Brown Fat Paucity Due to Impaired BMP Signaling Induces Compensatory Browning of White Fat

Summary Maintenance of body temperature is essential for survival of homeotherms. Brown adipose tissue (BAT) is a specialized fat tissue that is dedicated to thermoregulation1. Due to its remarkable capacity to dissipate stored energy and its demonstrated presence in adult humans2-5, BAT holds great promise for the treatment of obesity and metabolic syndrome1. Rodent data suggest the existence of two types of brown fat cells: the constitutive BAT (cBAT), which is of embryonic origin and anatomically located in the interscapular region of mice, and the recruitable BAT (rBAT) that resides within white adipose tissue (WAT)6 and skeletal muscle7, that has alternatively been called beige8, brite9, or inducible BAT10. Bone morphogenetic proteins (BMPs) regulate the formation and thermogenic activity of BAT10-12. We here provide evidence for a systemically active regulatory mechanism that serves to control whole body BAT-activity for thermoregulation and energy homeostasis. Genetic ablation of type 1A BMP-receptor (Bmpr1A) in brown adipogenic progenitor cells leads to a severe paucity of cBAT. This in turn increases sympathetic input to WAT, thereby promoting the formation of rBAT within white fat depots. This previously unknown compensatory mechanism, aimed at restoring total brown fat-mediated thermogenic capacity in the body, is sufficient to maintain normal temperature homeostasis and resistance to diet-induced obesity. These data suggest an important physiological cross-talk between the constitutive and recruitable brown fat cells. This sophisticated regulatory mechanism of body temperature may participate in the control of energy balance and metabolic disease

A novel chemo–mechano–biological model of arterial tissue growth and remodelling

Arterial growth and remodelling (GandR) is mediated by vascular cells in response to their chemical and mechanical environment. To date, mechanical and biochemical stimuli tend to be modelled separately, however this ignores their complex interplay. Here, we present a novel mathematical model of arterial chemo–mechano–biology. We illustrate its application to the development of an inflammatory aneurysm in the descending human aorta. The arterial wall is modelled as a bilayer cylindrical non–linear elastic membrane, which is internally pressurized and axially stretched. The medial degradation that accompanies aneurysm development is driven by an inflammatory response. Collagen remodelling is simulated by adaption of the natural reference configuration of constituents; growth is simulated by changes in normalised mass–densities. We account for the distribution of attachment stretches that collagen fibres are configured to the matrix and, innovatively, allow this distribution to remodel. This enables the changing functional role of the adventitia to be simulated. Fibroblast-mediated collagen growth is represented using a biochemical pathway model: a system of coupled non-linear ODEs governs the evolution of fibroblast properties and levels of key biomolecules under the regulation of Transforming Growth Factor (TGF)-β, a key promoter of matrix deposition. Given physiologically realistic targets, different modes of aneurysm development can be captured, while the predicted evolution of biochemical variables is qualitatively consistent with trends observed experimentally. Interestingly, we observe that increasing the levels of collagen–promoting TGF-β results in arrest of aneurysm growth, what seems to be consistent with experimental evidence. We conclude that this novel Chemo–Mechano–Biological (CMB) mathematical model has the potential to provide new mechanobiological insight into vascular disease progression and therapy.</p

The dynamics of experiential learning: Microprocesses and adaptation in a professional service INV

In international new ventures (INVs), experiential learning happens in quick succession and across a wide number of diverse contexts. Yet, we lack an empirical understanding of the microprocesses through which INVs learn and adapt in their foreign expansion. Understanding those microprocesses is important because timely adaptation can save the venture time and resources, thus promoting sustainable growth. In this study, we investigate the dynamics of experiential learning and adaptation in the internationalisation process of an INV in the professional service sector. Findings from our study illustrate that the firm applies deliberate experiential learning by developing, revising, and finalising criteria for important dimensions in the international growth process, and adapts its internationalisation practices accordingly. We further show that deliberate experiential learning is predicated on an actively and closely monitored learning process, involving critical evaluation, adjustment of criteria, and acceptance of affordable mistakes, as opposed to learning by defaul

Forgetting having denied: The "amnesic" consequences of denial

The concept of denial has its roots in psychoanalysis. Denial has been assumed to be effective in blocking unwanted memories. In two experiments, we report that denial has unique consequences for remembering. In two experiments, participants viewed a video of a theft and half of the participants had to deny seeing certain details in the video whereas the other half had to tell the truth. One day later, all participants were given a source monitoring recognition or recall task. In these tasks, they were instructed to indicate (1) whether they could remember talking about certain details and (2) whether they could recollect seeing those details in the video. In both experiments, we found that denial made participants forget that they talked about these details while leaving memory for the video unaffected. This denial-induced forgetting was evident for both the source monitoring recognition and recall tests. Furthermore, when we asked participants after the experiment whether they could still not remember talking about these details, participants who had to deny were most likely to report that they forgot this. In contrast to a widely held belief, we show that denial does not impair memory for the experienced stimuli, but that it has a unique ability to undermine memory for what was talked about

New Venture Internationalization: The Role of Venture Capital Types and Reputation

This study examines how different types of venture capital relate to new venture internationalization. Using a sample of 646 U.S. new ventures that executed IPOs between 1995 and 2010, we find that ventures with foreign or corporate venture capital have higher levels of international intensity. We also investigate the moderating role of VC reputation on the relationship between foreign venture capital and international intensity and corporate venture capital and international intensity. Our results suggest that VC reputation weakens the positive relationship between corporate VC and international intensity

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Advancing the entrepreneurial orientation construct: the role of passion and perseverance

Abstract of a paper that was presented at the 56th Annual Meeting of the Academy of International Business, Vancouver, Canada June 24-26, 2014

Exploring Supervisors’ Attitudes of Working with Youth Engaged in an Inclusive Employment Training Program

Background: Although employment is a right of citizenship, people with disabilities remain underrepresented in the workforce. Employment is especially important for people with disabilities because it can alleviate financial hardship, social isolation, improve confidence and quality of life. Most research exploring employers’ views of hiring employees with disabilities has focused on adults while little is known about employers’ experience of working with youth with disabilities. The purpose of this study was to explore supervisors’ views of working with an adolescent with disabilities as a part of an employment training program. Method: The sample was drawn from the supervisors of youth taking part in an employment training program, run through children’s rehabilitation hospital in a large urban centre. A descriptive questionnaire was sent to all supervisors who worked with a adolescent with disabilities as part of an employment training program. Thirty-six questionnaires were completed with a response rate of 92%. Results: Our findings show that most supervisors felt prepared when youth arrived and that supervising them did not take up much extra time. Some supervisors had a few initial concerns about workplace accommodations and workload but these were quickly resolved. Most supervisors who worked with youth with disabilities reported a positive experience and that having them in the workplace also had the added benefit of challenging some of their assumptions about people with disabilities. Conclusions: Our findings emphasize the importance of supervisors having an opportunity to work with a person with disabilities because it can help to break down negative attitudes and stereotypes.Bien que le droit au travail soit une composante essentielle de la citoyenneté, les personnes ayant des incapacités demeurent encore aujourd’hui sous-représentées sur le marché du travail. Occuper un emploi s’avère particulièrement important puisqu’il permet de réduire leurs probabilités d’affronter des difficultés financières et de vivre de l’isolement social, et ce, tout en augmentant l’estime de soi et la qualité de vie. La plupart des recherches sur les perceptions des employeurs en lien avec l’embauche de personnes ayant des incapacités se sont concentrées sur les adultes et peu sur les jeunes. L’objectif de cette étude était d’explorer les impressions des superviseurs quant au fait de travailler avec des jeunes ayant des incapacités dans le cadre d’un programme d’entraînement au travail. Méthode : L’échantillon a été constitué en collaboration avec les superviseurs des jeunes prenant part à un programme d’entraînement au travail, lequel était géré par un centre de réadaptation pour enfants situé dans un centre urbain important. Un questionnaire descriptif a été remis à tous les superviseurs concernés. Trente-six questionnaires ont été complétés pour un taux de 92% de réponse. Résultats : Nos résultats montrent que la plupart des superviseurs se sentaient préparés à l’arrivée du jeune et que les tâches de supervision ne leur demandaient pas de temps supplémentaire. Certains superviseurs ont eu certaines inquiétudes initiales quant aux aménagements nécessaires à apporter à la charge et au milieu de travail, mais ces dernières ont rapidement été dissipées. La plupart d’entre eux ont rapporté avoir eu une expérience positive et que le fait d’avoir travaillé avec ces jeunes leur a permis de remettre en question leurs perceptions sur les personnes ayant des incapacités. Conclusions : Nos résultats rappellent l’importance d’offrir des opportunités aux superviseurs de travailler avec des jeunes ayant des incapacités puisque cela leur permet de reconsidérer les stéréotypes et leurs attitudes négatives à l’égard des personnes ayant des incapacités

An ecological approach to understanding barriers to employment for youth with disabilities compared to their typically developing peers: views of youth, employers, and job counselors

This is an Accepted Manuscript of an article published by Taylor &Francis in Disability and Rehabilitation July 11th 2014, available online: http://www.tandfonline.com/10.3109/09638288.2014.939775Purpose: The purpose of this study is to explore the extent to which youth with physical disabilities encounter different barriers to finding employment compared to their typically developing peers. Methods: This study draws on 50 qualitative in-depth interviews with a purposive sample of 31 youth (16 typically developing and 15 with a disability), and youth employers and job counselors knowledgeable about employment readiness among adolescents (n = 19). We utilize Bronfrebrenner’s ecological framework to reveal the complex web of factors shaping youth’s labor market outcomes. Results: Only half of youth with a disability were working or looking for work compared to their peers. The findings show this was a result of different expectations of, and attitudes toward, youth with disabilities. For many youth with a disability, their peers, family and social networks often acted as a barrier to getting a job. Many youth also lacked independence and life skills that are needed to get a job (i.e. self-care and navigating public transportation) compared to their peers. Job counselors focused on linking youth to employers and mediating parental concerns. Employers appeared to have weaker links to youth with disabilities. System level barriers included lack of funding and policies to enhance disability awareness among employers. Conclusions: Youth with physical disabilities encounter some similar barriers to finding employment compared to their typically developing peers but in a stronger way. Barriers to employment exist at several levels including individual, sociostructural and environmental. The results highlight that although there are several barriers to employment for young people at the microsystem level, they are linked with larger social and environmental barriers.This study was funded by the Social Science and Humanities Research Council. The first author is supported through a career award from the Ontario Ministry of Research and Innovation