Challenges of Country Modeling with Databases, Newsfeeds, and Expert Surveys

According to expert practitioners and researchers in the field of human behavior modeling ([Silverman et al., 2002; Pew and Mavor, 1998; Ritter et al., 2003]), a common central challenge now confronting designers of HBM (human-behavior-modeling) applications is to increase the realism of the synthetic agents\u27 behavior and coping abilities. It is well accepted in the HBM (human-behavior-modeling) community that cognitively detailed, thick models are required to provide realism. These models require that synthetic agents be endowed with cognition and personality, physiology, and emotive components. (We will hereafter refer to these rich models as cognitively detailed models or thick agents. ) To make these models work, one must find ways to integrate scientific know-how from many disciplines, and to integrate concepts and insights from hitherto fragmented and partial models from the social sciences, particularly from psychology, cultural studies, and political science. One consequence of this kind of integration of multiple and heterogeneous concepts and models is that we frequently end up with a large feature space of parameters that then need to be filled in with data

Association between TCF7L2 gene polymorphisms and susceptibility to Type 2 Diabetes Mellitus: a large Human Genome Epidemiology (HuGE) review and meta-analysis

<p>Abstract</p> <p>Background</p> <p>Transcription factor 7-like 2 (<it>TCF7L2</it>) has been shown to be associated with type 2 diabetes mellitus (T2MD) in multiple ethnic groups in the past two years, but, contradictory results were reported for Chinese and Pima Indian populations. The authors then performed a large meta-analysis of 36 studies examining the association of type 2 diabetes mellitus (T2DM) with polymorphisms in the <it>TCF7L2 </it>gene in various ethnicities, containing rs7903146 C-to-T (IVS3C>T), rs7901695 T-to-C (IVS3T>C), a rs12255372 G-to-T (IVS4G>T), and rs11196205 G-to-C (IVS4G>C) polymorphisms and to evaluate the size of gene effect and the possible genetic mode of action.</p> <p>Methods</p> <p>Literature-based searching was conducted to collect data and three methods, that is, fixed-effects, random-effects and Bayesian multivariate mete-analysis, were performed to pool the odds ratio (<it>OR</it>). Publication bias and study-between heterogeneity were also examined.</p> <p>Results</p> <p>The studies included 35,843 cases of T2DM and 39,123 controls, using mainly primary data. For T2DM and IVS3C>T polymorphism, the Bayesian <it>OR </it>for TT homozygotes and TC heterozygotes versus CC homozygote was 1.968 (95% credible interval (<it>CrI</it>): 1.790, 2.157), 1.406 (95% <it>CrI</it>: 1.341, 1.476), respectively, and the population attributable risk (PAR) for the TT/TC genotypes of this variant is 16.9% for overall. For T2DM and IVS4G>T polymorphism, TT homozygotes and TG heterozygotes versus GG homozygote was 1.885 (95%<it>CrI</it>: 1.698, 2.088), 1.360 (95% <it>CrI</it>: 1.291, 1.433), respectively. Four <it>OR</it>s among these two polymorphisms all yielded significant between-study heterogeneity (P < 0.05) and the main source of heterogeneity was ethnic differences. Data also showed significant associations between T2DM and the other two polymorphisms, but with low heterogeneity (<it>P </it>> 0.10). Pooled <it>OR</it>s fit a codominant, multiplicative genetic model for all the four polymorphisms of <it>TCF7L2 </it>gene, and this model was also confirmed in different ethnic populations when stratification of IVS3C>T and IVS4G>T polymorphisms except for Africans, where a dominant, additive genetic mode is suggested for IVS3C>T polymorphism.</p> <p>Conclusion</p> <p>This meta-analysis demonstrates that four variants of <it>TCF7L2 </it>gene are all associated with T2DM, and indicates a multiplicative genetic model for all the four polymorphisms, as well as suggests the <it>TCF7L2 </it>gene involved in near 1/5 of all T2MD. Potential gene-gene and gene-environmental interactions by which common variants in the <it>TCF7L2 </it>gene influence the risk of T2MD need further exploration.</p

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

The nature and the timing of political stabilization.

I develop a game-theoretic model to examine the means by which political stability is attained, the timing of decisive action that brings about conflict resolution, and the overall duration of transitional conflicts. I view the transitional conflict process as an increasingly costly and high stakes political contest that ends only after the groups involved make major concessions that lead to negotiations or after they use decisive force to impose a settlement. This view is formalized as a war-of-attrition model with two exit options of either making concessions or using force with each contending group withholding the information about its own power. In the focal equilibrium, for a group whose power is below the threshold for using decisive force, the greater the power of the group, the longer major concessions will be delayed, while for a group above the threshold, the greater the power, the shorter the delay before the use of decisive force. The decision to use decisive force depends on the one-time cost of using decisive force and the net benefit of prevailing, but not on any appraisal of the everyday cost accumulation from crisis continuation. The greater the one-time cost to a group for using decisive force, the less likely the use of decisive force by its opponent, the sooner the time of concession by the opponent if the opponent is below the threshold, and the later the time of using decisive force by the opponent if the opponent is above the threshold. This result makes clear the role of such moves as building forces in a particular area---perhaps even if their long-term military indefensibility in that area is known---or of building housing settlements in areas that perhaps increase one side's own cost of reaching a resolution it favors. This study suggests that economic development is conducive to less violent and shorter transitional conflicts. It also suggests certain conditions that disfavor third party interventions in transitional conflicts and points out the conditions where economic diplomacy, in particular the idea that a promise of post-conflict aid can accelerate the timing of conflict resolution, can have perverse effects. To establish the theoretical model's empirical relevance and to illustrate its logic in the context of actual transitional conflicts, the dissertation examines the nature and the timing of political stabilizations in five episodes of transitional conflicts in South Africa (the Sharpeville Massacre in 1960, the Soweto Crisis from 1976 to 1977, and the Total Onslaught from 1984 to 1990) and in South Korea (the Kwangju Massacre in 1980 and the Voluntary Exit from 1986 to 1987). Overall, this study makes contributions to the literature on political transitions and civil conflicts by providing a new and rigorous theoretical framework to study the process of attaining political order and the timing of political stabilization in transitional conflicts.Ph.D.EconomicsInternational lawPolitical scienceSocial SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/126193/2/3237995.pd

Structures of Trypanosoma brucei methionyl-tRNA synthetase with urea-based inhibitors provide guidance for drug design against sleeping sickness.

Methionyl-tRNA synthetase of Trypanosoma brucei (TbMetRS) is an important target in the development of new antitrypanosomal drugs. The enzyme is essential, highly flexible and displaying a large degree of changes in protein domains and binding pockets in the presence of substrate, product and inhibitors. Targeting this protein will benefit from a profound understanding of how its structure adapts to ligand binding. A series of urea-based inhibitors (UBIs) has been developed with IC50 values as low as 19 nM against the enzyme. The UBIs were shown to be orally available and permeable through the blood-brain barrier, and are therefore candidates for development of drugs for the treatment of late stage human African trypanosomiasis. Here, we expand the structural diversity of inhibitors from the previously reported collection and tested for their inhibitory effect on TbMetRS and on the growth of T. brucei cells. The binding modes and binding pockets of 14 UBIs are revealed by determination of their crystal structures in complex with TbMetRS at resolutions between 2.2 Å to 2.9 Å. The structures show binding of the UBIs through conformational selection, including occupancy of the enlarged methionine pocket and the auxiliary pocket. General principles underlying the affinity of UBIs for TbMetRS are derived from these structures, in particular the optimum way to fill the two binding pockets. The conserved auxiliary pocket might play a role in binding tRNA. In addition, a crystal structure of a ternary TbMetRS•inhibitor•AMPPCP complex indicates that the UBIs are not competing with ATP for binding, instead are interacting with ATP through hydrogen bond. This suggests a possibility that a general 'ATP-engaging' binding mode can be utilized for the design and development of inhibitors targeting tRNA synthetases of other disease-causing pathogen