Contribution of poor blood pressure control to strokes

No abstract available

Virtual chemical reactions for drug design

Two methods for the fast, fragment-based combinatorial molecule assembly were developed. The software COLIBREE® (Combinatorial Library Breeding) generates candidate structures from scratch, based on stochastic optimization [1]. Result structures of a COLIBREE design run are based on a fixed scaffold and variable linkers and side-chains. Linkers representing virtual chemical reactions and side-chain building blocks obtained from pseudo-retrosynthetic dissection of large compound databases are exchanged during optimization. The process of molecule design employs a discrete version of Particle Swarm Optimization (PSO) [2]. Assembled compounds are scored according to their similarity to known reference ligands. Distance to reference molecules is computed in the space of the topological pharmacophore descriptor CATS [3]. In a case study, the approach was applied to the de novo design of potential peroxisome proliferator-activated receptor (PPAR gamma) selective agonists. In a second approach, we developed the formal grammar Reaction-MQL [4] for the in silico representation and application of chemical reactions. Chemical transformation schemes are defined by functional groups participating in known organic reactions. The substructures are specified by the linear Molecular Query Language (MQL) [5]. The developed software package contains a parser for Reaction-MQL-expressions and enables users to design, test and virtually apply chemical reactions. The program has already been used to create combinatorial libraries for virtual screening studies. It was also applied in fragmentation studies with different sets of retrosynthetic reactions and various compound libraries

Making the small oblique parameters large

We compute the oblique parameters, including the three new parameters $V$, $W$ and $X$ introduced recently by the Montreal group, for the case of one scalar multiplet of arbitrary weak isospin $J$ and weak hypercharge $Y$. We show that, when the masses of the heaviest and lightest components of the multiplet remain constant, but $J$ increases, the oblique parameter $U$ and the three new oblique parameters increase like $J^3$, while $T$ only increases like $J$. For large multiplets with masses not much higher than $m_Z$, the oblique parameters $U$ and $V$ may become much larger than $T$ and $S$.Comment: 9 pages, standard LATEX, 3 figures available from the authors, report CMU-HEP93-17 and DOE-ER/40682-4

A new look at C*-simplicity and the unique trace property of a group

We characterize when the reduced C*-algebra of a group has unique tracial state, respectively, is simple, in terms of Dixmier-type properties of the group C*-algebra. We also give a simple proof of the recent result by Breuillard, Kalantar, Kennedy and Ozawa that the reduced C*-algebra of a group has unique tracial state if and only if the amenable radical of the group is trivial.Comment: 8 page

Determining key research areas for healthier diets and sustainable food systems in Viet Nam

Vietnamese food systems are undergoing rapid transformation, with important implications for human and environmental health and economic development. Poverty has decreased, and diet quality and undernutrition have improved significantly since the end of the Doi Moi reform period (1986-1993) as a result of Viet Nam opening its economy and increasing its regional and global trade. Yet poor diet quality is still contributing the triple burden of malnutrition, with 25 percent stunting among children under age 5, 26 percent and 29 percent of women and children, respectively, anemic, and 21 percent of adults overweight. Agricultural production systems have shifted from predominantly diverse smallholder systems to larger more commercialized and specialized systems, especially for crops, while the ‘meatification’ of the Vietnamese diet is generating serious trade-offs between improved nutrition and sustainability of the Vietnamese food systems. The food processing industry has developed rapidly, together with food imports, resulting in new and processed food products penetrating the food retail outlets, trending towards an increase in the Westernized consumption patterns that are shifting nutrition-related problems towards overweight and obesity and, with it, an increase of non-communicable disease-related health risks. While regulatory policies exist across the food system, these are not systematically implemented, making food safety a major concern for consumers and policy makers alike. Where data exists, it is not easy to aggregate with data from across food system dimensions, making it difficult for Viet Nam to make an informed analysis of current and potential food system trade-offs. In our research, we reviewed existing literature and data, and applied a food systems framework to develop an initial food systems profile for Viet Nam and to identify a comprehensive set a of research questions to fill current data gaps identified through the review. Insights on these would provide the comprehensive evidence needed to inform policy makers on how to develop new food systems policies for Viet Nam, and further refine and improve existing policies to achieve better quality diets and more sustainable food systems in Viet Nam. Based on these, we then engaged with stakeholders to develop research priorities in the Viet Nam context and identified 25 priority research questions. This paper aims to stimulate such reflections by clearly outlining key areas for research, government policy, and development programs on priority investment to build the evidence base around inclusive food systems interventions that aim to result in healthier diets and more sustainable food systems for Viet Nam

A New Limit on the Antiproton Lifetime

Measurements of the cosmic ray pbar/p ratio are compared to predictions from an inhomogeneous disk-diffusion model of pbar production and propagation within the Galaxy, combined with a calculation of the modulation of the interstellar cosmic ray spectra as the particles propagate through the heliosphere to the Earth. The predictions agree with the observed pbar/p spectrum. Adding a finite pbar lifetime to the model, we obtain the limit tau_pbar > 0.8 Myr (90 % C.L.).Comment: 13 pages, 3 encapsulated Postscript figures, uses AASTeX; accepted by Astrophysical Journal; minor change

Kynurenine pathway inhibition reduces central nervous system inflammation in a model of human African trypanosomiasis

Human African trypanosomiasis, or sleeping sickness, is caused by the protozoan parasites <i>Trypanosoma brucei rhodesiense</i> or <i>Trypanosoma brucei gambiense</i>, and is a major cause of systemic and neurological disability throughout sub-Saharan Africa. Following early-stage disease, the trypanosomes cross the blood-brain barrier to invade the central nervous system leading to the encephalitic, or late stage, infection. Treatment of human African trypanosomiasis currently relies on a limited number of highly toxic drugs, but untreated, is invariably fatal. Melarsoprol, a trivalent arsenical, is the only drug that can be used to cure both forms of the infection once the central nervous system has become involved, but unfortunately, this drug induces an extremely severe post-treatment reactive encephalopathy (PTRE) in up to 10% of treated patients, half of whom die from this complication. Since it is unlikely that any new and less toxic drug will be developed for treatment of human African trypanosomiasis in the near future, increasing attention is now being focussed on the potential use of existing compounds, either alone or in combination chemotherapy, for improved efficacy and safety. The kynurenine pathway is the major pathway in the metabolism of tryptophan. A number of the catabolites produced along this pathway show neurotoxic or neuroprotective activities, and their role in the generation of central nervous system inflammation is well documented. In the current study, Ro-61-8048, a high affinity kynurenine-3-monooxygenase inhibitor, was used to determine the effect of manipulating the kynurenine pathway in a highly reproducible mouse model of human African trypanosomiasis. It was found that Ro-61-8048 treatment had no significant effect (P = 0.4445) on the severity of the neuroinflammatory pathology in mice during the early central nervous system stage of the disease when only a low level of inflammation was present. However, a significant (P = 0.0284) reduction in the severity of the neuroinflammatory response was detected when the inhibitor was administered in animals exhibiting the more severe, late central nervous system stage, of the infection. <i>In vitro</i> assays showed that Ro-61-8048 had no direct effect on trypanosome proliferation suggesting that the anti-inflammatory action is due to a direct effect of the inhibitor on the host cells and not a secondary response to parasite destruction. These findings demonstrate that kynurenine pathway catabolites are involved in the generation of the more severe inflammatory reaction associated with the late central nervous system stages of the disease and suggest that Ro-61-8048 or a similar drug may prove to be beneficial in preventing or ameliorating the PTRE when administered as an adjunct to conventional trypanocidal chemotherap