Genetic varients leading to atrial fibrillation

BACKGROUND: Atrial Fibrillation (AF) is the most common cardiac arrhythmia, affecting over 3 million Americans. Many people who suffer from AF have pre-disposing factors such as hypertension, ischemia, and structural heart disease, but recent research has also demonstrated the importance of genetic factors that can contribute to AF. In the present study, we sought to determine the causative mutation in a family with AF, atrial septal, and ventricular septal defects. METHODS: We evaluated a pedigree with 16 family members, one of whom had an ASD, one a VSD, and three had AF. Exome sequencing was performed on three of the five affected family members followed by confirmation with Sanger sequencing in all family members. A separate cohort from the MGH AF Study with early-onset AF (age at onset 47.1 ± 10.9 years, 79.3% male) was also screened for mutations using a combination of Sanger sequencing and high resolution melting. Variants were then functionally characterized using reporter assays in a mammalian cell line using wild-type and mutant constructs driving NPPA, αMHC and NPPB promoter reporters. RESULTS: Exome sequencing of the three affected individuals in the family identified a highly conserved mutation, R585L, in the transcription factor gene, GATA6. We also identified three additional GATA6 variants (P91S, A177T, and A543G) in the cases with early-onset AF from the MGH AF Study. We found that three of the four variants had a marked upregulation of luciferase activity (R585L; 4.1 fold, p<0.0001; P91S; 2.5 fold, p=0.0002; A177T; 1.7 fold, p=0.03). Additionally, when co-overexpressed with GATA4 and MEF2C, all GATA6 variants exhibited upregulation of the αMHC and NPPA activity compared to control. CONCLUSION: Overall, we found gain-of-function mutations in GATA6 in both a family with early-onset AF and atrioventricular septal defects as well as in patients with sporadic, early-onset AF. This evidence suggests that specific gain of function mutations in GATA6 contribute to the development of AF.2017-06-16T00:00:00

Conceptual Investigation of Partially Buckling Restrained Braces

Although in its infancy, leveraging high strength fiber reinforced polymer (FRP) materials for retrofit of steel structures has been the focus of recent investigations. Studies include the application of FRP to steel for flexural and fatigue or fracture retrofit as well as improving steel member stability. The research presented in this thesis attempts to introduce the concept of an FRP-stabilized steel member through a retrofit application creating a Partially Buckling Restrained Brace (PBRB). A PBRB seeks to increase steel brace stability and hysteretic energy dissipation during a seismic event through the strategic application of bonded FRP materials along its length. Six 65 ½" long A992 Gr. 50 WT6x7 steel braces were tested under cyclic compressive loading to failure. Two braces were retrofitted with carbon FRP (CFRP) and two braces were retrofitted with glass FRP (GFRP). One brace was encased in an HSS 7 x 0.125" steel tube and filled with grout to create a conventional Buckling Restrained Brace (BRB). The final brace was an unretrofit control specimen. Two arrangements of FRP materials were used for both the CFRP and GFRP retrofit braces: (1) 2" wide strip was applied to each side of the stem of the WT, and (2) 1" wide strips were applied to each side of the stem in an effort to optimize the retrofit application. The GFRP specimens increased the axial capacity of the brace by 6% and 9%, whereas the CFRP specimens had no effect. The observed variability in axial capacity was largely a result of initial loading eccentricities. The GFRP specimens did however show greater control over residual deflections suggesting that the retrofit can delay the formation of a plastic hinge within the brace and maintain compressive capacity through several cyclic loading loops. All of the FRP-retrofit specimens reduced weak-axis lateral displacement of the braces and showed increased control of local behavior. However, the brace is not dominated by local behavior due to its length, and this application may be better suited to shorter braces, similar to those found as cross frames between bridge girders, or to control local buckling in steel I-shaped beams

Impartial comparative analysis of measurement of leukocyte telomere length/DNA content by Southern blots and qPCR.

Telomere length/DNA content has been measured in epidemiological/clinical settings with the goal of testing a host of hypotheses related to the biology of human aging, but often the conclusions of these studies have been inconsistent. These inconsistencies may stem from various reasons, including the use of different telomere length measurement techniques. Here, we report the first impartial evaluation of measurements of leukocyte telomere length by Southern blot of the terminal restriction fragments and quantitative PCR (qPCR) of telomere DNA content, expressed as the ratio of telomeric product (T)/single copy gene (S) product. Blind measurements on the same samples from 50 donors were performed in two independent laboratories on two different occasions. Both the qPCR and Southern blots displayed highly reproducible results as shown by r values &gt; 0.9 for the correlations between results obtained by either method on two occasions. The inter-assay CV measurement for the qPCR was 6.45%, while that of the Southern blots was 1.74%. The relation between the results generated by Southern blots versus those generated by qPCR deviated from linearity. We discuss the ramifications of these findings with regard to measurements of telomere length/DNA content in epidemiological/clinical circumstances

Suppression of the rate of growth of dynamic heterogeneities and its relation to the local structure in a supercooled polydisperse liquid

The relationship between the microscopic arrangement of molecules in a supercooled liquid and its slow dynamics at low temperature near glass transition is studied by molecular dynamics simulations. A Lennard-Jones liquid with polydispersity in size and mass of constituent particles is chosen as the model system. Our studies reveal that the local structure (that varies with polydispersity) plays a crucial role both in the slowing down of dynamics and in the growth of the dynamic heterogeneities, besides determining the glass forming ability of the system. Increasing polydispersity at fixed volume fraction is found to suppress the rate of growth of dynamic correlations, as detected by the growth in the peak of the nonlinear density response function, &#967;4(t). The growth in dynamical correlation is manifested in a stronger than usual breakdown of Stokes-Einstein relation at lower polydispersity at low temperatures and also leads to a decrease in the fragility of the system with polydispersity. We show that the suppression of the rate of growth of the dynamic heterogeneity can be attributed to the loss of structural correlations (as measured by the structure factor and the local bond orientational order) with polydispersity. While a critical polydispersity is required to avoid crystallization, we find that a further increase in polydispersity lowers the glass forming ability

Unexpected Smoking-Linked High MMP-9 in Induced Sputum of Hazardous Dust-Exposed Workers

We investigated whether metalloproteinase-9 (MMP-9) values in induced sputum (IS) and pulmonary function tests can serve as a marker of damage and intensity of exposure to hazardous dust. Thirty-nine factory employees (28 workers exposed to metal particles and 11 supposedly nonexposed office workers) underwent IS induction. Samples were processed by conventional methods within 2 hours. The proportion of particles with diameters of 0–2 μ in IS samples was significantly higher in nonexposed than exposed workers and in smoker compared to nonsmoker workers. MMP-9 and TIMP-1 levels were similar for both groups. A linear regression model for MMP-9 based on exposure, smoking habits, and proportion of particles < 5 μ revealed a positive correlation between each of the explanatory variables and MMP-9 values. MMP-9 may serve as a marker for pulmonary injury

Desarrollo Turístico : Aplicación de Marketing en el Turismo Cultural del Departamento de León

La aplicación del marketing en el turismo cultural del departamento de León es inherente para cada empresa turística, porque ha sido uno de los principales factores de ingreso económico y generador de empleos, permitiendo permanecer en el mercado turístico con éxito. Se aborda los principios básicos para la elaboración de los objetivos corporativos, los cuales se harán mención en el documento con el propósito que sean dicho objetivo, realista, coherentes y alcanzables. El despliegue de los objetivos deben ser elementos claves en la dirección del marketing turístico cultural del departamento de León, su propósito es mejorar el engarce entre el mercado turístico, desarrollo y aplicación del marketing turístico en las empresas turistas Una medida adecuada para incentivar la demanda turística y consolidar el crecimiento del turismo internacional en un país consiste en mantener una estabilidad socio-política, proyectar una adecuada seguridad ciudadana y conservar cierta coherencia económica, inspirando una imagen de confianza que influya en los turistas. León posee una gran variedad de riquezas culturales que la convierten en un destino con un enorme potencial turístico por desarrollar. Es importante este sector desde el punto de vista económico, debido a que el turismo en el departamento de León es una actividad de mucha jerarquía por su incidencia en el desarrollo nacional, especialmente sobre la redistribución de la renta, sobre la balanza de pagos, sobre el nivel de empleo, sobre el producto interno bruto y sobre las economías regionales

Phenotypic Evolution of Therapeutic Salmonella enterica Serovar Typhimurium after Invasion of TRAMP Mouse Prostate Tumor

Salmonella has been of interest in cancer research due to its intrinsic ability to selectively target and colonize within tumors, leading to tumor cell death. Current research indicates promising use of Salmonella in regular administrations to remove tumors in mouse models while minimizing toxic side effects. However, selection of mutants during such long-term tumor colonization is a safety concern, and understanding selection of certain phenotypes within a tumor is an important consideration in predicting the long-term success of bacterium-based cancer treatment strategies. Thus, we have made an initial examination of selected phenotypes in a therapeutic Salmonella enterica serovar Typhimurium population developed from an archival wild-type LT2 strain and intraperitoneally injected into a 6-month-old TRAMP (transgenic adenocarcinoma of mouse prostate) mouse. We compared the original injected strain to isolates recovered from prostate tumors and those recovered from the spleen and liver of non-tumor-bearing TRAMP mice through phenotypic assessments of bacteriophage susceptibility, motility, growth rates, morphology, and metabolic activity. Tumor isolate traits, particularly the loss of wild-type motility and flagella, reflect the selective pressure of the tumor, while the maintenance of bacteriophage resistance indicates no active selection to remove this robust trait. We posit that the Salmonella population adopts certain strategies to minimize energy consumption and maximize survival and proliferation once within the tumor. We find these insights to be nonnegligible considerations in the development of cancer therapies involving bacteria and suggest further examinations into the evolution of therapeutic strains during passage through tumors.Center for Cancer Research (National Cancer Institute (U.S.)