STEREOCONVERGENT TRANSFORMATIONS OF CARBONYLS FOR EXPEDIENT SYNTHESIS OF STEREOCHEMICALLY COMPLEX SMALL MOLECULES

I. A Primer on Dynamic Kinetic Resolutions and Extant Methods for Oxo-Ester Synthesis: A two part overview that details: 1) the principles of dynamic kinetic resolution and its application in modern asymmetric catalysts and 2) current synthetic methods for generation of enolizable β-substituted α-keto esters and α-substituted β-oxo esters. II. Asymmetric Transfer Hydrogenation-Dynamic Kinetic Resolution of β-Stereogenic α-Keto Esters: Two systems for dynamic kinetic resolution via asymmetric transfer hydrogenation (DKR-ATH) of racemic β-stereogenic-α-keto esters yielding optically active α-hydroxy esters are presented. In the first of these reports a previously unreported Stetter addition of ethyl gloxylate provides β-stereogenic-α,δ-diketo esters, which are reduced to α-hydroxy δ-keto esters. Stereo- and chemoselective mono-reduction provides formal glycolate Michael products. In the second disclosure, β-amino α-keto esters are reduced to the corresponding anti-β-amino α-hydroxy esters. Both reports employ formic acid as the organic reductant , and use a Ru(II)-amido complex bearing a bulky m-terphenylsulfonamide ligand which imparts remarkable levels of diastereo- and enantiocontrol. III. N-Heterocyclic Carbene-Catalyzed Dynamic Kinetic Resolutions of β-Stereogenic α-Keto Esters: The development of two distinct N-Heterocyclic carbene catalyzed dynamic kinetic resolutions of β-halo-α-keto esters are discussed. In the first of these, an asymmetric cross-benzoin addition is described. The resulting fully substituted β-halo glycolic ester products are obtained with high levels of enantio- and diastereocontrol, and the reaction products undergo highly diastereoselective substrate-controlled reduction to give functionalized stereotriads. Mechanistic studies show that the high chemoselectivity observed is a result of greater electrophilicity of the α-keto ester toward the Breslow intermediate. In the second report development of an asymmetric homoenolate (a3 − d3-umpolung addition) of α,β-enals, forming γ-butyrolactones with three contiguous stereocenters is described. The addition occurs with high regio-, diastereo-, and enantiocontrol and constitutes the first stereoconvergent homoenolate process. IV. Complexity Generating Dynamic Kinetic Resolutions of β-Oxo Acid Derivatives: Dynamic kinetic resolutions of α-stereogenic-β-formyl amides in asymmetric 2-aza-Cope rearrangements are described. Chiral phosphoric acids catalyze this rare example of a non-hydrogenative DKR of a β-oxo acid derivative. The [3,3]-rearrangement occurs with high diastereo- and enantiocontrol, forming β-imino amides that can be deprotected to the primary β-amino amide or reduced to the corresponding diamine.Doctor of Philosoph

A Practical Methodology for Quantifying Random and Systematic Components of Unexplained Variance in a Wind Tunnel

This paper documents a check standard wind tunnel test conducted in the Langley 0.3-Meter Transonic Cryogenic Tunnel (0.3M TCT) that was designed and analyzed using the Modern Design of Experiments (MDOE). The test designed to partition the unexplained variance of typical wind tunnel data samples into two constituent components, one attributable to ordinary random error, and one attributable to systematic error induced by covariate effects. Covariate effects in wind tunnel testing are discussed, with examples. The impact of systematic (non-random) unexplained variance on the statistical independence of sequential measurements is reviewed. The corresponding correlation among experimental errors is discussed, as is the impact of such correlation on experimental results generally. The specific experiment documented herein was organized as a formal test for the presence of unexplained variance in representative samples of wind tunnel data, in order to quantify the frequency with which such systematic error was detected, and its magnitude relative to ordinary random error. Levels of systematic and random error reported here are representative of those quantified in other facilities, as cited in the references

Lessons learned from the application of BEES-C: Systematic assessment of study quality of epidemiologic research on BPA, neurodevelopment, and respiratory health

AbstractEpidemiologic studies evaluating associations between biomarkers of exposure to short-lived chemicals and health endpoints in humans face special challenges. Perhaps the most critical challenges are the need to determine the type and optimal number of samples, and the proper timing of specimen collection. Further, as many short-lived chemicals are ubiquitous in the environment, utmost care is required to avoid sample contamination. A separate set of challenges is associated with appropriate interpretation and reporting of results from multiple simultaneous analyses, which are becoming increasingly feasible. The Biomonitoring, Environmental Epidemiology, and Short-Lived Chemicals (BEES-C) instrument is specifically designed to evaluate the quality of epidemiologic studies that measure biomarkers of chemicals with short physiologic half-lives. The instrument provides systematic guidance for evaluating 14 different aspects of study quality divided into three broad categories: 1) biomarker selection and measurement, 2) strategy and execution of exposure assessment, and 3) general considerations of study design and reporting. We evaluated the utility of the BEES-C instrument using epidemiologic studies of exposure to bisphenol A and its association with neurodevelopmental and respiratory health indicators. Each BEES-C element was assessed with respect to needed modifications and concordance among reviewers using professional, scientific judgment. Based on this first use of the BEES-C instrument, we found that most of its elements were effective in comparing the quality of available studies, with reviews generally concordant and justifications consistent. However, we note that certain elements would be improved with slight adjustments and that one of the elements appeared redundant and should be removed

ALDH Activity Correlates with Metastatic Potential in Primary Sarcomas of Bone.

Osteosarcoma (OS), chondrosarcoma (CSA), and Ewings sarcoma (ES) are the most common primary malignancies of bone, and are rare diseases. As with all sarcomas, the prognosis of these diseases ultimately depends on the presence of metastatic disease. Survival is therefore closely linked with the biology and metastatic potential of a particular bone tumor's cells. Here we describe a significant correlation of aldehyde dehydrogenase (ALDH) activity and the presence/absence of distant metastases in ten consecutive cases of human bone sarcomas. Additionally, cultured human CSA cells, which are historically chemo- and radio-resistant, may be sensitive to the ALDH inhibitor, disulfiram. While it is premature to draw broad conclusions from such a small series, the importance of ALDH activity and inhibition in the metastatic potential of primary bone sarcomas should be investigated further

Inhalation of diesel exhaust and allergen alters human bronchial epithelium DNA methylation

Background Allergic disease affects 30% to 40% of the world's population, and its development is determined by the interplay between environmental and inherited factors. Air pollution, primarily consisting of diesel exhaust emissions, has increased at a similar rate to allergic disease. Exposure to diesel exhaust may play a role in the development and progression of allergic disease, in particular allergic respiratory disease. One potential mechanism underlying the connection between air pollution and increased allergic disease incidence is DNA methylation, an epigenetic process with the capacity to integrate gene-environment interactions. Objective We sought to investigate the effect of allergen and diesel exhaust exposure on bronchial epithelial DNA methylation. Methods We performed a randomized crossover-controlled exposure study to allergen and diesel exhaust in humans, and measured single-site (CpG) resolution global DNA methylation in bronchial epithelial cells. Results Exposure to allergen alone, diesel exhaust alone, or allergen and diesel exhaust together (coexposure) led to significant changes in 7 CpG sites at 48 hours. However, when the same lung was exposed to allergen and diesel exhaust but separated by approximately 4 weeks, significant changes in more than 500 sites were observed. Furthermore, sites of differential methylation differed depending on which exposure was experienced first. Functional analysis of differentially methylated CpG sites found genes involved in transcription factor activity, protein metabolism, cell adhesion, and vascular development, among others. Conclusions These findings suggest that specific exposures can prime the lung for changes in DNA methylation induced by a subsequent insult

Heritability of Obsessive-Compulsive symptom dimensions.

Recent research has shown that obsessive-compulsive symptoms (OCS) differ remarkably among patients and can be divided into several symptom dimensions. OCS are influenced by genetic components, but it is unknown to what extent these symptom dimensions are heritable. The phenotypic heterogeneity also raises the question to what extent the symptom dimensions are influenced by specific or shared genetic factors. We studied a population sample of 1,383 female twins from the Virginia Twin Registry. OCS was measured by a questionnaire with 20 items from the Padua Inventory. After factor analysis, three reliable OC symptom dimensions were retained: Rumination, Contamination, and Checking. These OC dimensions were analyzed with multivariate genetic models to investigate both the overlap and uniqueness of genetic and environmental contributions underlying OC symptom dimensions. The multivariate common pathway model provided the best description of the data. All symptom dimensions share variation with a latent common factor, that is, OC behavior. Variation in this common factor was explained by both genes (36%) and environmental factors (64%). Only the Contamination dimension was influenced by specific genes and seemed to be a relatively independent dimension. The results suggest that a broad OC behavioral phenotype exists, influenced by both genes and nonshared environment. In addition, we found evidence for specific genetic and environmental factors underlying the Contamination dimension. Use of the Contamination dimension could therefore provide a powerful approach for the detection of genetic susceptibility loci that contribute to OCS. © 2007 Wiley-Liss, Inc

Boceprevir for untreated chronic HCV genotype 1 infection.

International audienceBACKGROUND: Peginterferon-ribavirin therapy is the current standard of care for chronic infection with hepatitis C virus (HCV). The rate of sustained virologic response has been below 50% in cases of HCV genotype 1 infection. Boceprevir, a potent oral HCV-protease inhibitor, has been evaluated as an additional treatment in phase 1 and phase 2 studies. METHODS: We conducted a double-blind study in which previously untreated adults with HCV genotype 1 infection were randomly assigned to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (the control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peginterferon-ribavirin for an additional 20 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. Nonblack patients and black patients were enrolled and analyzed separately. RESULTS: A total of 938 nonblack and 159 black patients were treated. In the nonblack cohort, a sustained virologic response was achieved in 125 of the 311 patients (40%) in group 1, in 211 of the 316 patients (67%) in group 2 (P<0.001), and in 213 of the 311 patients (68%) in group 3 (P<0.001). In the black cohort, a sustained virologic response was achieved in 12 of the 52 patients (23%) in group 1, in 22 of the 52 patients (42%) in group 2 (P=0.04), and in 29 of the 55 patients (53%) in group 3 (P=0.004). In group 2, a total of 44% of patients received peginterferon-ribavirin for 28 weeks. Anemia led to dose reductions in 13% of controls and 21% of boceprevir recipients, with discontinuations in 1% and 2%, respectively. CONCLUSIONS: The addition of boceprevir to standard therapy with peginterferon-ribavirin, as compared with standard therapy alone, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection. The rates were similar with 24 weeks and 44 weeks of boceprevir

The burden of selected digestive diseases in the United States

AbstractBackground & Aims: Gastrointestinal (GI) and liver diseases inflict a heavy economic burden. Although the burden is considerable, current and accessible information on the prevalence, morbidity, and cost is sparse. This study was undertaken to estimate the economic burden of GI and liver disease in the United States for use by policy makers, health care providers, and the public. Methods: Data were extracted from a number of publicly available and proprietary national databases to determine the prevalence, direct costs, and indirect costs for 17 selected GI and liver diseases. Indirect cost calculations were purposefully very conservative. These costs were compared with National Institutes of Health (NIH) research expenditures for selected GI and liver diseases. Results: The most prevalent diseases were non–food-borne gastroenteritis (135 million cases/year), food-borne illness (76 million), gastroesophageal reflux disease (GERD; 19 million), and irritable bowel syndrome (IBS; 15 million). The disease with the highest annual direct costs in the United States was GERD ($9.3 billion), followed by gallbladder disease ($5.8 billion), colorectal cancer ($4.8 billion), and peptic ulcer disease ($3.1 billion). The estimated direct costs for these 17 diseases in 1998 dollars were $36.0 billion, with estimated indirect costs of$22.8 billion. The estimated direct costs for all digestive diseases were $85.5 billion. Total NIH research expenditures were$676 million in 2000. Conclusions: GI and liver diseases exact heavy economic and social costs in the United States. Understanding the prevalence and costs of these diseases is important to help set priorities to reduce the burden of illness.GASTROENTEROLOGY 2002;122:1500-151

Exoticism in Gertrude Bell's Persian pictures

Victorian travelers in colonial contexts encountered differences in landscape, mores and manners, society, politics and culture, among other things, and registered their responses to the places visited in their published travel books for the home audience. Postcolonial critics contend that exoticism, i.e., a Western traveler's response to and description of the differences encountered in the context of travel, was deeply informed by the asymmetrical power relation between the representer/colonizer and the represented/colonized. As a result, these critics argue, exoticism in colonial travel writing was appropriative since it tended to construct the dichotomy of self/other in such a way as to justify imperial interventions in other countries (Forsdick, “Sa(L)Vaging Exoticism” 30–34; Said 1–28). As Graham Huggan rightly argues, difference of the colonial other in its various aspects was denigrated and dismissed as exotic when “translated into the master code of empire,” since it superimposed “a dominant way of seeing, speaking and thinking onto marginalised peoples” (24)

Developmental pathways to autism: a review of prospective studies of infants at risk

Autism Spectrum Disorders (ASDs) are neurodevelopmental disorders characterized by impairments in social interaction and communication, and the presence of restrictive and repetitive behaviors. Symptoms of ASD likely emerge from a complex interaction between pre-existing neurodevelopmental vulnerabilities and the child's environment, modified by compensatory skills and protective factors. Prospective studies of infants at high familial risk for ASD (who have an older sibling with a diagnosis) are beginning to characterize these developmental pathways to the emergence of clinical symptoms. Here, we review the range of behavioral and neurocognitive markers for later ASD that have been identified in high-risk infants in the first years of life. We discuss theoretical implications of emerging patterns, and identify key directions for future work, including potential resolutions to several methodological challenges for the field. Mapping how ASD unfolds from birth is critical to our understanding of the developmental mechanisms underlying this disorder. A more nuanced understanding of developmental pathways to ASD will help us not only to identify children who need early intervention, but also to improve the range of interventions available to them