Unveiling a novel transient druggable pocket in BACE-1 through molecular simulations: conformational analysis and binding mode of multisite inhibitors

The critical role of BACE-1 in the formation of neurotoxic ß-amyloid peptides in the brain makes it an attractive target for an efficacious treatment of Alzheimer’s disease. However, the development of clinically useful BACE-1 inhibitors has proven to be extremely challeng- ing. In this study we examine the binding mode of a novel potent inhibitor (compound 1, with IC50 80 nM) designed by synergistic combination of two fragments—huprine and rhein— that individually are endowed with very low activity against BACE-1. Examination of crystal structures reveals no appropriate binding site large enough to accommodate 1. Therefore we have examined the conformational flexibility of BACE-1 through extended molecular dynamics simulations, paying attention to the highly flexible region shaped by loops 8–14, 154–169 and 307–318. The analysis of the protein dynamics, together with studies of pocket druggability, has allowed us to detect the transient formation of a secondary binding site, which contains Arg307 as a key residue for the interaction with small molecules, at the edge of the catalytic cleft. The formation of this druggable “floppy” pocket would enable the bind- ing of multisite inhibitors targeting both catalytic and secondary sites. Molecular dynamics simulations of BACE-1 bound to huprine-rhein hybrid compounds support the feasibility of this hypothesis. The results provide a basis to explain the high inhibitory potency of the two enantiomeric forms of 1, together with the large dependence on the length of the oligo- methylenic linker. Furthermore, the multisite hypothesis has allowed us to rationalize the inhibitory potency of a series of tacrine-chromene hybrid compounds, specifically regarding the apparent lack of sensitivity of the inhibition constant to the chemical modifications intro- duced in the chromene unit. Overall, these findings pave the way for the exploration of novel functionalities in the design of optimized BACE-1 multisite inhibitors

Can environment or allergy explain international variation in prevalence of wheeze in childhood?

Asthma prevalence in children varies substantially around the world, but the contribution of known risk factors to this international variation is uncertain. The International Study of Asthma and Allergies in Childhood (ISAAC) Phase Two studied 8–12 year old children in 30 centres worldwide with parent-completed symptom and risk factor questionnaires and aeroallergen skin prick testing. We used multilevel logistic regression modelling to investigate the effect of adjustment for individual and ecological risk factors on the between-centre variation in prevalence of recent wheeze. Adjustment for single individual-level risk factors changed the centre-level variation from a reduction of up to 8.4% (and 8.5% for atopy) to an increase of up to 6.8%. Modelling the 11 most influential environmental factors among all children simultaneously, the centre-level variation changed little overall (2.4% increase). Modelling only factors that decreased the variance, the 6 most influential factors (synthetic and feather quilt, mother’s smoking, heating stoves, dampness and foam pillows) in combination resulted in a 21% reduction in variance. Ecological (centre-level) risk factors generally explained higher proportions of the variation than did individual risk factors. Single environmental factors and aeroallergen sensitisation measured at the individual (child) level did not explain much of the between-centre variation in wheeze prevalence

The effect of multifactorial lifestyle interventions on cardiovascular risk factors: a systematic review and meta-analysis of trials conducted in the general population and high risk groups

Cardiovascular diseases (CVDs) are the leading cause of premature mortality and disability accounting for one third of all deaths worldwide with considerable impacts on economics and on the quality of life. The evidence suggests that a multifactorial lifestyle intervention might have a role in the CVDs risk reduction, especially in the risk populations, nonetheless the effects on modifiable CVDs risk factors have not been completely explored. Our work aimed at evaluating the impact of multifactorial lifestyle interventions on cardiovascular risk modification, both in the general and risk population. A systematic review and meta-analysis of the randomized controlled trials (RCTs) were performed by including articles published up to April 16th, 2016. RCTs were selected if they had investigated the impact of multifactorial lifestyle interventions on lipids, blood pressure, BMI and waist circumference, smoking and physical activity. Changes in the level of modifiable risk factors from baseline were evaluated. Search resulted in 19,847 studies, of which 36 were included in the analysis. Compared to a usual care, the multifactorial lifestyle intervention is able to lower the blood pressure, total cholesterol, BMI and waist circumference, at both 6 and 12 months, and to increase physical activity at 12 months. Better results were obtained in primary prevention and in moderate and high risk groups. Multifactorial lifestyle interventions clearly represent a valid tool for reducing the cardiovascular risk factors and should be implemented in the risk groups and in primary prevention

El Método PRINCONSER su aplicación en la teoría de la interacción universal y en la dimensión humana

Las bases fundamentales de esta tesis están en las ciencias. Los antecedentes de esta tesis están dispersos como información aislada en las diferentes ciencias básicas. La sistematización tiene como antecedente principal mi tesis de licenciatura titulada FILOSOFIA DE LA DESTRUCCION, que se desarrolla sobre la base del principio de Conservación y el principio de Destrucción. El método PRINCONSER se constituye en un marco teórico que se sustenta en los principios de conservación y destrucción y las leyes universales. Estos principios están presentes en todos los fenómenos de la naturaleza, la sociedad y el espíritu. La regularidad de las leyes del universo tiene su fundamento en los principios de conservación y destrucción. La interacción de estos principios hace que los fenómenos sean cíclicos en la naturaleza. Por otro lado, se entiende la temporalidad de los entes por la interacción de los principios de conservación y destrucción que en cada ente se manifiesta de un modo singular. Ahora bien, la ley de la conservación de la materia y energía, la inseparabilidad y la mutua transformación de las mismas, son el fundamento para afirmar que el ser humano tiene tres formas de interacción: biológica, social y espiritual. Estas interacciones responden a su naturaleza biológica, social y espiritual.Tesi

Grenzschichtprozesse ueber dem polaren Meereis

In recent years Field-Coupled devices, like Quantum dot Cel- lular Automata, are gaining an ever increasing attention from the scien- tific community. The computational paradigm beyond this device topol- ogy is based on the interaction among neighbor cells to propagate in- formation through circuits. Among the various implementations of this theoretical principle, NanoMagnet Logic (NML) is one the most studied, due to some interesting features, like the possibility to combine memory and logic in the same device and the possible low power consumption. Since the working principle of Field-Coupled devices is completely dif- ferent from CMOS technology, it is important to understand all the im- plications that this new computational paradigm has on complex circuit architectures. In this chapter we deeply analyze the major issues encountered in the design of complex circuits using Field-Coupled devices. Problems are analyzed and techniques to solve them and to improve performance are presented. Finally, a realistic analysis of the applications best suited for this technology is presented. While the analysis is performed using Nano- Magnet Logic as target, the results can be applied to all Field-Coupled devices. This chapter therefore supplies researchers and designers with the essential guidelines necessary to design complex circuits using Nano- Magnet Logic and, more in general, Field-Coupled devices