Investigation of molecular mechanisms underlying obesity and related metabolic disturbances.

I investigated genetic and epigenetic variants underlying obesity and related metabolic disturbances with the aim of identifying new disease mechanisms. I first examined the contribution of genetic variation to the increased risk of central obesity (waist-hip-ratio, WHR) in South Asians compared to Europeans by: i) genome-wide association in 10,318 South Asians; ii) exome-wide association in 2,637 South Asians; iii) comparison of risk allele frequencies and effect sizes of 48 known WHR SNPs in South Asians and Europeans. I found no associations between population-specific or cosmopolitan SNPs and WHR, and no evidence of larger genetic effects at known WHR loci in South Asians. I next investigated the cell lineages and causal pathways underlying DNA methylation markers associated with BMI in blood (187 loci, P<1x10-7) by: i. replication testing the loci in isolated white blood cells and adipocytes from obese cases and controls; ii. analysing the relationships between methylation, adiposity, and metabolic disturbances using genetic association. I showed that DNA methylation in blood reflects methylation in isolated white cells (enrichment P<1.2x10-9) and adipocytes (enrichment P<0.05), and is predominantly a consequence rather than a cause of adiposity. I finally evaluated genome-wide DNA methylation in isolated subcutaneous and visceral adipocytes from 24 morbidly obese cases and 24 controls (Illumina-450K) to identify putative obesogenic and diabetogenic processes. I discovered widespread differences in DNA methylation between: i. cases and controls (140 loci, P<1x10-7); ii. subcutaneous and visceral adipocytes (671 loci, P<1x10-7). Loci were enriched in multiple cellular/molecular pathways (case-control N=47, subcutaneous-visceral N=84, P<0.001), and identified known obesity and metabolic genes (e.g. IRX3/IRX5, TBX15, PRMD16). These discoveries will be replicated and functionally characterised in future work. Overall, my results suggest that DNA methylation in adipocytes may be important in obesity and metabolic disease pathogenesis, and that methylation in blood may serve as a biomarker of tissue-specific pathobiological processes.Open Acces

The utilization of neural nets in populating an object-oriented database

Existing NASA supported scientific data bases are usually developed, managed and populated in a tedious, error prone and self-limiting way in terms of what can be described in a relational Data Base Management System (DBMS). The next generation Earth remote sensing platforms (i.e., Earth Observation System, (EOS), will be capable of generating data at a rate of over 300 Mbs per second from a suite of instruments designed for different applications. What is needed is an innovative approach that creates object-oriented databases that segment, characterize, catalog and are manageable in a domain-specific context and whose contents are available interactively and in near-real-time to the user community. Described here is work in progress that utilizes an artificial neural net approach to characterize satellite imagery of undefined objects into high-level data objects. The characterized data is then dynamically allocated to an object-oriented data base where it can be reviewed and assessed by a user. The definition, development, and evolution of the overall data system model are steps in the creation of an application-driven knowledge-based scientific information system

Agglomerative Forces and Cluster Shapes

We model spatial clusters of similar firms. Our model highlights how agglomerative forces lead to localized, individual connections among firms, while interaction costs generate a defined distance over which attraction forces operate. Overlapping firm interactions yield agglomeration clusters that are much larger than the underlying agglomerative forces themselves. Empirically, we demonstrate that our model's assumptions are present in the structure of technology and labor flows within Silicon Valley and its surrounding areas. Our model further identifies how the lengths over which agglomerative forces operate influence the shapes and sizes of industrial clusters; we confirm these predictions using variations across patent technology clusters

Plea-Bargaining as a Social Contract

Most criminal prosecutions are settled without a trial. The parties to these settlements trade various risks and entitlements: the defendant relinquishes the right to go to trial (along with any chance of acquittal), while the prosecutor gives up the entitlement to seek the highest sentence or pursue the most serious charges possible. The resulting bargains differ predictably from what would have happened had the same cases been taken to trial. Defendants who bargain for a plea serve lower sentences than those who do not. On the other hand, everyone who pleads guilty is, by definition, convicted, while a substantial minority of those who go to trial are acquitted. There is something puzzling about the polarity of contemporary reactions to this practice. Most legal scholars oppose plea bargaining, finding it both inefficient and unjust. Nevertheless, most participants in the plea bargaining process, including (perhaps especially) the courts, seem remarkably untroubled by it. Not only is the practice widespread, but participants generally approve of it. Why is plea bargaining at once so widely condemned and so widely tolerated? One place to look for an answer is in the law and literature of plea bargaining as contract. Plea bargains are, as the name suggests, bargains; it seems natural to argue that they should be regulated and evaluated accordingly. But while that argument is common, there is little agreement on where it leads. Two of the harshest and most influential critics of plea bargaining, Albert Alschuler and Stephen Schulhofer, maintain that contract theory supports prohibiting any bargained-for allocation of criminal punishment. The courts, on the other hand, have proceeded to construct a body of contract-based law to regulate the plea bargaining process, taking for granted the efficiency and decency of the process being regulated. The many academic arguments for abolishing (or at least severely restricting) plea bargaining have thus been largely ignored. It is tempting to explain this reaction as a product of the chasm between an overly fastidious academic world and the unpleasant realities of modem criminal processes. But the intuition that plea bargaining is fundamentally flawed is too strong and too widespread to be so casually dismissed

Plea Bargaining as Contract

Most criminal prosecutions are settled without a trial. The parties to these settlements trade various risks and entitlements: the defendant relinquishes the right to go to trial (along with any chance of acquittal), while the prosecutor gives up the entitlement to seek the highest sentence or pursue the most serious charges possible. The resulting bargains differ predictably from what would have happened had the same cases been taken to trial. Defendants who bargain for a plea serve lower sentences than those who do not. On the other hand, everyone who pleads guilty is, by definition, convicted, while a substantial minority of those who go to trial are acquitted. There is something puzzling about the polarity of contemporary reactions to this practice. Most legal scholars oppose plea bargaining, finding it both inefficient and unjust. Nevertheless, most participants in the plea bargaining process, including (perhaps especially) the courts, seem remarkably untroubled by it. Not only is the practice widespread, but participants generally approve of it. Why is plea bargaining at once so widely condemned and so widely tolerated? One place to look for an answer is in the law and literature of plea bargaining as contract. Plea bargains are, as the name suggests, bargains; it seems natural to argue that they should be regulated and evaluated accordingly. But while that argument is common, there is little agreement on where it leads. Two of the harshest and most influential critics of plea bargaining, Albert Alschuler and Stephen Schulhofer, maintain that contract theory supports prohibiting any bargained-for allocation of criminal punishment. The courts, on the other hand, have proceeded to construct a body of contract-based law to regulate the plea bargaining process, taking for granted the efficiency and decency of the process being regulated. The many academic arguments for abolishing (or at least severely restricting) plea bargaining have thus been largely ignored. It is tempting to explain this reaction as a product of the chasm between an overly fastidious academic world and the unpleasant realities of modem criminal processes. But the intuition that plea bargaining is fundamentally flawed is too strong and too widespread to be so casually dismissed

Identifying Market Preferences for High Selenium Beef

Selenium is an element found in relatively high concentrations in crops and livestock raised on high-selenium soils located in North and South Dakota. Evidence suggests that a high-selenium diet such as would be obtained from consuming these products can reduce the risk of certain cancers. The region's livestock and grain producers are exploring potential high-selenium product marketing opportunities. A choice experiment was conducted to identify preferred attributes for a high-selenium beef product and the characteristics of potential market segments. In a national survey, participants chose between different levels of health claim approval and research, prices, and selenium origin. A multinomial logit regression model was estimated. Labeling reflecting scientific support linking selenium and reduced cancer risk, and natural-source selenium was ineffective. Marketing opportunities identified are consistent with existing functional food market segments and include consumers with higher income and education, 45 to 55 years of age, and with children.Choice Experiment, FDA approval, Functional Foods, Health Claim, Labeling, Selenium, Consumer/Household Economics, Livestock Production/Industries,

Report Presented to The Council of the Dublin Technical School : Kevin Street

Report by a deputation from a sub committee of the Public Libraries of the Committee of the Corporation of Dublin, named to visit technical schools and science and art schools in England to advise as to what branches of science and art could be most effectively and economically introduced in the Kevin Street Schools