Allele-Specific, Age-Dependent and BMI-Associated DNA Methylation of Human MCHR1

Background: Melanin-concentrating hormone receptor 1 (MCHR1) plays a significant role in regulation of energy balance, food intake, physical activity and body weight in humans and rodents. Several association studies for human obesity showed contrary results concerning the SNPs rs133072 (G/A) and rs133073 (T/C), which localize to the first exon of MCHR1. The variations constitute two main haplotypes (GT, AC). Both SNPs affect CpG dinucleotides, whereby each haplotype contains a potential methylation site at one of the two SNP positions. In addition, 15 CpGs in close vicinity of these SNPs constitute a weak CpG island. Here, we studied whether DNA methylation in this sequence context may contribute to population- and age-specific effects of MCHR1 alleles in obesity. \ud Principal Findings: We analyzed DNA methylation of a 315 bp region of MCHR1 encompassing rs133072 and rs133073 and the CpG island in blood samples of 49 individuals by bisulfite sequencing. The AC haplotype shows a significantly higher methylation level than the GT haplotype. This allele-specific methylation is age-dependent. In young individuals (20â\u80\u9330 years) the difference in DNA methylation between haplotypes is significant; whereas in individuals older than 60 years it is not detectable. Interestingly, the GT allele shows a decrease in methylation status with increasing BMI, whereas the methylation of the AC allele is not associated with this phenotype. Heterozygous lymphoblastoid cell lines show the same pattern of allele-specific DNA methylation. The cell line, which exhibits the highest difference in methylation levels between both haplotypes, also shows allele-specific transcription of MCHR1, which can be abolished by treatment with the DNA\ud methylase inhibitor 5-aza-2'-deoxycytidine.\ud Conclusions:We show that DNA methylation at MCHR1 is allele-specific, age-dependent, BMI-associated and affects transcription. Conceivably, this epigenetic regulation contributes to the age- and/or population specific effects reported for MCHR1 in several human obesity studies.\ud \ud doi: 10.1371/journal.pone.0017711\u

Channelopathies in Cav1.1, Cav1.3, and Cav1.4 voltage-gated L-type Ca2+ channels

Voltage-gated Ca2+ channels couple membrane depolarization to Ca2+-dependent intracellular signaling events. This is achieved by mediating Ca2+ ion influx or by direct conformational coupling to intracellular Ca2+ release channels. The family of Cav1 channels, also termed L-type Ca2+ channels (LTCCs), is uniquely sensitive to organic Ca2+ channel blockers and expressed in many electrically excitable tissues. In this review, we summarize the role of LTCCs for human diseases caused by genetic Ca2+ channel defects (channelopathies). LTCC dysfunction can result from structural aberrations within their pore-forming α1 subunits causing hypokalemic periodic paralysis and malignant hyperthermia sensitivity (Cav1.1 α1), incomplete congenital stationary night blindness (CSNB2; Cav1.4 α1), and Timothy syndrome (Cav1.2 α1; reviewed separately in this issue). Cav1.3 α1 mutations have not been reported yet in humans, but channel loss of function would likely affect sinoatrial node function and hearing. Studies in mice revealed that LTCCs indirectly also contribute to neurological symptoms in Ca2+ channelopathies affecting non-LTCCs, such as Cav2.1 α1 in tottering mice. Ca2+ channelopathies provide exciting disease-related molecular detail that led to important novel insight not only into disease pathophysiology but also to mechanisms of channel function

Thrust generation due to airfoil flapping

Thrust generation on a single flapping airfoil and a flapping/stationary airfoil combination in tandem is studied parametrically. A multiblock Navier-Stokes solver is employed to compute unsteady flowfields. The unsteady flow-field around a single flapping airfoil is also computed by an unsteady potential how code, The numerical solutions predict thrust generation in flapping airfoils and a significant augmentation of thrust in flapping/stationary airfoil combinations in tandem. The propulsive efficiency is found to be a strong function of reduced frequency and the amplitude of the flapping motion. At a flapping amplitude of 0.40 chord lengths and a reduced frequency of 0.10, the propulsive efficiency of a single NACA 0012 airfoil was computed to be more than 70%. For the airfoil combination in tandem, the propulsive efficiency was augmented more than 40% at a reduced frequency of 0.75 and a flapping amplitude of 0.20 chord lengths when the airfoils are separated by about two chord lengths

Computational study of flapping airfoil aerodynamics

Unsteady, viscous, low-speed flows over a NACA 0012 airfoil oscillated in plunge and/or pitch at various reduced frequency, amplitude, and phase shift are computed. Vortical wake formations, boundary-layer flows at the leading edge, the formation of leading-edge vortices and their downstream convection are presented in terms of unsteady particle traces. Flow separation characteristics and thrust-producing wake profiles are identified. Computed results compare well with water tunnel flow visualization and force data and other computational data. The maximum propulsive efficiency is obtained for cases where the flow remains mostly attached over the airfoil oscillated in a combined pitch and plunge

Potential flow solutions with wakes over an ogive cylinder

An incompressible panel code is employed to compute the flow over an ogive cylinder body with an overall length of 7.5 diameter. Flow separation is modeled by vortex wakes attached to the base region and the leeward sides of the cylinder body. The computed surface pressures and integrated normal force and pitching-moment coefficients are found to be in good agreement with the experimental data up to 20-deg incidence. This favorable agreement suggests that the panel codes may be a computationally efficient tool in the aerodynamic missile design process at low incidences

Computational study of subsonic flow over a delta canard-wing-body configuration

Subsonic flowfields over a close-coupled, delta canard-wing-body configuration at angles of attack of 20, 24,2, and 30 deg are computed using the OVERFLOW Navier-Stokes solver Computed flowfields are presented in terms of particle traces, surface streamlines, and leeward-side surface pressure distributions for the canard-on and -off configurations. The interaction between the canard and the wing vortices, wing vortex breakdown, and the influence of the canard on vortex breakdown are identified, The comparison of the pressure data with the available experimental data at Re = 0.32 x 10(6) and Re = 1.4 x 10(6) shows a significant Reynolds-number dependence. Good agreement is obtained with the experiment for the canard-off configuration at all three angles of attack, and for the canard-on configuration at 20-deg angle of attack

Navier-Stokes analysis of subsonic flowfields over a missile configuration

Subsonic flowfields over a missile configuration are computed at high angles of attack ranging from 15 to 60 deg with the NASA Ames Research Center OVERFLOW Navier-Stokes solver. The computed flowfields are presented in terms of particle traces, helicity contours; and surface streamlines. The dow separation over the missile body, the development of leeward-side vortex patterns, and the canard and tail vortices and their interaction are identified. The computed normal force and pitching moment coefficients compare well with the experimental data at an incidence of 15 deg; At higher incidences the normal force is underpredicted by up to 15%. The computed pitching moments agree qualitatively well with the,experimental data, but Percentage deviations are substantial in the higher incidence range