Regulation by phosphodiesterase isoforms of protein kinase A-mediated attenuation of myocardial protein kinase D activation

Protein kinase D (PKD) targets several proteins in the heart, including cardiac troponin I (cTnI) and class II histone deacetylases, and regulates cardiac contraction and hypertrophy. In adult rat ventricular myocytes (ARVM), PKD activation by endothelin-1 (ET1) occurs via protein kinase Cε and is attenuated by cAMP-dependent protein kinase (PKA). Intracellular compartmentalisation of cAMP, arising from localised activity of distinct cyclic nucleotide phosphodiesterase (PDE) isoforms, may result in spatially constrained regulation of the PKA activity that inhibits PKD activation. We have investigated the roles of the predominant cardiac PDE isoforms, PDE2, PDE3 and PDE4, in PKA-mediated inhibition of PKD activation. Pretreatment of ARVM with the non-selective PDE inhibitor isobutylmethylxanthine (IBMX) attenuated subsequent PKD activation by ET1. However, selective inhibition of PDE2 [by erythro-9-(2-hydroxy-3-nonyl) adenine, EHNA], PDE3 (by cilostamide) or PDE4 (by rolipram) individually had no effect on ET1-induced PKD activation. Selective inhibition of individual PDE isoforms also had no effect on the phosphorylation status of the established cardiac PKA substrates phospholamban (PLB; at Ser16) and cTnI (at Ser22/23), which increased markedly with IBMX. Combined administration of cilostamide and rolipram, like IBMX alone, attenuated ET1-induced PKD activation and increased PLB and cTnI phosphorylation, while combined administration of EHNA and cilostamide or EHNA and rolipram was ineffective. Thus, cAMP pools controlled by PDE3 and PDE4, but not PDE2, regulate the PKA activity that inhibits ET1-induced PKD activation. Furthermore, PDE3 and PDE4 play redundant roles in this process, such that inhibition of both isoforms is required to achieve PKA-mediated attenuation of PKD activation

A twin study into the genetic and environmental influences on academic performance in science in 9-year-old boys and girls

We investigated for the first time the genetic and environmental aetiology behind scientific achievement in primary school children, with a special focus on possible aetiological differences for boys and girls. For a representative community sample of 2602 twin pairs assessed at 9 years, scientific achievement in school was rated by teachers based on National Curriculum criteria in three domains: Scientific Enquiry, Life Processes and Physical Processes. Results indicate that genetic influences account for over 60% of the variance in scientific achievement, with environmental influences accounting for the remaining variance. Environmental influences were mainly of the non-shared variety, suggesting that children from the same family experience school environments differently. An analysis of sex differences considering differences in means, variances and aetiology of individual differences found only differences in variance between the sexes, with boys showing greater variance in performance than girls

Why do spatial abilities predict mathematical performance?

Spatial ability predicts performance in mathematics and eventual expertise in science, technology and engineering. Spatial skills have also been shown to rely on neuronal networks partially shared with mathematics. Understanding the nature of this association can inform educational practices and intervention for mathematical underperformance. Using data on two aspects of spatial ability and three domains of mathematical ability from 4174 pairs of 12-year-old twins, we examined the relative genetic and environmental contributions to variation in spatial ability and to its relationship with different aspects of mathematics. Environmental effects explained most of the variation in spatial ability (~70%) and in mathematical ability (~60%) at this age, and the effects were the same for boys and girls. Genetic factors explained about 60% of the observed relationship between spatial ability and mathematics, with a substantial portion of the relationship explained by common environmental influences (26% and 14% by shared and non-shared environments respectively). These findings call for further research aimed at identifying specific environmental mediators of the spatial–mathematics relationship

Microfocal X-Ray Computed Tomography Post-Processing Operations for Optimizing Reconstruction Volumes of Stented Arteries During 3D Computational Fluid Dynamics Modeling

Restenosis caused by neointimal hyperplasia (NH) remains an important clinical problem after stent implantation. Restenosis varies with stent geometry, and idealized computational fluid dynamics (CFD) models have indicated that geometric properties of the implanted stent may differentially influence NH. However, 3D studies capturing the in vivo flow domain within stented vessels have not been conducted at a resolution sufficient to detect subtle alterations in vascular geometry caused by the stent and the subsequent temporal development of NH. We present the details and limitations of a series of post-processing operations used in conjunction with microfocal X-ray CT imaging and reconstruction to generate geometrically accurate flow domains within the localized region of a stent several weeks after implantation. Microfocal X-ray CT reconstruction volumes were subjected to an automated program to perform arterial thresholding, spatial orientation, and surface smoothing of stented and unstented rabbit iliac arteries several weeks after antegrade implantation. A transfer function was obtained for the current post-processing methodology containing reconstructed 16 mm stents implanted into rabbit iliac arteries for up to 21 days after implantation and resolved at circumferential and axial resolutions of 32 and 50 μm, respectively. The results indicate that the techniques presented are sufficient to resolve distributions of WSS with 80% accuracy in segments containing 16 surface perturbations over a 16 mm stented region. These methods will be used to test the hypothesis that reductions in normalized wall shear stress (WSS) and increases in the spatial disparity of WSS immediately after stent implantation may spatially correlate with the temporal development of NH within the stented region

Distensibility Differs Between Sall Arteries and Veins in the Newborn Piglet Lung

BACKGROUND: We previously used micro-CT techniques to measure pulmonary artery distensibility in 3 week old piglets. Pressure/diameter relationships were measured for each artery and the slope (a) was then plotted against its diameter intercept at 0 pressure (Do). The resultant diameter independent distensibility parameter, a, was estimated by linear regression to be 1.6% per mmHg for arteries between 0.2 and 3.0 mm Do. OBJECTIVE: This study sought to determine whether; 1) distensibility of smaller arteries was similar to that of arteries with Do\u3e 0.2 mm; and 2) whether small vein and artery distensibility was similar. DESIGN/METHODS: Lower lobes were isolated and perfused with papaverine/saline to remove blood and tone. Lobar bronchi were cannulated and lobes inflated to 3 mmHg. Lobar arteries (n=13) or veins (n=12) were cannulated and perfluoroctyl bromide instilled. Small arteries (0.033 to 0.34 mm Do) and veins (0.024 to 0.33 mm Do) were imaged by planar X-ray at static pressures ranging from 21 to 3 mmHg in 3 mmHg increments. The slope of the pressure/diameter curve was estimated by linear regression (0 = Do + ~P ) for 4·8 arteries or veins per lobe. The linear relationship of all ~ vs their respective Do was plotted (0/00 = 1 + oP) to estimate distensibility. RESULTS: In small arteries, a determined by linear regression was 1.5 ± 0.1% per mmHg as previously described in larger arteries. a estimated in the same way in small veins was significantly lower at 0.9 ± 0.1% per mmHg (p \u3c 0.05). However, the X-ray images suggested that venous diameter increased more at lower than higher pressures. a estimated over the 3-9 mmHg pressure range was 1.4 ± 0.23% per mmHg. while over the 12-21 mmHg pressure range ~ was significantly lower at 0.9% ± 0.13%. CONCLUSIONS: Distensibility of the entire arterial tree over a wide range of pressures seems well described by a single, diameter independent parameter. In contrast, distensibility of small veins appears to be higher at low versus high pressures. Future studies must further examine distensibility of large and small veins at various pressures and relate the findings to pulmonary vascular hemodynamics

Transnational Legal Practice 2008

This article reviews developments in transnational legal practice during 2006 and 2007, including international developments, U.S. developments and regional developments in Australia and Europe. The primary focus of the international developments section is the WTO\u27s General Agreement on Trade in Services (GATS). This article discusses GATS Track 1 Activities related to legal services, including the Legal Services Collective Requests and issues related to GATS Track 2 and the potential development of GATS disciplines. This section also surveys GATS-related initiatives of the American Bar Association and the International Bar Association and U.S. implementation of foreign lawyer multi-jurisdictional practice rules. In other areas, the international developments section addresses the development of a code of conduct for defense counsel practicing before the International Criminal Court and developments in the Financial Action Task Force (FATF). With respect to U.S. transnational legal practice developments, the article reviews U.S. bilateral free trade initiatives, lawyer discipline cooperation initiatives and significant litigation. The regional developments section documents the emergence in Australia of the first publicly-traded law firm and Australia\u27s efforts to promote greater multijurisdictional practice for Australian lawyers in the U.S. This section also reviews various European developments, including European competition law initiatives, the Akzo Nobel case currently pending before the European Court of Justice, and developments related to the free movement of lawyers, codes of conduct, money laundering and lawyer education

Transnational Legal Practice 2008

The current financial turmoil shaking the world illustrates the connectedness of national markets and economies. Legal practice is no exception: lawyers and their firms are experiencing the upheaval along with their clients.1 This has resulted in new opportunities for lawyers and firms–in bankruptcy and restructuring and, likely in the future, in regulatory advising as well–and, at the same time, in substantial challenges. The promise of benefits from a diversified practice–in terms of both substance and geography–is being tested as lawyers and law firms follow their clients through the uncertainties of the current economic conditions. As law firms cut the size of their legal and non-legal staffs and decrease compensation expectations, they also are capitalizing on the benefits of a geographically diverse footprint of practice by looking to overseas activities as opportunities for growth. The number of firms announcing new offices in the Middle East, for example, has not slowed during the economic crisis.2 Over the last twenty years or so, the growth of overseas activities of the largest U.S.-based law firms has far outpaced their growth within the United States, by a rate of ten-to-one.3 In 2007, more than 15,000 lawyers worked for the National Law Journal 250 firms in more than 550 offices located outside the United States.4 Indeed, two U.S.-based law firms with substantial investments in overseas offices joined the ranks of four of the London “Magic Circle” firms in a new category dubbed the “global elite.”5 But the description so far relates only to the most visible part of the story of the importance of overseas-related work for U.S. lawyers. Overseas-related work also supports lawyers working for firms that do not have formal international footprints. These may be firms with foreign clients or U.S.-based clients involved in offshore activities or partnerships. They may be firms that are members of international networks or associations of lawyers that serve as a source of referral relationships, among other things. Each of these arrangements points to the continuing importance of keeping watch over the regulatory and business environment for lawyers outside the United States. The U.S. Department of Commerce Bureau of Economic Analysis estimates that the export of U.S. legal services generated $6.4 billion in receipts in 2007, while imports of legal services were valued at nearly$1.6 billion, yielding a four-to-one surplus for balance-of-payment accounts.6 If globalization continues, as appears likely, lawyers may be able to rely on overseas activities as a sort of hedge against instability at home. Access to overseas legal markets, then, remains an issue of high priority

Transnational Legal Practice 2008

The current financial turmoil shaking the world illustrates the connectedness of national markets and economies. Legal practice is no exception: lawyers and their firms are experiencing the upheaval along with their clients.1 This has resulted in new opportunities for lawyers and firms–in bankruptcy and restructuring and, likely in the future, in regulatory advising as well–and, at the same time, in substantial challenges. The promise of benefits from a diversified practice–in terms of both substance and geography–is being tested as lawyers and law firms follow their clients through the uncertainties of the current economic conditions. As law firms cut the size of their legal and non-legal staffs and decrease compensation expectations, they also are capitalizing on the benefits of a geographically diverse footprint of practice by looking to overseas activities as opportunities for growth. The number of firms announcing new offices in the Middle East, for example, has not slowed during the economic crisis.2 Over the last twenty years or so, the growth of overseas activities of the largest U.S.-based law firms has far outpaced their growth within the United States, by a rate of ten-to-one.3 In 2007, more than 15,000 lawyers worked for the National Law Journal 250 firms in more than 550 offices located outside the United States.4 Indeed, two U.S.-based law firms with substantial investments in overseas offices joined the ranks of four of the London “Magic Circle” firms in a new category dubbed the “global elite.”5 But the description so far relates only to the most visible part of the story of the importance of overseas-related work for U.S. lawyers. Overseas-related work also supports lawyers working for firms that do not have formal international footprints. These may be firms with foreign clients or U.S.-based clients involved in offshore activities or partnerships. They may be firms that are members of international networks or associations of lawyers that serve as a source of referral relationships, among other things. Each of these arrangements points to the continuing importance of keeping watch over the regulatory and business environment for lawyers outside the United States. The U.S. Department of Commerce Bureau of Economic Analysis estimates that the export of U.S. legal services generated $6.4 billion in receipts in 2007, while imports of legal services were valued at nearly$1.6 billion, yielding a four-to-one surplus for balance-of-payment accounts.6 If globalization continues, as appears likely, lawyers may be able to rely on overseas activities as a sort of hedge against instability at home. Access to overseas legal markets, then, remains an issue of high priority

Genome-wide association study of receptive language ability of 12 year olds

Purpose: We have previously shown that individual differences in measures of receptive language ability at age 12 are highly heritable. The current study attempted to identify some of the genes responsible for the heritability of receptive language ability using a genome-wide association (GWA) approach. Method: We administered four internet-based measures of receptive language (vocabulary, semantics, syntax, and pragmatics) to a sample of 2329 12-year-olds for whom DNA and genome-wide genotyping were available. Nearly 700,000 single-nucleotide polymorphisms (SNPs) and one million imputed SNPs were included in a GWA analysis of receptive language composite scores. Results: No SNP associations met the demanding criterion of genome-wide significance that corrects for multiple testing across the genome (p < 5 ×10-8). The strongest SNP association did not replicate in an additional sample of 2639 12-year-olds. Conclusion: These results indicate that individual differences in receptive language ability in the general population do not reflect common genetic variants that account for >3% of the phenotypic variance. The search for genetic variants associated with language skill will require larger samples and additional methods to identify and functionally characterize the full spectrum of risk variants

Understanding the science-learning environment: a genetically sensitive approach.

Previous studies have shown that environmental influences on school science performance increase in importance from primary to secondary school. Here we assess for the first time the relationship between the science-learning environment and science performance using a genetically sensitive approach to investigate the aetiology of this link. 3000 pairs of 14-year-old twins from the UK Twins Early Development Study reported on their experiences of the science-learning environment and were assessed for their performance in science using a web-based test of scientific enquiry. Multivariate twin analyses were used to investigate the genetic and environmental links between environment and outcome. The most surprising result was that the science-learning environment was almost as heritable (43%) as performance on the science test (50%), and showed negligible shared environmental influence (3%). Genetic links explained most (56%) of the association between learning environment and science outcome, indicating gene–environment correlation