation of a null-type, inverted pendulum thrust stand. The thrust stand design supports thrusters having a total mass up to 250 kg and measures thrust over a range of 1 mN to 5 N. The design uses a conventional inverted pendulum to increase sensitivity, coupled with a null-type feature to eliminate thrust alignment error due to deflection of thrust. The thrust stand position serves as the input to the null-circuit feedback control system and the output is the current to an electromagnetic actuator. Mechanical oscillations are actively damped with an electromagnetic damper. A closed-loop inclination system levels the stand while an active cooling system minimizes thermal effects. The thrust stand incorporates an in situ calibration rig. The thrust of a 3.4 kW Hall thruster is measured for thrust levels up to 230 mN. The uncertainty of the thrust measurements in this experiment is +/-0.6%, determined by examination of the hysteresis, drift of the zero offset and calibration slope variation. PMID:19485530

  12. Reverse optimization reconstruction method in non-null aspheric interferometry

    NASA Astrophysics Data System (ADS)

    Zhang, Lei; Liu, Dong; Shi, Tu; Yang, Yongying; Chong, Shiyao; Shen, Yibing; Bai, Jian

    2015-10-01

    Aspheric non-null test achieves more flexible measurements than the null test. However, the precision calibration for retrace error has always been difficult. A reverse optimization reconstruction (ROR) method is proposed for the retrace error calibration as well as the aspheric figure error extraction based on system modeling. An optimization function is set up with system model, in which the wavefront data from experiment is inserted as the optimization objective while the figure error under test in the model as the optimization variable. The optimization is executed by the reverse ray tracing in the system model until the test wavefront in the model is consistent with the one in experiment. At this point, the surface figure error in the model is considered to be consistent with the one in experiment. With the Zernike fitting, the aspheric surface figure error is then reconstructed in the form of Zernike polynomials. Numerical simulations verifying the high accuracy of the ROR method are presented with error considerations. A set of experiments are carried out to demonstrate the validity and repeatability of ROR method. Compared with the results of Zygo interferometer (null test), the measurement error by the ROR method achieves better than 1/10λ.

  13. Variational principle for gravity with null and non-null boundaries: a unified boundary counter-term

    NASA Astrophysics Data System (ADS)

    Parattu, Krishnamohan; Chakraborty, Sumanta; Padmanabhan, T.

    2016-03-01

    It is common knowledge that the Einstein-Hilbert action does not furnish a well-posed variational principle. The usual solution to this problem is to add an extra boundary term to the action, called a counter-term, so that the variational principle becomes well-posed. When the boundary is spacelike or timelike, the Gibbons-Hawking-York counter-term is the most widely used. For null boundaries, we had proposed a counter-term in a previous paper. In this paper, we extend the previous analysis and propose a counter-term that can be used to eliminate variations of the "off-the-surface" derivatives of the metric on any boundary, regardless of its spacelike, timelike or null nature.

  14. Metabolism of trans, trans-muconaldehyde, a cytotoxic metabolite of benzene, in mouse liver by alcohol dehydrogenase Adh1 and aldehyde reductase AKR1A4

    SciTech Connect

    Short, Duncan M.; Lyon, Robert; Watson, David G.; Barski, Oleg A.; McGarvie, Gail; Ellis, Elizabeth M. . E-mail: Elizabeth.ellis@strath.ac.uk

    2006-01-15

    The reductive metabolism of trans, trans-muconaldehyde, a cytotoxic metabolite of benzene, was studied in mouse liver. Using an HPLC-based stopped assay, the primary reduced metabolite was identified as 6-hydroxy-trans, trans-2,4-hexadienal (OH/CHO) and the secondary metabolite as 1,6-dihydroxy-trans, trans-2,4-hexadiene (OH/OH). The main enzymes responsible for the highest levels of reductase activity towards trans, trans-muconaldehyde were purified from mouse liver soluble fraction first by Q-sepharose chromatography followed by either blue or red dye affinity chromatography. In mouse liver, trans, trans-muconaldehyde is predominantly reduced by an NADH-dependent enzyme, which was identified as alcohol dehydrogenase (Adh1). Kinetic constants obtained for trans, trans-muconaldehyde with the native Adh1 enzyme showed a V {sub max} of 2141 {+-} 500 nmol/min/mg and a K {sub m} of 11 {+-} 4 {mu}M. This enzyme was inhibited by pyrazole with a K {sub I} of 3.1 {+-} 0.57 {mu}M. Other fractions were found to contain muconaldehyde reductase activity independent of Adh1, and one enzyme was identified as the NADPH-dependent aldehyde reductase AKR1A4. This showed a V {sub max} of 115 nmol/min/mg and a K {sub m} of 15 {+-} 2 {mu}M and was not inhibited by pyrazole.

  15. Cloning and Overexpression of the als, pflA, and adhB Genes in Streptococcus thermophilus and Their Effects on Metabolite Formation.

    PubMed

    Akyol, Ismail; Ozcelik, Fatma Gul; Karakas-Sen, Asuman; Ozkose, Emin; Gezginc, Yekta; Ekinci, M Sait

    2015-10-01

    Streptococcus thermophilus is a lactic acid bacterium and used as starter culture in the dairy industry, mainly in the manufacture of yoghurt, with Lactobacillus delbrueckii subsp. bulgaricus. It produces lactic acid as a major fermentation end product and some carbonyl compounds through sugar metabolism. The level of metabolites could be improved using molecular biotechnology. The genes of als, encoding α-acetolactate synthase (Als), the pflA, encoding pyruvate-formate lyase activating enzyme (PflA), and the adhB which encodes alcohol dehydrogenase (AdhB) of S. thermophilus NCFB2393 strain were amplified by polymerase chain reaction and separately cloned into the overexpression vector pNZ276 under the control of the lacA promoter. The strains were transformed individually with the constructed plasmids. Their abilities to generate important metabolites such as pyruvate, lactate, formate, acetaldehyde, acetoin, ethanol, and 2,3-butanediol in LM17 medium were analyzed using high-performance liquid chromatography. High level of 2,3-butanediol was obtained by overexpressing the als gene. The level of formate increased slightly by overexpressing the pflA gene. The overexpression of the adhB gene, on the other hand, resulted in a significant increase in the ethanol level. PMID:26280324

  16. Null controllable region of delta operator systems subject to actuator saturation

    NASA Astrophysics Data System (ADS)

    Yang, Hongjiu; Yan, Ce; Xia, Yuanqing; Zhang, Jinhui

    2016-07-01

    In this paper, we give exact description of null controllable regions for delta operator systems subject to actuator saturation. The null controllable region is in terms of a set of extremal trajectories of anti-stable subsystems. For the delta operator system with real eigenvalues or complex eigenvalues, the description is simplified to an explicit formula which is used to characterise the boundary of a null controllable region. The relations of null controllable regions are shown separately for continuous-time systems, discrete-time systems and delta operator systems. Two numerical examples are given to illustrate the effectiveness of the proposed techniques on null controllable regions.

  17. Understanding N-Acetyl-L-Glutamate Synthase Deficiency: Mutational Spectrum, Impact of Clinical Mutations on Enzyme Functionality, and Structural Considerations.

    PubMed

    Sancho-Vaello, Enea; Marco-Marín, Clara; Gougeard, Nadine; Fernández-Murga, Leonor; Rüfenacht, Véronique; Mustedanagic, Merima; Rubio, Vicente; Häberle, Johannes

    2016-07-01

    N-acetyl-L-glutamate synthase (NAGS) deficiency (NAGSD), the rarest urea cycle defect, is clinically indistinguishable from carbamoyl phosphate synthetase 1 deficiency, rendering the identification of NAGS gene mutations key for differentiation, which is crucial, as only NAGSD has substitutive therapy. Over the last 13 years, we have identified 43 patients from 33 families with NAGS mutations, of which 14 were novel. Overall, 36 NAGS mutations have been found so far in 56 patients from 42 families, of which 76% are homozygous for the mutant allele. 61% of mutations are missense changes. Lack or decrease of NAGS protein is predicted for ∼1/3 of mutations. Missense mutations frequency is inhomogeneous along NAGS: null for exon 1, but six in exon 6, which reflects the paramount substrate binding/catalytic role of the C-terminal domain (GNAT domain). Correspondingly, phenotypes associated with missense mutations mapping in the GNAT domain are more severe than phenotypes of amino acid kinase domain-mapping missense mutations. Enzyme activity and stability assays with 12 mutations introduced into pure recombinant Pseudomonas aeruginosa NAGS, together with in silico structural analysis, support the pathogenic role of most NAGSD-associated mutations found. The disease-causing mechanisms appear to be, from higher to lower frequency, decreased solubility/stability, aberrant kinetics/catalysis, and altered arginine modulation. PMID:27037498

  18. Mutation rates, spectra, and genome-wide distribution of spontaneous mutations in mismatch repair deficient yeast.

    PubMed

    Lang, Gregory I; Parsons, Lance; Gammie, Alison E

    2013-09-01

    DNA mismatch repair is a highly conserved DNA repair pathway. In humans, germline mutations in hMSH2 or hMLH1, key components of mismatch repair, have been associated with Lynch syndrome, a leading cause of inherited cancer mortality. Current estimates of the mutation rate and the mutational spectra in mismatch repair defective cells are primarily limited to a small number of individual reporter loci. Here we use the yeast Saccharomyces cerevisiae to generate a genome-wide view of the rates, spectra, and distribution of mutation in the absence of mismatch repair. We performed mutation accumulation assays and next generation sequencing on 19 strains, including 16 msh2 missense variants implicated in Lynch cancer syndrome. The mutation rate for DNA mismatch repair null strains was approximately 1 mutation per genome per generation, 225-fold greater than the wild-type rate. The mutations were distributed randomly throughout the genome, independent of replication timing. The mutation spectra included insertions/deletions at homopolymeric runs (87.7%) and at larger microsatellites (5.9%), as well as transitions (4.5%) and transversions (1.9%). Additionally, repeat regions with proximal repeats are more likely to be mutated. A bias toward deletions at homopolymers and insertions at (AT)n microsatellites suggests a different mechanism for mismatch generation at these sites. Interestingly, 5% of the single base pair substitutions might represent double-slippage events that occurred at the junction of immediately adjacent repeats, resulting in a shift in the repeat boundary. These data suggest a closer scrutiny of tumor suppressors with homopolymeric runs with proximal repeats as the potential drivers of oncogenesis in mismatch repair defective cells. PMID:23821616

  19. Broadband Achromatic Phase Shifter for a Nulling Interferometer

    NASA Technical Reports Server (NTRS)

    Bolcar, Matthew R.; Lyon, Richard G.

    2011-01-01

    Nulling interferometry is a technique for imaging exoplanets in which light from the parent star is suppressed using destructive interference. Light from the star is divided into two beams and a phase shift of radians is introduced into one of the beams. When the beams are recombined, they destructively interfere to produce a deep null. For monochromatic light, this is implemented by introducing an optical path difference (OPD) between the two beams equal to lambda/2, where lambda is the wavelength of the light. For broadband light, however, a different phase shift will be introduced at each wavelength and the two beams will not effectively null when recombined. Various techniques have been devised to introduce an achromatic phase shift a phase shift that is uniform across a particular bandwidth. One popular technique is to use a series of dispersive elements to introduce a wavelength-dependent optical path in one or both of the arms of the interferometer. By intelligently choosing the number, material and thickness of a series of glass plates, a nearly uniform, arbitrary phase shift can be introduced between two arms of an interferometer. There are several constraints that make choosing the number, type, and thickness of materials a difficult problem, such as the size of the bandwidth to be nulled. Several solutions have been found for bandwidths on the order of 20 to 30 percent (Delta(lambda)/lambda(sub c)) in the mid-infrared region. However, uniform phase shifts over a larger bandwidth in the visible regime between 480 to 960 nm (67 percent) remain difficult to obtain at the tolerances necessary for exoplanet detection. A configuration of 10 dispersive glass plates was developed to be used as an achromatic phase shifter in nulling interferometry. Five glass plates were placed in each arm of the interferometer and an additional vacuum distance was also included in the second arm of the interferometer. This configuration creates a phase shift of pi radians with

  20. Vacuum Nuller Testbed Performance, Characterization and Null Control

    NASA Technical Reports Server (NTRS)

    Lyon, R. G.; Clampin, M.; Petrone, P.; Mallik, U.; Madison, T.; Bolcar, M.; Noecker, C.; Kendrick, S.; Helmbrecht, M. A.

    2011-01-01

    The Visible Nulling Coronagraph (VNC) can detect and characterize exoplanets with filled, segmented and sparse aperture telescopes, thereby spanning the choice of future internal coronagraph exoplanet missions. NASA/Goddard Space Flight Center (GSFC) has developed a Vacuum Nuller Testbed (VNT) to advance this approach, and assess and advance technologies needed to realize a VNC as a flight instrument. The VNT is an ultra-stable testbed operating at 15 Hz in vacuum. It consists of a MachZehnder nulling interferometer; modified with a "W" configuration to accommodate a hexpacked MEMS based deformable mirror (DM), coherent fiber bundle and achromatic phase shifters. The 2-output channels are imaged with a vacuum photon counting camera and conventional camera. Error-sensing and feedback to DM and delay line with control algorithms are implemented in a real-time architecture. The inherent advantage of the VNC is that it is its own interferometer and directly controls its errors by exploiting images from bright and dark channels simultaneously. Conservation of energy requires the sum total of the photon counts be conserved independent of the VNC state. Thus sensing and control bandwidth is limited by the target stars throughput, with the net effect that the higher bandwidth offloads stressing stability tolerances within the telescope. We report our recent progress with the VNT towards achieving an incremental sequence of contrast milestones of 10(exp 8) , 10(exp 9) and 10(exp 10) respectively at inner working angles approaching 2A/D. Discussed will be the optics, lab results, technologies, and null control. Shown will be evidence that the milestones have been achieved.

  1. Null controllability in a fluid-solid structure model

    NASA Astrophysics Data System (ADS)

    Raymond, J.-P.; Vanninathan, M.

    We consider a system coupling the Stokes equations in a two-dimensional domain with a structure equation which is a system of ordinary differential equations corresponding to a finite dimensional approximation of equations modeling deformations of an elastic body or vibrations of a rigid body. For that system we establish a null controllability result for localized distributed controls acting only in the fluid equations and there is no control in the solid part. This controllability result follows from a Carleman inequality that we prove for the adjoint system.

  2. Optical fiber null coupler sensor for damage detection using ultrasonic

    NASA Astrophysics Data System (ADS)

    Xuan, HaiFeng; Liao, Yanbiao; Zhang, Ming; Lai, Shu R.

    2005-02-01

    A novel optical fiber null coupler (OFNC) sensor based on acousto-optic interaction is developed, which can be used in the structure health monitoring of the medical materials. The OFNC sensors can be response to 10MHz supersonic wave, and their signal-to noise ratio are higher then Piezo Ceramic Transducers(PZT). A kind of Perspex with a 1mm hole is employed as the sample, where the OFNC sensor is glued on, and the reflected signal of ultrasonic wave by the hole is detected .

  3. Mutations within the nuclear localization signal of the porcine reproductive and respiratory syndrome virus nucleocapsid protein attenuate virus replication

    SciTech Connect

    Lee, Changhee; Hodgins, Douglas; Calvert, Jay G.; Welch, Siao-Kun W.; Jolie, Rika; Yoo, Dongwan . E-mail: dyoo@uoguelph.ca

    2006-03-01

    Porcine reproductive and respiratory syndrome virus (PRRSV) is an RNA virus replicating in the cytoplasm, but the nucleocapsid (N) protein is specifically localized to the nucleus and nucleolus in virus-infected cells. A 'pat7' motif of 41-PGKK(N/S)KK has previously been identified in the N protein as the functional nuclear localization signal (NLS); however, the biological consequences of N protein nuclear localization are unknown. In the present study, the role of N protein nuclear localization during infection was investigated in pigs using an NLS-null mutant virus. When two lysines at 43 and 44 at the NLS locus were substituted to glycines, the modified NLS with 41-PGGGNKK restricted the N protein to the cytoplasm. This NLS-null mutation was introduced into a full-length infectious cDNA clone of PRRSV. Upon transfection of cells, the NLS-null full-length clone induced cytopathic effects and produced infectious progeny. The NLS-null virus grew to a titer 100-fold lower than that of wild-type virus. To examine the response to NLS-null PRRSV in the natural host, three groups of pigs, consisting of seven animals per group, were intranasally inoculated with wild-type, placebo, or NLS-null virus, and the animals were maintained for 4 weeks. The NLS-null-infected pigs had a significantly shorter mean duration of viremia than wild-type-infected pigs but developed significantly higher titers of neutralizing antibodies. Mutations occurred at the NLS locus in one pig during viremia, and four types of mutations were identified: 41-PGRGNKK, 41-PGGRNKK, and 41-PGRRNKK, and 41-PGKKSKK. Both wild-type and NLS-null viruses persisted in the tonsils for at least 4 weeks, and the NLS-null virus persisting in the tonsils was found to be mutated to either 41-PGRGNKK or 41-PGGRNKK in all pigs. No other mutation was found in the N gene. All types of reversions which occurred during viremia and persistence were able to translocate the mutated N proteins to the nucleus, indicating a

  4. Metabolic and Phenotypic Differences between Mice Producing a Werner Syndrome Helicase Mutant Protein and Wrn Null Mice.

    PubMed

    Aumailley, Lucie; Garand, Chantal; Dubois, Marie Julie; Johnson, F Brad; Marette, André; Lebel, Michel

    2015-01-01

    Werner syndrome (WS) is a premature aging disorder caused by mutations in a RecQ-family DNA helicase, WRN. Mice lacking part of the helicase domain of the WRN orthologue exhibit many phenotypic features of WS, including metabolic abnormalities and a shorter mean life span. In contrast, mice lacking the entire Wrn protein (i.e. Wrn null mice) do not exhibit a premature aging phenotype. In this study, we used a targeted mass spectrometry-based metabolomic approach to identify serum metabolites that are differentially altered in young Wrn helicase mutant and Wrn null mice. An antibody-based quantification of 43 serum cytokines and markers of cardiovascular disease risk complemented this study. We found that Wrn helicase mutants exhibited elevated and decreased levels, respectively, of the anti-inflammatory cytokine IL-10 and the pro-inflammatory cytokine IL-18. Wrn helicase mutants also exhibited an increase in serum hydroxyproline and plasminogen activator inhibitor-1, markers of extracellular matrix remodeling of the vascular system and inflammation in aging. We also observed an abnormal increase in the ratio of very long chain to short chain lysophosphatidylcholines in the Wrn helicase mutants underlying a peroxisome perturbation in these mice. Remarkably, the Wrn mutant helicase protein was mislocalized to the endoplasmic reticulum and the peroxisomal fractions in liver tissues. Additional analyses with mouse embryonic fibroblasts indicated a severe defect of the autophagy flux in cells derived from Wrn helicase mutants compared to wild type and Wrn null animals. These results indicate that the deleterious effects of the helicase-deficient Wrn protein are mediated by the dysfunction of several cellular organelles. PMID:26447695

  5. Metabolic and Phenotypic Differences between Mice Producing a Werner Syndrome Helicase Mutant Protein and Wrn Null Mice

    PubMed Central

    Aumailley, Lucie; Garand, Chantal; Dubois, Marie Julie; Johnson, F. Brad; Marette, André; Lebel, Michel

    2015-01-01

    Werner syndrome (WS) is a premature aging disorder caused by mutations in a RecQ-family DNA helicase, WRN. Mice lacking part of the helicase domain of the WRN orthologue exhibit many phenotypic features of WS, including metabolic abnormalities and a shorter mean life span. In contrast, mice lacking the entire Wrn protein (i.e. Wrn null mice) do not exhibit a premature aging phenotype. In this study, we used a targeted mass spectrometry-based metabolomic approach to identify serum metabolites that are differentially altered in young Wrn helicase mutant and Wrn null mice. An antibody-based quantification of 43 serum cytokines and markers of cardiovascular disease risk complemented this study. We found that Wrn helicase mutants exhibited elevated and decreased levels, respectively, of the anti-inflammatory cytokine IL-10 and the pro-inflammatory cytokine IL-18. Wrn helicase mutants also exhibited an increase in serum hydroxyproline and plasminogen activator inhibitor-1, markers of extracellular matrix remodeling of the vascular system and inflammation in aging. We also observed an abnormal increase in the ratio of very long chain to short chain lysophosphatidylcholines in the Wrn helicase mutants underlying a peroxisome perturbation in these mice. Remarkably, the Wrn mutant helicase protein was mislocalized to the endoplasmic reticulum and the peroxisomal fractions in liver tissues. Additional analyses with mouse embryonic fibroblasts indicated a severe defect of the autophagy flux in cells derived from Wrn helicase mutants compared to wild type and Wrn null animals. These results indicate that the deleterious effects of the helicase-deficient Wrn protein are mediated by the dysfunction of several cellular organelles. PMID:26447695

  6. Enhancement of postsynaptic GABAA and extrasynaptic NMDA receptor-mediated responses in the barrel cortex of Mecp2-null mice.

    PubMed

    Lo, Fu-Sun; Blue, Mary E; Erzurumlu, Reha S

    2016-03-01

    Rett syndrome (RTT) is a neurodevelopmental disorder that results from mutations in the X-linked gene for methyl-CpG-binding protein 2 (MECP2). The underlying cellular mechanism for the sensory deficits in patients with RTT is largely unknown. This study used the Bird mouse model of RTT to investigate sensory thalamocortical synaptic transmission in the barrel cortex of Mecp2-null mice. Electrophysiological results showed an excitation/inhibition imbalance, biased toward inhibition, due to an increase in efficacy of postsynaptic GABAA receptors rather than alterations in inhibitory network and presynaptic release properties. Enhanced inhibition impaired the transmission of tonic sensory signals from the thalamus to the somatosensory cortex. Previous morphological studies showed an upregulation of NMDA receptors in the neocortex of both RTT patients and Mecp2-null mice at early ages [Blue ME, Naidu S, Johnston MV. Ann Neurol 45: 541-545, 1999; Blue ME, Kaufmann WE, Bressler J, Eyring C, O'Driscoll C, Naidu S, Johnston MV. Anat Rec (Hoboken) 294: 1624-1634, 2011]. Although AMPA and NMDA receptor-mediated excitatory synaptic transmission was not altered in the barrel cortex of Mecp2-null mice, extrasynaptic NMDA receptor-mediated responses increased markedly. These responses were blocked by memantine, suggesting that extrasynaptic NMDA receptors play an important role in the pathogenesis of RTT. The results suggest that enhancement of postsynaptic GABAA and extrasynaptic NMDA receptor-mediated responses may underlie impaired somatosensation and that pharmacological blockade of extrasynaptic NMDA receptors may have therapeutic value for RTT. PMID:26683074

  7. Juvenile manifestation of ultrasound communication deficits in the neuroligin-4 null mutant mouse model of autism.

    PubMed

    Ju, Anes; Hammerschmidt, Kurt; Tantra, Martesa; Krueger, Dilja; Brose, Nils; Ehrenreich, Hannelore

    2014-08-15

    Neuroligin-4 (Nlgn4) is a member of the neuroligin family of postsynaptic cell adhesion molecules. Loss-of-function mutations of NLGN4 are among the most frequent, known genetic causes of heritable autism. Adult Nlgn4 null mutant (Nlgn4(-/-)) mice are a construct valid model of human autism, with both genders displaying a remarkable autistic phenotype, including deficits in social interaction and communication as well as restricted and repetitive behaviors. In contrast to adults, autism-related abnormalities in neonatal and juvenile Nlgn4(-/-) mice have not been reported yet. The present study has been designed to systematically investigate in male and female Nlgn4(-/-) pups versus wildtype littermates (WT, Nlgn4(+/+)) developmental milestones and stimulus-induced ultrasound vocalization (USV). Neonatal development, followed daily from postnatal days (PND) 4 to 21, including physical development, neurological reflexes and neuromotor coordination, did not yield any differences between Nlgn4(-/-) and their WT littermates. USV in pups (PND8-9) in response to brief separation from their mothers revealed remarkable gender effects, and a genotype influence in females regarding latency to first call. In juveniles (PND22-23), USV monitoring upon exposure to an anesthetized female intruder mouse uncovered a clear genotype effect with reduced USV in Nlgn4(-/-) mice, and again a more prominent phenotype in females. Together, these data support an early manifestation of communication deficits in Nlgn4(-/-) mice that appear more pronounced in immature females with their overall stronger USV as compared to males. PMID:24855039

  8. Forelimb contractures and abnormal tendon collagen fibrillogenesis in fibulin-4 null mice.

    PubMed

    Markova, Dessislava Z; Pan, Te-Cheng; Zhang, Rui-Zhu; Zhang, Guiyun; Sasaki, Takako; Arita, Machiko; Birk, David E; Chu, Mon-Li

    2016-06-01

    Fibulin-4 is an extracellular matrix glycoprotein essential for elastic fiber formation. Mice deficient in fibulin-4 die perinatally because of severe pulmonary and vascular defects associated with the lack of intact elastic fibers. Patients with fibulin-4 mutations demonstrate similar defects, and a significant number die shortly after birth or in early childhood from cardiopulmonary failure. The patients also demonstrate skeletal and other systemic connective tissue abnormalities, including joint laxity and flexion contractures of the wrist. A fibulin-4 null mouse strain was generated and used to analyze the roles of fibulin-4 in tendon fibrillogenesis. This mouse model displayed bilateral forelimb contractures, in addition to pulmonary and cardiovascular defects. The forelimb and hindlimb tendons exhibited disruption in collagen fibrillogenesis in the absence of fibulin-4 as analyzed by transmission electron microscopy. Fewer fibrils were assembled, and fibrils were disorganized compared with wild-type controls. The organization of developing tenocytes and compartmentalization of the extracellular space was also disrupted. Fibulin-4 was co-localized with fibrillin-1 and fibrillin-2 in limb tendons by using immunofluorescence microscopy. Thus, fibulin-4 seems to play a role in regulating tendon collagen fibrillogenesis, in addition to its essential function in elastogenesis. PMID:26711913

  9. Cognition and Mood-Related Behaviors in L3mbtl1 Null Mutant Mice

    PubMed Central

    Shen, Erica Y.; Jiang, Yan; Mao, Wenjie; Futai, Kensuke; Hock, Hanno; Akbarian, Schahram

    2015-01-01

    Alterations in histone lysine methylation and epigenetic regulators of gene expression could play a role in the neurobiology and treatment of patients diagnosed with mood spectrum disorder, including depression and anxiety. Mutations and altered expression of various lysine methyltransferases (KMTs) and demethylases (KDMs) have been linked to changes in motivational and emotional behaviors in preclinical model systems. However, it is not known whether regulators operating downstream of histone lysine methylation could affect mood-related behavior. Malignant Brain Tumor (MBT) domain ‘chromatin reader’ proteins bind to methylated histone lysine residues and associate with chromatin remodeling complexes to facilitate or repress gene expression. MBT proteins, including the founding member, L3mbtl1, maintain high levels of expression in neurons of the mature brain. Here, we exposed L3mbtl1 null mutant mice to a wide range of tests exploring cognition and mood-relevant behaviors at baseline and in the context of social isolation, as a stressor to elicit depression-related behavior in susceptible mice. L3mbtl1 loss-of-function was associated with significant decreases in depression and and anxiety in some of the behavioral paradigms. This was not associated with a more generalized neurological dysfunction because cognition and memory remained unaltered in comparison to controls. These findings warrant further investigations on the role of MBT chromatin reader proteins in the context of emotional and affective behaviors. PMID:25849281

  10. Extrasolar Planetary Imaging Coronagraph: Visible Nulling Coronagraph Testbed Results

    NASA Technical Reports Server (NTRS)

    Lyon, Richard G.

    2008-01-01

    The Extrasolar Planetary Imaging Coronagraph (EPIC) is a proposed NASA Discovery mission to image and characterize extrasolar giant planets in orbits with semi-major axes between 2 and 10 AU. EPIC will provide insights into the physical nature of a variety of planets in other solar systems complimenting radial velocity (RV) and astrometric planet searches. It will detect and characterize the atmospheres of planets identified by radial velocity surveys, determine orbital inclinations and masses, characterize the atmospheres around A and F stars, observed the inner spatial structure and colors of inner Spitzer selected debris disks. EPIC would be launched to heliocentric Earth trailing drift-away orbit, with a 3-year mission lifetime ( 5 year goal) and will revisit planets at least three times at intervals of 9 months. The starlight suppression approach consists of a visible nulling coronagraph (VNC) that enables high order starlight suppression in broadband light. To demonstrate the VNC approach and advance it's technology readiness the NASA Goddard Space Flight Center and Lockheed-Martin have developed a laboratory VNC and have demonstrated white light nulling. We will discuss our ongoing VNC work and show the latest results from the VNC testbed,

  11. Generation of mice with a conditional Lbh null allele.

    PubMed

    Lindley, Linsey E; Briegel, Karoline J

    2013-07-01

    Limb bud and heart (LBH) is a developmentally expressed, tissue-specific transcription cofactor in vertebrates that acts in the WNT signaling pathway, a genetic program critical for embryogenesis and adult tissue homeostasis. Aberrant gain-of-function of LBH is implicated in both human congenital disease and cancer. The normal physiological function of LBH has remained elusive owing to a lack of genetic loss-of-function models. Here, we have generated mice with a conditional null allele of Lbh by flanking exon 2 with loxP sites (Lbh(flox)). Homozygous Lbh(flox) and Lbh(loxP) mice, in which the Neo cassette was removed through FLPe-mediated recombination, were viable and fertile, indicating that these conditional Lbh alleles are fully functional. Lbh(loxP) mice were then crossed with a Rosa26-Cre line, resulting in ubiquitous deletion of exon 2 and abolishment of LBH protein expression. Mice homozygous for the Lbh null allele (Lbh(Δ)(2)) displayed normal embryonic development and postnatal growth with morphologies indistinguishable from wild-type littermates. However, mammary gland development, which occurs primarily after birth, was perturbed. Thus, the conditional Lbh allele will be a valuable tool to uncover the currently unknown tissue-specific roles of LBH in postnatal development and disease. PMID:23495064

  12. Conceptual design of the ALADDIN Antarctic nulling interferometer

    NASA Astrophysics Data System (ADS)

    Barillot, Marc; Courteau, Pascal; Absil, Olivier; Coudé du Foresto, Vincent; Swain, Mark

    2006-06-01

    It is commonly accepted that highly challenging planet finding missions such as Darwin and TPF need precursors on the ground, for both technological demonstration and study of the exozodiacal clouds around potential targets. A first instrument, GENIE, designed to be implemented in the interferometric laboratory of the VLTI, was studied by ESA and scientific/industrial teams. In this paper we present a concept for ALADDIN, an operational nulling instrument to be implemented at Dome C in Antarctica, and discuss the comparison with GENIE from the instrumental point of view. Our preliminary design involves moderate ~1m size telescopes mounted on a 40m long rotating beam allowing baselines up to 30m and feeding a 2-arm nulling beam combiner. When compared to GENIE, the rotating beam design has the advantage of removing the need for both long-stroke delay line and dispersion control equipments. As a side effect, the instrumental arrangement of ALADDIN finds itself more representative of what Darwin will be. Furthermore, critical issues like phase control, photometric balance and instrumental background suppression are expected to be relaxed by the improved atmospheric conditions, lower temperature, and simpler optical trains. Calibration of geometrical stellar leakage will make advantage of the continuously adjustable baseline. As results, a simpler instrument showing improved performance is expected. In conclusion, we see our ALADDIN concept as a valuable alternative to GENIE, with a quite stronger scientific potential and a considerably simplified instrumental design.

  13. Osteoclast differentiation and function in aquaglyceroporin AQP9 null mice

    PubMed Central

    Liu, Yangjian; Song, Linhua; Wang, Yiding; Rojek, Aleksandra; Nielsen, Søren; Agre, Peter; Carbrey, Jennifer M.

    2008-01-01

    Background Information Osteoclasts are cells specialized for bone resorption and play important roles in bone growth and calcium homeostasis. Differentiation of osteoclasts involves fusion of bone marrow macrophage mononuclear precursors in response to extracellular signals. A dramatic increase in osteoclast cell volume occurs during osteoclast biogenesis and is believed to be mediated by Aquaporin 9 (AQP9), a membrane protein that can rapidly transport water and other small neutral solutes across cell membranes. Results Here we report an increase in expression of AQP9 during differentiation of a mouse macrophage cell line into osteoclasts. Bone marrow macrophages from wild type and AQP9 null mice differentiate into osteoclasts that have similar morphology, contain comparable numbers of nuclei, and digest synthetic bone to the same extent. Bones from wild type and AQP9 null mice contain similar numbers of osteoclasts and have comparable density and structure as measured by X-ray absorptiometry and micro-computed tomography. Conclusions Our data confirm that AQP9 expression rises during osteoclast biogenesis but indicate that AQP9 is not essential for osteoclast function or differentiation under normal physiological conditions. PMID:18666888

  14. Exoplanet detection and characterization via parallel broadband nulling coronagraphy

    NASA Astrophysics Data System (ADS)

    Hicks, Brian A.

    2016-01-01

    The contrast and angular resolution required to directly image and characterize mature exoplanetary systems place stringent requirements on the space-based telescopes and starlight suppression systems needed to study spatial distributions of debris disks, exozodiacal dust, and individual planets at multiple epochs in their orbits. A nulling interferometer (nuller) is a coronagraphic suppression system that can be used with all telescope types, including those with obscured and segmented apertures envisioned for upcoming and future observatories. One of the challenges for detection and characterization of exoplanetary signals is achieving high contrast with broad spectral coverage. This work presents design concepts for broadband nulling over four parallel ˜20% bandpasses spanning the visible spectrum. Contrast-limiting effects of stellar angular extent, residual chromaticity of broadband phase shifters, and aperture diffraction are considered to reach simultaneous ≲2×10-8 contrast over separations spanning 0.2 to 0.9 arc sec for a 2.4-m telescope observing a Sun-like star at 10 pc. With added dark hole wavefront control and postprocessing point spread function subtraction techniques to further reduce scattered starlight, such a system could be capable of detecting the very the nearest Earth-like exoplanets and spectral characterization of several nearby extrasolar gas giants.

  15. Adaptive Nulling: A New Enabling Technology for Interferometric Exoplanet

    NASA Technical Reports Server (NTRS)

    Lay, Oliver P.; Jeganathan, Muthu; Peters, Robert

    2003-01-01

    Deep, stable nulling of starlight requires careful control of the amplitudes and phases of the beams that are being combined. The detection of earth-like planets using the interferometer architectures currently being considered for the Terrestrial Planet Finder mission require that the E-field amplitudes are balanced at the level of approx. 0.1%, and the phases are controlled at the level of 1 mrad (corresponding to approx.1.5 nm for a wavelength of 10 microns). These conditions must be met simultaneously at all wavelengths across the science band, and for both polarization states, imposing unrealistic tolerances on the symmetry between the optical beamtrains. We introduce the concept of a compensator that is inserted into the beamtrain, which can adaptively correct for the mismatches across the spectrum, enabling deep nulls with realistic, imperfect optics. The design presented uses a deformable mirror to adjust the amplitude and phase of each beam as an arbitrary function of wavelength and polarization. A proof-of-concept experiment will be conducted at visible/near-IR wavelengths, followed by a system operating in the Mid-IR band.

  16. Geometry of extended null supersymmetry in M theory

    SciTech Connect

    Conamhna, Oisin A.P. Mac

    2006-02-15

    For supersymmetric spacetimes in 11 dimensions admitting a null Killing spinor, a set of explicit necessary and sufficient conditions for the existence of any number of arbitrary additional Killing spinors is derived. The necessary and sufficient conditions are comprised of algebraic relationships, linear in the spinorial components, between the spinorial components and their first derivatives, and the components of the spin connection and four-form. The integrability conditions for the Killing spinor equation are also analyzed in detail, to determine which components of the field equations are implied by arbitrary additional supersymmetries and the four-form Bianchi identity. This provides a complete formalism for the systematic and exhaustive investigation of all spacetimes with extended null supersymmetry in 11 dimensions. The formalism is employed to show that the general bosonic solution of 11 dimensional supergravity admitting a G{sub 2} structure defined by four Killing spinors is either locally the direct product of R{sup 1,3} with a seven-manifold of G{sub 2} holonomy, or locally the Freund-Rubin direct product of AdS{sub 4} with a seven-manifold of weak G{sub 2} holonomy. In addition, all supersymmetric spacetimes admitting a (G{sub 2}xR{sup 7})xR{sup 2} structure are classified.

  17. Adding light to the gravitational waves on the null cone

    NASA Astrophysics Data System (ADS)

    Babiuc, Maria

    2014-03-01

    Recent interesting astrophysical observations point towards a multi-messenger, multi-wavelength approach to understanding strong gravitational sources, like compact stars or black hole collisions, supernovae explosions, or even the big bang. Gravitational radiation is properly defined only at future null infinity, but usually is estimated at a finite radius, and then extrapolated. Our group developed a characteristic waveform extraction tool, implemented in an open source code, which computes the gravitational waves infinitely far from their source, in terms of compactified null cones, by numerically solving Einstein equation in Bondi space-time coordinates. The goal is extend the capabilities of the code, by solving Einstein-Maxwell's equations together with the Maxwell's equations, to obtain the energy radiated asymptotically at infinity, both in gravitational and electromagnetic waves. The purpose is to analytically derive and numerically calculate both the gravitational waves and the electromagnetic counterparts at infinity, in this characteristic framework. The method is to treat the source of gravitational and electromagnetic radiation as a black box, and therefore the code will be very flexible, with potentially large applicability.

  18. A search for optical beacons: implications of null results.

    PubMed

    Blair, David G; Zadnik, Marjan G

    2002-01-01

    Over the past few years a series of searches for interstellar radio beacons have taken place using the Parkes radio telescope. Here we report hitherto unpublished results from a search for optical beacons from 60 solar-type stars using the Perth-Lowell telescope. We discuss the significance of the null results from these searches, all of which were based on the interstellar contact channel hypothesis. While the null results of all searches to date can be explained simply by the nonexistence of electromagnetically communicating life elsewhere in the Milky Way, four other possible explanations that do not preclude its existence are proposed: (1) Extraterrestrial civilizations desiring to make contact through the use of electromagnetic beacons have a very low density in the Milky Way. (2) The interstellar contact channel hypothesis is incorrect, and beacons exist at frequencies that have not yet been searched. (3) The search has been incomplete in terms of sensitivity and/or target directions: Beacons exist, but more sensitive equipment and/or more searching is needed to achieve success. (4) The search has occurred before beacon signals can be expected to have arrived at the Earth, and beacon signals may be expected in the future. Based on consideration of the technology required for extraterrestrial civilizations to identify target planets, we argue that the fourth possibility is likely to be valid and that powerful, easily detectable beacons could be received in coming centuries. PMID:12530240

  19. Lack of the nucleoside transporter ENT1 results in the Augustine-null blood type and ectopic mineralization.

    PubMed

    Daniels, Geoff; Ballif, Bryan A; Helias, Virginie; Saison, Carole; Grimsley, Shane; Mannessier, Lucienne; Hustinx, Hein; Lee, Edmond; Cartron, Jean-Pierre; Peyrard, Thierry; Arnaud, Lionel

    2015-06-01

    The Augustine-negative alias At(a-) blood type, which seems to be restricted to people of African ancestry, was identified half a century ago but remains one of the last blood types with no known genetic basis. Here we report that a nonsynonymous single nucleotide polymorphism in SLC29A1 (rs45458701) is responsible for the At(a-) blood type. The resulting p.Glu391Lys variation in the last extracellular loop of the equilibrative nucleoside transporter 1 (ENT1; also called SLC29a1) is known not to alter its ability to transport nucleosides and nucleoside analog drugs. Furthermore, we identified 3 individuals of European ancestry who are homozygous for a null mutation in SLC29A1 (c.589+1G>C) and thus have the Augustine-null blood type. These individuals lacking ENT1 exhibit periarticular and ectopic mineralization, which confirms an important role for ENT1/SLC29A1 in human bone homeostasis as recently suggested by the skeletal phenotype of aging Slc29a1(-/-) mice. Our results establish Augustine as a new blood group system and place SLC29A1 as a new candidate gene for idiopathic disorders characterized with ectopic calcification/mineralization. PMID:25896650

  20. Role of Duplicate Genes in Robustness against Deleterious Human Mutations

    PubMed Central

    Hsiao, Tzu-Lin; Vitkup, Dennis

    2008-01-01

    It is now widely recognized that robustness is an inherent property of biological systems [1],[2],[3]. The contribution of close sequence homologs to genetic robustness against null mutations has been previously demonstrated in simple organisms [4],[5]. In this paper we investigate in detail the contribution of gene duplicates to back-up against deleterious human mutations. Our analysis demonstrates that the functional compensation by close homologs may play an important role in human genetic disease. Genes with a 90% sequence identity homolog are about 3 times less likely to harbor known disease mutations compared to genes with remote homologs. Moreover, close duplicates affect the phenotypic consequences of deleterious mutations by making a decrease in life expectancy significantly less likely. We also demonstrate that similarity of expression profiles across tissues significantly increases the likelihood of functional compensation by homologs. PMID:18369440

  1. Drastic effect of germline TP53 missense mutations in Li-Fraumeni patients.

    PubMed

    Zerdoumi, Yasmine; Aury-Landas, Juliette; Bonaïti-Pellié, Catherine; Derambure, Céline; Sesboüé, Richard; Renaux-Petel, Mariette; Frebourg, Thierry; Bougeard, Gaëlle; Flaman, Jean-Michel

    2013-03-01

    In contrast to other tumor suppressor genes, the majority of TP53 alterations are missense mutations. We have previously reported that in the Li-Fraumeni syndrome (LFS), germline TP53 missense mutations are associated with an earlier age of tumor onset. In a larger series, we observed that mean age of tumor onset in patients harboring dominant negative missense mutations and clearly null mutations was 22.6 and 37.5 years, respectively. To assess the impact of heterozygous germline TP53 mutations in the genetic context of the patients, we developed a new functional assay of the p53 pathway on the basis of induction of DNA damage in Epstein-Barr-virus-immortalized lymphocytes, followed by comparative gene-expression profiling. In wild-type lymphocytes, we identified a core of 173 genes whose expression was induced more than twofold, of which 46 were known p53 target genes. In LFS lymphocytes with canonical missense mutations, the number of induced genes and the level of known p53 target genes induction were strongly reduced as compared with controls and LFS lymphocytes with null mutations. These results show that certain germline missense TP53 mutations, such as those with dominant negative effect, dramatically alter the response to DNA damage. This probably explains why TP53 alterations are predominantly missense mutations. PMID:23172776

  2. Error analysis and system optimization of non-null aspheric testing system

    NASA Astrophysics Data System (ADS)

    Luo, Yongjie; Yang, Yongying; Liu, Dong; Tian, Chao; Zhuo, Yongmo

    2010-10-01

    A non-null aspheric testing system, which employs partial null lens (PNL for short) and reverse iterative optimization reconstruction (ROR for short) technique, is proposed in this paper. Based on system modeling in ray tracing software, the parameter of each optical element is optimized and this makes system modeling more precise. Systematic error of non-null aspheric testing system is analyzed and can be categorized into two types, the error due to surface parameters of PNL in the system modeling and the rest from non-null interferometer by the approach of error storage subtraction. Experimental results show that, after systematic error is removed from testing result of non-null aspheric testing system, the aspheric surface is precisely reconstructed by ROR technique and the consideration of systematic error greatly increase the test accuracy of non-null aspheric testing system.

  3. Estimating mutation rate: how to count mutations?

    PubMed Central

    Fu, Yun-Xin; Huai, Haying

    2003-01-01

    Mutation rate is an essential parameter in genetic research. Counting the number of mutant individuals provides information for a direct estimate of mutation rate. However, mutant individuals in the same family can share the same mutations due to premeiotic mutation events, so that the number of mutant individuals can be significantly larger than the number of mutation events observed. Since mutation rate is more closely related to the number of mutation events, whether one should count only independent mutation events or the number of mutants remains controversial. We show in this article that counting mutant individuals is a correct approach for estimating mutation rate, while counting only mutation events will result in underestimation. We also derived the variance of the mutation-rate estimate, which allows us to examine a number of important issues about the design of such experiments. The general strategy of such an experiment should be to sample as many families as possible and not to sample much more offspring per family than the reciprocal of the pairwise correlation coefficient within each family. To obtain a reasonably accurate estimate of mutation rate, the number of sampled families needs to be in the same or higher order of magnitude as the reciprocal of the mutation rate. PMID:12807798

  4. Col6a1 Null Mice as a Model to Study Skin Phenotypes in Patients with Collagen VI Related Myopathies: Expression of Classical and Novel Collagen VI Variants during Wound Healing

    PubMed Central

    Lettmann, Sandra; Bloch, Wilhelm; Maaß, Tobias; Niehoff, Anja; Schulz, Jan-Niklas; Eckes, Beate; Eming, Sabine A.; Bonaldo, Paolo; Paulsson, Mats; Wagener, Raimund

    2014-01-01

    Patients suffering from collagen VI related myopathies caused by mutations in COL6A1, COL6A2 and COL6A3 often also display skin abnormalities, like formation of keloids or “cigarette paper” scars, dry skin, striae rubrae and keratosis pilaris (follicular keratosis). Here we evaluated if Col6a1 null mice, an established animal model for the muscle changes in collagen VI related myopathies, are also suitable for the study of mechanisms leading to the skin pathology. We performed a comprehensive study of the expression of all six collagen VI chains in unwounded and challenged skin of wild type and Col6a1 null mice. Expression of collagen VI chains is regulated in both skin wounds and bleomycin-induced fibrosis and the collagen VI α3 chain is proteolytically processed in both wild type and Col6a1 null mice. Interestingly, we detected a decreased tensile strength of the skin and an altered collagen fibril and basement membrane architecture in Col6a1 null mice, the latter being features that are also found in collagen VI myopathy patients. Although Col6a1 null mice do not display an overt wound healing defect, these mice are a relevant animal model to study the skin pathology in collagen VI related disease. PMID:25158062

  5. Chromatism compensation in wide-band nulling interferometry for exoplanet detection.

    PubMed

    Spronck, Julien; Pereira, Silvania F; Braat, Joseph J M

    2006-02-01

    We introduce the concept of chromatism compensation in nulling interferometry that enables a high rejection ratio in a wide spectral band. Therefore the achromaticity condition considered in most nulling interferometers can be relaxed. We show that this chromatism compensation cannot be applied to a two-beam nulling interferometer, and we make an analysis of the particular case of a three-telescope configuration. PMID:16485668

  6. Survival of glucose phosphate isomerase null somatic cells and germ cells in adult mouse chimaeras.

    PubMed

    Keighren, Margaret A; Flockhart, Jean H; West, John D

    2016-01-01

    The mouse Gpi1 gene encodes the glycolytic enzyme glucose phosphate isomerase. Homozygous Gpi1(-/-) null mouse embryos die but a previous study showed that some homozygous Gpi1(-/-) null cells survived when combined with wild-type cells in fetal chimaeras. One adult female Gpi1(-/-)↔Gpi1(c/c) chimaera with functional Gpi1(-/-) null oocytes was also identified in a preliminary study. The aims were to characterise the survival of Gpi1(-/-) null cells in adult Gpi1(-/-)↔Gpi1(c/c) chimaeras and determine if Gpi1(-/-) null germ cells are functional. Analysis of adult Gpi1(-/-)↔Gpi1(c/c) chimaeras with pigment and a reiterated transgenic lineage marker showed that low numbers of homozygous Gpi1(-/-) null cells could survive in many tissues of adult chimaeras, including oocytes. Breeding experiments confirmed that Gpi1(-/-) null oocytes in one female Gpi1(-/-)↔Gpi1(c/c) chimaera were functional and provided preliminary evidence that one male putative Gpi1(-/-)↔Gpi1(c/c) chimaera produced functional spermatozoa from homozygous Gpi1(-/-) null germ cells. Although the male chimaera was almost certainly Gpi1(-/-)↔Gpi1(c/c), this part of the study is considered preliminary because only blood was typed for GPI. Gpi1(-/-) null germ cells should survive in a chimaeric testis if they are supported by wild-type Sertoli cells. It is also feasible that spermatozoa could bypass a block at GPI, but not blocks at some later steps in glycolysis, by using fructose, rather than glucose, as the substrate for glycolysis. Although chimaera analysis proved inefficient for studying the fate of Gpi1(-/-) null germ cells, it successfully identified functional Gpi1(-/-) null oocytes and revealed that some Gpi1(-/-) null cells could survive in many adult tissues. PMID:27103217

  7. Metabolic process engineering of Clostridium tyrobutyricum Δack-adhE2 for enhanced n-butanol production from glucose: effects of methyl viologen on NADH availability, flux distribution, and fermentation kinetics.

    PubMed

    Du, Yinming; Jiang, Wenyan; Yu, Mingrui; Tang, I-Ching; Yang, Shang-Tian

    2015-04-01

    Butanol biosynthesis through aldehyde/alcohol dehydrogenase (adhE2) is usually limited by NADH availability, resulting in low butanol titer, yield, and productivity. To alleviate this limitation and improve n-butanol production by Clostridium tyrobutyricum Δack-adhE2 overexpressing adhE2, the NADH availability was increased by using methyl viologen (MV) as an artificial electron carrier to divert electrons from ferredoxin normally used for H2 production. In the batch fermentation with the addition of 500 μM MV, H2 , acetate, and butyrate production was reduced by more than 80-90%, while butanol production increased more than 40% to 14.5 g/L. Metabolic flux analysis revealed that butanol production increased in the fermentation with MV because of increased NADH availability as a result of reduced H2 production. Furthermore, continuous butanol production of ∼55 g/L with a high yield of ∼0.33 g/g glucose and extremely low ethanol, acetate, and butyrate production was obtained in fed-batch fermentation with gas stripping for in situ butanol recovery. This study demonstrated a stable and reliable process for high-yield and high-titer n-butanol production by metabolically engineered C. tyrobutyricum by applying MV as an electron carrier to increase butanol biosynthesis. PMID:25363722

  8. Leigh Syndrome Caused by the MT-ND5 m.13513G>A Mutation: A Case Presenting with WPW-Like Conduction Defect, Cardiomyopathy, Hypertension and Hyponatraemia.

    PubMed

    Brecht, Marcus; Richardson, Malcolm; Taranath, Ajay; Grist, Scott; Thorburn, David; Bratkovic, Drago

    2015-01-01

    Mitochondrial disease can present with a wide range of clinical phenotypes, and knowledge of the clinical spectrum of mitochondrial DNA mutation is constantly expanding. Leigh syndrome (LS) has been reported to be caused by the m.13513G>A mutation in the ND5 subunit of complex I (MT-ND5 m.13513G>A). We present a case of a 12-month-old infant initially diagnosed with tachyarrhythmia requiring defibrillation, subsequent presentation with hypertension and hyponatraemia secondary to renal salt loss and presumed inappropriate ADH secretion. Complex I activity in the muscle tissue was 54%, and mutation load in the muscle and lymphocytes was 50%. This case of Leigh syndrome caused by the m.13513G>A mutation in the ND5 gene illustrates that hyponatraemia due to renal sodium loss and inappropriate ADH secretion and hypertension can be features of this entity in addition to the previously reported cardiomyopathy and WPW-like conduction pattern and that they present additional challenges in diagnosis and management. PMID:25681084

  9. Principles: when there should be no difference--how to fail to reject the null hypothesis.

    PubMed

    Lew, Michael J

    2006-05-01

    It is common to perform experiments in which a 'success' is claimed when the null hypothesis is discarded. However, there is a category of experiment that has become important in which a success is when the null hypothesis is not rejected. Failing to discard the null hypothesis is different from proving it to be valid, a distinction that is particularly important in experiments in which any inadequacy of experimental design or implementation enhances the likelihood of a success. The appropriate analysis of such experiments tests for evidence of the validity of the null hypothesis rather than simply failing to find evidence against it. PMID:16595154

  10. Alignment of optical system components using an ADM beam through a null assembly

    NASA Technical Reports Server (NTRS)

    Hayden, Joseph E. (Inventor); Olczak, Eugene G. (Inventor)

    2010-01-01

    A system for testing an optical surface includes a rangefinder configured to emit a light beam and a null assembly located between the rangefinder and the optical surface. The null assembly is configured to receive and to reflect the emitted light beam toward the optical surface. The light beam reflected from the null assembly is further reflected back from the optical surface toward the null assembly as a return light beam. The rangefinder is configured to measure a distance to the optical surface using the return light beam.

  11. A highly efficient ADH-coupled NADH-recycling system for the asymmetric bioreduction of carbon-carbon double bonds using enoate reductases.

    PubMed

    Tauber, Katharina; Hall, Melanie; Kroutil, Wolfgang; Fabian, Walter M F; Faber, Kurt; Glueck, Silvia M

    2011-06-01

    The asymmetric bioreduction of activated alkenes catalyzed by flavin-dependent enoate reductases from the OYE-family represents a powerful method for the production of optically active compounds. For its preparative-scale application, efficient and economic NADH-recycling is crucial. A novel enzyme-coupled NADH-recycling system is proposed based on the concurrent oxidation of a sacrificial sec-alcohol catalyzed by an alcohol dehydrogenase (ADH-A). Due to the highly favorable position of the equilibrium of ene-reduction versus alcohol-oxidation, the cosubstrate is only required in slight excess. PMID:21328323

  12. A matrix model for the null-brane

    NASA Astrophysics Data System (ADS)

    Robbins, Daniel

    The null-brave quotient is a simple smooth time-dependent solution of string or M-theory. By tuning a parameter, this background develops a big crunch/big bang type singularity. We construct a matrix model description of this background as a Yang-Mills theory on a time-dependent space-time. This dual description provides a non-perturbative framework to study the fate of space-times with cosmological singularities. We study the dynamics of this theory, including particle production and the one-loop effective action for Higgs VEVs in the theory, and we present some evidence that space-time itself breaks down, even while the underlying theory remains unitary and well-defined. Finally, we speculate about which lessons can be carried over to more general situations and propose several future directions for research.

  13. Null polarimetry near shot noise limit at 1 Hz

    NASA Astrophysics Data System (ADS)

    He, Dechao; Xie, Boya; Feng, Sheng

    2016-04-01

    We describe the principle and report on the realization of a null polarimeter with two demonstrated features: (1) the sensitivity of the system is near shot noise limit and (2) quasi-stationary signals at 1 Hz can be measured without signal modulation. The achieved single-pass sensitivity is 7 × 10-9 rad/ √{ Hz } with a pair of Glan-Taylor polarizers, which should be of great interest for experiments such as observation of vacuum magnetic birefringence and search for new particles. The system is brought near its shot noise limit by appropriate polarization control and coherent heterodyne detection of light, resulting in a sensitivity improvement by two orders of magnitude in comparison with the case of no control on light polarization.

  14. Solvable null model for the distribution of word frequencies

    NASA Astrophysics Data System (ADS)

    Fontanari, J. F.; Perlovsky, L. I.

    2004-10-01

    Zipf’s law asserts that in all natural languages the frequency of a word is inversely proportional to its rank. The significance, if any, of this result for language remains a mystery. Here we examine a null hypothesis for the distribution of word frequencies, a so-called discourse-triggered word choice model, which is based on the assumption that the more a word is used, the more likely it is to be used again. We argue that this model is equivalent to the neutral infinite-alleles model of population genetics and so the degeneracy of the different words composing a sample of text is given by the celebrated Ewens sampling formula [Theor. Pop. Biol. 3, 87 (1972)], which we show to produce an exponential distribution of word frequencies.

  15. Polarization interferometric nulling coronagraph for high-contrast imaging.

    PubMed

    Murakami, Naoshi; Yokochi, Kaito; Nishikawa, Jun; Tamura, Motohide; Kurokawa, Takashi; Takeda, Mitsuo; Baba, Naoshi

    2010-06-01

    We propose a novel, high-contrast imager called a polarization interferometric nulling coronagraph (PINC) for direct detection of extrasolar planets. The PINC uses achromatic half-wave plates (HWPs) installed in a fully symmetric beam combiner based on polarizing beam splitters. Jones calculus suggests that a stellar halo suppression level of 10(-10) can be achieved at 5 lambda/D for a broad wavelength range from 1.6 to 2.2 microm by using Fresnel-rhomb HWPs made of BK7. Laboratory experiments on the PINC used two laser light sources (wavelengths of lambda=532 and 671 nm), and we obtained a halo suppression level of approximately 10(-6) at 5 lambda/D for both wavelengths. PMID:20517351

  16. Null polarimetry near shot noise limit at 1 Hz.

    PubMed

    He, Dechao; Xie, Boya; Feng, Sheng

    2016-04-01

    We describe the principle and report on the realization of a null polarimeter with two demonstrated features: (1) the sensitivity of the system is near shot noise limit and (2) quasi-stationary signals at 1 Hz can be measured without signal modulation. The achieved single-pass sensitivity is 7 × 10(-9) rad/Hz with a pair of Glan-Taylor polarizers, which should be of great interest for experiments such as observation of vacuum magnetic birefringence and search for new particles. The system is brought near its shot noise limit by appropriate polarization control and coherent heterodyne detection of light, resulting in a sensitivity improvement by two orders of magnitude in comparison with the case of no control on light polarization. PMID:27131649

  17. Dilute Aperture Visible Nulling Coronagraph Imaging (DAViNCI)

    NASA Technical Reports Server (NTRS)

    Shao, Michael; Levine, B. M.; Vasisht, G.; Lane, B. F.; Woodruff, R.; Vasudevan, G.; Samuele R.; Harvey, K.; Clampin, M.; Lyon, R.; Guyon, O.; Tolls, V.

    2008-01-01

    The presentation focuses on instrument and mission overview, science case, Team X study, and technology status. Topics include DAViNCI study milestones, number of targets versus inner working angle, planet orbit and IWA, combiner/nuller instrument, DAViNCI Team X costs, technology status and near future plans, and deep laser null 1.23 x 10(exp -7) suppression. Summary points are: dilute aperture concept advantages, lower cost than a comparable 7-8m coronagraph working at 2 lambda/D, technology progress prior to 2008 was seriously limited by available funding but showed 1e-y suppression (2006) of laser light needed for 1e-9 to approximately 1e-10 contrast, and current technology effort is off to a fast date with a demonstration of less than 100pm wavefront measurement in Nov 08.

  18. Five-dimensional null and time-like supersymmetric geometries

    NASA Astrophysics Data System (ADS)

    Pasini, Giulio; Shahbazi, C. S.

    2016-09-01

    We show that there exist supersymmetric solutions of five-dimensional, pure, { N }=1 supergravity such that the norm of the supersymmetric Killing vector, built out of the Killing spinor, is a real not-everywhere analytic function such that all its derivatives vanish at a point where the Killing vector field becomes null. The norm of the Killing vector field then is not an analytic function on a neighborhood around this point. We explicitly construct such solutions by using a multi-center Gibbons–Hawking base. Although many of these solutions have infinite charges, we find explicit examples with finite charges that asymptote to {{AdS}}3× {S}2 and discuss their physical interpretation.

  19. Null space and resolution in dynamic computerized tomography

    NASA Astrophysics Data System (ADS)

    Hahn, Bernadette N.

    2016-02-01

    One major challenge in computerized tomography is to image objects which change during the data acquisition and hence lead to inconsistent data sets. Motion artefacts in the reconstructions can be reduced by applying specially adapted algorithms which take the dynamic behaviour into account. Within this article, we analyse the achievable resolution in the dynamic setting in case of two-dimensional affine deformations. To this end, we characterize the null space of the operator describing the dynamic case, using its singular value decomposition and a necessary dynamic consistency condition. This shows that independent of any reconstruction method, the specimen’s dynamics results in a loss of resolution compared to the stationary setting. Our theoretical results are illustrated at a numerical example.

  20. Status of the Visible Nulling Coronagraph Technology Demonstration Program

    NASA Technical Reports Server (NTRS)

    Clampin, M.; Lyon, R.

    2012-01-01

    We report on the development, sensing and control of the Vacuum Nuller Testbed to realize a Visible Nulling Coronagraphy (VNC) for exoplanet detection and characterization. The VNC is one of the few approaches that works with filled, segmented and sparse or diluted-aperture telescope systems. It thus spans a range of potential future NASA telescopes and could be flown as a separate instrument on such a future mission. NASA/Goddard Space Flight Center has an established effort to develop VNC technologies, and an incremental sequence of testbeds to advance this approach and its critical technologies. We will highlight results demonstrating the achievement of our TDEM contrast milestones, and highlight the performance of our wavefront sensing and control concept.

  1. Recent Contrast Measurements Made Using the PICTURE Visible Nulling Coronagraph

    NASA Astrophysics Data System (ADS)

    Mendillo, Christopher Bernard; Douglas, Ewan S.; Finn, Susanna C.; Hicks, Brian; Martel, Jason; Cook, Timothy; Chakrabarti, Supriya

    2014-06-01

    The PICTURE-B (Planetary Imaging Concept Testbed Using a Rocket Experiment - B) sounding rocket mission will use a visible nulling coronagraph to directly image the exozodiacal dust disk of Epsilon Eridani (K2V, 3.22 pc) in reflected visible light down to an inner radius of 1.5 AU (1.7 λ/D). This mission will demonstrate a number of key technologies for future space-based direct exoplanet imaging missions. These include: wavefront sensing and control using deformable mirrors in space, a lightweight SiC 0.5 meter primary mirror and a milliarcsecond-class fine pointing system. The mission is scheduled for launch in October, 2014. We present laboratory contrast measurements made using the PICTURE-B instrument and model predictions of exozodiacal dust detection limits based on these measurements.

  2. Power spectrum nulls due to nonstandard inflationary evolution

    NASA Astrophysics Data System (ADS)

    Goswami, Gaurav; Souradeep, Tarun

    2011-01-01

    The simplest models of inflation based on slow roll produce nearly scale invariant primordial power spectra (PPS). But there are also numerous models that predict radically broken scale invariant PPS. In particular, markedly cuspy dips in the PPS correspond to nulls where the perturbation amplitude, hence PPS, goes through a zero at a specific wave number. Near this wave number, the true quantum nature of the generation mechanism of the primordial fluctuations may be revealed. Naively these features may appear to arise from fine-tuned initial conditions. However, we show that this behavior arises under fairly generic set of conditions involving super-Hubble scale evolution of perturbation modes during inflation. We illustrate this with the well-studied examples of punctuated inflation and the Starobinsky-break model.

  3. On the null trajectories in conformal Weyl gravity

    SciTech Connect

    Villanueva, J.R.; Olivares, Marco E-mail: marco.olivaresrubilar@gmail.com

    2013-06-01

    In this work we find analytical solutions to the null geodesics around a black hole in the conformal Weyl gravity. Exact expressions for the horizons are found, and they depend on the cosmological constant and the coupling constants of the conformal Weyl gravity. Then, we study the radial motion from the point of view of the proper and coordinate frames, and compare it with that found in spacetimes of general relativity. The angular motion is also examined qualitatively by means of an effective potential; quantitatively, the equation of motion is solved in terms of wp-Weierstrass elliptic function. Thus, we find the deflection angle for photons without using any approximation, which is a novel result for this kind of gravity.

  4. Review of OCA activities on nulling testbench PERSEE

    NASA Astrophysics Data System (ADS)

    Hénault, François; Girard, Paul; Marcotto, Aurélie; Mauclert, Nicolas; Bailet, Christophe; Clausse, Jean-Michel; Mourard, Denis; Rabbia, Yves; Roussel, Alain; Barillot, Marc; Cassaing, Frédéric; Le Duigou, Jean-Michel

    2010-07-01

    We present a review of our activities on PERSEE (Pégase Experiment for Research and Stabilization of Extreme Extinction) at Observatoire de la Côte d'Azur (OCA). PERSEE is a laboratory testbench aiming at achieving a stabilized nulling ratio better than 10-4 in the astronomical bands K and M, in presence of flight-representative spacecraft perturbations. The bench has been jointly developed by a Consortium of six French institutes and companies, among which OCA was responsible for the star simulator and of the opto-mechanical studies, procurement and manufacturing of the optical train. In this communication are presented the alignment and image quality requirements and the optomechanical design of the illumination module and main optical train, including a periscope Achromatic Phase Shifter (APS), tip-tilt mirrors used to introduce and then compensate for dynamic disturbances, delay lines, beam compressors and fiber injection optics. Preliminary test results of the star simulator are also provided.

  5. Histone H1 null vertebrate cells exhibit altered nucleosome architecture

    PubMed Central

    Hashimoto, Hideharu; Takami, Yasunari; Sonoda, Eiichiro; Iwasaki, Tomohito; Iwano, Hidetomo; Tachibana, Makoto; Takeda, Shunichi; Nakayama, Tatsuo; Kimura, Hiroshi; Shinkai, Yoichi

    2010-01-01

    In eukaryotic nuclei, DNA is wrapped around an octamer of core histones to form nucleosomes, and chromatin fibers are thought to be stabilized by linker histones of the H1 type. Higher eukaryotes express multiple variants of histone H1; chickens possess six H1 variants. Here, we generated and analyzed the phenotype of a complete deletion of histone H1 genes in chicken cells. The H1-null cells showed decreased global nucleosome spacing, expanded nuclear volumes, and increased chromosome aberration rates, although proper mitotic chromatin structure appeared to be maintained. Expression array analysis revealed that the transcription of multiple genes was affected and was mostly downregulated in histone H1-deficient cells. This report describes the first histone H1 complete knockout cells in vertebrates and suggests that linker histone H1, while not required for mitotic chromatin condensation, plays important roles in nucleosome spacing and interphase chromatin compaction and acts as a global transcription regulator. PMID:20156997

  6. Dinucleotide controlled null models for comparative RNA gene prediction

    PubMed Central

    Gesell, Tanja; Washietl, Stefan

    2008-01-01

    Background Comparative prediction of RNA structures can be used to identify functional noncoding RNAs in genomic screens. It was shown recently by Babak et al. [BMC Bioinformatics. 8:33] that RNA gene prediction programs can be biased by the genomic dinucleotide content, in particular those programs using a thermodynamic folding model including stacking energies. As a consequence, there is need for dinucleotide-preserving control strategies to assess the significance of such predictions. While there have been randomization algorithms for single sequences for many years, the problem has remained challenging for multiple alignments and there is currently no algorithm available. Results We present a program called SISSIz that simulates multiple alignments of a given average dinucleotide content. Meeting additional requirements of an accurate null model, the randomized alignments are on average of the same sequence diversity and preserve local conservation and gap patterns. We make use of a phylogenetic substitution model that includes overlapping dependencies and site-specific rates. Using fast heuristics and a distance based approach, a tree is estimated under this model which is used to guide the simulations. The new algorithm is tested on vertebrate genomic alignments and the effect on RNA structure predictions is studied. In addition, we directly combined the new null model with the RNAalifold consensus folding algorithm giving a new variant of a thermodynamic structure based RNA gene finding program that is not biased by the dinucleotide content. Conclusion SISSIz implements an efficient algorithm to randomize multiple alignments preserving dinucleotide content. It can be used to get more accurate estimates of false positive rates of existing programs, to produce negative controls for the training of machine learning based programs, or as standalone RNA gene finding program. Other applications in comparative genomics that require randomization of multiple

  7. Cadmium modulates adipocyte functions in metallothionein-null mice

    SciTech Connect

    Kawakami, Takashige; Nishiyama, Kaori; Kadota, Yoshito; Sato, Masao; Inoue, Masahisa; Suzuki, Shinya

    2013-11-01

    Our previous study has demonstrated that exposure to cadmium (Cd), a toxic heavy metal, causes a reduction of adipocyte size and the modulation of adipokine expression. To further investigate the significance of the Cd action, we studied the effect of Cd on the white adipose tissue (WAT) of metallothionein null (MT{sup −/−}) mice, which cannot form atoxic Cd–MT complexes and are used for evaluating Cd as free ions, and wild type (MT{sup +/+}) mice. Cd administration more significantly reduced the adipocyte size of MT{sup −/−} mice than that of MT{sup +/+} mice. Cd exposure also induced macrophage recruitment to WAT with an increase in the expression level of Ccl2 (MCP-1) in the MT{sup −/−} mice. The in vitro exposure of Cd to adipocytes induce triglyceride release into culture medium, decrease in the expression levels of genes involved in fatty acid synthesis and lipid hydrolysis at 24 h, and at 48 h increase in phosphorylation of the lipid-droplet-associated protein perilipin, which facilitates the degradation of stored lipids in adipocytes. Therefore, the reduction in adipocyte size by Cd may arise from an imbalance between lipid synthesis and lipolysis. In addition, the expression levels of leptin, adiponectin and resistin decreased in adipocytes. Taken together, exposure to Cd may induce unusually small adipocytes and modulate the expression of adipokines differently from the case of physiologically small adipocytes, and may accelerate the risk of developing insulin resistance and type 2 diabetes. - Highlights: • Cd causes a marked reduction in adipocyte size in MT-null mice. • Cd enhances macrophage migration into adipose tissue and disrupt adipokine secretion. • MT gene alleviates Cd-induced adipocyte dysfunctions. • Cd enhances the degradation of stored lipids in adipocytes, mediated by perilipin. • Cd induces unusually small adipocytes and the abnormal expression of adipokines.

  8. Genetic Correlations Greatly Increase Mutational Robustness and Can Both Reduce and Enhance Evolvability

    PubMed Central

    Greenbury, Sam F.; Schaper, Steffen; Ahnert, Sebastian E.; Louis, Ard A.

    2016-01-01

    Mutational neighbourhoods in genotype-phenotype (GP) maps are widely believed to be more likely to share characteristics than expected from random chance. Such genetic correlations should strongly influence evolutionary dynamics. We explore and quantify these intuitions by comparing three GP maps—a model for RNA secondary structure, the HP model for protein tertiary structure, and the Polyomino model for protein quaternary structure—to a simple random null model that maintains the number of genotypes mapping to each phenotype, but assigns genotypes randomly. The mutational neighbourhood of a genotype in these GP maps is much more likely to contain genotypes mapping to the same phenotype than in the random null model. Such neutral correlations can be quantified by the robustness to mutations, which can be many orders of magnitude larger than that of the null model, and crucially, above the critical threshold for the formation of large neutral networks of mutationally connected genotypes which enhance the capacity for the exploration of phenotypic novelty. Thus neutral correlations increase evolvability. We also study non-neutral correlations: Compared to the null model, i) If a particular (non-neutral) phenotype is found once in the 1-mutation neighbourhood of a genotype, then the chance of finding that phenotype multiple times in this neighbourhood is larger than expected; ii) If two genotypes are connected by a single neutral mutation, then their respective non-neutral 1-mutation neighbourhoods are more likely to be similar; iii) If a genotype maps to a folding or self-assembling phenotype, then its non-neutral neighbours are less likely to be a potentially deleterious non-folding or non-assembling phenotype. Non-neutral correlations of type i) and ii) reduce the rate at which new phenotypes can be found by neutral exploration, and so may diminish evolvability, while non-neutral correlations of type iii) may instead facilitate evolutionary exploration and so

  9. Over-fitting Time Series Models of Air Pollution Health Effects: Smoothing Tends to Bias Non-Null Associations Towards the Null.

    EPA Science Inventory

    Background: Simulation studies have previously demonstrated that time-series analyses using smoothing splines correctly model null health-air pollution associations. Methods: We repeatedly simulated season, meteorology and air quality for the metropolitan area of Atlanta from cyc...

  10. How to find magnetic null and construct field topology with MMS data?

    NASA Astrophysics Data System (ADS)

    Fu, Huishan; Vaivads, Andris; Khotyaintsev, Yuri; Olshevsky, Vyacheslav; Andre, Mats; Cao, Jinbin; Huang, Shiyong; Retino, Alessandro; Eastwood, Jonathan

    2015-04-01

    In this study, we apply a new method'Taylor expansion'to find magnetic null and construct magnetic field topology, in order to use it with the data from the forth-coming MMS mission. We compare this method with the previously used Poincare index (PI), and find that they are generally consistent, except that the PI method can only find a null inside the spacecraft (SC) tetrahedron, while the Taylor expansion can find a null both inside and outside the tetrahedron and also deduce its drift velocity. Taylor expansion can also: (1) avoid the limitations of PI method such as data resolution, instrument uncertainty (Bz offset), and SC separation; (2) identify 3D null types (A, B, As, and Bs) and determine whether these types can degenerate into 2D (X and O); (3) construct the magnetic field topology. We quantitively test the accurateness of Taylor expansion in positioning magnetic null and constructing field topology, by using the data from 3D kinetic simulations. The influences of SC separation (from 0.05 to 1 di) and null-SC distance (from 0 to 1 di) on the accurateness are both considered. We find that: (1) for single null, the method is accurate when the SC separation is smaller than 1 di, and the null-SC distance is smaller than 0.5 di (weakly chaotic reconnection) or 0.25 di (strongly chaotic reconnection); (2) for null pair, the accurateness is same as the single-null situation, except at the null-null line, where the field is nonlinear. We invent a parameter ξ ≡|(λ1 + λ2 + λ3)|/ |λ|max to quantify the quality of the method'the smaller this parameter the better the results. Comparing to the previously used one (η ≡|downtriangle -B|/ |downtriangle × B |), this parameter is more relevant. Using the new method, we construct the magnetic field topology around a radial-type null and a spiral-type null, and find that the topologies are well consistent with those predicted in theory. This means that our method is reliable. We therefore suggest using this

  11. FAK mediates a compensatory survival signal parallel to PI3K-AKT in PTEN-null T-ALL cells.

    PubMed

    You, Dewen; Xin, Junping; Volk, Andrew; Wei, Wei; Schmidt, Rachel; Scurti, Gina; Nand, Sucha; Breuer, Eun-Kyoung; Kuo, Paul C; Breslin, Peter; Kini, Ameet R; Nishimura, Michael I; Zeleznik-Le, Nancy J; Zhang, Jiwang

    2015-03-31

    Mutations and inactivation of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) are observed in 15%-25% of cases of human T cell acute lymphoblastic leukemia (T-ALL). Pten deletion induces myeloproliferative disorders (MPDs), acute myeloid leukemia (AML), and/or T-ALL in mice. Previous studies attributed Pten-loss-related hematopoietic defects and leukemogenesis to excessive activation of phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signaling. Although inhibition of this signal dramatically suppresses the growth of PTEN-null T-ALL cells in vitro, treatment with inhibitors of this pathway does not cause a complete remission in vivo. Here, we report that focal adhesion kinase (Fak), a protein substrate of Pten, also contributes to T-ALL development in Pten-null mice. Inactivation of the FAK signaling pathway by either genetic or pharmacologic methods significantly sensitizes both murine and human PTEN-null T-ALL cells to PI3K/AKT/mTOR inhibition when cultured in vitro on feeder layer cells or a matrix and in vivo. PMID:25801032

  12. Characterization and purification of Adh distal promoter factor 2, Adf-2, a cell-specific and promoter-specific repressor in Drosophila.

    PubMed Central

    Benyajati, C; Ewel, A; McKeon, J; Chovav, M; Juan, E

    1992-01-01

    Chromatin footprinting in Drosophila tissue culture cells has detected the binding of a non-histone protein at +8 of the distal Adh RNA start site, on a 10-bp direct repeat motif abutting a nucleosome positioned over the inactive Adh distal promoter. Alternatively the active promoter is bound by a transcription initiation complex. We have characterized and purified a protein Adf-2 that binds specifically to this direct repeat motif 5'TCTCAGTGCA3', present at +8 and -202 of the distal RNA start site. DNase I footprinting, methylation interference, and UV-crosslinking analyses showed that both direct repeats interact in vitro with a nuclear protein of approximately 120 kilodaltons (kDa). We purified Adf-2 through multiple rounds of sequence-specific DNA affinity chromatography. Southwestern analysis showed that the purified 120 KDa polypeptide binds the Adf-2 motif efficiently as a monomer or homomultimer. In vivo titrations of Adf-2 activity with the Adf-2 motif by transient co-transfection competitions in different Drosophila cell lines suggested that Adf-2 is a cell-specific repressor. Adf-2 has been detected ubiquitously in vitro, but is functional in vivo as a sequence-specific DNA binding protein and repressor only in the cells that have the inactive distal promoter. We discuss the possibility that an activation process is required for Adf-2 protein to bind DNA and function in vivo. Images PMID:1408750

  13. Efficient production of lycopene in Saccharomyces cerevisiae by expression of synthetic crt genes from a plasmid harboring the ADH2 promoter.

    PubMed

    Bahieldin, Ahmed; Gadalla, Nour O; Al-Garni, Saleh M; Almehdar, Hussein; Noor, Samah; Hassan, Sabah M; Shokry, Ahmed M; Sabir, Jamal S M; Murata, Norio

    2014-03-01

    Lycopene is an effective antioxidant proposed as a possible treatment for some cancers and other degenerative human conditions. This study aims at generation of a yeast strain (Saccharomyces cerevisiae) of efficient productivity of lycopene by overexpressing synthetic genes derived from crtE, crtB and crtI genes of Erwinia uredovora. These synthetic genes were constructed in accordance with the preferred codon usage in S. cerevisiae but with no changes in amino acid sequences of the gene products. S. cerevisiae cells were transformed with these synthetic crt genes, whose expression was regulated by the ADH2 promoter, which is de-repressed upon glucose depletion. The RT-PCR and Western blotting analyses indicated that the synthetic crt genes were efficiently transcribed and translated in crt-transformed S. cerevisiae cells. The highest level of lycopene in one of the transformed lines was 3.3mglycopene/g dry cell weight, which is higher than the previously reported levels of lycopene in other microorganisms transformed with the three genes. These results suggest the excellence of using the synthetic crt genes and the ADH2 promoter in generation of recombinant S. cerevisiae that produces a high level of lycopene. The level of ergosterol was reversely correlated to that of lycopene in crt-transformed S. cerevisiae cells, suggesting that two pathways for lycopene and ergosterol syntheses compete for the use of farnesyl diphosphate. PMID:24680933

  14. One-step fabrication of integrated disposable biosensor based on ADH/NAD+/meldola's blue/graphitized mesoporous carbons/chitosan nanobiocomposite for ethanol detection.

    PubMed

    Hua, Erhui; Wang, Li; Jing, Xiaoying; Chen, Changtao; Xie, Guoming

    2013-07-15

    A novel strategy to simplify the dehydrogenase-based electrochemical biosensor fabrication through one-step drop-coating nanobiocomposite on a screen printed electrode (SPE) was developed. The nanobiocomposite was prepared by successively adding graphitized mesoporous carbons (GMCs), meldola's blue (MDB), alcohol dehydrogenase (ADH) and cofactor nicotinamide adenine dinucleotide (NAD(+)) in chitosan (CS) solution. MDB/GMCs/CS film was prepared. Cyclic voltammetry measurements demonstrated that MDB was strongly adsorbed on GMCs. After optimizing the concentration of MDB and the working potential, the MDB/GMCs/CS film presented a fast amperometric response (5s), excellent sensitivity (10.36 nA μM(-1)), wide linear range (10-410 μM) toward NADH and without any other interference signals (such as AA, UA, DA, H2O2 and metal ions). Furthermore, concentrations of ADH and NAD(+) in nanobiocomposite and the detection conditions (temperature and pH) were also optimized. The constructed disposable ethanol biosensor showed an excellent linear response ranged from 0.5 to 15 mM with high sensitivity (67.28 nA mM(-1)) and a low limit of detection (80 μM) and a remarkable long-term stability (40 days). The intra-batch and inter-batch variation coefficients were both less than 5% (n=5). The ethanol recovery test demonstrated that the proposed biosensor offered a remarkable and accurate method for ethanol detection in the real blood samples. PMID:23622540

  15. Language Learnability and Empirical Plausibility: Null Subjects and Indirect Negative Evidence.

    ERIC Educational Resources Information Center

    Saleemi, Anjum P.

    Children's ability to learn aspects of their language in the absence of supportive evidence is discussed. Specifically, the learnability of null subjects in languages in which they appear is examined when indirect negative evidence is present. It is concluded that parameters such as the null subject parameter may not generate languages, strictly…

  16. Qualification of a Null Lens Using Image-Based Phase Retrieval

    NASA Technical Reports Server (NTRS)

    Bolcar, Matthew R.; Aronstein, David L.; Hill, Peter C.; Smith, J. Scott; Zielinski, Thomas P.

    2012-01-01

    In measuring the figure error of an aspheric optic using a null lens, the wavefront contribution from the null lens must be independently and accurately characterized in order to isolate the optical performance of the aspheric optic alone. Various techniques can be used to characterize such a null lens, including interferometry, profilometry and image-based methods. Only image-based methods, such as phase retrieval, can measure the null-lens wavefront in situ - in single-pass, and at the same conjugates and in the same alignment state in which the null lens will ultimately be used - with no additional optical components. Due to the intended purpose of a Dull lens (e.g., to null a large aspheric wavefront with a near-equal-but-opposite spherical wavefront), characterizing a null-lens wavefront presents several challenges to image-based phase retrieval: Large wavefront slopes and high-dynamic-range data decrease the capture range of phase-retrieval algorithms, increase the requirements on the fidelity of the forward model of the optical system, and make it difficult to extract diagnostic information (e.g., the system F/#) from the image data. In this paper, we present a study of these effects on phase-retrieval algorithms in the context of a null lens used in component development for the Climate Absolute Radiance and Refractivity Observatory (CLARREO) mission. Approaches for mitigation are also discussed.

  17. Overt vs. Null Direct Objects in Spoken Brazilian Portuguese: A Semantic/Pragmatic Account.

    ERIC Educational Resources Information Center

    Schwenter, Scott A.; Silva, Glaucia

    2002-01-01

    Examines the semantic/pragmatic constraints on null objects spoken in Brazilian Portuguese (BP) in detail, and situates BP null objects in the broader crosslinguistic perspective of differential object marking. Demonstrates that semantic/pragmatic dimensions of animacy and specificity, and in particular their interaction, must be taken into…

  18. Agreement and Null Subjects in German L2 Development: New Evidence from Reaction-Time Experiments.

    ERIC Educational Resources Information Center

    Clahsen, Harald; Hong, Upyong

    1995-01-01

    Reports on reaction time experiments investigating subject-verb agreement and null subjects in 33 Korean learners of German and a control group of 20 German native speakers. Results found that the two phenomena do not covary in the Korean learners, indicating that properties of agreement and null subjects are acquired separately from one another.…

  19. A Minimalist Approach to Null Subjects and Objects in Second Language Acquisition

    ERIC Educational Resources Information Center

    Park, H.

    2004-01-01

    Studies of the second language acquisition of pronominal arguments have observed that: (1) L1 speakers of null subject languages of the Spanish type drop more subjects in their second language (L2) English than first language (L1) speakers of null subject languages of the Korean type and (2) speakers of Korean-type languages drop more objects than…

  20. BMPER Mutation in Diaphanospondylodysostosis Identified by Ancestral Autozygosity Mapping and Targeted High-Throughput Sequencing

    PubMed Central

    Funari, Vincent A.; Krakow, Deborah; Nevarez, Lisette; Chen, Zugen; Funari, Tara L.; Vatanavicharn, Nithiwat; Wilcox, William R.; Rimoin, David L.; Nelson, Stanley F.; Cohn, Daniel H.

    2010-01-01

    Diaphanospondylodysostosis (DSD) is a rare, recessively inherited, perinatal lethal skeletal disorder. The low frequency and perinatal lethality of DSD makes assembling a large set of families for traditional linkage-based genetic approaches challenging. By searching for evidence of unknown ancestral consanguinity, we identified two autozygous intervals, comprising 34 Mbps, unique to a single case of DSD. Empirically testing for ancestral consanguinity was effective in localizing the causative variant, thereby reducing the genomic space within which the mutation resides. High-throughput sequence analysis of exons captured from these intervals demonstrated that the affected individual was homozygous for a null mutation in BMPER, which encodes the bone morphogenetic protein-binding endothelial cell precursor-derived regulator. Mutations in BMPER were subsequently found in three additional DSD cases, confirming that defects in BMPER produce DSD. Phenotypic similarities between DSD and Bmper null mice indicate that BMPER-mediated signaling plays an essential role in vertebral segmentation early in human development. PMID:20869035

  1. Mutation and the environment

    SciTech Connect

    Mendelsohn, M.L. ); Albertini, R.J. )

    1990-01-01

    This book is organized under the following headings: Plenary lectures; Brook mutational mechanisms; Adduction and DNA damage; Recombination and gene conversion; Repair: Prokoyote mechanisms and induction; Repair: Lower eukaryote and plant mechanisms; Repair: Higher eukaryote mechanisms and selectivity; Repair: Human genes and mechanisms; Mutation: Spectra and mechanisms; Mutation: Shuttle vectors; Mutation: Transgenic animals; New methods: Polymerase chain reaction.

  2. Mutation of either G box or I box sequences profoundly affects expression from the Arabidopsis rbcS-1A promoter.

    PubMed Central

    Donald, R G; Cashmore, A R

    1990-01-01

    A deletion analysis of the Arabidopsis thaliana rbcS-1A promoter defined a 196 bp region (-320 to -125) sufficient to confer light-regulated expression on a heterologous Arabidopsis alcohol dehydrogenase (Adh) reporter gene in transgenic Nicotiana tabacum (tobacco) leaves. This region, which contains DNA sequences I, G and GT boxes, with homology to other ribulose-1,5-bisphosphate carboxylase small subunit (RBCS) gene promoter sequences, directed expression independent of orientation and relative position in the Adh promoter. Site-specific mutagenesis of these conserved sequences and subsequent expression analysis in transgenic tobacco showed that both G box and I box mutations in the context of the full (-1700 to +21) rbcS-1A promoter substantially reduced the expression of Adh and beta-glucuronidase (GUS) reporter genes. The G box has previously been shown to specifically bind in vitro a factor isolated from nuclear extracts of tomato and Arabidopsis. This factor (GBF) is distinct from the factor GT-1 which binds to adjacent GT boxes in the pea rbcS-3A promoter. Multiple mutations in putative Arabidopsis rbcS-1A promoter GT boxes had no pronounced affect on expression, possibly due to a redundancy of these sites. Experiments in which rbcS-1A promoter fragments were fused to truncated 35S CaMV (cauliflower mosaic virus) promoter--GUS reporter constructs showed that cis-acting CaMV promoter elements could partially restore expression to G-box-mutated rbcS-1A sequences. Images Fig. 1. Fig. 2. Fig. 4. Fig. 5. Fig. 6. PMID:2347304

  3. Mutations in the circadian gene period alter behavioral and biochemical responses to ethanol in Drosophila.

    PubMed

    Liao, Jennifer; Seggio, Joseph A; Ahmad, S Tariq

    2016-04-01

    Clock genes, such as period, which maintain an organism's circadian rhythm, can have profound effects on metabolic activity, including ethanol metabolism. In turn, ethanol exposure has been shown in Drosophila and mammals to cause disruptions of the circadian rhythm. Previous studies from our labs have shown that larval ethanol exposure disrupted the free-running period and period expression of Drosophila. In addition, a recent study has shown that arrhythmic flies show no tolerance to ethanol exposure. As such, Drosophila period mutants, which have either a shorter than wild-type free-running period (perS) or a longer one (perL), may also exhibit altered responses to ethanol due to their intrinsic circadian differences. In this study, we tested the initial sensitivity and tolerance of ethanol exposure on Canton-S, perS, and perL, and then measured their Alcohol Dehydrogenase (ADH) and body ethanol levels. We showed that perL flies had slower sedation rate, longer recovery from ethanol sedation, and generated higher tolerance for sedation upon repeated ethanol exposure compared to Canton-S wild-type flies. Furthermore, perL flies had lower ADH activity and had a slower ethanol clearance compared to wild-type flies. The findings of this study suggest that period mutations influence ethanol induced behavior and ethanol metabolism in Drosophila and that flies with longer circadian periods are more sensitive to ethanol exposure. PMID:26802726

  4. Tumor microvasculature with endothelial fenestrations in VHL null clear cell renal cell carcinomas as a potent target of anti-angiogenic therapy.

    PubMed

    Yamasaki, Toshinari; Kamba, Tomomi; Kanno, Toru; Inoue, Takahiro; Shibasaki, Noboru; Arakaki, Ryuichiro; Yamada, Tomomi; Kondo, Keiichi; Kamoto, Toshiyuki; Nishiyama, Hiroyuki; Ogawa, Osamu; Nakamura, Eijiro

    2012-11-01

    Vascular endothelial growth factor (VEGF)-targeted therapies show significant antitumor effects for advanced clear cell renal cell carcinomas (CC-RCCs). Previous studies using VEGF inhibitors in mice models revealed that VEGF-dependent capillaries were characterized by the existence of endothelial fenestrations (EFs). In this study, we revealed that capillaries with abundant EFs did exist, particularly in CC-RCCs harboring VHL mutation. This finding was recapitulated in mice xenograft models, in which tumors from VHL null cells showed more abundant EFs compared to those from VHL wild-type cells. Importantly, treatment with bevacizumab resulted in a significant decrease of tumor size established from VHL null cells. Additionally, a significant reduction of EFs and microvessel density was observed in VHL null tumors. Indeed, xenograft from 786-O/mock (pRC3) cells developed four times more abundant EFs than that from 786-O/VHL (WT8). However, introduction of the constitutively active form of hypoxia-inducible factor (HIF)-2α to WT8 cells failed to either augment the number of EFs or restore the sensitivity to bevacizumab in mice xenograft, irrespective of the equivalent production of VEGF to 786-O/mock cells. These results indicated that HIF-2α independent factors also play significant roles in the development of abundant EFs. In fact, several angiogenesis-related genes including CCL2 were upregulated in 786-O cells in a HIF-2α independent manner. Treatment with CCL2 neutralizing antibody caused significant reduction of capillaries with EFs in 786-O xenograft, indicating that they were also sensitive to CCL2 inhibition as well as VEGF. Collectively, these results strongly indicated that capillaries with distinctive phenotype developed in VHL null CC-RCCs are potent targets for anti-angiogenic therapy. PMID:22931246

  5. Homozygosity and Heterozygosity for Null Col5a2 Alleles Produce Embryonic Lethality and a Novel Classic Ehlers-Danlos Syndrome-Related Phenotype.

    PubMed

    Park, Arick C; Phillips, Charlotte L; Pfeiffer, Ferris M; Roenneburg, Drew A; Kernien, John F; Adams, Sheila M; Davidson, Jeffrey M; Birk, David E; Greenspan, Daniel S

    2015-07-01

    Null alleles for the COL5A1 gene and missense mutations for COL5A1 or the COL5A2 gene underlie cases of classic Ehlers-Danlos syndrome, characterized by fragile, hyperextensible skin and hypermobile joints. However, no classic Ehlers-Danlos syndrome case has yet been associated with COL5A2 null alleles, and phenotypes that might result from such alleles are unknown. We describe mice with null alleles for the Col5a2. Col5a2(-/-) homozygosity is embryonic lethal at approximately 12 days post conception. Unlike previously described mice null for Col5a1, which die at 10.5 days post conception and virtually lack collagen fibrils, Col5a2(-/-) embryos have readily detectable collagen fibrils, thicker than in wild-type controls. Differences in Col5a2(-/-) and Col5a1(-/-) fibril formation and embryonic survival suggest that α1(V)3 homotrimers, a rare collagen V isoform that occurs in the absence of sufficient levels of α2(V) chains, serve functional roles that partially compensate for loss of the most common collagen V isoform. Col5a2(+/-) adults have skin with marked hyperextensibility and reduced tensile strength at high strain but not at low strain. Col5a2(+/-) adults also have aortas with increased compliance and reduced tensile strength. Results thus suggest that COL5A2(+/-) humans, although unlikely to present with frank classic Ehlers-Danlos syndrome, are likely to have fragile connective tissues with increased susceptibility to trauma and certain chronic pathologic conditions. PMID:25987251

  6. Local recombination and mutation effects on molecular evolution in Drosophila.

    PubMed Central

    Takano-Shimizu, T

    1999-01-01

    I studied the cause of the significant difference in the synonymous-substitution pattern found in the achaete-scute complex genes in two Drosophila lineages, higher codon bias in Drosophila yakuba, and lower bias in D. melanogaster. Besides these genes, the functionally unrelated yellow gene showed the same substitution pattern, suggesting a region-dependent phenomenon in the X-chromosome telomere. Because the numbers of A/T --> G/C substitutions were not significantly different from those of G/C --> A/T in the yellow noncoding regions of these species, a AT/GC mutational bias could not completely account for the synonymous-substitution biases. In contrast, we did find an approximately 14-fold difference in recombination rates in the X-chromosome telomere regions between the two species, suggesting that the reduction of recombination rates in this region resulted in the reduction of the efficacy of selection in D. melanogaster. In addition, the D. orena yellow showed a 5% increase in the G + C content at silent sites in the coding and noncoding regions since the divergence from D. erecta. This pattern was significantly different from those at the orena Adh and Amy loci. These results suggest that local changes in recombination rates and mutational pressures are contributing to the irregular synonymous-substitution patterns in Drosophila. PMID:10545459

  7. Molecular basis for the catalytic inactivity of a naturally occurring near-null variant of human ALOX15.

    PubMed

    Horn, Thomas; Ivanov, Igor; Di Venere, Almerinda; Kakularam, Kumar Reddy; Reddanna, Pallu; Conrad, Melanie L; Richter, Constanze; Scheerer, Patrick; Kuhn, Hartmut

    2013-12-01

    Mammalian lipoxygenases belong to a family of lipid-peroxidizing enzymes, which have been implicated in cardiovascular, hyperproliferative and neurodegenerative diseases. Here we report that a naturally occurring mutation in the hALOX15 gene leads to expression of a catalytically near-null enzyme variant (hGly422Glu). The inactivity may be related to severe misfolding of the enzyme protein, which was concluded from CD-spectra as well as from thermal and chemical stability assays. In silico mutagenesis experiments suggest that most mutations at hGly422 have the potential to induce sterical clash, which might be considered a reason for protein misfolding. hGly422 is conserved among ALOX5, ALOX12 and ALOX15 isoforms and corresponding hALOX12 and hALOX5 mutants also exhibited a reduced catalytic activity. Interestingly, in the hALOX5 Gly429Glu mutants the reaction specificity of arachidonic acid oxygenation was shifted from 5S- to 8S- and 12R-H(p)ETE formation. Taken together, our data indicate that the conserved glycine is of functional importance for these enzyme variants and most mutants at this position lose catalytic activity. PMID:23958500

  8. Why Are Flare Ribbons Associated with the Spines of Magnetic Null Points Generically Elongated?

    NASA Astrophysics Data System (ADS)

    Pontin, David; Galsgaard, Klaus; Démoulin, Pascal

    2016-08-01

    Coronal magnetic null points exist in abundance, as demonstrated by extrapolations of the coronal field, and have been inferred to be important for a broad range of energetic events. These null points and their associated separatrix and spine field lines represent discontinuities of the field line mapping, making them preferential locations for reconnection. This field line mapping also exhibits strong gradients adjacent to the separatrix (fan) and spine field lines, which can be analysed using the "squashing factor", Q. In this article we analyse in detail the distribution of Q in the presence of magnetic nulls. While Q is formally infinite on both the spine and fan of the null, the decay of Q away from these structures is shown in general to depend strongly on the null-point structure. For the generic case of a non-radially-symmetric null, Q decays most slowly away from the spine or fan in the direction in which |{B}| increases most slowly. In particular, this demonstrates that the extended elliptical high-Q halo around the spine footpoints observed by Masson et al. ( Astrophys. J. 700, 559, 2009) is a generic feature. This extension of the Q halos around the spine or fan footpoints is important for diagnosing the regions of the photosphere that are magnetically connected to any current layer that forms at the null. In light of this, we discuss how our results can be used to interpret the geometry of observed flare ribbons in circular ribbon flares, in which typically a coronal null is implicated. We conclude that both the physics in the vicinity of the null and how this is related to the extension of Q away from the spine or fan can be used in tandem to understand observational signatures of reconnection at coronal null points.

  9. Why Are Flare Ribbons Associated with the Spines of Magnetic Null Points Generically Elongated?

    NASA Astrophysics Data System (ADS)

    Pontin, David; Galsgaard, Klaus; Démoulin, Pascal

    2016-06-01

    Coronal magnetic null points exist in abundance, as demonstrated by extrapolations of the coronal field, and have been inferred to be important for a broad range of energetic events. These null points and their associated separatrix and spine field lines represent discontinuities of the field line mapping, making them preferential locations for reconnection. This field line mapping also exhibits strong gradients adjacent to the separatrix (fan) and spine field lines, which can be analysed using the "squashing factor", Q. In this article we analyse in detail the distribution of Q in the presence of magnetic nulls. While Q is formally infinite on both the spine and fan of the null, the decay of Q away from these structures is shown in general to depend strongly on the null-point structure. For the generic case of a non-radially-symmetric null, Q decays most slowly away from the spine or fan in the direction in which |{B}| increases most slowly. In particular, this demonstrates that the extended elliptical high- Q halo around the spine footpoints observed by Masson et al. (Astrophys. J. 700, 559, 2009) is a generic feature. This extension of the Q halos around the spine or fan footpoints is important for diagnosing the regions of the photosphere that are magnetically connected to any current layer that forms at the null. In light of this, we discuss how our results can be used to interpret the geometry of observed flare ribbons in circular ribbon flares, in which typically a coronal null is implicated. We conclude that both the physics in the vicinity of the null and how this is related to the extension of Q away from the spine or fan can be used in tandem to understand observational signatures of reconnection at coronal null points.

  10. Mecp2-Null Mice Provide New Neuronal Targets for Rett Syndrome

    PubMed Central

    Urdinguio, Rocio G.; Lopez-Serra, Lidia; Lopez-Nieva, Pilar; Alaminos, Miguel; Diaz-Uriarte, Ramon; Fernandez, Agustin F.; Esteller, Manel

    2008-01-01

    Background Rett syndrome (RTT) is a complex neurological disorder that is one of the most frequent causes of mental retardation in women. A great landmark in research in this field was the discovery of a relationship between the disease and the presence of mutations in the gene that codes for the methyl-CpG binding protein 2 (MeCP2). Currently, MeCP2 is thought to act as a transcriptional repressor that couples DNA methylation and transcriptional silencing. The present study aimed to identify new target genes regulated by Mecp2 in a mouse model of RTT. Methodology/Principal Findings We have compared the gene expression profiles of wild type (WT) and Mecp2-null (KO) mice in three regions of the brain (cortex, midbrain, and cerebellum) by using cDNA microarrays. The results obtained were confirmed by quantitative real-time PCR. Subsequent chromatin immunoprecipitation assays revealed seven direct target genes of Mecp2 bound in vivo (Fkbp5, Mobp, Plagl1, Ddc, Mllt2h, Eya2, and S100a9), and three overexpressed genes due to an indirect effect of a lack of Mecp2 (Irak1, Prodh and Dlk1). The regions bound by Mecp2 were always methylated, suggesting the involvement of the methyl-CpG binding domain of the protein in the mechanism of interaction. Conclusions We identified new genes that are overexpressed in Mecp2-KO mice and are excellent candidate genes for involvement in various features of the neurological disease. Our results demonstrate new targets of MeCP2 and provide us with a better understanding of the underlying mechanisms of RTT. PMID:18989361

  11. Mitochondrial impairment observed in fibroblasts from South African Parkinson’s disease patients with parkin mutations

    SciTech Connect

    Merwe, Celia van der; Loos, Ben; Swart, Chrisna; Kinnear, Craig; Merwe, Lize van der; Pillay, Komala; Muller, Nolan; Zaharie, Dan; Engelbrecht, Lize; Carr, Jonathan; and others

    2014-05-02

    Highlights: • Mitochondrial dysfunction observed in patients with parkin-null mutations. • Mitochondrial ATP levels were decreased. • Electron-dense vacuoles were observed in the patients. • Mitochondria from muscle biopsies appeared within normal limits. • One patient did not show these defects possibly due to compensatory mechanisms. - Abstract: Parkinson’s disease (PD), defined as a neurodegenerative disorder, is characterized by the loss of dopaminergic neurons in the substantia nigra in the midbrain. Loss-of-function mutations in the parkin gene are a major cause of autosomal recessive, early-onset PD. Parkin has been implicated in the maintenance of healthy mitochondria, although previous studies show conflicting findings regarding mitochondrial abnormalities in fibroblasts from patients harboring parkin-null mutations. The aim of the present study was to determine whether South African PD patients with parkin mutations exhibit evidence for mitochondrial dysfunction. Fibroblasts were cultured from skin biopsies obtained from three patients with homozygous parkin-null mutations, two heterozygous mutation carriers and two wild-type controls. Muscle biopsies were obtained from two of the patients. The muscle fibers showed subtle abnormalities such as slightly swollen mitochondria in focal areas of the fibers and some folding of the sarcolemma. Although no differences in the degree of mitochondrial network branching were found in the fibroblasts, ultrastructural abnormalities were observed including the presence of electron-dense vacuoles. Moreover, decreased ATP levels which are consistent with mitochondrial dysfunction were observed in the patients’ fibroblasts compared to controls. Remarkably, these defects did not manifest in one patient, which may be due to possible compensatory mechanisms. These results suggest that parkin-null patients exhibit features of mitochondrial dysfunction. Involvement of mitochondria as a key role player in PD

  12. Identification of a null allele in genetic tests for bovine leukocyte adhesion deficiency in Pakistani Bos indicus × Bos taurus cattle.

    PubMed

    Nasreen, Fozia; Malik, Naveed A; Qureshi, Javed A; Raadsma, Herman W; Tammen, Imke

    2012-12-01

    Two clinically healthy mature Pakistani Bos indicus × Bos taurus cattle were genotyped as homozygous affected for the lethal immunodeficiency disorder bovine leukocyte adhesion deficiency (BLAD) using previously described PCR-RFLP based DNA tests which was confirmed by sequencing. Sequencing of Bos taurus and B. indicus × B. taurus genomic DNA surrounding the disease causing mutation (c.383A > G) in the ITGB2 gene identified numerous variations in exonic and intronic regions within and between species, including substantial variation in primer annealing sites for three PCR-RFLP tests for one of the B. indicus allelic variants. These variations in the primer annealing sites resulted in a null allele in the DNA tests causing the misdiagnosis of some heterozygous B. taurus × B. indicus cattle to be classified as homozygous affected. New primers were designed and a modified test was developed which simultaneously identified the disease mutation and the Pakistani B. indicus allelic variant associated with the null allele in the previous test. PMID:22374219

  13. Caveolin-3 null mice show a loss of caveolae, changes in the microdomain distribution of the dystrophin-glycoprotein complex, and t-tubule abnormalities.

    PubMed

    Galbiati, F; Engelman, J A; Volonte, D; Zhang, X L; Minetti, C; Li, M; Hou, H; Kneitz, B; Edelmann, W; Lisanti, M P

    2001-06-15

    Caveolin-3, a muscle-specific caveolin-related protein, is the principal structural protein of caveolae membrane domains in striated muscle cells. Recently, we identified a novel autosomal dominant form of limb-girdle muscular dystrophy (LGMD-1C) in humans that is due to mutations within the coding sequence of the human caveolin-3 gene (3p25). These LGMD-1C mutations lead to an approximately 95% reduction in caveolin-3 protein expression, i.e. a caveolin-3 deficiency. Here, we created a caveolin-3 null (CAV3 -/-) mouse model, using standard homologous recombination techniques, to mimic a caveolin-3 deficiency. We show that these mice lack caveolin-3 protein expression and sarcolemmal caveolae membranes. In addition, analysis of skeletal muscle tissue from these caveolin-3 null mice reveals: (i) mild myopathic changes; (ii) an exclusion of the dystrophin-glycoprotein complex from lipid raft domains; and (iii) abnormalities in the organization of the T-tubule system, with dilated and longitudinally oriented T-tubules. These results have clear mechanistic implications for understanding the pathogenesis of LGMD-1C at a molecular level. PMID:11259414

  14. Spatial effects in real networks: Measures, null models, and applications

    NASA Astrophysics Data System (ADS)

    Ruzzenenti, Franco; Picciolo, Francesco; Basosi, Riccardo; Garlaschelli, Diego

    2012-12-01

    Spatially embedded networks are shaped by a combination of purely topological (space-independent) and space-dependent formation rules. While it is quite easy to artificially generate networks where the relative importance of these two factors can be varied arbitrarily, it is much more difficult to disentangle these two architectural effects in real networks. Here we propose a solution to this problem, by introducing global and local measures of spatial effects that, through a comparison with adequate null models, effectively filter out the spurious contribution of nonspatial constraints. Our filtering allows us to consistently compare different embedded networks or different historical snapshots of the same network. As a challenging application we analyze the World Trade Web, whose topology is known to depend on geographic distances but is also strongly determined by nonspatial constraints (degree sequence or gross domestic product). Remarkably, we are able to detect weak but significant spatial effects both locally and globally in the network, showing that our method succeeds in retrieving spatial information even when nonspatial factors dominate. We finally relate our results to the economic literature on gravity models and trade globalization.

  15. Impairment in motor learning of somatostatin null mutant mice.

    PubMed

    Zeyda, T; Diehl, N; Paylor, R; Brennan, M B; Hochgeschwender, U

    2001-07-01

    Somatostatin was first identified as a hypothalamic factor which inhibits the release of growth hormone from the anterior pituitary (somatotropin release inhibitory factor, SRIF). Both SRIF and its receptors were subsequently found widely distributed within and outside the nervous system, in the adult as well as in the developing organism. Reflecting this wide distribution, somatostatin has been implicated regulating a diverse array of biological processes. These include body growth, homeostasis, sensory perception, autonomous functions, rate of intestinal absorption, behavior, including cognition and memory, and developmental processes. We produced null mutant mice lacking somatostatin through targeted mutagenesis. The mutant mice are healthy, fertile, and superficially indistinguishable from their heterozygous and wildtype littermates. A 'first round' phenotype screen revealed that mice lacking somatostatin have elevated plasma growth hormone levels, despite normal body size, and have elevated basal plasma corticosterone levels. In order to uncover subtle and unexpected differences, we carried out a systematic behavioral phenotype screen which identified a significant impairment in motor learning revealed when increased demands were made on motor coordination. Motor coordination and motor learning require an intact cerebellum. While somatostatin is virtually absent from the adult cerebellum, the ligand and its receptor(s) are transiently expressed at high levels in the developing cerebellum. This result suggests the functional significance of transient expression of SRIF and its receptors in the development of the cerebellum. PMID:11430867

  16. Identification of Siglec-1 null individuals infected with HIV-1

    PubMed Central

    Martinez-Picado, Javier; McLaren, Paul J.; Erkizia, Itziar; Martin, Maureen P.; Benet, Susana; Rotger, Margalida; Dalmau, Judith; Ouchi, Dan; Wolinsky, Steven M.; Penugonda, Sudhir; Günthard, Huldrych F.; Fellay, Jacques; Carrington, Mary; Izquierdo-Useros, Nuria; Telenti, Amalio

    2016-01-01

    Siglec-1/CD169 is a myeloid-cell surface receptor critical for HIV-1 capture and infection of bystander target cells. To dissect the role of SIGLEC1 in natura, we scan a large population genetic database and identify a loss-of-function variant (Glu88Ter) that is found in ∼1% of healthy people. Exome analysis and direct genotyping of 4,233 HIV-1-infected individuals reveals two Glu88Ter homozygous and 97 heterozygous subjects, allowing the analysis of ex vivo and in vivo consequences of SIGLEC1 loss-of-function. Cells from these individuals are functionally null or haploinsufficient for Siglec-1 activity in HIV-1 capture and trans-infection ex vivo. However, Siglec-1 protein truncation does not have a measurable impact on HIV-1 acquisition or AIDS outcomes in vivo. This result contrasts with the known in vitro functional role of Siglec-1 in HIV-1 trans-infection. Thus, it provides evidence that the classical HIV-1 infectious routes may compensate for the lack of Siglec-1 in fuelling HIV-1 dissemination within infected individuals. PMID:27510803

  17. Characterization of deformable elastic lenses using PDI and null screen

    NASA Astrophysics Data System (ADS)

    Santiago Alvarado, A.; Granados Agustín, F. S.; Vázquez Montiel, S.; Campos García, M.; Dìaz Uribe, R.

    2009-06-01

    In recent years there has been a considerable increase in the use of variable focal length lenses (VFLL), due to the fact that they are used as micro lenses in photographic cameras, endoscope, etc. The VFLL's come mainly in three types, one of them are formed of two transparent elastic membranes with a liquid medium between them, those made of an elastic material inside a mount which allow radial forces to be applied on its perimeter, and finally those which are made of a dielectric liquid medium. In these VFLL always have a mechanism that allows the shape of the lens and its geometrical parameters can be changed. In this study, we implement a mechanical mount to applied radial force, in the perimeter of a solid elastic lens. We measure the aberrations of wavefront present in deformable solid elastic lens (VFLL), when we change the radial forces applied on its borders. The wave sensor used were the Point Diffraction Interferometer (PDI) and null screen tests. Theoretical and experimental results are presented.

  18. Identification of Siglec-1 null individuals infected with HIV-1.

    PubMed

    Martinez-Picado, Javier; McLaren, Paul J; Erkizia, Itziar; Martin, Maureen P; Benet, Susana; Rotger, Margalida; Dalmau, Judith; Ouchi, Dan; Wolinsky, Steven M; Penugonda, Sudhir; Günthard, Huldrych F; Fellay, Jacques; Carrington, Mary; Izquierdo-Useros, Nuria; Telenti, Amalio

    2016-01-01

    Siglec-1/CD169 is a myeloid-cell surface receptor critical for HIV-1 capture and infection of bystander target cells. To dissect the role of SIGLEC1 in natura, we scan a large population genetic database and identify a loss-of-function variant (Glu88Ter) that is found in ∼1% of healthy people. Exome analysis and direct genotyping of 4,233 HIV-1-infected individuals reveals two Glu88Ter homozygous and 97 heterozygous subjects, allowing the analysis of ex vivo and in vivo consequences of SIGLEC1 loss-of-function. Cells from these individuals are functionally null or haploinsufficient for Siglec-1 activity in HIV-1 capture and trans-infection ex vivo. However, Siglec-1 protein truncation does not have a measurable impact on HIV-1 acquisition or AIDS outcomes in vivo. This result contrasts with the known in vitro functional role of Siglec-1 in HIV-1 trans-infection. Thus, it provides evidence that the classical HIV-1 infectious routes may compensate for the lack of Siglec-1 in fuelling HIV-1 dissemination within infected individuals. PMID:27510803

  19. Cosmologies with null singularities and their gauge theory duals

    SciTech Connect

    Das, Sumit R.; Michelson, Jeremy; Narayan, K.; Trivedi, Sandip P.

    2007-01-15

    We investigate backgrounds of Type IIB string theory with null singularities and their duals proposed in S. R. Das, J. Michelson, K. Narayan, S. P. Trivedi, hep-th/0602107. The dual theory is a deformed N=4 Yang-Mills theory in 3+1 dimensions with couplings dependent on a lightlike direction. We concentrate on backgrounds which become AdS{sub 5}xS{sup 5} at early and late times and where the string coupling is bounded, vanishing at the singularity. Our main conclusion is that in these cases the dual gauge theory is nonsingular. We show this by arguing that there exists a complete set of gauge invariant observables in the dual gauge theory whose correlation functions are nonsingular at all times. The two-point correlator for some operators calculated in the gauge theory does not agree with the result from the bulk supergravity solution. However, the bulk calculation is invalid near the singularity where corrections to the supergravity approximation become important. We also obtain pp-waves which are suitable Penrose limits of this general class of solutions, and construct the matrix membrane theory which describes these pp-wave backgrounds.

  20. Magnetic flipping - Reconnection in three dimensions without null points

    NASA Technical Reports Server (NTRS)

    Priest, E. R.; Forbes, T. G.

    1992-01-01

    In three dimensions, magnetic reconnection may take place in a sheared magnetic field at any singular field line, where the nearby field has X-type topology in planes perpendicular to the field line and where an electric field is present parallel to the field line. In the ideal region around the singular line there will, in general, be singularities in the plasma flow and electric field, both at the singular line and at 'magnetic flipping layers', which are remnants of local magnetic separatrices. In the absence of a three-dimensional magnetic neutral point or null point, reconnection of field lines can still occur by a process of magnetic flipping, in which the plasma crosses the flipping layers but the field lines rapidly flip along them by magnetic diffusion. Depending on the boundary conditions, there may be two or four flipping layers which converge on the singular line. A boundary layer analysis of a flipping layer is given, in which the magnetic field parallel to the layer decreases as one crosses it while the plasma pressure (or magnetic pressure associated with the field along the singular line) increases. The width of the flipping layer decreases with distance from the singular line.

  1. Aspects of QCD current algebra on a null plane

    NASA Astrophysics Data System (ADS)

    Beane, S. R.; Hobbs, T. J.

    2016-09-01

    Consequences of QCD current algebra formulated on a light-like hyperplane are derived for the forward scattering of vector and axial-vector currents on an arbitrary hadronic target. It is shown that current algebra gives rise to a special class of sum rules that are direct consequences of the independent chiral symmetry that exists at every point on the two-dimensional transverse plane orthogonal to the lightlike direction. These sum rules are obtained by exploiting the closed, infinite-dimensional algebra satisfied by the transverse moments of null-plane axial-vector and vector charge distributions. In the special case of a nucleon target, this procedure leads to the Adler-Weisberger, Gerasimov-Drell-Hearn, Cabibbo-Radicati and Fubini-Furlan-Rossetti sum rules. Matching to the dispersion-theoretic language which is usually invoked in deriving these sum rules, the moment sum rules are shown to be equivalent to algebraic constraints on forward S-matrix elements in the Regge limit.

  2. A Null Relationship between Media Multitasking and Well-Being

    PubMed Central

    Shih, Shui-I

    2013-01-01

    There is a rapidly increasing trend in media-media multitasking or MMM (using two or more media concurrently). In a recent conference, scholars from diverse disciplines expressed concerns that indulgence in MMM may compromise well-being and/or cognitive abilities. However, research on MMM's impacts is too sparse to inform the general public and policy makers whether MMM should be encouraged, managed, or minimized. The primary purpose of the present study was to develop an innovative computerized instrument – the Survey of the Previous Day (SPD) – to quantify MMM as well as media-nonmedia and nonmedia-nonmedia multitasking and sole-tasking. The secondary purpose was to examine whether these indices could predict a sample of well-being related, psychosocial measures. In the SPD, participants first recalled (typed) what they did during each hour of the previous day. In later parts of the SPD, participants analysed activities and their timing and duration for each hour of the previous day, while relevant recall was on display. Participants also completed the Media Use Questionnaire. The results showed non-significant relationship between tasking measures and well-being related measures. Given how little is known about the associations between MMM and well-being, the null results may offer some general reassurance to those who are apprehensive about negative impacts of MMM. PMID:23691236

  3. Identifying True Cortical Interactions in MEG using the Nulling Beamformer

    PubMed Central

    Hui, Hua Brian; Pantazis, Dimitrios; Bressler, Steven L.; Leahy, Richard M.

    2009-01-01

    Modeling functional brain interaction networks using non-invasive EEG and MEG data is more challenging than using intracranial recording data. This is because most interaction measures are not robust to the cross-talk (interference) between cortical regions, which may arise due to the limited spatial resolution of EEG/MEG inverse procedures. In this paper we describe a modified beam-forming approach to accurately measure cortical interactions from EEG/MEG data, designed to suppress cross-talk between cortical regions. We estimate interaction measures from the output of the modified beamformer and test for statistical significance using permutation tests. Since the underlying neuronal sources and their interactions are unknown in real MEG data, we demonstrate the performance of the proposed beamforming method in a novel simulation scheme, where intracranial recordings from a macaque monkey are used as neural sources to simulate realistic MEG signals. The advantage of this approach is that local field potentials are more realistic representations of true neuronal sources than simulation models and therefore are more suitable to indicate the performance of our nulling beamforming method. PMID:19896541

  4. Invariance Techniques And High-Resolution Null Steering

    NASA Astrophysics Data System (ADS)

    Roy, R.; Kailath, T.

    1988-02-01

    Over the past several decades, a significant amount of research has been performed in the area of high-resolution signal parameter estimation. It is a problem of significance in many signal processing applications including direction-of-arrival estimation in which the locations of multiple sources whose radiation is received by an array of sensors are sought. Much of the research has focussed on approaches based on the formation of optimal weight or copy vectors, procedures derived from the conventional practice of beamforming. This class of approached to parameter estimation problems has come to be known as high-resolution spectral analysis/beamforming since the introduction of the maximum entropy (MEM) method by Burg in 1967, and the maximum-likelihood (ML) method by Capon in 1969. These techniques provide increased resolution and accuracy over their predecessors (including conventional beamforming, but suffer from model mismatch. MUSIC and ESPRIT are recently developed geometric techniques that exploit the underlying model and thereby achieve significant improvements in performance. In this paper, these techniques are summarized. From basic physical principles, it is shown that ESPRIT is actually a multidimensional null steering algorithm, an interpretation with significant intuitive appeal. Finally, optimal signal copy vectors that naturally arise from the algorithm are presented, and their properties as beamforming vectors for this class of problems are discussed.

  5. Transgenic expression of Dspp partially rescued the long bone defects of Dmp1-null mice.

    PubMed

    Jani, Priyam H; Gibson, Monica P; Liu, Chao; Zhang, Hua; Wang, Xiaofang; Lu, Yongbo; Qin, Chunlin

    2016-01-01

    Dentin matrix protein 1 (DMP1) and dentin sialophosphoprotein (DSPP) belong to the Small Integrin-Binding Ligand N-linked Glycoprotein (SIBLING) family. In addition to the features common to all SIBLING members, DMP1 and DSPP share several unique similarities in chemical structure, proteolytic activation and tissue localization. Mutations in, or deletion of DMP1, cause autosomal recessive hypophosphatemic rickets along with dental defects; DSPP mutations or its ablation are associated with dentinogenesis imperfecta. While the roles and functional mechanisms of DMP1 in osteogenesis have been extensively studied, those of DSPP in long bones have been studied only to a limited extent. Previous studies by our group revealed that transgenic expression of Dspp completely rescued the dentin defects of Dmp1-null (Dmp1(-/-)) mice. In this investigation, we assessed the effects of transgenic Dspp on osteogenesis by analyzing the formation and mineralization of the long bones in Dmp1(-/-) mice that expresses a transgene encoding full-length DSPP driven by a 3.6-kb rat Col1a1 promoter (referred as "Dmp1(-/-);Dspp-Tg mice"). We characterized the long bones of the Dmp1(-/-);Dspp-Tg mice at different ages and compared them with those from Dmp1(-/-) and Dmp1(+/-) (normal control) mice. Our analyses showed that the long bones of Dmp1(-/-);Dspp-Tg mice had a significant increase in cortical bone thickness, bone volume and mineral density along with a remarkable restoration of trabecular thickness compared to those of the Dmp1(-/-) mice. The long bones of Dmp1(-/-);Dspp-Tg mice underwent a dramatic reduction in the amount of osteoid, significant improvement of the collagen fibrillar network, and better organization of the lacunocanalicular system, compared to the Dmp1(-/-) mice. The elevated levels of biglycan, bone sialoprotein and osteopontin in Dmp1(-/-) mice were also noticeably corrected by the transgenic expression of Dspp. These findings suggest that DSPP and DMP1 may function

  6. Enhanced Tumor Formation in Mice Heterozygous for Blm Mutation

    NASA Astrophysics Data System (ADS)

    Heppner Goss, Kathleen; Risinger, Mary A.; Kordich, Jennifer J.; Sanz, Maureen M.; Straughen, Joel E.; Slovek, Lisa E.; Capobianco, Anthony J.; German, James; Boivin, Gregory P.; Groden, Joanna

    2002-09-01

    Persons with the autosomal recessive disorder Bloom syndrome are predisposed to cancers of many types due to loss-of-function mutations in the BLM gene, which encodes a recQ-like helicase. Here we show that mice heterozygous for a targeted null mutation of Blm, the murine homolog of BLM, develop lymphoma earlier than wild-type littermates in response to challenge with murine leukemia virus and develop twice the number of intestinal tumors when crossed with mice carrying a mutation in the Apctumor suppressor. These observations indicate that Blm is a modifier of tumor formation in the mouse and that Blm haploinsufficiency is associated with tumor predisposition, a finding with important implications for cancer risk in humans.

  7. The association of glutathione S-transferase gene mutations (including GSTT1 and GSTM1) with the prognostic factors and relapse in acute lymphoblastic leukemia.

    PubMed

    Zareifar, Soheila; Monabati, Ahmad; Saeed, Amir; Fakhraee, Farzaneh; Cohan, Nader

    2013-09-01

    Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. It accounts for one fourth of all childhood cancers and approximately 75% of all childhood leukemias. Some prognostic factors determine the outcome of therapy [e.g. age, sex, initial white blood cell count (WBC), etc.]; however, it is believed that other mechanisms such as glutathione S-transferase (GST) gene mutation, the expression of lung resistance protein (LRP), and multidrug resistance-associated protein (MRP) also plays a role in treatment failure. In this study, GST gene mutations including GSTM1 and GSTT1 were evaluated in patients with leukemia. Thirty newly diagnosed ALL patients younger than 15 years of age participated in the present study. Bone marrow aspiration and biopsy were evaluated for immune phenotyping and DNA was extracted for GST genotyping. All data plus sex, age, initial WBC count, central nervous system (CNS) or testicular involvement, immune phenotype, and outcome (relapse or not) were analyzed statistically. Genotyping showed that 46% were double null, 50% were M1 null and 93.3% were T1 null for GST mutations. There was no statistically significant relationship between GSTT1 and GSTM1 mutations, or between double null status, prognostic factors and relapse (P > .05). So, although the results of GST mutations were consistent, it seems that these mutations are not statistically significant. PMID:23444902

  8. Why are flare ribbons generically elongated in configurations with magnetic null points?

    NASA Astrophysics Data System (ADS)

    Pontin, David Iain; Galsgaard, Klaus; Demoulin, Pascal

    2016-05-01

    Coronal magnetic null points exist in abundance as demonstrated by extrapolations of the coronal field, and have been inferred to be important for a broad range of energetic events. These null points and their associated separatrix and spine field lines represent discontinuities of the field line mapping, making them preferential locations for reconnection in the corona. In addition, the field line mapping in the vicinity of these null points exhibits strong gradients as measured by the “squashing factor”, Q. We demonstrate that the extension of the Q halos around the spine/fan footpoints is in general important for diagnosing the regions of the photosphere that are magnetically connected to any current layer that forms at the null. In light of this, we discuss the extent to which our results can be used to interpret the geometry of observed flare ribbons in events in which a coronal null is implicated. We conclude that together the physics in the vicinity of the null and how this is related to the extension of Q away from the spine/fan can be used in tandem to understand observational signatures of reconnection at coronal null points.

  9. Progesterone facilitates chromosome instability (aneuploidy) in p53 null normal mammary epithelial cells

    NASA Technical Reports Server (NTRS)

    Goepfert, T. M.; McCarthy, M.; Kittrell, F. S.; Stephens, C.; Ullrich, R. L.; Brinkley, B. R.; Medina, D.

    2000-01-01

    Mammary epithelial cells from p53 null mice have been shown recently to exhibit an increased risk for tumor development. Hormonal stimulation markedly increased tumor development in p53 null mammary cells. Here we demonstrate that mammary tumors arising in p53 null mammary cells are highly aneuploid, with greater than 70% of the tumor cells containing altered chromosome number and a mean chromosome number of 56. Normal mammary cells of p53 null genotype and aged less than 14 wk do not exhibit aneuploidy in primary cell culture. Significantly, the hormone progesterone, but not estrogen, increases the incidence of aneuploidy in morphologically normal p53 null mammary epithelial cells. Such cells exhibited 40% aneuploidy and a mean chromosome number of 54. The increase in aneuploidy measured in p53 null tumor cells or hormonally stimulated normal p53 null cells was not accompanied by centrosome amplification. These results suggest that normal levels of progesterone can facilitate chromosomal instability in the absence of the tumor suppressor gene, p53. The results support the emerging hypothesis based both on human epidemiological and animal model studies that progesterone markedly enhances mammary tumorigenesis.

  10. Reduced arsenic clearance and increased toxicity in aquaglyceroporin-9-null mice

    PubMed Central

    Carbrey, Jennifer M.; Song, Linhua; Zhou, Yao; Yoshinaga, Masafumi; Rojek, Aleksandra; Wang, Yiding; Liu, Yangjian; Lujan, Heidi L.; DiCarlo, Stephen E.; Nielsen, Søren; Rosen, Barry P.; Agre, Peter; Mukhopadhyay, Rita

    2009-01-01

    Expressed in liver, aquaglyceroporin-9 (AQP9) is permeated by glycerol, arsenite, and other small, neutral solutes. To evaluate a possible protective role, AQP9-null mice were evaluated for in vivo arsenic toxicity. After injection with NaAsO2, AQP9-null mice suffer reduced survival rates (LD50, 12 mg/kg) compared with WT mice (LD50, 15 mg/kg). The highest tissue level of arsenic is in heart, with AQP9-null mice accumulating 10–20 times more arsenic than WT mice. Within hours after NaAsO2 injection, AQP9-null mice sustain profound bradycardia, despite normal serum electrolytes. Increased arsenic levels are also present in liver, lung, spleen, and testis of AQP9-null mice. Arsenic levels in the feces and urine of AQP9-null mice are only ≈10% of the WT levels, and reduced clearance of multiple arsenic species by the AQP9-null mice suggests that AQP9 is involved in the export of multiple forms of arsenic. Immunohistochemical staining of liver sections revealed that AQP9 is most abundant in basolateral membrane of hepatocytes adjacent to the sinusoids. AQP9 is not detected in heart or kidney by PCR or immunohistochemistry. We propose that AQP9 provides a route for excretion of arsenic by the liver, thereby providing partial protection of the whole animal from arsenic toxicity. PMID:19805235

  11. Investigation of nulling and subpulse drifting properties of PSR J1727-2739

    NASA Astrophysics Data System (ADS)

    Wen, Z. G.; Wang, N.; Yuan, J. P.; Yan, W. M.; Manchester, R. N.; Yuen, R.; Gajjar, V.

    2016-08-01

    Aims: We intend to study of the nulling and subpulse drifting in PSR J1727-2739 in detail to investigate its radiation properties. Methods: The observations were carried out on 20 March, 2004 using the Parkes 64-m radio telescope with a central frequency of 1518 MHz. A total of 5568 single pulses were analysed. Results: This pulsar shows well-defined nulls with lengths lasting from 6 to 281 pulses and separated by burst phases ranging from 2 to 133 pulses. We estimate a nulling fraction of around 68%. No emission in the average pulse profile integrated over all null pulses is detected with significance above 3σ. Most transitions from nulls to bursts are within a few pulses, whereas the transitions from bursts to nulls exhibit two patterns of decay; these transitions either decrease gradually or rapidly. In the burst phase, we find that there are two distinct subpulse drift modes with vertical spacing between the drift bands of 9.7 ± 1.6 and 5.2 ± 0.9 pulse periods, while sometimes there is a third mode with no subpulse drifting. Some mode transitions occur within a single burst, while others are separated by nulls. Different modes have different average pulse profiles. Possible physical mechanisms are discussed.

  12. Functional expression and cellular distribution of diastrophic dysplasia sulfate transporter (DTDST) gene mutations in HEK cells.

    PubMed

    Karniski, Lawrence P

    2004-10-01

    Defects in sulfate transport in chondrocytes lead to undersulfation of the cartilage extracellular matrix proteoglycans. Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene have been linked to four chondrodysplasias of varying severity. To characterize disease-causing mutations of DTDST, we expressed DTDST-mediated sulfate transport in mammalian HEK-293 cells and determined that the wild-type protein is glycosylated and localized to the cell plasma membrane. Four mutations, A715V, C653S, Q454P and R279W, stimulated sulfate transport at rates only 39-62% of wild-type DTDST. These four mutations were expressed on the plasma membrane of the cell, but the amount of expressed protein was reduced when compared with wild-type DTDST. The Q454P mutant is unique in that it is not properly glycosylated in HEK cells. There was no difference in sulfate transport activity between cells transfected with either the DeltaV340 or the G678V mutations and control HEK cells. Furthermore, the G678V mutation is not expressed along the plasma membrane, but is trapped within the cytoplasm. When comparing the sulfate transport capacity of each DTDST mutation with the chondrodysplasia in which it has been identified, we find that individuals with severe achondrogenesis 1B phenotype have null mutations on both DTDST alleles. Heterozygotes for both a null mutation and a partial-function mutation result in either atelosteogenesis type 2 or DTD, whereas the milder, recessive multiple epiphyseal dysplasia phenotype is homozygous for partial-function mutations. In contrast to previous studies in Xenopus laevis oocytes, we find a strong correlation between the severity of the phenotype and the level of residual transport function in mammalian cells. PMID:15294877

  13. Mechanical Forces Exacerbate Periodontal Defects in Bsp-null Mice

    PubMed Central

    Soenjaya, Y.; Foster, B.L.; Nociti, F.H.; Ao, M.; Holdsworth, D.W.; Hunter, G.K.; Somerman, M.J.

    2015-01-01

    Bone sialoprotein (BSP) is an acidic phosphoprotein with collagen-binding, cell attachment, and hydroxyapatite-nucleating properties. BSP expression in mineralized tissues is upregulated at onset of mineralization. Bsp-null (Bsp-/-) mice exhibit reductions in bone mineral density, bone turnover, osteoclast activation, and impaired bone healing. Furthermore, Bsp-/- mice have marked periodontal tissue breakdown, with a lack of acellular cementum leading to periodontal ligament detachment, extensive alveolar bone and tooth root resorption, and incisor malocclusion. We hypothesized that altered mechanical stress from mastication contributes to periodontal destruction observed in Bsp-/- mice. This hypothesis was tested by comparing Bsp-/- and wild-type mice fed with standard hard pellet diet or soft powder diet. Dentoalveolar tissues were analyzed using histology and micro–computed tomography. By 8 wk of age, Bsp-/- mice exhibited molar and incisor malocclusion regardless of diet. Bsp-/- mice with hard pellet diet exhibited high incidence (30%) of severe incisor malocclusion, 10% lower body weight, 3% reduced femur length, and 30% elevated serum alkaline phosphatase activity compared to wild type. Soft powder diet reduced severe incisor malocclusion incidence to 3% in Bsp-/- mice, supporting the hypothesis that occlusal loading contributed to the malocclusion phenotype. Furthermore, Bsp-/- mice in the soft powder diet group featured normal body weight, long bone length, and serum alkaline phosphatase activity, suggesting that tooth dysfunction and malnutrition contribute to growth and skeletal defects reported in Bsp-/- mice. Bsp-/- incisors also erupt at a slower rate, which likely leads to the observed thickened dentin and enhanced mineralization of dentin and enamel toward the apical end. We propose that the decrease in eruption rate is due to a lack of acellular cementum and associated defective periodontal attachment. These data demonstrate the importance of BSP

  14. Mechanical Forces Exacerbate Periodontal Defects in Bsp-null Mice.

    PubMed

    Soenjaya, Y; Foster, B L; Nociti, F H; Ao, M; Holdsworth, D W; Hunter, G K; Somerman, M J; Goldberg, H A

    2015-09-01

    Bone sialoprotein (BSP) is an acidic phosphoprotein with collagen-binding, cell attachment, and hydroxyapatite-nucleating properties. BSP expression in mineralized tissues is upregulated at onset of mineralization. Bsp-null (Bsp(-/-)) mice exhibit reductions in bone mineral density, bone turnover, osteoclast activation, and impaired bone healing. Furthermore, Bsp(-/-) mice have marked periodontal tissue breakdown, with a lack of acellular cementum leading to periodontal ligament detachment, extensive alveolar bone and tooth root resorption, and incisor malocclusion. We hypothesized that altered mechanical stress from mastication contributes to periodontal destruction observed in Bsp(-/-) mice. This hypothesis was tested by comparing Bsp(-/-) and wild-type mice fed with standard hard pellet diet or soft powder diet. Dentoalveolar tissues were analyzed using histology and micro-computed tomography. By 8 wk of age, Bsp(-/-) mice exhibited molar and incisor malocclusion regardless of diet. Bsp(-/-) mice with hard pellet diet exhibited high incidence (30%) of severe incisor malocclusion, 10% lower body weight, 3% reduced femur length, and 30% elevated serum alkaline phosphatase activity compared to wild type. Soft powder diet reduced severe incisor malocclusion incidence to 3% in Bsp(-/-) mice, supporting the hypothesis that occlusal loading contributed to the malocclusion phenotype. Furthermore, Bsp(-/-) mice in the soft powder diet group featured normal body weight, long bone length, and serum alkaline phosphatase activity, suggesting that tooth dysfunction and malnutrition contribute to growth and skeletal defects reported in Bsp(-/-) mice. Bsp(-/-) incisors also erupt at a slower rate, which likely leads to the observed thickened dentin and enhanced mineralization of dentin and enamel toward the apical end. We propose that the decrease in eruption rate is due to a lack of acellular cementum and associated defective periodontal attachment. These data demonstrate the

  15. Integrated optics for nulling interferometry in the thermal infrared

    NASA Astrophysics Data System (ADS)

    Barillot, Marc; Barthelemy, Eleonore; Broquin, Jean-Emmanuel; Frayret, Jérôme; Grelin, Jérôme; Hawkins, Gary; Kirschner, Volker; Parent, Gilles; Pradel, Annie; Rossi, Emmanuel; Vigreux, Caroline; Zhang, Shaoqian; Zhang, Xianghua

    2008-07-01

    Modal filtering is based on the capability of single-mode waveguides to transmit only one complex amplitude function to eliminate virtually any perturbation of the interfering wavefronts, thus making very high rejection ratios possible in a nulling interferometer. In the present paper we focus on the progress of Integrated Optics in the thermal infrared [6-20μm] range, one of the two candidate technologies for the fabrication of Modal Filters, together with fiber optics. In conclusion of the European Space Agency's (ESA) "Integrated Optics for Darwin" activity, etched layers of chalcogenide material deposited on chalcogenide glass substrates was selected among four candidates as the technology with the best potential to simultaneously meet the filtering efficiency, absolute and spectral transmission, and beam coupling requirements. ESA's new "Integrated Optics" activity started at mid-2007 with the purpose of improving the technology until compliant prototypes can be manufactured and validated, expectedly by the end of 2009. The present paper aims at introducing the project and the components requirements and functions. The selected materials and preliminary designs, as well as the experimental validation logic and test benches are presented. More details are provided on the progress of the main technology: vacuum deposition in the co-evaporation mode and subsequent etching of chalcogenide layers. In addition, preliminary investigations of an alternative technology based on burying a chalcogenide optical fiber core into a chalcogenide substrate are presented. Specific developments of anti-reflective solutions designed for the mitigation of Fresnel losses at the input and output surface of the components are also introduced.

  16. Lateral shearing with a pair of double Fresnel rhombs for nulling interferometry.

    PubMed

    Baba, Naoshi; Kobayashi, Keita; Kogoma, Yusuke; Murakami, Naoshi

    2011-09-15

    A lateral-shearing interferometer with a pair of double Fresnel rhombs is proposed. Use of Fresnel rhombs enables us to accomplish simultaneously lateral shearing and achromatic nulling. Nulling interferometry with lateral shearing is one of the basic methods for searching directly for extrasolar planets with a segmented-mirror telescope. Here the Thirty-Meter Telescope is considered as a model of a segmented-mirror telescope. Our computer simulations show high extinction for the K-band (2.0-2.4 μm). Optical experiments are conducted to verify the lateral shearing and nulling with a pair of double Fresnel rhombs. PMID:21931407

  17. Survival of glucose phosphate isomerase null somatic cells and germ cells in adult mouse chimaeras

    PubMed Central

    Keighren, Margaret A.; Flockhart, Jean H.

    2016-01-01

    ABSTRACT The mouse Gpi1 gene encodes the glycolytic enzyme glucose phosphate isomerase. Homozygous Gpi1−/− null mouse embryos die but a previous study showed that some homozygous Gpi1−/− null cells survived when combined with wild-type cells in fetal chimaeras. One adult female Gpi1−/−↔Gpi1c/c chimaera with functional Gpi1−/− null oocytes was also identified in a preliminary study. The aims were to characterise the survival of Gpi1−/− null cells in adult Gpi1−/−↔Gpi1c/c chimaeras and determine if Gpi1−/− null germ cells are functional. Analysis of adult Gpi1−/−↔Gpi1c/c chimaeras with pigment and a reiterated transgenic lineage marker showed that low numbers of homozygous Gpi1−/− null cells could survive in many tissues of adult chimaeras, including oocytes. Breeding experiments confirmed that Gpi1−/− null oocytes in one female Gpi1−/−↔Gpi1c/c chimaera were functional and provided preliminary evidence that one male putative Gpi1−/−↔Gpi1c/c chimaera produced functional spermatozoa from homozygous Gpi1−/− null germ cells. Although the male chimaera was almost certainly Gpi1−/−↔Gpi1c/c, this part of the study is considered preliminary because only blood was typed for GPI. Gpi1−/− null germ cells should survive in a chimaeric testis if they are supported by wild-type Sertoli cells. It is also feasible that spermatozoa could bypass a block at GPI, but not blocks at some later steps in glycolysis, by using fructose, rather than glucose, as the substrate for glycolysis. Although chimaera analysis proved inefficient for studying the fate of Gpi1−/− null germ cells, it successfully identified functional Gpi1−/− null oocytes and revealed that some Gpi1−/− null cells could survive in many adult tissues. PMID:27103217

  18. Visualization of redundancy resolution for kinematically redundant robots through the Jacobian null space

    NASA Technical Reports Server (NTRS)

    Chen, Yu-Che; Walker, Ian D.; Cheatham, John B., Jr.

    1992-01-01

    We present a unified formulation for the inverse kinematics of redundant arms, based on a special formulation of the null space of the Jacobian. By extending (appropriately re-scaling) previously used null space parameterizations, we obtain, in a unified fashion, the manipulability measure, the null space projector, and particular solutions for the joint velocities. We obtain the minimum norm pseudo-inverse solution as a projection from any particular solution, and the method provides an intuitive visualization of the self-motion. The result is a computationally efficient, consistent approach to computing redundant robot inverse kinematics.

  19. Effets du Parecoxib dans la Prévention des Adhérences abdominales postopératoires: étude expérimentale randomisée chez les rats

    PubMed Central

    Arung, Willy; Tshilombo, François; Odimba, Etienne

    2015-01-01

    Introduction Bien d’études ont été menées sur les adhérences intrapéritonéales, mais aucune unanimité n'est encore acquise sur leur prévention. Le but de notre étude a été d’évaluer le potentiel effet d'un antiinflammatoire, parecoxib dans la prévention des adhérences ainsi que sur la cicatrisation chez des rats. Méthodes Dans un modèle expérimental d'adhérences postopératoires secondaires à des lésions péritonéales par brûlure, 30 rats furent randomisés en trois groupes suivant le mode d'administration de parecoxib (groupe contrôle; intrapéritonéal; intramusculaire. Résultats Le parecoxib a significativement diminué la quantité (p < .05) et la sévérité (p < .01) des adhérences postopératoires dans les deux modèles expérimentaux. Au total, 21 rats ont développé des adhérences, respectivement 9 (100%) dans le groupe A, 5 (50%) dans le groupe B et 7 (70%) dans le groupe C (p = 0.05). Du point de vue de la formation des adhérences au site du traumatisme, dix-neuf rats en ont développé: 9 (100%) dans le groupe A et 5 (50%) pour chacun de deux autres groupes B et C. Une différence significative a été constatée en comparant ces groupes deux à deux: A vs B (p < 0.05); A vs C (p < 0,05). Parecoxib n'a pas compromis la cicatrisation intestinale, ni cutanée. Conclusion Cette étude a montré que le parecoxib pouvait réduire la formation des adhérences postopératoires. La confirmation de la sécurité du parecoxib sur les anastomoses intestinales doit être investiguée au cours d'autres expérimentations. PMID:26966478

  20. Mutagenic effect of tritium on DNA of Drosophila melanogaster: Comprehensive performance report, June 1, 1988--June 30, 1989

    SciTech Connect

    Lee, W.R.

    1989-01-01

    The first objective was to induce mutations at the Adh locus in Drosophila melanogaster using the procedures and dosimetry that we have reprints developed. The linear dose response for the doses used by others would indicate that at that high dose, the mutations will be based predominately on the same mechanisms of mutagenesis as that of lower exposure levels. The frequency of mutations induced at 25G is 100 times the spontaneous frequency; therefore, the mutation spectrum should be that of the tritium beta radiation with a non significant contribution from spontaneous mutations. These tritium induced null mutations were then analyzed by complementation genetic tests using both deletions and specific locus mutations near the Adh locus. Following the genetic analysis, molecular analysis will be conducted on these mutations. 1 tab.

  1. Feedback Control of Sex Determination by Dosage Compensation Revealed through Caenorhabditis Elegans Sdc-3 Mutations

    PubMed Central

    DeLong, L.; Plenefisch, J. D.; Klein, R. D.; Meyer, B. J.

    1993-01-01

    In Caenorhabditis elegans, sex determination and dosage compensation are coordinately controlled through a group of genes that respond to the primary sex determination signal. Here we describe a new gene, sdc-3, that also controls these processes. In contrast to previously described genes, the sex determination and dosage compensation activities of sdc-3 are separately mutable, indicating that they function independently. Paradoxically, the sdc-3 null phenotype fails to reveal the role of sdc-3 in sex determination: sdc-3 null mutations that lack both activities disrupt dosage compensation but cause no overt sexual transformation. We demonstrate that the dosage compensation defect of sdc-3 null alleles suppresses their sex determination defect. This self-suppression phenomenon provides a striking example of how a disruption in dosage compensation can affect sexual fate. We propose that the suppression occurs via a feedback mechanism that acts at an early regulatory step in the sex determination pathway to promote proper sexual identity. PMID:8462848

  2. CF Mutation Panel

    MedlinePlus

    ... page: Was this page helpful? Also known as: Cystic Fibrosis Genotyping; CF DNA Analysis; CF Gene Mutation Panel; CF Molecular Genetic Testing Formal name: Cystic Fibrosis Gene Mutation Panel Related tests: Sweat Test ; Trypsinogen ; ...

  3. Colorectal cancer prognosis: is it all mutation, mutation, mutation?

    PubMed Central

    Hassan, A B; Paraskeva, C

    2005-01-01

    For the 500 000 new cases of colorectal cancer in the world each year, identification of patients with a worse prognosis and those who are more likely to respond to treatment is a challenge. There is an increasing body of evidence correlating genetic mutations with outcome in tumours derived from human colorectal cancer cohorts. K-ras, but not p53 or APC, mutations appear to be associated with poorer overall survival in colorectal cancer patients. PMID:16099785

  4. U-Pb zircon geochronology and Nd-Hf-O isotopic systematics of the Neoproterozoic Hadb adh Dayheen ring complex, Central Arabian Shield, Saudi Arabia

    NASA Astrophysics Data System (ADS)

    Ali, Kamal A.; Jeon, Heejin; Andresen, Arild; Li, Shuang-Qing; Harbi, Hesham M.; Hegner, Ernst

    2014-10-01

    A combined study of single zircon U-Pb dating, Hf-O zircon isotopic analyses and whole-rock Nd isotopic compositions was carried out to infer the magma sources of Neoproterozoic post-collisional A-type granitoids in Saudi Arabia. U-Pb zircon dating of magmatic zircons of two samples from the Hadb adh Dayheen ring complex yielded ages of 625 ± 11 Ma for a hornblende-biotite granite sample, and 613 ± 4 Ma for a monzogranite sample. The granitic rocks show initial εNd values of + 4.1 to + 5.3 and εHf of + 4.5 to + 8.4 that are lower than those of a model depleted mantle (εHf ~+ 14 and εNd ~+ 6.5) and consistent with melting of subduction-related crustal protoliths that were formed during the Neoproterozoic assembly of the Arabian-Nubian Shield (ANS). Crustal-model ages (Hf-tNC) of 0.81 to 1.1 Ga are inconsistent with depleted-mantle Nd model ages of 0.71 to 0.81 Ga and indicate that the post-collisional Hadb adh Dayheen granites were derived mostly from juvenile crust formed in Neoproterozoic time. Single zircons data show a wide range in δ18O values from + 3.2‰ to + 6.4‰, possibly indicating crystallization of zircon from magma derived from magmatic rocks altered by meteoric water in a magma chamber-caldera system.

  5. Dynamics-independent null experiment for testing time-reversal invariance

    NASA Astrophysics Data System (ADS)

    Arash, Firooz; Moravcsik, Michael J.; Goldstein, Gary R.

    1985-06-01

    It is shown that it is impossible to construct, in any reaction in atomic, nuclear, or particle physics, a null experiment that would unambiguously test the validity of time-reversal invariance independently of dynamical assumptions.

  6. High-resolution adaptive nulling performance for a lightweight agile EHF multiple beam antenna

    NASA Astrophysics Data System (ADS)

    Fenn, A. J.; Johnson, J. R.; Rispin, L. W.; Cummings, W. C.; Potts, B. M.

    The design and experimental performance of a lightweight high-resolution adaptive nulling extremely high-frequency multiple beam antenna (MBA) are addressed. A 127-beam MBA and a four-channel RF nulling network operating over the 43.5-to-45.5-GHz band were used to adaptively null a jammer in anechoic chamber measurements. Lightweight waveguide transmission lines together with ferrite switches were used to select beam ports from the 127-beam MBA. The MBA was designed to provide simultaneous coverage for three communications system users while providing pattern discrimination or nulling of jammers located within 0.1 deg of the user. Cancellation greater than 30 dB when operating in a wideband mode was experimentally demonstrated.

  7. Addressing the "Null Curriculum": Teaching about Genocides Other than the Holocaust.

    ERIC Educational Resources Information Center

    Totten, Samuel

    2001-01-01

    Describes the idea of the null curriculum in the context of teaching about genocide. Explores obstacles that prevent educators from teaching about genocides other than the Holocaust. Explains how teachers can begin teaching about other genocides in their classrooms. (CMK)

  8. Asymptotical null structure of an electro-vacuum spacetime with a cosmological constant

    NASA Astrophysics Data System (ADS)

    He, Xiaokai; Cao, Zhoujian; Jing, Jiliang

    2016-05-01

    Bondi-Sachs (BS) framework is a powerful tool to analyze the asymptotical null structure of a spacetime. Based on Bondi’s outgoing boundary condition, the asymptotical null structure of an electro-vacuum spacetime without a cosmological constant has been constructed clearly. Recently more and more observations imply that the Einstein equation should be modified with an nonzero cosmological constant. It is interesting to investigate the asymptotical null structure of a spacetime with a cosmological constant. In this paper, we extend our previous result from vacuum case to electro-vacuum case. We find that the gravitational sector of the asymptotical null structure depends strongly on the boundary conditions, while the electrical sector is independent of the boundary condition.

  9. ON THE NATURE OF RECONNECTION AT A SOLAR CORONAL NULL POINT ABOVE A SEPARATRIX DOME

    SciTech Connect

    Pontin, D. I.; Priest, E. R.; Galsgaard, K.

    2013-09-10

    Three-dimensional magnetic null points are ubiquitous in the solar corona and in any generic mixed-polarity magnetic field. We consider magnetic reconnection at an isolated coronal null point whose fan field lines form a dome structure. Using analytical and computational models, we demonstrate several features of spine-fan reconnection at such a null, including the fact that substantial magnetic flux transfer from one region of field line connectivity to another can occur. The flux transfer occurs across the current sheet that forms around the null point during spine-fan reconnection, and there is no separator present. Also, flipping of magnetic field lines takes place in a manner similar to that observed in the quasi-separatrix layer or slip-running reconnection.

  10. Null test of the cosmic curvature using H (z ) and supernovae data

    NASA Astrophysics Data System (ADS)

    Cai, Rong-Gen; Guo, Zong-Kuan; Yang, Tao

    2016-02-01

    We introduce a model-independent approach to the null test of the cosmic curvature, which is geometrically related to the Hubble parameter H (z ) and luminosity distance dL(z ). Combining the independent observations of H (z ) and dL(z ), we use the model-independent smoothing technique, Gaussian processes, to reconstruct them and determine the cosmic curvature ΩK(0 ) in the null test relation. The null test is totally geometrical and does not assume any cosmological model. We show that the cosmic curvature ΩK(0 )=0 is consistent with current observational data sets, falling within the 1 σ limit. To demonstrate the effect on the precision of the null test, we produce a series of simulated data of the models with different ΩK(0 ). Future observations in better quality can provide a greater improvement to constrain or refute the flat universe with ΩK(0 )=0 .

  11. Vlasov Fluid stability of a 2-D plasma with a linear magnetic field null

    SciTech Connect

    Kim, J.S.

    1984-01-01

    Vlasov Fluid stability of a 2-dimensional plasma near an O type magnetic null is investigated. Specifically, an elongated Z-pinch is considered, and applied to Field Reversed Configurations at Los Alamos National Laboratory by making a cylindrical approximation of the compact torus. The orbits near an elliptical O type null are found to be very complicated; the orbits are large and some are stochastic. The kinetic corrections to magnetohydrodynamics (MHD) are investigated by evaluating the expectation values of the growth rates of a Vlasov Fluid dispersion functional by using a set of trial functions based on ideal MHD. The dispersion functional involves fluid parts and orbit dependent parts. The latter involves phase integral of two time correlations. The phase integral is replaced by the time integral both for the regular and for the stochastic orbits. Two trial functions are used; one has a large displacement near the null and the other away from the null.

  12. Non-null testing for aspheric surfaces using elliptical sub-aperture stitching technique.

    PubMed

    Zhao, Zixin; Zhao, Hong; Gu, Feifei; Du, Hubing; Li, Kaixing

    2014-03-10

    We propose an elliptical sub-aperture stitching (ESAS) method to measure the aspheric surfaces. In our method, the non-null configuration is used to overcome the disadvantages of the null testing. By adding the dynamic tilt, the different local nearly null fringe patterns are obtained and the corresponding phase data in the elliptical masks is extracted with negligible retrace errors. In order to obtain the full aperture result, a stitching algorithm is developed to stitch all the phase data together. We firstly show the principle of our method. Then the performance of the proposed method is analyzed by simulation experiments. In the end, practical examples are given to demonstrate the correctness of the proposed method. The stitching result shows a good agreement with the full-aperture null testing result. PMID:24663891

  13. Theoretical and experimental arguments suporting the non-null photonic mass hypothesis

    NASA Astrophysics Data System (ADS)

    Popescu, Silvestru; Griga, Violeta

    The authors review the problem of the photonic non-null mass since Kobzarev and Okun' papres till Goldhaber and Nieto's papers. A calculus is made for the electromagnetic field in a spherical cavity supposing that the photonic mass is non-null. It is shown, that the force between the center of the sphere and the sphere's surface is null, while the force between any other point inside and a point on the sphere is non-null. A review of the experimental results has been given also. A more accurate stile will be desired for Physicists names as well as for some physical notions. As well the upper limit for the photonic mass as obtained in Pioneer 10 experiment (1974) is 8x10^-52 Kg not 10^-52 Kg. The authors are asked to be more accurate in their writings.

  14. Divertor with a third-order null of the poloidal field

    SciTech Connect

    Ryutov, D. D.; Umansky, M. V.

    2013-09-15

    A concept and preliminary feasibility analysis of a divertor with the third-order poloidal field null is presented. The third-order null is the point where not only the field itself but also its first and second spatial derivatives are zero. In this case, the separatrix near the null-point has eight branches, and the number of strike-points increases from 2 (as in the standard divertor) to six. It is shown that this magnetic configuration can be created by a proper adjustment of the currents in a set of three divertor coils. If the currents are somewhat different from the required values, the configuration becomes that of three closely spaced first-order nulls. Analytic approach, suitable for a quick orientation in the problem, is used. Potential advantages and disadvantages of this configuration are briefly discussed.

  15. Dynamic Stability of Lateral and Yawing Motions in the Double Null-Flux EDS System

    NASA Astrophysics Data System (ADS)

    Murai, Toshiaki; Yoshioka, Hiroshi; Sugino, Motohiko

    The double null-flux electro-dynamic suspension (EDS) in the superconducting maglev has the coupling lateral and yawing stiffness, which does not coincide with each other, so special attention should be paid to the dynamic stability of lateral and yawing motions. This paper describes their intrinsic dynamic stability by analyzing the lateral and yawing motions of bogie levitated by the double null-flux EDS.

  16. Delayed development of specific thyroid hormone-regulated events in transthyretin null mice

    PubMed Central

    Monk, Julie A.; Sims, Natalie A.; Dziegielewska, Katarzyna M.; Weiss, Roy E.; Ramsay, Robert G.

    2013-01-01

    Thyroid hormones (THs) are vital for normal postnatal development. Extracellular TH distributor proteins create an intravascular reservoir of THs. Transthyretin (TTR) is a TH distributor protein in the circulatory system and is the only TH distributor protein synthesized in the central nervous system. We investigated the phenotype of TTR null mice during development. Total and free 3′,5′,3,5-tetraiodo-l-thyronine (T4) and free 3′,3,5-triiodo-l-thyronine (T3) in plasma were significantly reduced in 14-day-old (P14) TTR null mice. TTR null mice also displayed a delayed suckling-to-weaning transition, decreased muscle mass, delayed growth, and retarded longitudinal bone growth. In addition, ileums from postnatal day 0 (P0) TTR null mice displayed disordered architecture and contained fewer goblet cells than wild type. Protein concentrations in cerebrospinal fluid from P0 and P14 TTR null mice were higher than in age-matched wild-type mice. In contrast to the current literature based on analyses of adult TTR null mice, our results demonstrate that TTR has an important and nonredundant role in influencing the development of several organs. PMID:23092911

  17. [Development of a new type soybean germplasm with null lipoxygenase isozymes].

    PubMed

    Han, Fen-Xia; Ding, An-Lin; Sun, Jun-Ming; Li, Gui-Ying

    2005-02-01

    Soybean protein is a kind of high-quality protein composed of balanced amino acids. It contains all kinds of amino acids, especially eight amino acids necessary for human, but also contains some components that are not good for human and affect food quality, such as Lipoxygenase (Lox) and Trypsin inhibitor (Ti). Nutritional value and processing quality of soybean can be improved by means of development of new variety with null Lox and Ti. In this paper, a new type soybean germplasm with null lipoxygenase isozymes was developed by Institute of Crop Sciences, Chinese Academy of Agricultural Sciences through years of biochemical marker assistant selection for null lipoxygenase by means of isoelectric focusing-polyacrylamid gel electrophoresis (IEF-PAGE) in the hybrid progenies of "96P17" (Female parent, a null lipoxygenase 2.3 line) and "93704" (Male parent, a null lipoxygenase 1.3 line). It is the first new soybean germplasm with null Lox1.2.3 genes in our country, which will contribute to soybean breeding for high quality, soybean production and utilization. In this paper, the development process of new type soybean germplasm is described. PMID:15759868

  18. Location of the non-tidal current null zone in northern San Francisco Bay

    USGS Publications Warehouse

    Peterson, D.H.; Conomos, T.J.; Broenkow, W.W.; Doherty, P.C.

    1975-01-01

    Variations in Sacramento-San Joaquin River discharge into northern San Francisco Bay causes shifts in location of the bottom density current null zone. At a river flow of 2000 m3/s this null zone is approximately 20 km from the seaward end of the estuary, whereas at a river flow of 100 m3/s it is 80 km from the seaward end; the corresponding distances of salinity penetration are approximately 40 and 90 km from the seaward end. Seaward of the null zone, during low (summer) river discharge conditions, the inward-flowing bottom density current appears typically strong (5-15 cm/s) relative to the outward-flowing river current (river discharge per unit cross-channel area) of <2 cm/s. Landward from this null zone the average river current increases with decreasing cross-channel area. This circulation implies that during the summer water within the null zone has the longest average advective replacement time relative to water seaward or landward of the null zone. ?? 1975.

  19. pyNSMC: A Python Module for Null-Space Monte Carlo Uncertainty Analysis

    NASA Astrophysics Data System (ADS)

    White, J.; Brakefield, L. K.

    2015-12-01

    The null-space monte carlo technique is a non-linear uncertainty analyses technique that is well-suited to high-dimensional inverse problems. While the technique is powerful, the existing workflow for completing null-space monte carlo is cumbersome, requiring the use of multiple commandline utilities, several sets of intermediate files and even a text editor. pyNSMC is an open-source python module that automates the workflow of null-space monte carlo uncertainty analyses. The module is fully compatible with the PEST and PEST++ software suites and leverages existing functionality of pyEMU, a python framework for linear-based uncertainty analyses. pyNSMC greatly simplifies the existing workflow for null-space monte carlo by taking advantage of object oriented design facilities in python. The core of pyNSMC is the ensemble class, which draws and stores realized random vectors and also provides functionality for exporting and visualizing results. By relieving users of the tedium associated with file handling and command line utility execution, pyNSMC instead focuses the user on the important steps and assumptions of null-space monte carlo analysis. Furthermore, pyNSMC facilitates learning through flow charts and results visualization, which are available at many points in the algorithm. The ease-of-use of the pyNSMC workflow is compared to the existing workflow for null-space monte carlo for a synthetic groundwater model with hundreds of estimable parameters.

  20. Proving the achronal averaged null energy condition from the generalized second law

    SciTech Connect

    Wall, Aron C.

    2010-01-15

    A null line is a complete achronal null geodesic. It is proven that for any quantum fields minimally coupled to semiclassical Einstein gravity, the averaged null energy condition (ANEC) on null lines is a consequence of the generalized second law of thermodynamics for causal horizons. This result is shown to leading order in Planck's constant for perturbations to classical backgrounds satisfying the null energy condition. Auxiliary assumptions include CPT and the existence of a suitable renormalization scheme for the generalized entropy. Although the ANEC can be violated on general geodesics in curved spacetimes, as long as the ANEC holds on null lines there exist theorems showing that semiclassical gravity should satisfy positivity of energy, topological censorship, and should not admit closed timelike curves. It is pointed out that these theorems fail once the linearized graviton field is quantized, because then the renormalized shear-squared term in the Raychaudhuri equation can be negative. A 'shear-inclusive' generalization of the ANEC is proposed to remedy this, and is proven under an additional assumption about perturbations to horizons in classical general relativity.

  1. Losses at magnetic nulls in pulsed-power transmission line systems

    NASA Astrophysics Data System (ADS)

    Mendel, C. W.; Pointon, T. D.; Savage, M. E.; Seidel, D. B.; Magne, I.; Vézinet, R.

    2006-04-01

    Pulsed-power systems operating in the terawatt regime must deal with large electron flows in vacuum transmission lines. In most parts of these transmission lines the electrons are constrained by the self-magnetic field to flow parallel to the conductors. In very low impedance systems, such as those used to drive Z-pinch radiation sources, the currents from multiple transmission lines are added together. This addition necessarily involves magnetic nulls that connect the positive and negative electrodes. The resultant local loss of magnetic insulation results in electron losses at the anode in the vicinity of the nulls. The lost current due to the magnetic null might or might not be appreciable. In some cases the lost current due to the null is not large, but is spatially localized, and may create a gas and plasma release from the anode that can lead to an excessive loss, and possibly to catastrophic damage to the hardware. In this paper we describe an analytic model that uses one geometric parameter (aside from straightforward hardware size measurements) that determines the loss to the anode, and the extent of the loss region when the driving source and load are known. The parameter can be calculated in terms of the magnetic field in the region of the null calculated when no electron flow is present. The model is compared to some experimental data, and to simulations of several different hardware geometries, including some cases with multiple nulls, and unbalanced feeds.

  2. Losses at magnetic nulls in pulsed-power transmission line systems

    SciTech Connect

    Mendel, C.W. Jr.; Pointon, T.D.; Savage, M.E.; Seidel, D.B.; Magne, I.; Vezinet, R.

    2006-04-15

    Pulsed-power systems operating in the terawatt regime must deal with large electron flows in vacuum transmission lines. In most parts of these transmission lines the electrons are constrained by the self-magnetic field to flow parallel to the conductors. In very low impedance systems, such as those used to drive Z-pinch radiation sources, the currents from multiple transmission lines are added together. This addition necessarily involves magnetic nulls that connect the positive and negative electrodes. The resultant local loss of magnetic insulation results in electron losses at the anode in the vicinity of the nulls. The lost current due to the magnetic null might or might not be appreciable. In some cases the lost current due to the null is not large, but is spatially localized, and may create a gas and plasma release from the anode that can lead to an excessive loss, and possibly to catastrophic damage to the hardware. In this paper we describe an analytic model that uses one geometric parameter (aside from straightforward hardware size measurements) that determines the loss to the anode, and the extent of the loss region when the driving source and load are known. The parameter can be calculated in terms of the magnetic field in the region of the null calculated when no electron flow is present. The model is compared to some experimental data, and to simulations of several different hardware geometries, including some cases with multiple nulls, and unbalanced feeds.

  3. Losses at magnetic nulls in pulsed-power transmission line systems.

    SciTech Connect

    Magne, I.; Savage, Mark Edward; Seidel, David Bruce; Mendel, Clifford Will, Jr.; Pointon, Timothy David; Vezinet, R.

    2004-08-01

    Pulsed-power systems operating in the terawatt regime must deal with large electron flows in vacuum transmission lines. In most parts of these transmission lines the electrons are constrained by the self-magnetic field to flow parallel to the conductors. In very low impedance systems, such as those used to drive Z-pinch radiation sources, the currents from multiple transmission lines are added together. This addition necessarily involves magnetic nulls that connect the positive and negative electrodes. The resultant local loss of magnetic insulation results in electron losses at the anode in the vicinity of the nulls. The lost current due to the magnetic null might or might not be appreciable. In some cases the lost current due to the null is not large, but is spatially localized, and may create a gas and plasma release from the anode that can lead to an excessive loss, and possibly to catastrophic damage to the hardware. In this paper we describe an analytic model that uses one geometric parameter (aside from straightforward hardware size measurements) that determines the loss to the anode, and the extent of the loss region when the driving source and load are known. The parameter can be calculated in terms of the magnetic field in the region of the null calculated when no electron flow is present. The model is compared to some experimental data, and to simulations of several different hardware geometries, including some cases with multiple nulls, and unbalanced feeds.

  4. UV Signature Mutations

    PubMed Central

    2014-01-01

    Sequencing complete tumor genomes and exomes has sparked the cancer field's interest in mutation signatures for identifying the tumor's carcinogen. This review and meta-analysis discusses signatures and their proper use. We first distinguish between a mutagen's canonical mutations – deviations from a random distribution of base changes to create a pattern typical of that mutagen – and the subset of signature mutations, which are unique to that mutagen and permit inference backward from mutations to mutagen. To verify UV signature mutations, we assembled literature datasets on cells exposed to UVC, UVB, UVA, or solar simulator light (SSL) and tested canonical UV mutation features as criteria for clustering datasets. A confirmed UV signature was: ≥60% of mutations are C→T at a dipyrimidine site, with ≥5% CC→TT. Other canonical features such as a bias for mutations on the non-transcribed strand or at the 3' pyrimidine had limited application. The most robust classifier combined these features with criteria for the rarity of non-UV canonical mutations. In addition, several signatures proposed for specific UV wavelengths were limited to specific genes or species; non-signature mutations induced by UV may cause melanoma BRAF mutations; and the mutagen for sunlight-related skin neoplasms may vary between continents. PMID:25354245

  5. A null-mutation in the Znt7 gene accelerates prostate tumor formation in a transgenic adenocarcinoma mouse prostate model

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Decrease of cellular zinc in the epithelium of the prostate has been implicated in the development of prostate cancer. To investigate whether ZnT7, a zinc transporter involved in intracellular zinc accumulation, plays a role in prostate cancer development, we have generated and characterized a trans...

  6. Null mutation of chloride channel 7 (Clcn7) impairs dental root formation but does not affect enamel mineralization.

    PubMed

    Guo, Jing; Bervoets, Theodore J M; Henriksen, Kim; Everts, Vincent; Bronckers, Antonius L J J

    2016-02-01

    ClC-7, located in late endosomes and lysosomes, is critical for the function of osteoclasts. Secretion of Cl(-) by the ruffled border of osteoclasts enables H(+) secretion by v-H(+)-ATPases to dissolve bone mineral. Mice lacking ClC-7 show altered lysosomal function that leads to severe lysosomal storage. Maturation ameloblasts are epithelial cells with a ruffled border that secrete Cl(-) as well as endocytose and digest large quantities of enamel matrix proteins during formation of dental enamel. We tested the hypothesis that ClC-7 in maturation ameloblasts is required for intracellular digestion of matrix fragments to complete enamel mineralization. Craniofacial bones and developing teeth in Clcn7(-/-) mice were examined by micro-CT, immunohistochemistry, quantified histomorphometry and electron microscopy. Osteoclasts and ameloblasts in wild-type mice stained intensely with anti-ClC-7 antibody but not in Clcn7(-/-) mice. Craniofacial bones in Clcn7(-/-) mice were severely osteopetrotic and contained 1.4- to 1.6-fold more bone volume, which was less mineralized than the wild-type littermates. In Clcn7(-/-) mice maturation ameloblasts and osteoclasts highly expressed Ae2 as in wild-type mice. However, teeth failed to erupt, incisors were much shorter and roots were disfigured. Molars formed a normal dental crown. In compacted teeth, dentin was slightly less mineralized, enamel did not retain a matrix and mineralized fairly normal. We concluded that ClC-7 is essential for osteoclasts to resorb craniofacial bones to enable tooth eruption and root development. Disruption of Clcn7 reduces bone and dentin mineral density but does not affect enamel mineralization. PMID:26346547

  7. A case of Amelogenin Y-null: a simple primer binding site mutation or unusual genetic anomaly?

    PubMed

    Davis, Carey; Illescas, María; Tirado, Carmen; Lopez, Roberto; Budowle, Bruce; Cruz, Tracey Dawson

    2012-11-01

    A thirteen year old boy was murdered by a gunshot wound to the head. In order to confirm identity of the boy, samples were sent to the Instituto de Ciencias Forenses de Puerto Rico (PR-ICF) DNA laboratory. Autosomal DNA results exhibited only an X at the Amelogenin locus, whereas the autopsy results reported the child to be anatomically male. The sample was amplified with four separate YSTR marker systems. While a full Y-STR profile for the father of the boy was obtained, the boy only amplified at STR markers on the p arm of the Y chromosome. Theories that could account for this large absence of Y-STR results include an X-Y translocation or Yp isochromosome. PMID:22721879

  8. Hemoglobin adducts from acrylonitrile and ethylene oxide in cigarette smokers: effects of glutathione S-transferase T1-null and M1-null genotypes.

    PubMed

    Fennell, T R; MacNeela, J P; Morris, R W; Watson, M; Thompson, C L; Bell, D A

    2000-07-01

    Acrylonitrile (ACN) is used to manufacture plastics and fibers. It is carcinogenic in rats and is found in cigarette smoke. Ethylene oxide (EO) is a metabolite of ethylene, also found in cigarette smoke, and is carcinogenic in rodents. Both ACN and EO undergo conjugation with glutathione. The objectives of this study were to examine the relationship between cigarette smoking and hemoglobin adducts derived from ACN and EO and to investigate whether null genotypes for glutathione transferase (GSTM1 and GSTT1) alter the internal dose of these agents. The hemoglobin adducts N-(2-cyanoethyl)valine (CEVal), which is formed from ACN, and N-(2-hydroxyethyl)valine (HEVal), which is formed from EO, and GST genotypes were determined in blood samples obtained from 16 nonsmokers and 32 smokers (one to two packs/day). Smoking information was obtained by questionnaire, and plasma cotinine levels were determined by immunoassay. Glutathione transferase null genotypes (GSTM1 and GSTT1) were determined by PCR. Both CEVal and HEVal levels increased with increased cigarette smoking dose (both self-reported and cotinine-based). CEVal and HEVal levels were also correlated. GSTM1 and GSTT1 genotypes had little effect on CEVal concentrations. GSTM1 null genotypes had no significant impact on HEVal. However, HEVal levels were significantly elevated in GSTT1-null individuals when normalized to smoking status or cotinine levels. The ratio of HEVal:CEVal was also elevated in GSTT1-null smokers (1.50 +/- 0.57 versus 0.88 +/- 0.24; P = 0.0002). The lack of a functional GSTT1 is estimated to increase the internal dose of EO derived from cigarette smoke by 50-70%. PMID:10919741

  9. Cystic fibrosis mice carrying the missense mutation G551D replicate human genotype-phenotype correlations.

    PubMed Central

    Delaney, S J; Alton, E W; Smith, S N; Lunn, D P; Farley, R; Lovelock, P K; Thomson, S A; Hume, D A; Lamb, D; Porteous, D J; Dorin, J R; Wainwright, B J

    1996-01-01

    We have generated a mouse carrying the human G551D mutation in the cystic fibrosis transmembrane conductance regulator gene (CFTR) by a one-step gene targeting procedure. These mutant mice show cystic fibrosis pathology but have a reduced risk of fatal intestinal blockage compared with 'null' mutants, in keeping with the reduced incidence of meconium ileus in G551D patients. The G551D mutant mice show greatly reduced CFTR-related chloride transport, displaying activity intermediate between that of cftr(mlUNC) replacement ('null') and cftr(mlHGU) insertional (residual activity) mutants and equivalent to approximately 4% of wild-type CFTR activity. The long-term survival of these animals should provide an excellent model with which to study cystic fibrosis, and they illustrate the value of mouse models carrying relevant mutations for examining genotype-phenotype correlations. Images PMID:8605891

  10. ENU-induced phenovariance in mice: inferences from 587 mutations

    PubMed Central

    2012-01-01

    Background We present a compendium of N-ethyl-N-nitrosourea (ENU)-induced mouse mutations, identified in our laboratory over a period of 10 years either on the basis of phenotype or whole genome and/or whole exome sequencing, and archived in the Mutagenetix database. Our purpose is threefold: 1) to formally describe many point mutations, including those that were not previously disclosed in peer-reviewed publications; 2) to assess the characteristics of these mutations; and 3) to estimate the likelihood that a missense mutation induced by ENU will create a detectable phenotype. Findings In the context of an ENU mutagenesis program for C57BL/6J mice, a total of 185 phenotypes were tracked to mutations in 129 genes. In addition, 402 incidental mutations were identified and predicted to affect 390 genes. As previously reported, ENU shows strand asymmetry in its induction of mutations, particularly favoring T to A rather than A to T in the sense strand of coding regions and splice junctions. Some amino acid substitutions are far more likely to be damaging than others, and some are far more likely to be observed. Indeed, from among a total of 494 non-synonymous coding mutations, ENU was observed to create only 114 of the 182 possible amino acid substitutions that single base changes can achieve. Based on differences in overt null allele frequencies observed in phenotypic vs. non-phenotypic mutation sets, we infer that ENU-induced missense mutations create detectable phenotype only about 1 in 4.7 times. While the remaining mutations may not be functionally neutral, they are, on average, beneath the limits of detection of the phenotypic assays we applied. Conclusions Collectively, these mutations add to our understanding of the chemical specificity of ENU, the types of amino acid substitutions it creates, and its efficiency in causing phenovariance. Our data support the validity of computational algorithms for the prediction of damage caused by amino acid substitutions

  11. UV signature mutations.

    PubMed

    Brash, Douglas E

    2015-01-01

    Sequencing complete tumor genomes and exomes has sparked the cancer field's interest in mutation signatures for identifying the tumor's carcinogen. This review and meta-analysis discusses signatures and their proper use. We first distinguish between a mutagen's canonical mutations—deviations from a random distribution of base changes to create a pattern typical of that mutagen—and the subset of signature mutations, which are unique to that mutagen and permit inference backward from mutations to mutagen. To verify UV signature mutations, we assembled literature datasets on cells exposed to UVC, UVB, UVA, or solar simulator light (SSL) and tested canonical UV mutation features as criteria for clustering datasets. A confirmed UV signature was: ≥60% of mutations are C→T at a dipyrimidine site, with ≥5% CC→TT. Other canonical features such as a bias for mutations on the nontranscribed strand or at the 3' pyrimidine had limited application. The most robust classifier combined these features with criteria for the rarity of non-UV canonical mutations. In addition, several signatures proposed for specific UV wavelengths were limited to specific genes or species; UV's nonsignature mutations may cause melanoma BRAF mutations; and the mutagen for sunlight-related skin neoplasms may vary between continents. PMID:25354245

  12. Hepatic Effects of a Methionine-Choline-Deficient Diet in Hepatocyte RXRα-null Mice

    PubMed Central

    Gyamfi, Maxwell Afari; Tanaka, Yuji; He, Lin; Klaassen, Curtis D.; Wan, Yu-Jui Yvonne

    2009-01-01

    Retinoid X receptor-α (RXRα) is an obligate partner for several nuclear hormone receptors that regulate important physiological processes in the liver. In this study the impact of hepatocyte RXRα deficiency on methionine and choline deficient (MCD) diet-induced steatosis, oxidative stress, inflammation, and hepatic transporters gene expression were examined. The mRNA of sterol regulatory element-binding protein (SREBP)-regulated genes, important for lipid synthesis, were not altered in wild type (WT) mice, but were increased 2.0- to 5.4-fold in hepatocyte RXRα-null (H-RXRα-null) mice fed a MCD diet for 14 days. Furthermore, hepatic mRNAs and proteins essential for fatty acid β-oxidation were not altered in WT mice, but were decreased in the MCD diet-fed H-RXRα-null mice, resulting in increased hepatic free fatty acid levels. Cyp2e1 enzyme activity and lipid peroxide levels were induced only in MCD-fed WT mice. In contrast, hepatic mRNA levels of pro-inflammatory factors were increased only in H-RXRα-null mice fed the MCD diet. Hepatic uptake transporters Oatp1a1 and Oatp1b2 mRNA levels were decreased in WT mice fed the MCD diet, whereas the efflux transporter Mrp4 was increased. However, in the H-RXRα-null mice, the MCD diet only moderately decreased Oatp1a1 and induced both Oatp1a4 and Mrp4 gene expression. Whereas the MCD diet increased serum bile acid levels and alkaline phosphatase activity in both WT and H-RXRα-null mice, serum ALT levels were induced (2.9-fold) only in the H-RXRα-null mice. In conclusion, these data suggest a critical role for RXRα in hepatic fatty acid homeostasis and protection against MCD-induced hepatocyte injury. PMID:18952117

  13. Behavioural signs of chronic back pain in the SPARC-null mouse

    PubMed Central

    Millecamps, Magali; Tajerian, Maral; Sage, E. Helene; Stone, Laura S

    2010-01-01

    Study Design SPARC-null mice were examined for behavioural signs of chronic low back and/or radicular pain. Objective To assess SPARC-null mice as a rodent model of chronic low back and/or radicular pain due to degenerative disc disease. Summary of Background Data Degeneration of intervertebral discs is a major cause of chronic low back and radicular pain in humans. Inactivation of the SPARC (Secreted Protein, Acidic and Rich in Cysteine, also known as osteonectin and BM-40) gene in mice results in premature intervertebral disc degeneration. The impact of disc degeneration on behavioural measures of chronic pain has not been evaluated in this model. Methods Cohorts of young and old (3 and 6–12 months, respectively) SPARC-null and wild-type control mice were screened for behavioural indices of low back and/or radiating pain. Sensitivity to mechanical, cold and heat stimuli, locomotor impairment, and movement-evoked hypersensitivity were determined. Animals were challenged with three analgesic agents with different mechanisms: morphine, dexamethasone, and gabapentin. Results SPARC-null mice showed signs of movement-evoked discomfort as early as 3 months of age. Hypersensitivity to cold stimuli on both the lower back and hindpaws developed with increasing age. SPARC-null mice had normal sensitivity to tactile and heat stimuli, and locomotor skills were not impaired. The hypersensitivity to cold was reversed by morphine, but not by dexamethasone or gabapentin. Conclusion SPARC-null mice display behavioural signs consistent with chronic low back and radicular pain that we attribute to intervertebral disc degeneration. We predict that the SPARC-null mouse is a useful model of chronic back pain due to degenerative disc disease. PMID:20714283

  14. Nonlinear Alfvén wave dynamics at a 2D magnetic null point: ponderomotive force

    NASA Astrophysics Data System (ADS)

    Thurgood, J. O.; McLaughlin, J. A.

    2013-07-01

    Context. In the linear, β = 0 MHD regime, the transient properties of magnetohydrodynamic (MHD) waves in the vicinity of 2D null points are well known. The waves are decoupled and accumulate at predictable parts of the magnetic topology: fast waves accumulate at the null point; whereas Alfvén waves cannot cross the separatricies. However, in nonlinear MHD mode conversion can occur at regions of inhomogeneous Alfvén speed, suggesting that the decoupled nature of waves may not extend to the nonlinear regime. Aims: We investigate the behaviour of low-amplitude Alfvén waves about a 2D magnetic null point in nonlinear, β = 0 MHD. Methods: We numerically simulate the introduction of low-amplitude Alfvén waves into the vicinity of a magnetic null point using the nonlinear LARE2D code. Results: Unlike in the linear regime, we find that the Alfvén wave sustains cospatial daughter disturbances, manifest in the transverse and longitudinal fluid velocity, owing to the action of nonlinear magnetic pressure gradients (viz. the ponderomotive force). These disturbances are dependent on the Alfvén wave and do not interact with the medium to excite magnetoacoustic waves, although the transverse daughter becomes focused at the null point. Additionally, an independently propagating fast magnetoacoustic wave is generated during the early stages, which transports some of the initial Alfvén wave energy towards the null point. Subsequently, despite undergoing dispersion and phase-mixing due to gradients in the Alfvén-speed profile (∇cA ≠ 0) there is no