Adam Smith and the theory of punishment

A distinctive theory of punishment plays a central role in Smith's moral and legal theory. According to this theory, we regard the punishment of a crime as deserved only to the extent that an impartial spectator would go along with the actual or supposed resentment of the victim. The first part of this paper argues that Smith's theory deserves serious consideration and relates it to other theories such as utilitarianism and more orthodox forms of retributivism. The second part considers the objection that, because Smith's theory implies that punishment is justified only when there is some person or persons who is the victim of the crime, it cannot explain the many cases where punishment is imposed purely for the public good. It is argued that Smith's theory could be extended to cover such cases. The third part defends Smith's theory against the objection that, because it relies on our natural feelings, it cannot provide an adequate moral justification of punishment

Ablation debris control by means of closed thick film filtered water immersion

The performance of laser ablation generated debris control by means of open immersion techniques have been shown to be limited by flow surface ripple effects on the beam and the action of ablation plume pressure loss by splashing of the immersion fluid. To eradicate these issues a closed technique has been developed which ensured a controlled geometry for both the optical interfaces of the flowing liquid film. This had the action of preventing splashing, ensuring repeatable machining conditions and allowed for control of liquid flow velocity. To investigate the performance benefits of this closed immersion technique bisphenol A polycarbonate samples have been machined using filtered water at a number of flow velocities. The results demonstrate the efficacy of the closed immersion technique: a 93% decrease in debris is produced when machining under closed filtered water immersion; the average debris particle size becomes larger, with an equal proportion of small and medium sized debris being produced when laser machining under closed flowing filtered water immersion; large debris is shown to be displaced further by a given flow velocity than smaller debris, showing that the action of flow turbulence in the duct has more impact on smaller debris. Low flow velocities were found to be less effective at controlling the positional trend of deposition of laser ablation generated debris than high flow velocities; but, use of excessive flow velocities resulted in turbulence motivated deposition. This work is of interest to the laser micromachining community and may aide in the manufacture of 2.5D laser etched patterns covering large area wafers and could be applied to a range of wavelengths and laser types

Loss of oestrogen receptor alpha in long-term antioestrogen-resistant cells: reversal by a c-src inhibitor

Background Tamoxifen still remains the most frequently used antioestrogen for the treatment of breast cancer. However, its efficacy is often limited by the emergence of acquired resistance and it has been suggested that, in some instances, this may involve oestrogen receptor (ER) loss. This study addresses this issue by examining long-term tamoxifen treatment of breast cancer cells and identifies that progressive ER loss does occur, leading to greatly increased aggressive tumour cell behaviour. Encouragingly, even after 30 months treatment, ER loss is reversible by a c-src inhibitor. Our data therefore provide a new model to study the cellular mechanisms associated with antihormone promoted ER loss and its possible prevention/reversal by signal transduction inhibitors. Methods Using quantitative PCR based on SYBR Green fluorescence, the expression of total ERα mRNA and its constituent mRNA variants were quantified in MCF7 cells and in our in vitro developed tamoxifen-resistant breast cancer cells (TamR), which have been cultured in the presence of tamoxifen for 30 months. Specific PCR amplification of all ERα mRNA variants was possible using forward primers designed to bind specifically to the 5' untranslated regions of ERα mRNA and used separately with a common reverse primer that anneals to the 5' end of the protein encoding region of exon 1 of ERα cDNA. Expression of ERα protein was assessed by western blot and immunohistochemistry. Results In MCF7 cells, the ERα mRNA isoforms A, B and C were detected as the most predominant variants, with C ERα mRNA showing the highest expression level. In TamR cells, about a 40% fall in total ERα mRNA was observed in comparison with MCF7 cells and was most apparent for the C variant. Extension of the tamoxifen treatment period to 30 months produced a further dramatic decrease in ERα mRNA (all variants) and protein levels, resulting in ER negativity being recorded in >90% of the cells by immunohistochemistry. These cells show increased levels of phosphorylated Erk 1&2, AKT, PKCα and src, and are highly aggressive in their growth behaviour, with increased cell motility and invasiveness. Treatment of the cells with the demethylating agent 5-azacytidine did not restore ERα expression, suggesting that epigenetic alterations are unlikely to be responsible for the reduced ER levels. However, Affymetrix data in the TamR cells showed that some positive regulators of ER expression, such as p53 and Foxo3A, are downregulated during the development of the resistant phenotype and their continued absence may contribute to the progressive ER loss. Significantly, pathway inhibitor studies revealed c-src to be an important regulator of ER loss, since its inhibition rapidly restored ER levels. Conclusion Our data indicate that considerable ER loss can occur during antihormonal treatment of breast cancer cells and that this can lead to a more aggressive phenotype. Encouragingly, however, even after 30 months exposure to tamoxifen, the process is reversible by inhibition of c-src. These data suggest that combinations of antihormones with signal transduction inhibitors could retain ER functions in treated cells and prevent a drift towards more aggressive cancer cell behaviour

Growth and Development of F-1 (Brahman x Hereford) Heifers Under Various Short-Term Grazing Pressures

Last updated: 6/1/200

Temporal Progression of Aortic Valve Pathogenesis in a Mouse Model of Osteogenesis Imperfecta.

Organization of extracellular matrix (ECM) components, including collagens, proteoglycans, and elastin, is essential for maintaining the structure and function of heart valves throughout life. Mutations in ECM genes cause connective tissue disorders, including Osteogenesis Imperfecta (OI), and progressive debilitating heart valve dysfunction is common in these patients. Despite this, effective treatment options are limited to end-stage interventions. Mice with a homozygous frameshift mutation in col1a2 serve as a murine model of OI (oim/oim), and therefore, they were used in this study to examine the pathobiology of aortic valve (AoV) disease in this patient population at structural, functional, and molecular levels. Temporal echocardiography of oim/oim mice revealed AoV dysfunction by the late stages of disease in 12-month-old mice. However, structural and proteomic changes were apparent much earlier, at 3 months of age, and were associated with disturbances in ECM homeostasis primarily related to collagen and proteoglycan abnormalities and disorganization. Together, findings from this study provide insights into the underpinnings of late onset AoV dysfunction in connective tissue disease patients that can be used for the development of mechanistic-based therapies administered early to halt progression, thereby avoiding late-stage surgical intervention

Tandem Cylinder Noise Predictions

In an effort to better understand landing-gear noise sources, we have been examining a simplified configuration that still maintains some of the salient features of landing-gear flow fields. In particular, tandem cylinders have been studied because they model a variety of component level interactions. The present effort is directed at the case of two identical cylinders spatially separated in the streamwise direction by 3.7 diameters. Experimental measurements from the Basic Aerodynamic Research Tunnel (BART) and Quiet Flow Facility (QFF) at NASA Langley Research Center (LaRC) have provided steady surface pressures, detailed off-surface measurements of the flow field using Particle Image Velocimetry (PIV), hot-wire measurements in the wake of the rear cylinder, unsteady surface pressure data, and the radiated noise. The experiments were conducted at a Reynolds number of 166 105 based on the cylinder diameter. A trip was used on the upstream cylinder to insure a fully turbulent shedding process and simulate the effects of a high Reynolds number flow. The parallel computational effort uses the three-dimensional Navier-Stokes solver CFL3D with a hybrid, zonal turbulence model that turns off the turbulence production term everywhere except in a narrow ring surrounding solid surfaces. The current calculations further explore the influence of the grid resolution and spanwise extent on the flow and associated radiated noise. Extensive comparisons with the experimental data are used to assess the ability of the computations to simulate the details of the flow. The results show that the pressure fluctuations on the upstream cylinder, caused by vortex shedding, are smaller than those generated on the downstream cylinder by wake interaction. Consequently, the downstream cylinder dominates the noise radiation, producing an overall directivity pattern that is similar to that of an isolated cylinder. Only calculations based on the full length of the model span were able to capture the complete decay in the spanwise correlation, thereby producing reasonable noise radiation levels

The Time-Dependent Role of Bisphosphonates on Atherosclerotic Plaque Calcification

Atherosclerotic plaque calcification directly contributes to the leading cause of morbidity and mortality by affecting plaque vulnerability and rupture risk. Small microcalcifications can increase plaque stress and promote rupture, whereas large calcifications can stabilize plaques. Drugs that target bone mineralization may lead to unintended consequences on ectopic plaque calcification and cardiovascular outcomes. Bisphosphonates, common anti-osteoporotic agents, have elicited unexpected cardiovascular events in clinical trials. Here, we investigated the role of bisphosphonate treatment and timing on the disruption or promotion of vascular calcification and bone minerals in a mouse model of atherosclerosis. We started the bisphosphonate treatment either before plaque formation, at early plaque formation times associated with the onset of calcification, or at late stages of plaque development. Our data indicated that long-term bisphosphonate treatment (beginning prior to plaque development) leads to higher levels of plaque calcification, with a narrower mineral size distribution. When given later in plaque development, we measured a wider distribution of mineral size. These morphological alterations might be associated with a higher risk of plaque rupture by creating stress foci. Yet, bone mineral density positively correlated with the duration of the bisphosphonate treatment

Aeroacoustic Simulations of Tandem Cylinders with Subcritical Spacing

Tandem cylinders are being studied because they model a variety of component level interactions of landing gear. The present effort is directed at the case of two identical cylinders with their centroids separated in the streamwise direction by 1.435 diameters. Experiments in the Basic Aerodynamic Research Tunnel and Quiet Flow Facility at NASA Langley Research Center have provided an extensive experimental database of the nearfield flow and radiated noise. The measurements were conducted at a Mach number of 0.1285 and Reynolds number of 1.66x10(exp 5) based on the cylinder diameter. A trip was used on the upstream cylinder to insure a fully turbulent flow separation and, hence, to simulate a major aspect of high Reynolds number flow. The parallel computational effort uses the three-dimensional Navier-Stokes solver CFL3D with a hybrid, zonal turbulence model that turns off the turbulence production term everywhere except in a narrow ring surrounding solid surfaces. The experiments exhibited an asymmetry in the surface pressure that was persistent despite attempts to eliminate it through small changes in the configuration. To model the asymmetry, the simulations were run with the cylinder configuration at a nonzero but small angle of attack. The computed results and experiments are in general agreement that vortex shedding for the spacing studied herein is weak relative to that observed at supercritical spacings. Although the shedding was subdued in the simulations, it was still more prominent than in the experiments. Overall, the simulation comparisons with measured near-field data and the radiated acoustics are reasonable, especially if one is concerned with capturing the trends relative to larger cylinder spacings. However, the flow details of the 1.435 diameter spacing have not been captured in full even though very fine grid computations have been performed. Some of the discrepancy may be associated with the simulation s inexact representation of the experimental configuration, but numerical and flow modeling errors are also likely contributors to the observed differences