Molecular Mechanisms Underlying the Early Life Programming of the Liver

Clinical studies have demonstrated that intrauterine growth restriction (IUGR) offspring, faced with a nutritional mismatch postpartum, have an increased risk of developing the metabolic syndrome. The maternal protein restriction (MPR) rat model has been extensively studied to investigate the adverse effects of a nutritional mismatch in postnatal life of IUGR offspring. Previous studies have demonstrated that MPR leads to impaired function of the liver, an important metabolic organ. However the underlying mechanisms which predispose these offspring to the metabolic syndrome remain elusive. In the following studies, low protein diet during pregnancy and lactation led to IUGR offspring with decreased liver to body weight ratios, followed by increased circulating and hepatic cholesterol levels in both sexes at day 21 and exclusively in the male offspring at day 130. This was attributed to long-term repressive changes in histone modifications at the promoter of cholesterol 7α-hydroxylase, a rate-limiting enzyme that catabolizes cholesterol to bile acids. It was later demonstrated that these IUGR offspring exhibited increased molecular markers of hepatic endoplasmic reticulum (ER) stress and insulin resistance. Finally, these offspring were observed to have an increase in activity of Phase I drug metabolizing hepatic cytochrome p450 (Cyp) dependent enzymes. Collectively, these findings suggest that stable promoter-specific changes to post-translational histone modifications and elevated ER stress in the liver, are key molecular mechanisms whereby IUGR offspring receiving a nutritional mismatch in postnatal life develop high cholesterol and insulin resistance. Moreover, these offspring may require augmented doses of drugs in order to alleviate these symptoms

International Medical Graduates and the Physician Shortage

This is a letter to the editor regarding the physician supply

Adaptive, efficient, parallel execution of parallel programs

Future parallel processors will be heterogeneous, be increasingly less reliable, and operate in dynamically changing operating conditions. This will result in a constantly varying pool of hardware resources which can greatly complicate the task of efficiently exposing a program's parallelism onto these resources. Coupled with this uncertainty is the diverse set of efficiency metrics that users may desire. This talk will describe Varuna, a system that dynamically, continuously, rapidly and transparently adapts a program's parallelism to best match the instantaneous capabilities of the hardware resources while satisfying different efficiency metrics. Varuna is applicable to both multithreaded and task-based programs and can be seamlessly inserted between the program and the operating system without needing to change the source code of either. The talk will also present results demonstrating Varuna's effectiveness in diverse execution environments using unaltered C/C++ parallel programs from various benchmark suites

The effect of resin toughness and modulus on compressive failure modes of quasi-isotropic graphite/epoxy laminates

Compressive failure mechanisms in quasi-isotropic graphite/epoxy laminates were characterized for both unnotched and notched specimens and also following damage by impact. Two types of fibers (Thornel 300 and 700) and four resin systems (Narmco 5208, American Cyanamid BP907, and Union Carbide 4901/MDA and 4901/mPDA) were studied. For all material combinations, failure of unnotched specimens was initiated by kinking of fibers in the 0-degree plies. A major difference was observed, however, in the mode of failure propagation after the 0-degree ply failure. The strength of quasi-isotropic laminates in general increased with increasing resin tensile modulus. The laminates made with Thornel 700 fibers exhibited slightly lower compressive strengths than did the laminates made with Thornel 300 fibers. The notch sensitivity as measured by the hole strength was lowest for the BP907 resin and highest for the 5208 resin. For the materials studied, however, the type of fiber had no effect on the notch sensitivity

Early lifestyle determinants of adiposity trajectories from childhood into late adolescence

Contexte: L'obésité infantile est un facteur de risque majeur de mortalité et de morbidité, car les enfants avec obésité ont tendance à maintenir leur obésité à l’âge adulte. Parmi les enfants canadiens, 27% ont un surpoids ou une obésité, ce qui pose un grave problème de santé publique, vu les conséquences en termes de morbidité et mortalité de l’obésité à l’âge adulte. Objectifs: Les principaux objectifs de ma recherche sont les suivants: (1) examiner le lien entre l'activité physique durant la pré-puberté et les trajectoires d'adiposité de l’enfance à l'adolescence; (2) examiner le lien entre les comportements sédentaires dans la pré-puberté et les trajectoires d'adiposité de l’enfance à l'adolescence; et (3) examiner les associations entre les apports alimentaires dans la pré-puberté et les trajectoires d'adiposité de l’enfance à l'adolescence. Mon hypothèse est que moins d'activité physique, plus de temps sédentaire et une alimentation moins saine (ex. moins de fruits et légumes, plus de boissons sucrées) pendant l'enfance seront associés à des trajectoires défavorables d’obésité de l’enfance à l'adolescence. Méthodes: Cette recherche porte sur les données de l’étude QUALITY (QUebec Adipose and Lifestyle Investigation in Youth). Cette cohorte comprend 630 enfants caucasiens âgés de 8 à 10 ans, recrutés au départ sur la base d’antécédent d'obésité chez leurs parents. De ce nombre, 377 ont été suivis à 10-12 ans et à 15-17 ans. Les comportements sédentaires et l'activité physique ont été mesurés par accélérométrie sur une période de 7 jours, le temps d'écran a été mesuré par questionnaire et l'apport alimentaire avec trois rappels alimentaires de 24 heures. Le poids et la taille ont été mesurés à chaque période et transformés en scores z de l'indice de masse corporelle (IMC-z) selon les normes de l'OMS (Organisation Mondiale de la Santé). La modélisation des trajectoires basée sur les groupes a été utilisée pour identifier les trajectoires longitudinales de l'IMC-z. Des régressions logistiques multinomiales ont ensuite été utilisées pour examiner les associations entre les habitudes de vie durant l’enfance et les trajectoires d’adiposité, en ajustant l’âge, le sexe, les stades du développement pubertaire de Tanner et l’éducation parentale. Résultats principaux: Six trajectoires distinctes d’IMC-z ont été identifiées: Poids-Faible-à-Normal-Stable (5,7%), deux groupes de Poids-Normal-Stable qui ont ensuite été combinés (33,0% et 24,8%), Surpoids-Stable (19,8%), Obèse-Stable (8,8%) et Surpoids-Décroissants (7,9%). Pour chaque portion supplémentaire de fruits et légumes à 8-10 ans, la probabilité de faire partie du groupe en Surpoids-Décroissants est augmentée de 26% (OR 1,26, IC 95% 1,06-1,49) par rapport à ceux du groupe Poids-Normal-Stable. Pour chaque heure supplémentaire de comportement sédentaire mesurée par l'accéléromètre à 8-10 ans, la probabilité d'appartenir au groupe Surpoids-Décroissants est augmentée de 51% (OR 1,51, IC à 95% 1,03- 2,22) par rapport au groupe Poids-Normal-Stable. En termes d'activité physique, toutes les 10 minutes supplémentaires d'activité physique modérée à vigoureuse (APMV) au départ étaient associées à une probabilité plus faible d'appartenir au groupe Obèse-Stable (OR 0,75, IC à 95% 0,61-0,91) et Groupe Surpoids-Décroissants (OR 0,78, IC 95% 0,62-0,98) par rapport au groupe Poids-Normal-Stable. Importance: Cette étude a permis d’identifier différents groupes de trajectoires de développement du score IMC-z qui restent stables de l’enfance à la fin de l'adolescence ainsi qu’un groupe d’enfants qui sont passés d'un surpoids à un poids normal. Ces derniers avaient un apport alimentaire plus favorable en fruits et légumes à 8-10 ans. Cependant, ils avaient également une APMV inférieure et un comportement plus sédentaire comparativement au groupe de Poids-Normal-Stable.Background: Childhood obesity is a major risk factor for mortality and morbidity as children with obesity tend to remain obese into adulthood. Among Canadian children, 27 % have overweight or obesity, which is a serious public health concern. Objectives: The main objectives of my research are to (1) examine the associations between physical activity in pre-puberty or early puberty and obesity trajectories across childhood and adolescence; (2) examine the associations between sedentary behaviors in pre-puberty or early puberty and obesity trajectories across childhood and adolescence; and (3) to examine associations between dietary intake in pre-puberty or early puberty and obesity trajectories across childhood and adolescence. My hypothesis is that lower physical activity, more time spent in sedentary behaviours and unhealthy diets (e.g., higher sugar-sweetened beverage consumption, lower fruit and vegetable intake) in childhood (pre to early puberty) will be associated with adverse patterns of obesity into adolescence. Methods: This study uses data from the Quebec Adipose and Lifestyle Investigation in Youth (QUALITY) study. This cohort includes 630 Caucasian children aged 8-10 years, recruited at baseline based on a parental history of obesity. Of these, 377 were re-assessed at 10-12 years and at 15-17 years. Sedentary behavior and physical activity using 7-day accelerometry, self-reported screen time and dietary intake with three 24-hr diet recalls were measured. Weight and height were measured at each time period and transformed to body mass index (BMI) z-scores using WHO (World Health Organization) Standards. Group based trajectory modeling was used to identify longitudinal trajectories of z-BMI. Multinomial logistic regressions were used to examine associations between lifestyle behaviors at 8-10 years and distinct obesity trajectory groups, while adjusting for age, sex, tanner stage and parental education. Results: Six distinct z-BMI trajectory groups were identified: Stable-Low-Normal-Weight (5.7%), two Stable-Normal-Weight groups that were subsequently combined (33.0% and 24.8%), Stable-Overweight (19.8%), Stable-Obese (8.8%) and Overweight-Decreasers (7.9%). For every additional vegetable and fruit serving at baseline, the likelihood of being in the Overweight–Decreasers group increased by 26% (OR 1.26, 95% CI: 1.06, 1.49) compared to those in the Stable-Normal-Weight group. For every additional hour of sedentary behavior at baseline, the likelihood of belonging to the Overweight-Decreasers group increased by 51% (OR 1.51, 95% CI: 1.03, 2.22) as compared to Stable-Normal-Weight group. In terms of physical activity, every additional 10 mins of Moderate to Vigorous Physical Activity (MVPA) at baseline was associated with a lower likelihood of belonging to the Stable-Obese group (OR 0.75, 95% CI: 0.61, 0.91) and to the Overweight-Decreasers group (OR=0.78, 95% CI: 0.62, 0.98) compared to the Stable-Normal-Weight group. Conclusion: Stable trajectories of z-BMI from childhood to late adolescence were found, with the exception of one decreasing trajectory from overweight in childhood to normal weight in adolescence. The latter had more favourable dietary intake of fruits and vegetables at baseline, however, they also had lower MVPA and more sedentary behavior

The Effects of Environment Dynamism and Heterogeneity on Salespeople\u27s Role Perceptions, Performance and Job Satisfaction

This article develops a structural equations model which examines the effects of environmental dynamism and heterogeneity on salespeople’s role conflict, role ambiguity, performance and job satisfaction. The model is tested with EQS, using data collected from 230 salespeople in multiple companies and industries. Indicates that environmental dynamism reduces satisfaction and performance, and increases role conflict and ambiguity. Notes that environmental heterogeneity also reduces performance and increases role conflict, but does not have a significant effect on role ambiguity

The Cloak of Copyright: How Costco v. Omega Enabled Price Discrimination

In December of 2010, Costco v. Omega came down from the Supreme Court. The Switzerland-based watchmaker Omega sold Seamaster Collection watches, which were affixed with its copyrighted logo, in the United States as well as in foreign markets. Omega priced watches in the United States market higher than elsewhere. Costco obtained Omega’s watches from a third party that had purchased the watches abroad, then sold them at its membership warehouses for cheaper prices than authorized Omega dealers in the United States. Consequently, Omega sued Costco for copyright infringement. Costco pursued a defense based on the first sale doctrine in response. While from a legal perspective the case was a copyright dispute, this categorization does not make sense from an economic view. Rather, the application of economic models reveals that the core issue in Costco centers about price discrimination, not copyright. This thesis uses a law and economics framework to analyze the facts of and the decision in Costco to determine whether the outcome was welfare maximizing and to assess the implications that the case will have on copyright law in the future

A new species and new record of the leafhopper genus Seriana Dworakowska (Hemiptera, Cicadellidae, Typhlocybinae) from China

Seriana menglaensis sp. n. (Hemiptera: Cicadellidae: Typhlocybinae: Erythroneurini) is described and illustrated from Southwest China. Seriana equata (Singh, 1969) is recorded for the first time from China

The Difficult Case of Crystallization and Structure Solution for the ParC55 Breakage-Reunion Domain of Topoisomerase IV from Streptococcus pneumoniae

BACKGROUND: Streptococcus pneumoniae is the major cause of community-acquired pneumonia and is also associated with bronchitis, meningitis, otitis and sinusitis. The emergence and increasing prevalence of resistance to penicillin and other antibiotics has led to interest in other anti-pneumonococcal drugs such as quinolones that target the enzymes DNA gyrase and topoisomerase IV. During crystallization and in the avenues to finding a method to determine phases for the structure of the ParC55 breakage-reunion domain of topoisomerase IV from Streptococcus pneumoniae, obstacles were faced at each stage of the process. These problems included: majority of the crystals being twinned, either non-diffracting or exhibiting a high mosaic spread. The crystals, which were grown under conditions that favoured diffraction, were difficult to flash-freeze without loosing diffraction. The initial structure solution by molecular replacement failed and the approach proved to be unviable due to the complexity of the problem. In the end the successful structure solution required an in-depth data analysis and a very detailed molecular replacement search. METHODOLOGY/PRINCIPAL FINDINGS: Crystal anti-twinning agents have been tested and two different methods of flash freezing have been compared. The fragility of the crystals did not allow the usual method of transferring the crystals into the heavy atom solution. Consequently, it was necessary to co-crystallize in the presence of the heavy atom compound. The multiple isomorphous replacement approach was unsuccessful because the 7 cysteine mutants which were engineered could not be successfully derivatized. Ultimately, molecular replacement was used to solve the structure by sorting through a large number of solutions in space group P1 using CNS. CONCLUSIONS/SIGNIFICANCE: The main objective of this paper is to describe the obstacles which were faced and overcome in order to acquire data sets on such difficult crystals and determine phases for successful structure solution