Asymmetric Synthesis of 1,3-anti-Diol Containing Subunits using Phosphorus-Based Tethers: Application in the Total Synthesis of Dolabelide C

The focus of this dissertation is the desymmetrization of C2-symmetric 1,3-anti-diols through the construction of pseudo-C2-symmetric phosphorus heterocycles, bearing a chirotopic, non-stereogenic center at phosphorus. Diastereotopic differentiation is achieved through cyclization via ring-closing metathesis (RCM), affording a chiral, non-racemic bicyclic P-heterocycle, which is stereogenic at phosphorus. This strategy is central to building skeletally diverse polyol subunits, which are commonly seen in polyketide-based natural products. Terminus differentiation and chain elongation through selective transformations on the previously reported bicyclo[4.3.1]phosphate (both antipodes), e.g. cross-metathesis, regioselective olefin reduction and regio- and diastereoselective allylic phosphate displacements, provide a rapid protocol to accessing the aforementioned motifs. The development of this methodology advanced into an application toward the total synthesis of dolabelide C (bearing two separate 1,3-anti-diol containing fragments), which exhibits cytotoxicity against cervical cancer HeLa-S3 cells with an IC50 value of 1.9 μg/mL. A route to this target was devised, where the final step was amending the 24-membered marcocycle through RCM. The result provided a diastereomeric mixture of E and Z isomers, which proved to be difficult to separate during initial efforts. However, LC-MS analysis of the mixture showed the contaminants were by-products arising from isomerization events occurring prior to RCM. Other reports coincide with this observation, mainly in the synthesis of medium to larger sized rings. Scale-up was required after this initial study to provide ample material for final characterization and the re-synthesis provided a copious amount of the RCM precursor. The large amount of material allowed for optimization studies and finally resulted in 14 mgs of analytically pure dolabelide C and 10 mgs of the non-natural Z-isomer, which to the best of our knowledge is the first synthesis of both compounds and the most synthetic material available of each to date

s- and d-wave superconductivity in a two-band model

Superconductivity in strongly correlated systems is a remarkable phenomenon that attracts a huge interest. The study of this problem is relevant for materials as the high Tc oxides, pnictides and heavy fermions. In this work we study a realistic model that includes the relevant physics of superconductivity in the presence of strong Coulomb correlations. We consider a two-band model, since most of these correlated systems have electrons from at least two different atomic orbitals coexisting at their Fermi surface. The Coulomb repulsion is taken into account through a local repulsive interaction. Pairing is considered among quasi- particles in neighbouring sites and we allow for different symmetries of the order parameter. In order to deal with the strong local correlations, we use the well known slave boson approach that has proved very successful for this problem. Here we are interested in obtaining the zero temperature properties of the model, specifically its phase diagram and the existence and nature of superconducting quantum critical points. We show that these can arise by increasing the mixing between the two bands. Since this can be controlled by external pressure or doping, our results have a direct relation with experiments. We show that the superconductor-to-normal transition can be either to a metal, a correlated metal or to an insulator. Also we compare the relative stability of s and d-wave paired states for different regions of parameter space and investigate the BCS- BEC crossover in the two-band lattice model as function of the strength of the pairing interaction.Comment: 21 pages, 14 figure

Multivariate Design of Experiments for Engineering Dimensional Analysis

We consider the design of dimensional analysis experiments when there is more than a single response. We first give a brief overview of dimensional analysis experiments and the dimensional analysis (DA) procedure. The validity of the DA method for univariate responses was established by the Buckingham $\Pi$-Theorem in the early 20th century. We extend the theorem to the multivariate case, develop basic criteria for multivariate design of DA and give guidelines for design construction. Finally, we illustrate the construction of designs for DA experiments for an example involving the design of a heat exchanger

HETEROGENEOUS CONSTRAINTS, INCENTIVES AND INCOME DIVERSIFICATION STRATEGIES IN RURAL AFRICA

A burgeoning recent literature emphasizes "livelihood" diversification among smallholder populations (Chambers and Conway 1992, Davies 1993, Ellis 1998, Bryceson 1999, Ellis 2000, Little et al. 2001). While definitions vary within this literature, the concept of livelihoods revolves around the opportunity set afforded an individual or household by their asset endowment and their chosen allocation of those assets across various activities to generate a stream of benefits, most commonly measured as income. This holistic perspective has the potential to enhance our understanding of the strategies that farm households pursue to ensure food and income security given the natural and economic environment in which they operate. Diversification patterns reflect individuals' voluntary exchange of assets and their allocation of assets across various activities so as to achieve an optimal balance between expected returns and risk exposure conditional on the constraints they face (e.g., due to missing or incomplete markets for credit, labor, or land). Because it offers a glimpse as to what people presently consider their most attractive options, given the incentives and constraints they face, the study of diversification behavior offers important insights as to what policy or project interventions might effectively improve either the poor's asset holdings or their access to higher return or lower risk uses of the assets they already possess. Since diversification is not an end unto itself, it is essential to connect observed livelihood strategies back to resulting income distributions and poverty. Not all diversification into off-farm or non-farm income earning activities offers the same benefits and not all households have equal access to the more lucrative diversification options. Yet the livelihoods literature offers little documentation or explanation of important differences between observed diversification strategies. This paper addresses that gap by offering a comparative analysis using data from three different countries, Cote d'Ivoire, Kenya and Rwanda. Like Dercon and Krishnan (1996) and Omamo (1999), we emphasize that interhousehold heterogeneity in constraints and incentives must factor prominently in any sensible explanation of observed diversification behaviors. Indeed, section 4 demonstrates that at a very fundamental level - the choice of basic livelihood strategy - households would prefer locally available livelihood strategies other than those they choose, were they not constrained from doing so. A simple appeal to the principle of revealed preference thus suggests that heterogeneous constraints and incentives play a fundamental role in determining livelihood diversification patterns manifest in income diversification data. The plan for the remainder of this paper is as follows. The next section presents the basic conceptual foundation from which we operate. Section 3 then introduces the data sets and definitions employed in the analysis. Section 4 presents findings relating to the observed variation in income sources across the income distribution, to distinct livelihood strategies pursued by rural African households, to the determinants of strategy choice, and to the effects of alternative livelihood strategies on income dynamics. These findings point especially to significant rural markets failures - especially with respect to finance and land - that force poorer subpopulations to select strategies offering demonstrably lower returns while wealthier subpopulations are able to enjoy higher return strategies to which entry is at least partly impeded by fixed costs and lower marginal costs of participation. Section 5 concludes.Labor and Human Capital, O & Q12,

Genome-wide association study of electrocardiographic and heart rate variability traits: the Framingham Heart Study

BACKGROUND: Heritable electrocardiographic (ECG) and heart rate variability (HRV) measures, reflecting pacemaking, conduction, repolarization and autonomic function in the heart have been associated with risks for cardiac arrhythmias. Whereas several rare monogenic conditions with extreme phenotypes have been noted, few common genetic factors contributing to interindividual variability in ECG and HRV measures have been identified. We report the results of a community-based genomewide association study of six ECG and HRV intermediate traits. METHODS: Genotyping using Affymetrix 100K GeneChip was conducted on 1345 related Framingham Heart Study Original and Offspring cohort participants. We analyzed 1175 Original and Offspring participants with ECG data (mean age 52 years, 52% women) and 548 Offspring participants with HRV data (mean age 48 years, 51% women), in relation to 70,987 SNPs with minor allele frequency ≥ 0.10, call rate ≥ 80%, Hardy-Weinberg p-value ≥ 0.001. We used generalized estimating equations to test association of SNP alleles with multivariable-adjusted residuals for QT, RR, and PR intervals, the ratio of low frequency to high frequency power (LF/HFP), total power (TP) and the standard deviation of normal RR intervals (SDNN). RESULTS: Associations at p < 10-3 were found for 117 (QT), 105 (RR), 111 (PR), 102 (LF/HF), 121 (TP), and 102 (SDNN) SNPs. Several common variants in NOS1AP (4 SNPs with p-values < 10-3; lowest p-value, rs6683968, p = 1 × 10-4) were associated with adjusted QT residuals, consistent with our previously reported finding for NOS1AP in an unrelated sample of FHS Offspring and other cohorts. All results are publicly available at NCBI's dbGaP at. CONCLUSION: In the community-based Framingham Heart Study none of the ECG and HRV results individually attained genomewide significance. However, the presence of bona fide QT-associated SNPs among the top 117 results for QT duration supports the importance of efforts to validate top results from the reported scans. Finding genetic variants associated with ECG and HRV quantitative traits may identify novel genes and pathways implicated in arrhythmogenesis and allow for improved recognition of individuals at high risk for arrhythmias in the general population.National Institutes of Health (K23 N01-HC25195); Doris Duke Charitable Foundation Clinical Scientist Developement Award; Pfizer; National Institutes of Health National Center for Research Resources Shared Instrumentation grant (1S10RR163736-01A1

Social capital and geographical variation in the incidence of COVID-19: an ecological study

BACKGROUND: The new behavioural norms needed to reduce the spread of COVID-19 are likely scaffolded by social capital. Research on social capital and COVID-19 has yielded mixed results, with some studies finding it to be protective while others identifying it as a risk factor. We examined the association between social capital and COVID-19 at a finer spatial scale than previous research, and examined changes in the relationship over the course of the pandemic. METHODS: Routine COVID-19 surveillance data from Wales were linked to estimates of social capital at a small area level. Generalised linear mixed effects models predicting COVID-19 case rates across areas using social capital estimates and possible confounding variables were fitted to the data. A moving window version of the analysis explored whether this relationship varied across time. RESULTS: Areas with higher levels of social capital had lower rates of COVID-19 (rate ratio for trust=0.94, 95% CI 0.92 to 0.96; rate ratio for belonging=0.94, 95% CI 0.92 to 0.96). These associations were strongest during periods of lockdown, with evidence that social capital was less protective, and potentially even a risk factor, during periods when restrictions were eased. Trust, but not belonging, remained protective after adjusting for deprivation, population density, ethnicity and proportion population aged over 65 years. CONCLUSIONS: Social capital is an important public health resource, which should be considered in future pandemic preparedness. Its importance may be greatest during times when social activity is most restricted

Frequency Of Development Of Connective Tissue Disease In Statin-Users Versus Nonusers

Statins have pleiotropic properties that may affect the development of connective tissue diseases (CTD). The objective of this study was to compare the risk of CTD diagnoses in statin users and nonusers. This study was a propensity score-matched analysis of adult patients (30 to 85 years old) in the San Antonio military medical community. The study was divided into baseline (October 1, 2003 to September 30, 2005), and follow-up (October 1, 2005 to March 5, 2010) periods. Statin users received a statin prescription during fiscal year 2005. Nonusers did not receive a statin at any time during the study. The outcome measure was the occurrence of 3 diagnosis codes of the International Classification of Diseases, 9th Revision, Clinical Modification consistent with CTD. We described co-morbidities during the baseline period using the Charlson Comorbidity Index. We created a propensity score based on 41 variables. We then matched statin users and nonusers 1:1, using a caliper of 0.001. Of 46,488 patients who met study criteria (13,640 statin users and 32,848 nonusers), we matched 6,956 pairs of statin users and nonusers. Matched groups were similar in terms of patient age, gender, incidence of co-morbidities, total Charlson Comorbidity Index, health care use, and medication use. The odds ratio for CTD was lower in statin users than nonusers (odds ratio: 0.80; 95% confidence interval: 0.64 to 0.99; p = 0.05). Secondary analysis and sensitivity analysis confirmed these results. In conclusion, statin use was associated with a lower risk of CTD. Published by Elsevier Inc.Pharmac

Optical dilution and feedback cooling of a gram-scale oscillator to 6.9 mK

We report on use of a radiation pressure induced restoring force, the optical spring effect, to optically dilute the mechanical damping of a 1 gram suspended mirror, which is then cooled by active feedback (cold damping). Optical dilution relaxes the limit on cooling imposed by mechanical losses, allowing the oscillator mode to reach a minimum temperature of 6.9 mK, a factor of ~40000 below the environmental temperature. A further advantage of the optical spring effect is that it can increase the number of oscillations before decoherence by several orders of magnitude. In the present experiment we infer an increase in the dynamical lifetime of the state by a factor of ~200

Large–Scale Laboratory Observations of Wave Forces on a Highway Bridge Superstructure

A. Objectives The objectives of this study are to: (1) conduct the first, large-scale physical model study of wave loads on a highway bridge superstructure under realistic wave conditions and bridge geometries, and (2) evaluate the application of existing design formulas developed for deep water, wave-in-deck loading of offshore structures to shallow water, highway bridge geometries. This will aid in our understanding of the dynamic loads by hurricane waves on highway bridge superstructures and assess the accuracy of present methods for safer design of new bridges or retrofit of existing bridges. B. Scope In their 2006 report titled Wave Forces on Bridge Decks prepared for the US Department of Transportation, Office of Bridge Technology, Douglass et al. provide a synthesis of existing knowledge related to hurricane wave forces on highway bridge superstructures. Their extensive literature search found that the existing methods to evaluate wave loads on highway bridge geometries were not adequate. One of the uncertainties is due to a lack of physical model test data with highway bridge geometries using modern wave generating capabilities to simulate realistic sea states. One of their conclusions is that more research with hydraulic models is necessary to develop new analytical tools to advance bridge design. This one-year project will conduct the first-of-its-kind, large-scale, hydraulic model test of wave forces on a highway bridge superstructure cross-section, similar to those bridges that failed during Hurricanes Katrina in 2005 and Ivan in 2004. One graduate student will be trained in the area of wave-structure interaction, and two undergraduate students will be involved in this research. Project results will be disseminated through peer-reviewed publications. C. Methodology The hydraulic model study will be conducted in the Large Wave Flume at the O.H. Hinsdale Wave Research Laboratory at Oregon State University, the largest facility of its kind in North America, and in conjunction with the Kiewit Center for Infrastructure and Transportation at OSU. The model will be scaled 1:4 for length and 1:2 for time using Froude similitude. The model will be constructed of concrete and steel using a realistic cross-section and will be instrumented with sensors to provide wave conditions, impact pressures, dynamic horizontal and vertical loads, and moments. The wave climate will be derived from available buoy data and existing wave modeling studies. Existing methods developed for wave-indeck loading of offshore platforms as outlined by McConnel, Allsop and Cruickshank (2004) will be compared with the data to evaluate the accuracy of these methods. D. Relevant OTREC theme This project advances technologies leading to safer design and repair of bridges subjected to wave loadings. It will develop new knowledge in this area, will train one graduate student and two undergraduate students, and will develop national leadership in this area at Oregon State University. E. USDOT priorities Safety Assurance of Highway Structures for Extreme Events to improve the performance of bridges and other highway structures under the impacts of extreme events. Safety, Structures Research to provide highway managers and engineers with information and tools to design, build, and maintain safer and better performing infrastructure assets