Dynamic simulations on the mitochondrial fatty acid Beta-oxidation network

<p>Abstract</p> <p>Background</p> <p>The oxidation of fatty acids in mitochondria plays an important role in energy metabolism and genetic disorders of this pathway may cause metabolic diseases. Enzyme deficiencies can block the metabolism at defined reactions in the mitochondrion and lead to accumulation of specific substrates causing severe clinical manifestations. Ten of the disorders directly affecting mitochondrial fatty acid oxidation have been well-defined, implicating episodic hypoketotic hypoglycemia provoked by catabolic stress, multiple organ failure, muscle weakness, or hypertrophic cardiomyopathy. Additionally, syndromes of severe maternal illness (HELLP syndrome and AFLP) have been associated with pregnancies carrying a fetus affected by fatty acid oxidation deficiencies. However, little is known about fatty acids kinetics, especially during fasting or exercise when the demand for fatty acid oxidation is increased (catabolic stress).</p> <p>Results</p> <p>A computational kinetic network of 64 reactions with 91 compounds and 301 parameters was constructed to study dynamic properties of mitochondrial fatty acid β-oxidation. Various deficiencies of acyl-CoA dehydrogenase were simulated and verified with measured concentrations of indicative metabolites of screened newborns in Middle Europe and South Australia. The simulated accumulation of specific acyl-CoAs according to the investigated enzyme deficiencies are in agreement with experimental data and findings in literature. Investigation of the dynamic properties of the fatty acid β-oxidation reveals that the formation of acetyl-CoA – substrate for energy production – is highly impaired within the first hours of fasting corresponding to the rapid progress to coma within 1–2 hours. LCAD deficiency exhibits the highest accumulation of fatty acids along with marked increase of these substrates during catabolic stress and the lowest production rate of acetyl-CoA. These findings might confirm gestational loss to be the explanation that no human cases of LCAD deficiency have been described.</p> <p>Conclusion</p> <p>In summary, this work provides a detailed kinetic model of mitochondrial metabolism with specific focus on fatty acid β-oxidation to simulate and predict the dynamic response of that metabolic network in the context of human disease. Our findings offer insight into the disease process (e.g. rapid progress to coma) and might confirm new explanations (no human cases of LCAD deficiency), which can hardly be obtained from experimental data alone.</p

Frustrated potential, false promise or complicated possibilities?: empowerment and participation amongst female health volunteers in South Africa

We present a longitudinal case study of lay women's participation in a project seeking to facilitate home-based care of people dying of AIDS in a rural community in South Africa, drawing on four sets of interviews conducted with volunteers over a five-year period. We link participation in the project to three dimensions of women's agency: their knowledge and skills, their confidence; and their personal experiences of efficacy. We show that whilst the experience of participation enhanced each of these dimensions of volunteers’ agency at various stages of the project, the empowerment that did take place appeared to be limited to women's project-related roles, rather than generalising to other areas of their lives beyond the project. The project had limited impact on women's ability to negotiate condom use with husbands, to assert themselves in relation to male project leaders and to become more involved in wider community decision-making and leadership. We discuss three possible interpretations of our findings: (i) that greater empowerment might have occurred had the project run for a longer time period; (ii) that whilst such projects play a vital role in providing services, the more general ‘empowerment via participation’ agenda is a false promise in highly marginalised communities; or (iii) that whilst generalised positive impacts of such projects on volunteers are hard to track, such projects do open up glimpses of increased agency for many women. These might have positive but unpredictable results in ways that defy formulation in linear conceptualisations of social transformation and development, understood in terms of clearly observable and measurable inputs and outputs

Mismatches between youth aspirations and participatory HIV/AIDS programmes in South Africa

Although youth participation is a pillar of international HIV/AIDS policy, it is notoriously difficult to facilitate. We explore this challenge through a case study of a community-led HIV/AIDS management project in a South African rural area, in which anticipated youth participation failed to materialise. We take a social psychological view, examining ways in which opportunities offered by the project failed to resonate with the social identities and aspirations of local young people. Interviews and focus group discussions were conducted with 37 young people prior to the programme's establishment and with 21 young people four years later. In response to questions about what they wanted to achieve in life, the young people emphasized: career success through migrating to urban areas to seek education and paid work, non-tokenistic involvement in community affairs, and 'having fun.' We look at how the project unintentionally evolved in ways that undermined these goals. Its strong local focus was inappropriately tailored to young people whose views of the future focused on getting away to urban areas as quickly as possible. The volunteer nature of the work held little appeal for ambitious young people who instead saw paid work as their way out of poverty and were reluctant to take unpaid time out from schoolwork. The project failed to develop new and democratic ways of operatingquickly becoming mired in traditional, adult-dominated social relations, in which young people with initiative and independent views were sometimes belittled by adults as being 'smart' or 'clever.' Finally, the project's focus on sexual abstinence held little interest for young people who took an enthusiastic interest in sex. The article concludes with a discussion of the complexities of implementing youth-friendly projects in communities steeped in top-down adult-dominated social interactions, and recommends ways in which similar projects might seek to involve youths more effectively