Thioredoxin interacting protein genetic variation is associated with diabetes and hypertension in the Brazilian general population

Objective: To investigate the relationship between TXNIP polymorphisms, diabetes and hypertension phenotypes in the Brazilian general population. Methods: Five hundred seventy-six individuals randomly selected from the general urban population according to the MONICA-WHO project guidelines were phenotyped for cardiovascular risk factors. A second, independent, sample composed of 487 family-trios from a different site was also selected. Nine TXNIP polymorphisms were studied. The potential association between TXNIP variability and glucose-phenotypes in children was also explored. TXNIP expression was quantified by real-time PCR in 53 samples from human smooth muscle cells primary culture. Results: TXNIP rs7211 and rs7212 polymorphisms were significantly associated with glucose and blood pressure related phenotypes. In multivariate logistic regression models the studied markers remained associated with diabetes even after adjustment for covariates. TXNIP rs7211 T/rs7212 G haplotype (present in approximately 17% of individuals) was significantly associated to diabetes in both samples. In children, the TXNIP rs7211 T/rs7212 G haplotype was associated with fasting insulin concentrations. Finally, cells harboring TXNIP rs7212 G allele presented higher TXNIP expression levels compared with carriers of TXNIP rs7212 CC genotype (p = 0.02). Conclusion: Carriers of TXNIP genetic variants presented higher TXNIP expression, early signs of glucose homeostasis derangement and increased susceptibility to chronic metabolic conditions such as diabetes and hypertension. Our data suggest that genetic variation in the TXNIP gene may act as a "common ground" modulator of both traits: diabetes and hypertension. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

The Prelude from Suite for solo Piano Le Tombeau de Couperin by Maurice Ravel: compositional and interpretive considerations

This article, part of a doctoral research conducted at the Department of Music of the ECA/USP/FAPESP aims to elucidate compositional and technical procedures in the Prelude from the suite Le Tombeau de Couperin (1914-1917) by french composer Maurice Ravel. Such procedures are traced back to French barroque composer Francois Couperin (1668-1733) harpsichord pieces, and are translated by Ravel to the modern piano. Thus, by studying the works for harpsichord by Couperin it was possible to see a kind of fusion of two languages and two instrumental techniques apart in time. This fusion of languages poses several interpretive questions.

ALDH1A2 (RALDH2) genetic variation in human congenital heart disease

Abstract Background Signaling by the vitamin A-derived morphogen retinoic acid (RA) is required at multiple steps of cardiac development. Since conversion of retinaldehyde to RA by retinaldehyde dehydrogenase type II (ALDH1A2, a.k.a RALDH2) is critical for cardiac development, we screened patients with congenital heart disease (CHDs) for genetic variation at the ALDH1A2 locus. Methods One-hundred and thirty-three CHD patients were screened for genetic variation at the ALDH1A2 locus through bi-directional sequencing. In addition, six SNPs (rs2704188, rs1441815, rs3784259, rs1530293, rs1899430) at the same locus were studied using a TDT-based association approach in 101 CHD trios. Observed mutations were modeled through molecular mechanics (MM) simulations using the AMBER 9 package, Sander and Pmemd programs. Sequence conservation of observed mutations was evaluated through phylogenetic tree construction from ungapped alignments containing ALDH8 s, ALDH1Ls, ALDH1 s and ALDH2 s. Trees were generated by the Neighbor Joining method. Variations potentially affecting splicing mechanisms were cloned and functional assays were designed to test splicing alterations using the pSPL3 splicing assay. Results We describe in Tetralogy of Fallot (TOF) the mutations Ala151Ser and Ile157Thr that change non-polar to polar residues at exon 4. Exon 4 encodes part of the highly-conserved tetramerization domain, a structural motif required for ALDH oligomerization. Molecular mechanics simulation studies of the two mutations indicate that they hinder tetramerization. We determined that the SNP rs16939660, previously associated with spina bifida and observed in patients with TOF, does not affect splicing. Moreover, association studies performed with classical models and with the transmission disequilibrium test (TDT) design using single marker genotype, or haplotype information do not show differences between cases and controls. Conclusion In summary, our screen indicates that ALDH1A2 genetic variation is present in TOF patients, suggesting a possible causal role for this gene in rare cases of human CHD, but does not support the hypothesis that variation at the ALDH1A2 locus is a significant modifier of the risk for CHD in humans.

Applying many-body expansion aiming to make ab in initio molecular dynamics more efficient

In this present work we present a methodology that aims to apply the many-body expansion to decrease the computational cost of ab initio molecular dynamics, keeping acceptable accuracy on the results. We implemented this methodology in a program which we called ManBo. In the many-body expansion approach, we partitioned the total energy E of the system in contributions of one body, two bodies, three bodies, etc., until the contribution of the Nth body [1-3]: E = E1 + E2 + E3 + …EN. The E1 term is the sum of the internal energy of the molecules; the term E2 is the energy due to interaction between all pairs of molecules; E3 is the energy due to interaction between all trios of molecules; and so on. In Manbo we chose to truncate the expansion in the contribution of two or three bodies, both for the calculation of the energy and for the calculation of the atomic forces. In order to partially include the many-body interactions neglected when we truncate the expansion, we can include an electrostatic embedding in the electronic structure calculations, instead of considering the monomers, pairs and trios as isolated molecules in space. In simulations we made we chose to simulate water molecules, and use the Gaussian 09 as external program to calculate the atomic forces and energy of the system, as well as reference program for analyzing the accuracy of the results obtained with the ManBo. The results show that the use of the many-body expansion seems to be an interesting approach for reducing the still prohibitive computational cost of ab initio molecular dynamics. The errors introduced on atomic forces in applying such methodology are very small. The inclusion of an embedding electrostatic seems to be a good solution for improving the results with only a small increase in simulation time. As we increase the level of calculation, the simulation time of ManBo tends to largely decrease in relation to a conventional BOMD simulation of Gaussian, due to better scalability of the methodology presented. References [1] E. E. Dahlke and D. G. Truhlar; J. Chem. Theory Comput., 3, 46 (2007). [2] E. E. Dahlke and D. G. Truhlar; J. Chem. Theory Comput., 4, 1 (2008). [3] R. Rivelino, P. Chaudhuri and S. Canuto; J. Chem. Phys., 118, 10593 (2003).