MSH3 polymorphisms and protein levels affect CAG repeat instability in huntington's disease mice

Expansions of trinucleotide CAG/CTG repeats in somatic tissues are thought to contribute to ongoing disease progression through an affected individual's life with Huntington's disease or myotonic dystrophy. Broad ranges of repeat instability arise between individuals with expanded repeats, suggesting the existence of modifiers of repeat instability. Mice with expanded CAG/CTG repeats show variable levels of instability depending upon mouse strain. However, to date the genetic modifiers underlying these differences have not been identified. We show that in liver and striatum the R6/1 Huntington's disease (HD) (CAG)~100 transgene, when present in a congenic C57BL/6J (B6) background, incurred expansion-biased repeat mutations, whereas the repeat was stable in a congenic BALB/cByJ (CBy) background. Reciprocal congenic mice revealed the Msh3 gene as the determinant for the differences in repeat instability. Expansion bias was observed in congenic mice homozygous for the B6 Msh3 gene on a CBy background, while the CAG tract was stabilized in congenics homozygous for the CBy Msh3 gene on a B6 background. The CAG stabilization was as dramatic as genetic deficiency of Msh2. The B6 and CBy Msh3 genes had identical promoters but differed in coding regions and showed strikingly different protein levels. B6 MSH3 variant protein is highly expressed and associated with CAG expansions, while the CBy MSH3 variant protein is expressed at barely detectable levels, associating with CAG stability. The DHFR protein, which is divergently transcribed from a promoter shared by the Msh3 gene, did not show varied levels between mouse strains. Thus, naturally occurring MSH3 protein polymorphisms are modifiers of CAG repeat instability, likely through variable MSH3 protein stability. Since evidence supports that somatic CAG instability is a modifier and predictor of disease, our data are consistent with the hypothesis that variable levels of CAG instability associated with polymorphisms of DNA repair genes may have prognostic implications for various repeat-associated diseases

Identifying Patients at High Risk of a Cardiovascular Event in the Near Future Current Status and Future Directions: Report of a National Heart, Lung, and Blood Institute Working Group

The National Heart, Lung, and Blood Institute convened a working group to provide basic and clinical research recommendations to the National Heart, Lung, and Blood Institute on the development of an integrated approach for identifying those individuals who are at high risk for a cardiovascular event such as acute coronary syndromes (ACS) or sudden cardiac death in the “near term.” The working group members defined near-term as occurring within 1 year of the time of assessment. The participants reviewed current clinical cardiology practices for risk assessment and state-of-the-science techniques in several areas, including biomarkers, proteomics, genetics, psychosocial factors, imaging, coagulation, and vascular and myocardial susceptibility. This report presents highlights of these reviews and a summary of suggested research directions

Precision Measurement of B(D+ -> mu+ nu) and the Pseudoscalar Decay Constant fD+

We measure the branching ratio of the purely leptonic decay of the D+ meson with unprecedented precision as B(D+ -> mu+ nu) = (3.82 +/- 0.32 +/- 0.09)x10^(-4), using 818/pb of data taken on the psi(3770) resonance with the CLEO-c detector at the CESR collider. We use this determination to derive a value for the pseudoscalar decay constant fD+, combining with measurements of the D+ lifetime and assuming |Vcd| = |Vus|. We find fD+ = (205.8 +/- 8.5 +/- 2.5) MeV. The decay rate asymmetry [B(D+ -> mu+ nu)-B(D- -> mu- nu)]/[B(D+ -> mu+ nu)+B(D- -> mu- nu)] = 0.08 +/- 0.08, consistent with no CP violation. We also set 90% confidence level upper limits on B(D+ -> tau+ nu) < 1.2x10^(-3) and B(D+ -> e+ nu) < 8.8x10^(-6).Comment: 24 pages, 11 figures and 6 tables, v2 replaced some figure vertical axis scales, v3 corrections from PRD revie

Precision Measurement of the Mass of the h_c(1P1) State of Charmonium

A precision measurement of the mass of the h_c(1P1) state of charmonium has been made using a sample of 24.5 million psi(2S) events produced in e+e- annihilation at CESR. The reaction used was psi(2S) -> pi0 h_c, pi0 -> gamma gamma, h_c -> gamma eta_c, and the reaction products were detected in the CLEO-c detector. Data have been analyzed both for the inclusive reaction and for the exclusive reactions in which eta_c decays are reconstructed in fifteen hadronic decay channels. Consistent results are obtained in the two analyses. The averaged results of the present measurements are M(h_c)=3525.28+-0.19 (stat)+-0.12(syst) MeV, and B(psi(2S) -> pi0 h_c)xB(h_c -> gamma eta_c)= (4.19+-0.32+-0.45)x10^-4. Using the 3PJ centroid mass, Delta M_hf(1P)= - M(h_c) = +0.02+-0.19+-0.13 MeV.Comment: 9 pages, available through http://www.lns.cornell.edu/public/CLNS/, submitted to PR

Measurement of the Absolute Branching Fraction of D_s^+ --> tau^+ nu_tau Decay

Using a sample of tagged D_s decays collected near the D^*_s D_s peak production energy in e+e- collisions with the CLEO-c detector, we study the leptonic decay D^+_s to tau^+ nu_tau via the decay channel tau^+ to e^+ nu_e bar{nu}_tau. We measure B(D^+_s to tau^+ nu_tau) = (6.17 +- 0.71 +- 0.34) %, where the first error is statistical and the second systematic. Combining this result with our measurements of D^+_s to mu^+ nu_mu and D^+_s to tau^+ nu_tau (via tau^+ to pi^+ bar{nu}_tau), we determine f_{D_s} = (274 +- 10 +- 5) MeV.Comment: 9 pages, postscript also available through http://www.lns.cornell.edu/public/CLNS/2007/, revise

J/psi and psi(2S) Radiative Transitions to eta_c

Using 24.5 million psi(2S) decays collected with the CLEO-c detector at CESR we present the most precise measurements of magnetic dipole transitions in the charmonium system. We measure B(psi(2S)->gamma eta_c) = (4.32+/-0.16+/-0.60)x10^-3, B(J/psi->gamma eta_c)/B(psi(2S)->gamma eta_c) = 4.59+/-0.23+/-0.64, and B(J/psi->gamma eta_c) = (1.98+/-0.09+/-0.30)%. We observe a distortion in the eta_c line shape due to the photon-energy dependence of the magnetic dipole transition rate. We find that measurements of the eta_c mass are sensitive to the line shape, suggesting an explanation for the discrepancy between measurements of the eta_c mass in radiative transitions and other production mechanisms.Comment: 11 pages, 3 figure

Inclusive chi_bJ(nP) Decays to D0 X

Using Upsilon(2S) and Upsilon(3S) data collected with the CLEO III detector we have searched for decays of chi_bJ to final states with open charm. We fully reconstruct D0 mesons with p_D0 > 2.5 GeV/c in three decay modes (K-pi+, K-pi+pi0, and K-pi-pi+pi+) in coincidence with radiative transition photons that tag the production of one of the chi_bJ(nP) states. We obtain significant signals for the two J=1 states. Recent NRQCD calculations of chi_{bJ}(nP) --> c cbar X depend on one non-perturbative parameter per chi_bJ triplet. The extrapolation from the observed D0 X rate over a limited momentum range to a full c cbar X rate also depends on these same parameters. Using our data to fit for these parameters, we extract results which agree well with NRQCD predictions, confirming the expectation that charm production is largest for the J=1 states. In particular, for J=1, our results are consistent with c cbar g accounting for about one-quarter of all hadronic decays.Comment: Version 2 updates include corrections to important errors in Table V and VII column headers which summarize results, and additional minor edits. 17 pages, available through http://www.lns.cornell.edu/public/CLNS

Generation of human vascular smooth muscle subtypes provides insight into embryological origin-dependent disease susceptibility.

Heterogeneity of embryological origins is a hallmark of vascular smooth muscle cells (SMCs) and may influence the development of vascular disease. Differentiation of human pluripotent stem cells (hPSCs) into developmental origin-specific SMC subtypes remains elusive. Here we describe a chemically defined protocol in which hPSCs were initially induced to form neuroectoderm, lateral plate mesoderm or paraxial mesoderm. These intermediate populations were further differentiated toward SMCs (>80% MYH11(+) and ACTA2(+)), which displayed contractile ability in response to vasoconstrictors and invested perivascular regions in vivo. Derived SMC subtypes recapitulated the unique proliferative and secretory responses to cytokines previously documented in studies using aortic SMCs of distinct origins. Notably, this system predicted increased extracellular matrix degradation by SMCs derived from lateral plate mesoderm, which was confirmed using rat aortic SMCs from corresponding origins. This differentiation approach will have broad applications in modeling origin-dependent disease susceptibility and in developing bioengineered vascular grafts for regenerative medicine

Correlation of Inter-Locus Polyglutamine Toxicity with CAG•CTG Triplet Repeat Expandability and Flanking Genomic DNA GC Content

Dynamic expansions of toxic polyglutamine (polyQ)-encoding CAG repeats in ubiquitously expressed, but otherwise unrelated, genes cause a number of late-onset progressive neurodegenerative disorders, including Huntington disease and the spinocerebellar ataxias. As polyQ toxicity in these disorders increases with repeat length, the intergenerational expansion of unstable CAG repeats leads to anticipation, an earlier age-at-onset in successive generations. Crucially, disease associated alleles are also somatically unstable and continue to expand throughout the lifetime of the individual. Interestingly, the inherited polyQ length mediating a specific age-at-onset of symptoms varies markedly between disorders. It is widely assumed that these inter-locus differences in polyQ toxicity are mediated by protein context effects. Previously, we demonstrated that the tendency of expanded CAG•CTG repeats to undergo further intergenerational expansion (their ‘expandability’) also differs between disorders and these effects are strongly correlated with the GC content of the genomic flanking DNA. Here we show that the inter-locus toxicity of the expanded polyQ tracts of these disorders also correlates with both the expandability of the underlying CAG repeat and the GC content of the genomic DNA flanking sequences. Inter-locus polyQ toxicity does not correlate with properties of the mRNA or protein sequences, with polyQ location within the gene or protein, or steady state transcript levels in the brain. These data suggest that the observed inter-locus differences in polyQ toxicity are not mediated solely by protein context effects, but that genomic context is also important, an effect that may be mediated by modifying the rate at which somatic expansion of the DNA delivers proteins to their cytotoxic state

Genetic variation in Fcγ receptor IIa and risk of coronary heart disease: negative results from two large independent populations

Background The role of the Fcgamma receptor IIa (FcgammaRIIa), a receptor for C-reactive protein (CRP), the classical acute phase protein, in atherosclerosis is not yet clear. We sought to investigate the association of FcgammaRIIa genotype with risk of coronary heart disease (CHD) in two large population-based samples. Methods FcgammaRIIa-R/H131 polymorphisms were determined in a population of 527 patients with a history of myocardial infarction and 527 age and gender matched controls drawn from a population-based MONICA- Augsburg survey. In the LURIC population, 2227 patients with angiographically proven CHD, defined as having at least one stenosis [greater than or equal to]50%, were compared with 1032 individuals with stenosis H genotype was not independently associated with lower risk of CHD after multivariable adjustments, neither in the MONICA population (odds ratio (OR) 1.08; 95% confidence interval (CI) 0.81 to 1.44), nor in LURIC (OR 0.96; 95% CI 0.81 to 1.14). Conclusion Our results do not confirm an independent relationship between FcgammaRIIa genotypes and risk of CHD in these populations