Strong metal-support interactions

It has been demonstrated that synergistic metal-support effects can occur which markedly enhance specific activity and alter selectivity in certain reactions. Because of the presence of such effects in certain reactions conducted under reducing conditions (that is, under H2 pressure), but not others, the creation of unique sites at the metal-support interface seems to be the best model at the present time to explain this behavior. The postulation of these sites, which are specific for a certain reactant such as CO, provides an effective explanation for the higher methanation rates that have been reported over some catalysts. The creation of these sites in the adlineation zone is facilitated by hydrogen spillover from the metal surface, and this same process can also enhance the reduction of many oxide supports. Although oxygen spillover is much less probable due to its higher heat of adsorption, it is much less well understood and the possibility of rate enhancements in CO oxidation caused by special interface sites cannot be discounted at the present time. Consequently, this seems to be an important area of future research

Position of the Academy of Nutrition and Dietetics: Dietary Fatty Acids for Healthy Adults

It is the position of the Academy of Nutrition and Dietetics (the Academy) that dietary fat for the healthy adult population should provide 20% to 35% of energy, with an increased consumption of n-3 polyunsaturated fatty acids and limited intake of saturated and trans fats. The Academy recommends a food-based approach through a diet that includes regular consumption of fatty fish, nuts and seeds, lean meats and poultry, low-fat dairy products, vegetables, fruits, whole grains, and legumes. These recommendations are made within the context of rapidly evolving science delineating the influence of dietary fat and specific fatty acids on human health. In addition to fat as a valuable and calorically dense macronutrient with a central role in supplying essential nutrition and supporting healthy body weight, evidence on individual fatty acids and fatty acid groups is emerging as a key factor in nutrition and health. Small variations in the structure of fatty acids within broader categories of fatty acids, such as polyunsaturated and saturated, appear to elicit different physiological functions. The Academy recognizes that scientific knowledge about the effects of dietary fats on human health is young and takes a prudent approach in recommending an increase in fatty acids that benefit health and a reduction in fatty acids shown to increase risk of disease. Registered dietitian nutritionists are uniquely positioned to translate fat and fatty acid research into practical and effective dietary recommendations

Discovery of Enzymes Responsible for an Alternate Mevalonate Pathway in Haloferax volcanii

Title from PDF of title page, viewed July 10, 2015Dissertation advisor: Henry M. MiziorkoVitaIncludes bibliographic references (pages 90-103)Thesis (Ph.D.)--School of Biological Sciences. University of Missouri--Kansas City, 2015Archaea are a distinct evolutionary domain of microorganisms that contain isoprenoids in ether linkages to glycerol rather than the ester linked fatty acids that characterize membranes of bacteria or eukaryotes. Radiolabeling experiments with acetate and mevalonate strongly implicate the mevalonate pathway in providing the isoprenoids for archaeal lipid biosynthesis. However, the enzymes responsible for mevalonate metabolism in archaea have remained either cryptic or poorly characterized. To identify the enzymes responsible for the mevalonate pathway in Haloferax volcanii, open-reading frames from the H. volcanii genome were candidate screened against bacterial and eukaryotic mevalonate pathway enzymes and overexpressed in a Haloferax host. This approach has revealed that H. volcanii encodes (HVO_2419) a 3-hydroxy-3-methylglutaryl-CoA synthase (EC 2.3.310) which is the first committed step of the mevalonate pathway. Kinetic characterization shows that H. volcanii 3-hydroxy-3-methylglutaryl-CoA synthase (HvHMGCS) exhibits substrate saturation and catalytic efficiency similar to known bacterial and eukaryotic forms of the enzyme. HvHMGCS is unique in that it does not exhibit substrate inhibition by acetoacetyl-CoA. HvHMGCS is inhibited by hymeglusin, a specific inhibitor of bacterial and eukaryotic HMGCS, with experimentally determined Ki of 570 ± 120 nM and kinact of 17 ± 3 min-1. Hymeglusin also prevents the growth of H. volcanii cells in vivo suggesting the essentiality of the enzyme and the mevalonate pathway in these microbes. H. volcanii also encodes (HVO_2762) an isopentenyl monophosphate kinase (EC 2.7.4.26) and a novel decarboxylase (HVO_1412) that has been proposed, but never demonstrated, to produce isopentenyl monophosphate. This enzyme uses phosphomevalonate and ATP as substrates while exhibiting negligible decarboxylase activity with either mevalonate or mevalonate diphosphate. Phosphomevalonate decarboxylase (PMD) exhibits an IC50 = 16 μM for 6-fluoromevalonate monophosphate but negligible inhibition by 6-fluoromevalonate diphosphate, reinforcing its selectivity for monophosphorylated ligands. Inhibition by the fluorinated analog also suggests that PMD utilizes the reaction mechanism that has been demonstrated for the classical mevalonate pathway decarboxylase. These observations mark the accomplishment of the identification of a novel phosphomevalonate decarboxylase in H. volcanii. Identification and functional characterization of these enzymes also demonstrate, for the first time, the existence of the enzymes responsible for an alternate mevalonate pathway in H. volcaniiIntroduction -- Methods and materials -- Expression, characterization, and essentiality of 3-hydroxy-3-methylglutaryl synthase from h. volcanii -- Discovery of a phosphomevalonate decarboxylase and the alternate mevalonte pathway in h. volcanii -- Conclusions and future direction

Assessing dengue vaccination impact: Model challenges and future directions.

In response to the sharp rise in the global burden caused by dengue virus (DENV) over the last few decades, the WHO has set out three specific key objectives in its disease control strategy: (i) to estimate the true burden of dengue by 2015; (ii) a reduction in dengue mortality by at least 50% by 2020 (used as a baseline); and (iii) a reduction in dengue morbidity by at least 25% by 2020. Although various elements will all play crucial parts in achieving this goal, from diagnosis and case management to integrated surveillance and outbreak response, sustainable vector control, vaccine implementation and finally operational and implementation research, it seems clear that new tools (e.g. a safe and effective vaccine and/or effective vector control) are key to success. The first dengue vaccine was licensed in December 2015, Dengvaxia® (CYD-TDV) developed by Sanofi Pasteur. The WHO has provided guidance on the use of CYD-TDV in endemic countries, for which there are a variety of considerations beyond the risk-benefit evaluation done by regulatory authorities, including public health impact and cost-effectiveness. Population-level vaccine impact and economic and financial aspects are two issues that can potentially be considered by means of mathematical modelling, especially for new products for which empirical data are still lacking. In December 2014 a meeting was convened by the WHO in order to revisit the current status of dengue transmission models and their utility for public health decision-making. Here, we report on the main points of discussion and the conclusions of this meeting, as well as next steps for maximising the use of mathematical models for vaccine decision-making

Assessing dengue vaccination impact: Model challenges and future directions.

In response to the sharp rise in the global burden caused by dengue virus (DENV) over the last few decades, the WHO has set out three specific key objectives in its disease control strategy: (i) to estimate the true burden of dengue by 2015; (ii) a reduction in dengue mortality by at least 50% by 2020 (used as a baseline); and (iii) a reduction in dengue morbidity by at least 25% by 2020. Although various elements will all play crucial parts in achieving this goal, from diagnosis and case management to integrated surveillance and outbreak response, sustainable vector control, vaccine implementation and finally operational and implementation research, it seems clear that new tools (e.g. a safe and effective vaccine and/or effective vector control) are key to success. The first dengue vaccine was licensed in December 2015, Dengvaxia® (CYD-TDV) developed by Sanofi Pasteur. The WHO has provided guidance on the use of CYD-TDV in endemic countries, for which there are a variety of considerations beyond the risk-benefit evaluation done by regulatory authorities, including public health impact and cost-effectiveness. Population-level vaccine impact and economic and financial aspects are two issues that can potentially be considered by means of mathematical modelling, especially for new products for which empirical data are still lacking. In December 2014 a meeting was convened by the WHO in order to revisit the current status of dengue transmission models and their utility for public health decision-making. Here, we report on the main points of discussion and the conclusions of this meeting, as well as next steps for maximising the use of mathematical models for vaccine decision-making

Live-attenuated tetravalent dengue vaccines: The needs and challenges of post-licensure evaluation of vaccine safety and effectiveness.

Since December 2015, the first dengue vaccine has been licensed in several Asian and Latin American countries for protection against disease from all four dengue virus serotypes. While the vaccine demonstrated an overall good safety and efficacy profile in clinical trials, some key research questions remain which make risk-benefit-assessment for some populations difficult. As for any new vaccine, several questions, such as very rare adverse events following immunization, duration of vaccine-induced protection and effectiveness when used in public health programs, will be addressed by post-licensure studies and by data from national surveillance systems after the vaccine has been introduced. However, the complexity of dengue epidemiology, pathogenesis and population immunity, as well as some characteristics of the currently licensed vaccine, and potentially also future, live-attenuated dengue vaccines, poses a challenge for evaluation through existing monitoring systems, especially in low and middle-income countries. Most notable are the different efficacies of the currently licensed vaccine by dengue serostatus at time of first vaccination and by dengue virus serotype, as well as the increased risk of dengue hospitalization among young vaccinated children observed three years after the start of vaccination in one of the trials. Currently, it is unknown if the last phenomenon is restricted to younger ages or could affect also seronegative individuals aged 9years and older, who are included in the group for whom the vaccine has been licensed. In this paper, we summarize scientific and methodological considerations for public health surveillance and targeted post-licensure studies to address some key research questions related to live-attenuated dengue vaccines. Countries intending to introduce a dengue vaccine should assess their capacities to monitor and evaluate the vaccine's effectiveness and safety and, where appropriate and possible, enhance their surveillance systems accordingly. Targeted studies are needed, especially to better understand the effects of vaccinating seronegative individuals

Clinical development and regulatory points for consideration for second-generation live attenuated dengue vaccines.

Licensing and decisions on public health use of a vaccine rely on a robust clinical development program that permits a risk-benefit assessment of the product in the target population. Studies undertaken early in clinical development, as well as well-designed pivotal trials, allow for this robust characterization. In 2012, WHO published guidelines on the quality, safety and efficacy of live attenuated dengue tetravalent vaccines. Subsequently, efficacy and longer-term follow-up data have become available from two Phase 3 trials of a dengue vaccine, conducted in parallel, and the vaccine was licensed in December 2015. The findings and interpretation of the results from these trials released both before and after licensure have highlighted key complexities for tetravalent dengue vaccines, including concerns vaccination could increase the incidence of dengue disease in certain subpopulations. This report summarizes clinical and regulatory points for consideration that may guide vaccine developers on some aspects of trial design and facilitate regulatory review to enable broader public health recommendations for second-generation dengue vaccines