Pseudo-peptide amyloid-ß blocking inhibitors: molecular dynamics and single molecule force spectroscopy study.

By combining MD simulations and AFS experimental technique, we demonstrated a powerful approach for rational design and single molecule testing of novel inhibitor molecules which can block amyloid-amyloid binding - the first step of toxic amyloid oligomer formation. We designed and tested novel pseudo-peptide amyloid-ß (Aß) inhibitors that bind to the Aß peptide and effectively prevent amyloid-amyloid binding. First, molecular dynamics (MD) simulations have provided information on the structures and binding characteristics of the designed pseudo-peptides targeting amyloid fragment Aß (13-23). The binding affinities between the inhibitor and Aß as well as the inhibitor to itself have been estimated using Umbrella Sampling calculations. Atomic Force Spectroscopy (AFS) was used to experimentally test several proposed inhibitors in their ability to block amyloid-amyloid binding - the first step of toxic amyloid oligomer formation. The experimental AFS data are in a good agreement with theoretical MD calculations and demonstrate that three proposed pseudo-peptides bind to amyloid fragment with different affinities and all effectively prevent Aß-Aß binding in similar way. We propose that the designed pseudo-peptides can be used as potential drug candidates to prevent Aß toxicity in Alzheimer's disease.

[Ageing and chronic diseases in Senegal. A comparison between rural (Ferlo) and urban (Dakar) populations]. / Vieillissement et pathologies chroniques au Sénégal. Comparaison entre des populations vivant en milieu rural (Ferlo) et urbain (Dakar).

The objectives of this study were: to compare the prevalence of hypertension, overweight and obesity in rural (Ferlo) and urban (Dakar) Senegalese populations aged 50 and over. The survey was conducted on individuals aged 50 and older living in the rural area (N=478) and in the urban area (N=220). We have collected data about age, gender, marital status, education level, and knowledge, treatment of hypertension, height, weight and blood pressure. We have observed that overweight and obesity were more prevalent in the urban area (Dakar) than in the rural one (Ferlo). The risk of overweight or obesity decreased when age increased, and women had weight problems more often than men. The prevalence of arterial hypertension was lower in rural area (55.86%) than in Dakar (66.36%), but increased at an older age. However, the logistic regression showed that these increased proportion of hypertension in Dakar is linked to the more important proportion of overweight and obese people in this area. Moreover, rates of knowledge, treatment and control of hypertension are particularly low in the rural area of Senegal. In conclusion, age-associated diseases should be better managed in Senegal, particularly in rural areas.

Amyloid-ß (1-40) restores adhesion properties of pulmonary surfactant, counteracting the effect of cholesterol.

A pulmonary surfactant (PS) is a thin lipid-protein film covering the surface of the lung alveoli at the air/liquid interface. The primary purpose of a PS is to control the surface tension of the air/liquid interface and to reduce the work of breathing. High levels of cholesterol in a PS are associated with life-threatening acute respiratory distress syndrome (ARDS) and acute lung injury (ALI). Finding therapeutics to counteract the effect of cholesterol in a PS is a matter of contemporary research. In our earlier work, we showed that the addition of amyloid-ß (1-40) (Aß40), the protein implicated in Alzheimer's disease, can reverse the detrimental effects of cholesterol in surfactants by improving multilayer formation and restoring PS surface active properties. We hypothesized that this phenomenon was due to Aß40 improving adhesion properties of a surfactant. In this work we used atomic force spectroscopy to demonstrate that Aß40 counteracts the adhesive properties of a PS compromised by high levels of cholesterol in a PS and helps to restore the functionality of a PS.

Comparison of three competing dynamic force spectroscopy models to study binding forces of amyloid-ß (1-42).

We performed single molecule dynamic force spectroscopy experiments to study the dimerization of two amyloid-ß (1-42) peptides and compared three different theoretical models used to fit experimental data: Bell-Evans, Dudko-Hummer-Szabo, and Friddle-De Yoreo. Using these models we extracted values of the dissociation rate at zero force, k0, and height and the width of the energy barrier, ΔG and xß. We show the importance of including the effect of the linker molecule. All three models corrected for the linker effect give comparable results for xß and show more discrepancy for k0 and ΔG values, ΔG parameter correlates well between Dudko-Hummer-Szabo and Friddle-De Yoreo models but differs for the Bell-Evans model.

Identifying barriers to effective tuberculosis control in Senegal: an anthropological approach.

SETTING: Low tuberculosis (TB) cure rates (average 53%) and high treatment default rates (average 28%) were reported in Senegal between 1999 and 2001. OBJECTIVE: To qualitatively evaluate the ability of TB patients to access and complete treatment in Senegal, with a view to helping to develop suitable strategies to improve TB control. METHODS: Anthropological study conducted in a series of public and private, urban and rural health facilities in 2001 and 2002. The qualitative methods used included semi-structured and in-depth interviews of health staff, patients and relatives, focus group discussions, and observations carried in health facilities. RESULTS: Problems were identified at several levels of health care. The main impediments to successful patient outcomes identified were: limited access to TB diagnosis and treatment facilities, poor communication between health personnel and patients, poor quality information provided to patients, poorly applied directly observed treatment, lack of a strategy to trace defaulting patients and limited supervision of the treatment units by the district leadership team. CONCLUSION: The anthropological analysis of patient care is an appropriate means of addressing complex public health problems in disease control and identifying solutions that are acceptable, sustainable and adapted to the local context.