Abstract-Although human atherosclerosis is associated with aging, direct evidence of cellular senescence and the mechanism of senescence in vascular smooth muscle cells (VSMCs) in atherosclerotic plaques is lacking. We examined normal vessels and plaques by histochemistry, Southern blotting, and fluorescence in situ hybridization for telomere signals. (VSMCs), and intracellular and extracellular lipids. Plaque disruption results in acute myocardial infarction and stroke, whereas repeated rounds of subclinical rupture and repair also promote plaque growth. Although VSMC proliferation occurs in atherogenesis, most proliferating cells are macrophages, and VSMC mitotic rates are lower in advanced plaques than early lesions, even after plaque rupture, 1 suggesting that plaque VSMCs may exhibit senescence.Cellular senescence can be defined as cell cycle arrest accompanying the exhaustion of replicative potential. 2 Senescent cells display a characteristic morphology (vacuolated, flattened cells) and gene expression, including markers such as senescence-associated ␤-galactosidase (SA␤G). 3 Senescence may be triggered by 2 broadly different mechanisms. In most primary cells, the telomeres of chromosomes shorten at each cell division because of incomplete chromosomal replication. Replicative senescence may be induced at critical telomere lengths or structures, such as telomeric fusion or dicentrics or loss of telomere-bound factors. 4,5 Cells also undergo "stress-induced premature senescence" (SIPS), for example, in response to activated oncogenes (eg, Ha-Ras) and suboptimal culture conditions. 6 Although telomere loss occurs with replication, both premature senescence and telomere breaks may be induced by oxidative DNA damage. Reactive oxygen species (ROS), particularly superoxide anions, hydrogen peroxide, and hydroxyl radicals, can produce a large variety of DNA damage, including DNA strand breaks and DNA base modifications. ROS can accelerate telomere loss during replication in some cell types 7 but also induces premature senescence independently of telomere shortening. 8 Increased levels of ROS are Original

In this article, we focus on the sampling of the configurational Gibbs-Boltzmann distribution, that is, the calculation of averages of functions of the position coordinates of a molecular N -body system modelled at constant temperature. We show how a formal series expansion of the invariant measure of a Langevin dynamics numerical method can be obtained in a straightforward way using the Baker-Campbell-Hausdorff lemma. We then compare Langevin dynamics integrators in terms of their invariant distributions and demonstrate a superconvergence property (4th order accuracy where only 2nd order would be expected) of one method in the high friction limit; this method, moreover, can be reduced to a simple modification of the Euler-Maruyama method for Brownian dynamics involving a non-Markovian (coloured noise) random process. In the Brownian dynamics case, 2nd order accuracy of the invariant density is achieved. All methods considered are efficient for molecular applications (requiring one force evaluation per timestep) and of a simple form. In fully resolved (long run) molecular dynamics simulations, for our favoured method, we observe up to two orders of magnitude improvement in configurational sampling accuracy for given stepsize with no evident reduction in the size of the largest usable timestep compared to common alternative methods.

An agency theory framework is used to test the effects of founding family control on firm performance, capital structure, and value. Both the finance and management literatures regarding the relationship between firm control and firm value are explored. Controlling for size, industry, and managerial ownership, the results suggest that firms controlled by the founding family have greater value, are operated more efficiently, and carry less debt than other firms.

We consider numerical methods for thermodynamic sampling, i.e. computing sequences of points distributed according to the Gibbs-Boltzmann distribution, using Langevin dynamics and overdamped Langevin dynamics (Brownian dynamics). A wide variety of numerical methods for Langevin dynamics may be constructed based on splitting the stochastic differential equations into various component parts, each of which may be propagated exactly in the sense of distributions. Each such method may be viewed as generating samples according to an associated invariant measure that differs from the exact canonical invariant measure by a stepsize-dependent perturbation. We provide error estimatesà la Talay-Tubaro on the invariant distribution for small stepsize, and compare the sampling bias obtained for various choices of splitting method. We further investigate the overdamped limit and apply the methods in the context of driven systems where the goal is sampling with respect to a nonequilibrium steady state. Our analyses are illustrated by numerical experiments.

A wide variety of numerical methods are evaluated and compared for solving the stochastic differential equations encountered in molecular dynamics. The methods are based on the application of deterministic impulses, drifts, and Brownian motions in some combination. The Baker-Campbell-Hausdorff expansion is used to study sampling accuracy following recent work by the authors, which allows determination of the stepsize-dependent bias in configurational averaging. For harmonic oscillators, configurational averaging is exact for certain schemes, which may result in improved performance in the modelling of biomolecules where bond stretches play a prominent role. For general systems, an optimal method can be identified that has very low bias compared to alternatives. In simulations of the alanine dipeptide reported here (both solvated and unsolvated), higher accuracy is obtained without loss of computational efficiency, while allowing large timestep, and with no impairment of the conformational exploration rate (the effective diffusion rate observed in simulation).The optimal scheme is a uniformly better performing algorithm for molecular sampling, with overall efficiency improvements of 25% or more in practical timestep size achievable in vacuum, and with reductions in the error of configurational averages of a factor of ten or more attainable in solvated simulations at large timestep.

We report a woman with primary amenorrhoea and infertility associated with an isolated deficiency of pituitary follicle-stimulating hormone (FSH), but normal luteinizing hormone (LH) secretion. Ovulation was induced by administration of exogenous FSH and resulted in a successful pregnancy. Sequence analysis of the FSH beta-subunit gene indicated that she is homozygous for a two nucleotide frameshift deletion in the coding sequence. Her mother and son are heterozygous for this mutation. This deletion results in an alteration of amino acid codons 61-86 followed by a premature termination codon. The predicted truncated beta-subunit peptide lacks regions which are important for association with the alpha subunit and for binding to and activation of the FSH receptor. Abnormalities of FSH structure or function might be an under recognised but treatable cause of infertility.

Resistance to thyroid hormone (RTH), with elevated serum free thyroid hormones and nonsuppressed thyrotropin levels, is either relatively asymptomatic, suggesting a generalized disorder (GRTH) Invest. 1994. 94:506-515.)

The role of opportunities in the entrepreneurial process remains relatively underdeveloped. To address this issue, we develop a definition of an entrepreneurial opportunity and draw upon a distinction from the domain of knowledge management to suggest a continuum of entrepreneurial opportunities ranging from codified to tacit. Though both traditional and contemporary research has examined how individual differences relate to the identification of opportunities, we focus instead on the importance of differences in the opportunities themselves. Specifically, we examine how relative differences in the degree of opportunity tacitness relate to the process of opportunity identification. We find that relatively more codified opportunities are more likely to be discovered through systematic search, whereas more tacit opportunities are more likely to be identified due to prior experience. These findings contribute to an increased understanding of the role of the opportunity in entrepreneurship research and have important implications for economic theories of entrepreneurship, entrepreneurial learning, entrepreneurial networks, and entrepreneurial education.