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Articles by S Wagner
Total Records ( 4 ) for S Wagner
  L van Burck , A Blutke , S Kautz , B Rathkolb , M Klaften , S Wagner , E Kemter , M Hrabe de Angelis , E Wolf , B Aigner , R Wanke and N. Herbach
 

Several mutant mouse models for human diseases such as diabetes mellitus have been generated in the large-scale Munich ENU (N-ethyl-N-nitrosourea) mouse mutagenesis project. The aim of this study was to identify the causal mutation of one of these strains and to characterize the resulting diabetic phenotype. Mutants exhibit a T to G transversion mutation at nt 629 in the glucokinase (Gck) gene, leading to an amino acid exchange from methionine to arginine at position 210. Adult Munich GckM210R mutant mice demonstrated a significant reduction of hepatic glucokinase enzyme activity but equal glucokinase mRNA and protein abundances. While homozygous mutant mice exhibited growth retardation and died soon after birth in consequence of severe hyperglycemia, heterozygous mutant mice displayed only slightly elevated blood glucose levels, present from birth, with development of disturbed glucose tolerance and glucose-induced insulin secretion. Additionally, insulin sensitivity and fasting serum insulin levels were slightly reduced in male mutant mice from an age of 90 days onward. While β-cell mass was unaltered in neonate heterozygous and homozygous mutant mice, the total islet and β-cell volumes and the total volume of isolated β-cells were significantly decreased in 210-day-old male, but not female heterozygous mutant mice despite undetectable apoptosis. These findings indicate that reduced total islet and β-cell volumes of male mutants might emerge from disturbed postnatal islet neogenesis. Considering the lack of knowledge about the pathomorphology of maturity-onset diabetes of the young type 2 (MODY 2), this glucokinase mutant model of reduced total islet and total β-cell volume provides the opportunity to elucidate the impact of a defective glucokinase on development and maintenance of β-cell mass and its relevance in MODY 2 patients.

  S Wagner , E Hacker , E Grandi , S. L Weber , N Dybkova , S Sossalla , T Sowa , L Fabritz , P Kirchhof , D. M Bers and L. S. Maier
 

Background— Potassium currents contribute to action potential duration (APD) and arrhythmogenesis. In heart failure, Ca/calmodulin-dependent protein kinase II (CaMKII) is upregulated and can alter ion channel regulation and expression.

Methods and Results— We examine the influence of overexpressing cytoplasmic CaMKIIC, both acutely in rabbit ventricular myocytes (24-hour adenoviral gene transfer) and chronically in CaMKIIC-transgenic mice, on transient outward potassium current (Ito), and inward rectifying current (IK1). Acute and chronic CaMKII overexpression increases Ito,slow amplitude and expression of the underlying channel protein KV1.4. Chronic but not acute CaMKII overexpression causes downregulation of Ito,fast, as well as KV4.2 and KChIP2, suggesting that KV1.4 expression responds faster and oppositely to KV4.2 on CaMKII activation. These amplitude changes were not reversed by CaMKII inhibition, consistent with CaMKII-dependent regulation of channel expression and/or trafficking. CaMKII (acute and chronic) greatly accelerated recovery from inactivation for both Ito components, but these effects were acutely reversed by AIP (CaMKII inhibitor), suggesting that CaMKII activity directly accelerates Ito recovery. Expression levels of IK1 and Kir2.1 mRNA were downregulated by CaMKII overexpression. CaMKII acutely increased IK1, based on inhibition by AIP (in both models). CaMKII overexpression in mouse prolonged APD (consistent with reduced Ito,fast and IK1), whereas CaMKII overexpression in rabbit shortened APD (consistent with enhanced IK1 and Ito,slow and faster Ito recovery). Computational models allowed discrimination of contributions of different channel effects on APD.

Conclusion— CaMKII has both acute regulatory effects and chronic expression level effects on Ito and IK1 with complex consequences on APD.

  A Peter , A Cegan , S Wagner , R Lehmann , N Stefan , A Konigsrainer , I Konigsrainer , H. U Haring and E. Schleicher
 

Background: Stearoyl-coenzyme A desaturase 1 (SCD1) catalyzes the limiting step of monounsaturated fatty acid synthesis in humans and is an important player in triglyceride generation. SCD1 has been repeatedly implicated in the pathogenesis of metabolic and inflammatory diseases. Therefore it is of great importance to determine SCD1 activity in human samples. In this study we aimed to evaluate a hepatic SCD1 activity index derived from plasma VLDL triglyceride composition as a tool to estimate hepatic SCD1 expression in humans. Additionally, we further evaluated commonly used fatty acid ratios [elongase, de novo lipogenesis, and 5 and 6 desaturase] in plasma VLDL and hepatic lipid fractions.

Design and methods: Liver biopsies and plasma samples were simultaneously collected from 15 individuals. Plasma VLDL was obtained by ultracentrifugation. Hepatic and plasma VLDL lipids were fractionated by thin-layer chromatography, and the fatty acid composition of each fraction was analyzed by gas chromatography. Hepatic SCD1 expression was determined by real-time PCR.

Results: Hepatic SCD1 mRNA expression was associated with the product/precursor ratios (16:1/16:0 and 18:1/18:0) of hepatic lipid fractions. The 16:1/16:0 ratio in hepatic and VLDL triglycerides as well as the 18:1/18:0 ratio in plasma VLDL were closely associated with hepatic SCD1 expression. The hepatic de novo lipogenesis index from triglycerides was associated with expression of lipogenic genes [fatty acid synthase (FASN), acetyl-Coenzyme A carboxylase alpha (ACACA), and sterol regulatory element binding transcription factor 1 (SREBP-1)] and is closely reflected by the de novo lipogenesis index in VLDL triglycerides.

Conclusion: We demonstrated for the first time that hepatic SCD1 expression can be estimated noninvasively from routine blood samples by measuring the SCD1 activity index in fasting plasma VLDL.

  Temple The MGC Project Team , D. S Gerhard , R Rasooly , E. A Feingold , P. J Good , C Robinson , A Mandich , J. G Derge , J Lewis , D Shoaf , F. S Collins , W Jang , L Wagner , C. M Shenmen , L Misquitta , C. F Schaefer , K. H Buetow , T. I Bonner , L Yankie , M Ward , L Phan , A Astashyn , G Brown , C Farrell , J Hart , M Landrum , B. L Maidak , M Murphy , T Murphy , B Rajput , L Riddick , D Webb , J Weber , W Wu , K. D Pruitt , D Maglott , A Siepel , B Brejova , M Diekhans , R Harte , R Baertsch , J Kent , D Haussler , M Brent , L Langton , C. L.G Comstock , M Stevens , C Wei , M. J van Baren , K Salehi Ashtiani , R. R Murray , L Ghamsari , E Mello , C Lin , C Pennacchio , K Schreiber , N Shapiro , A Marsh , E Pardes , T Moore , A Lebeau , M Muratet , B Simmons , D Kloske , S Sieja , J Hudson , P Sethupathy , M Brownstein , N Bhat , J Lazar , H Jacob , C. E Gruber , M. R Smith , J McPherson , A. M Garcia , P. H Gunaratne , J Wu , D Muzny , R. A Gibbs , A. C Young , G. G Bouffard , R. W Blakesley , J Mullikin , E. D Green , M. C Dickson , A. C Rodriguez , J Grimwood , J Schmutz , R. M Myers , M Hirst , T Zeng , K Tse , M Moksa , M Deng , K Ma , D Mah , J Pang , G Taylor , E Chuah , A Deng , K Fichter , A Go , S Lee , J Wang , M Griffith , R Morin , R. A Moore , M Mayo , S Munro , S Wagner , S. J.M Jones , R. A Holt , M. A Marra , S Lu , S Yang , J Hartigan , M Graf , R Wagner , S Letovksy , J. C Pulido , K Robison , D Esposito , J Hartley , V. E Wall , R. F Hopkins , O Ohara and S. Wiemann
 

Since its start, the Mammalian Gene Collection (MGC) has sought to provide at least one full-protein-coding sequence cDNA clone for every human and mouse gene with a RefSeq transcript, and at least 6200 rat genes. The MGC cloning effort initially relied on random expressed sequence tag screening of cDNA libraries. Here, we summarize our recent progress using directed RT-PCR cloning and DNA synthesis. The MGC now contains clones with the entire protein-coding sequence for 92% of human and 89% of mouse genes with curated RefSeq (NM-accession) transcripts, and for 97% of human and 96% of mouse genes with curated RefSeq transcripts that have one or more PubMed publications, in addition to clones for more than 6300 rat genes. These high-quality MGC clones and their sequences are accessible without restriction to researchers worldwide.

 
 
 
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