ANKRD1, the gene encoding cardiac ankyrin repeat protein, is a novel dilated cardiomyopathy gene.

OBJECTIVES: We evaluated ankyrin repeat domain 1 (ANKRD1), the gene encoding cardiac ankyrin repeat protein (CARP), as a novel candidate gene for dilated cardiomyopathy (DCM) through mutation analysis of a cohort of familial or idiopathic DCM patients, based on the hypothesis that inherited dysfunction of mechanical stretch-based signaling is present in a subset of DCM patients. BACKGROUND: CARP, a transcription coinhibitor, is a member of the titin-N2A mechanosensory complex and translocates to the nucleus in response to stretch. It is up-regulated in cardiac failure and hypertrophy and represses expression of sarcomeric proteins. Its overexpression results in contractile dysfunction. METHODS: In all, 208 DCM patients were screened for mutations/variants in the coding region of ANKRD1 using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct deoxyribonucleic acid sequencing. In vitro functional analyses of the mutation were performed using yeast 2-hybrid assays and investigating the effect on stretch-mediated gene expression in myoblastoid cell lines using quantitative real-time reverse transcription-polymerase chain reaction. RESULTS: Three missense heterozygous ANKRD1 mutations (P105S, V107L, and M184I) were identified in 4 DCM patients. The M184I mutation results in loss of CARP binding with Talin 1 and FHL2, and the P105S mutation in loss of Talin 1 binding. Intracellular localization of mutant CARP proteins is not altered. The mutations result in differential stretch-induced gene expression compared with wild-type CARP. CONCLUSIONS: ANKRD1 is a novel DCM gene, with mutations present in 1.9% of DCM patients. The ANKRD1 mutations may cause DCM as a result of disruption of the normal cardiac stretch-based signaling

Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD

Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p 10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10−392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group

Modeling of setting stresses in particle-reinforced polymer composites using finite element analysis

This work uses three-dimensional Finite Element Analysis (FEA) to investigate the effect of geometric arrangement of particulate reinforcement in highly filled polymer composites (such as polymer concrete) on the setting stresses that develop in these materials during cure due to resin shrinkage during polymerization. These composites were initially modeled by systems reinforced with spherical particles packed in simple cubic (SC) and face-centered cubic (FCC) arrangements within the polymer matrix. A pronounced decrease in setting stresses was observed in the FCC system, which has a greater aggregate to resin ratio and more of resin domains per unit cell. A hexagonal-close-packed arrangement of hexagonal, prism-shaped aggregate was also analyzed and found to develop higher stresses, indicating that aggregate shape has an effect on setting stresses. A second set of models investigated the effect of size gradation and geometric arrangement of spherical reinforcing particles on setting stresses. The maximum stresses occur at the particle-resin interface, underlining the importance of resin/aggregate adhesion. Reduction of setting stresses by a factor of two was observed in systems with efficient packing, achieved with proper size gradation and close-packed geometry. A microstructural model for a polymer composite system based on a fairly random arrangement (FRA) of aggregate particles was also developed. This model gives a realistic representation of actual particle reinforced polymer composites. FEA results were used to develop an empirical equation for maximum setting stresses for Particle reinforced polymer composites. A probabilistic model for the distribution of voids in polymer composites was developed by solving a non-linear constrained optimization problem. The probability distributions of voids was used with a specially developed algorithm to generate the voids distributions in specific composites. The effect of voids on setting stresses in FRA models was discussed. In polymer composites voids tend to act as stress relief. This effect is more pronounced in poorly packed systems. This study provides an understanding of setting stress distribution in polymer composites. This work provides guidelines for optimizing the amount, shape and particle size distribution of the reinforcing aggregate in polymer composites so as to minimize setting stresses, thus leading to composites with significantly enhanced strength

Identification of Regional Variation in the Constitutive Response of Axisymmetric Membranes

: We demonstrate that the equilibrium equations for an axisymmetric, nonlinear, anisotropic membrane under hydrostatic pressure allow explicit representation of the longitudinal and azimuthal stresses in terms of the associated longitudinal and azimuthal strains. We apply this result in a numerical simulation of the canine diaphragm. More precisely, we compute the deformation of the membrane under a quasi--static increase in the intensity of the applied hydrostatic load. The associated strains are easily estimated via finite differences. As the membrane is inflated the set of acheived strains grows and, as a result of our explicit representation formula, we recover larger and larger patches of the associated stress surfaces. Keywords: Material Identification, Constitutive Response, Membrane, Diaphragm 1. Introduction Our goal is the construction of a practical means by which the constitutive response of a nonlinear anisotropic membrane may be discerned from snap--shots recorded throu..

Mechanics of the respiratory muscles.

This article examines the mechanics of the muscles that drive expansion or contraction of the chest wall during breathing. The diaphragm is the main inspiratory muscle. When its muscle fibers are activated in isolation, they shorten, the dome of the diaphragm descends, pleural pressure (P(pl)) falls, and abdominal pressure (P(ab)) rises. As a result, the ventral abdominal wall expands, but a large fraction of the rib cage contracts. Expansion of the rib cage during inspiration is produced by the external intercostals in the dorsal portion of the rostral interspaces, the intercartilaginous portion of the internal intercostals (the so-called parasternal intercostals), and, in humans, the scalenes. By elevating the ribs and causing an additional fall in P(pl), these muscles not only help the diaphragm expand the chest wall and the lung, but they also increase the load on the diaphragm and reduce the shortening of the diaphragmatic muscle fibers. The capacity of the diaphragm to generate pressure is therefore enhanced. In contrast, during expiratory efforts, activation of the abdominal muscles produces a rise in P(ab) that leads to a cranial displacement of the diaphragm into the pleural cavity and a rise in P(pl). Concomitant activation of the internal interosseous intercostals in the caudal interspaces and the triangularis sterni during such efforts contracts the rib cage and helps the abdominal muscles deflate the lung.Journal ArticleSCOPUS: ar.jinfo:eu-repo/semantics/publishe