Use of a Robust Dehydrogenase from an Archael Hyperthermophile in Asymmetric Catalysis–Dynamic Reductive Kinetic Resolution Entry into (S)-Profens

Hyperthermophilic archaea are of great interest in evolutionary microbiology, owing to their ability to withstand high temperatures, and often extremes of pressure, pH and salinity. Enzymes from these organisms1 may offer particular opportunities for asymmetric synthesis, complementary to approaches with mesophilic enzymes,2 or those involving enzyme3 and pathway4 reengineering. However, perhaps due to a bias that hyperthermophilic enzymes have “narrow substrate specificities,”5 archaeal extremophiles remain a largely untapped resource in asymmetric synthesis.6 Herein, we disclose a remarkably general Dynamic Reductive Kinetic Resolution (DYRKR) entry into (S)-profens, including several important NSAIDs. The enzyme employed is alcohol dehydrogenase (ADH)-10, one of 13 annotated ADHs in the hyperthermophile Sulfolobus solfataricus. Protein phylogenetic analysis of this paralogous family indicates SsADH-10 is most closely related to homologues in distant taxa (Fig. 1). The highest identity between SsADH-10 and any other SsADHs is only 34%, suggesting that the SsADH family was established prior to the emergence of other archaeal lineages. Though not described as such, the SsADH-10 appears to be the only SsADH isozyme for which structural information is available in the pdb.

Use of a Robust Dehydrogenase from an Archael Hyperthermophile in Asymmetric Catalysis–Dynamic Reductive Kinetic Resolution Entry into (S)-Profens

Hyperthermophilic archaea are of great interest in evolutionary microbiology, owing to their ability to withstand high temperatures, and often extremes of pressure, pH and salinity. Enzymes from these organisms1 may offer particular opportunities for asymmetric synthesis, complementary to approaches with mesophilic enzymes,2 or those involving enzyme3 and pathway4 reengineering. However, perhaps due to a bias that hyperthermophilic enzymes have “narrow substrate specificities,”5 archaeal extremophiles remain a largely untapped resource in asymmetric synthesis.6 Herein, we disclose a remarkably general Dynamic Reductive Kinetic Resolution (DYRKR) entry into (S)-profens, including several important NSAIDs. The enzyme employed is alcohol dehydrogenase (ADH)-10, one of 13 annotated ADHs in the hyperthermophile Sulfolobus solfataricus. Protein phylogenetic analysis of this paralogous family indicates SsADH-10 is most closely related to homologues in distant taxa (Fig. 1). The highest identity between SsADH-10 and any other SsADHs is only 34%, suggesting that the SsADH family was established prior to the emergence of other archaeal lineages. Though not described as such, the SsADH-10 appears to be the only SsADH isozyme for which structural information is available in the pdb.

Advanced stratified charge rotary aircraft engine design study

A technology base of new developments which offered potential benefits to a general aviation engine was compiled and ranked. Using design approaches selected from the ranked list, conceptual design studies were performed of an advanced and a highly advanced engine sized to provide 186/250 shaft Kw/HP under cruise conditions at 7620/25,000 m/ft altitude. These are turbocharged, direct-injected stratified charge engines intended for commercial introduction in the early 1990's. The engine descriptive data includes tables, curves, and drawings depicting configuration, performance, weights and sizes, heat rejection, ignition and fuel injection system descriptions, maintenance requirements, and scaling data for varying power. An engine-airframe integration study of the resulting engines in advanced airframes was performed on a comparative basis with current production type engines. The results show airplane performance, costs, noise & installation factors. The rotary-engined airplanes display substantial improvements over the baseline, including 30 to 35% lower fuel usage

Physical Electronics

Contains research objectives and reports on two research projects

Trends in food insecurity for adults with cardiometabolic disease in the United States: 2005-2012

Background: Food insecurity, the uncertain ability to access adequate food, can limit adherence to dietary measures needed to prevent and manage cardiometabolic conditions. However, little is known about temporal trends in food insecurity among those with diet-sensitive cardiometabolic conditions. Methods: We used data from the Continuous National Health and Nutrition Examination Survey (NHANES) 2005–2012, analyzed in 2015–2016, to calculate trends in age-standardized rates of food insecurity for those with and without the following diet-sensitive cardiometabolic conditions: diabetes mellitus, hypertension, coronary heart disease, congestive heart failure, and obesity. Results: 21,196 NHANES participants were included from 4 waves (4,408 in 2005–2006, 5,607 in 2007–2008, 5,934 in 2009–2010, and 5,247 in 2011–2012). 56.2% had at least one cardiometabolic condition, 24.4% had 2 or more, and 8.5% had 3 or more. The overall age-standardized rate of food insecurity doubled during the study period, from 9.06% in 2005–2006 to 10.82% in 2007–2008 to 15.22% in 2009–2010 to 18.33% in 2011–2012 (p for trend < .001). The average annual percentage change in food insecurity for those with a cardiometabolic condition during the study period was 13.0% (95% CI 7.5% to 18.6%), compared with 5.8% (95% CI 1.8% to 10.0%) for those without a cardiometabolic condition, (parallelism test p = .13). Comparing those with and without the condition, age-standardized rates of food insecurity were greater in participants with diabetes (19.5% vs. 11.5%, p < .0001), hypertension (14.1% vs. 11.1%, p = .0003), coronary heart disease (20.5% vs. 11.9%, p < .001), congestive heart failure (18.4% vs. 12.1%, p = .004), and obesity (14.3% vs. 11.1%, p < .001). Conclusions: Food insecurity doubled to historic highs from 2005–2012, particularly affecting those with diet-sensitive cardiometabolic conditions. Since adherence to specific dietary recommendations is a foundation of the prevention and treatment of cardiometabolic disease, these results have important implications for clinical management and public health

Human serine racemase structure/activity relationship studies provide mechanistic insight and point to position 84 as a hot spot for \u3ci\u3eβ\u3c/i\u3e-elimination function

There is currently great interest in human serine racemase, the enzyme responsible for producing the NMDA co-agonist D-serine. Reported correlation of D-serine levels with disorders including Alzheimer’s disease, ALS, and ischemic brain damage (elevated D-serine) and schizophrenia (reduced D-serine) has further piqued this interest. Reported here is a structure/activity relationship study of position Ser84, the putative re-face base. In the most extreme case of functional reprogramming, the S84D mutant displays a dramatic reversal of β-elimination substrate specificity in favor of L-serine over the normally preferred L-serine-O-sulfate (~1200-fold change in kcat/Km ratios) and L (L-THA; ~5000-fold change in kcat/Km ratios) alternative substrates. On the other hand, the S84T (which performs L-Ser racemization activity), S84A (good kcat but high Km for L-THA elimination), and S84N mutants (nearly WT efficiency for L-Ser elimination) displayed intermediate activity, all showing a preference for the anionic substrates, but generally attenuated compared with the native enzyme. Inhibition studies with L-erythro-β-hydroxyaspartate follow this trend, with both WT serine racemase and the S84N mutant being competitively inhibited, with Ki = 31 ± 1.5 μM and 1.5 ± 0.1mM, respectively, and the S84D being inert to inhibition. Computational modeling pointed to a key role for residue Arg-135 in binding and properly positioning the L-THA and L-serine-O-sulfate substrates and the L-erythro-β-hydroxyaspartate inhibitor. Examination of available sequence data suggests that Arg-135 may have originated for L-THA-like-β-elimination function in earlier evolutionary variants, and examination of available structural data suggests that a Ser84-H2O-Lys114 hydrogen-bonding network in human serine racemase lowers the pKa of the Ser84 re-face base

Getting More from Less in Defined Benefit Plans: Three Levers for a Low-Return World

As global interest rates hover near historic lows, defined benefit pension plan sponsors must grapple with the prospect of lower investment returns. This paper examines three levers that can enhance portfolio outcomes in a low-return world. The levers include: increased contributions; reduced investment costs; and increased portfolio risk. We use portfolio simulations based on a stochastic asset class forecasting model to evaluate each lever according to two criteria—its magnitude of impact and the certainty that this impact will be realized. Our analysis indicates that increased contributions have the greatest and most certain impact. Reduced costs have a more modest, but equally certain impact. Increased risk can deliver a significant impact, but with the least certainty

Building Community Practice Competencies Globally through the Community Tool Box

People throughout the world are working together to improve conditions in which they live. Although the issues and resources vary by context, what people actually do to effect change—core competencies of assessment, planning, action, evaluation, and sustainability—may be quite similar. To examine what competencies may be most valued in community practice, this report uses data analytics for what users are accessing in the Community Tool Box http://ctb.ku.edu/. This free resource for community health and development, with over 1.7 million unique visitors annually from over 200 countries, showed a six-fold increase in users during the past year (from November 2011 to November 2012). When we examined what users were accessing, the results showed greater interest in some particular competencies such as assessing community needs and resources, developing strategic and action plans, and enhancing cultural competence. Patterns of use suggest that there may be core competencies valued by community members seeking to change conditions and outcomes that matter, which may help inform training and professional development for the millions of people worldwide working to promote health, human development, and social justice.&nbsp

Building Community Practice Competencies Globally through the Community Tool Box

People throughout the world are working together to improve conditions in which they live. Although the issues and resources vary by context, what people actually do to effect change—core competencies of assessment, planning, action, evaluation, and sustainability—may be quite similar. To examine what competencies may be most valued in community practice, this report uses data analytics for what users are accessing in the Community Tool Box http://ctb.ku.edu/. This free resource for community health and development, with over 1.7 million unique visitors annually from over 200 countries, showed a six-fold increase in users during the past year (from November 2011 to November 2012). When we examined what users were accessing, the results showed greater interest in some particular competencies such as assessing community needs and resources, developing strategic and action plans, and enhancing cultural competence. Patterns of use suggest that there may be core competencies valued by community members seeking to change conditions and outcomes that matter, which may help inform training and professional development for the millions of people worldwide working to promote health, human development, and social justice.&nbsp

Evidence for Possible Phase-Separations in RuSr2(Gd,Ce)2Cu2O10-delta

An unusual thermal-magnetic hysteresis was observed between a minor magnetic transition around 120 K and the main one at 80 K in superconducting RuSr2(R,Ce)2Cu2O10-delta (Ru1222R) samples, where R = Gd or Eu, down to a submicron length-scale. The observation suggests a possible phase-separation and is consistent with the very small but universal demagnetizing factor observed, which is difficult to reconcile with the canted spin-structure previously proposed. In such a scenario, the unusual superconducting properties of the Ru-based cuprates can also be understood naturally.Comment: 8 pages, 3 figures, submitted to Phys. Rev. B, "Rapid Communications" (September 26, 2001