Advances in structure and small molecule docking predictions for crystallized G-Protein coupled receptors

This dissertation discusses two main aspects of protein-ligand interaction for G-Protein coupled receptors: structure predictions of the flexible loop domains and docking into these receptors. The prediction of loop structure has been long worked on in the context of native, globular proteins. In this work it is extended to transmembrane proteins, which requires an explicit integration of the lipid bilayer into the loop prediction calculation. In the initial work, this new approach to loop prediction yields highly accurate 3-dimensional structures of the intra and intercellular loops of four G-protein coupled receptors--the A2A adenosine, bovine rhodopsin, β1 and β2 adronergic receptors. For these cases, the loops were predicted in the context of a completely native crystal structure. In subsequent work the approach was extended to work on perturbed cases, where all loops and tails were removed, and side chains near the loop being predicted were in nonnative conformations. Lastly, a full homology model of the β2 adronergic receptor was successfully built from the β1 adronegric receptor as its template. Work on docking into these receptors focuses on the kappa opioid receptor. Known antagonist binders are discriminated from a set of decoy nonbinders via docking calculations. Two new terms were added to the scoring function, WScore to achieve this, based on a detailed molecular understanding of how the receptor works

Weyl group multiple Dirichlet series constructed from quadratic characters

We construct multiple Dirichlet series in several complex variables whose coefficients involve quadratic residue symbols. The series are shown to have an analytic continuation and satisfy a certain group of functional equations. These are the first examples of an infinite collection of unstable Weyl group multiple Dirichlet series in greater than two variables.Comment: incorporated referee's comment

Causal inference in multi-cohort studies using the target trial approach

Longitudinal cohort studies provide the opportunity to examine causal effects of complex exposures on long-term health outcomes. Utilizing data from multiple cohorts has the potential to add further benefit by improving precision of estimates through data pooling and allowing examination of effect heterogeneity across contexts. However, the interpretation of findings can be complicated by biases that may be compounded when pooling data or may contribute to discrepant findings when analyses are replicated across cohorts. Here we extend the target trial framework, already well established as a powerful tool for causal inference in single-cohort studies, to address the specific challenges that can arise in the multi-cohort setting. The approach considers the target trial as a central point of reference, as opposed to comparing one study to another. This enables clear definition of the target estimand and systematic consideration of sources of bias within each cohort and additional sources of bias arising from data pooling. Consequently, analyses can be designed to reduce these biases and the resulting findings appropriately interpreted. We use a case study to demonstrate the approach and its potential to strengthen causal inference in multi-cohort studies through improved analysis design and clarity in the interpretation of findings.Comment: 34 pages, 3 figure

NFAT5 binds to the TNF promoter distinctly from NFATp, c, 3 and 4, and activates TNF transcription during hypertonic stress alone

Tumor necrosis factor (TNF) is a pro-inflammatory cytokine that plays an important role in a variety of infectious and autoimmune disorders. Its transcription is regulated in a stimulus- and cell-type-specific manner via the recruitment of distinct DNA/activator complexes forming secondary structures or enhanceosomes. NFATp, a member of the nuclear factor of activated T cells (NFAT) family of transcription factors, plays a critical role in TNF gene regulation under a variety of conditions. In this study, we show that NFAT5, the most recently described NFAT family member, binds to the TNF promoter in a manner distinct from other NFAT proteins and is a key mediator in the activation of TNF gene transcription during hypertonic stress alone

Accelerometer and GPS Data to Analyze Built Environments and Physical Activity

Purpose: Most built environment studies have quantified characteristics of the areas around participants' homes. However, the environmental exposures for physical activity (PA) are spatially dynamic rather than static. Thus, merged accelerometer and global positioning system (GPS) data were utilized to estimate associations between the built environment and PA among adults. Methods: Participants (N = 142) were recruited on trails in Massachusetts and wore an accelerometer and GPS unit for 1-4 days. Two binary outcomes were created: moderate-to-vigorous PA (MVPA vs. light PA-to-sedentary); and light-to-vigorous PA (LVPA vs. sedentary). Five built environment variables were created within 50-meter buffers around GPS points: population density, street density, land use mix (LUM), greenness, and walkability index. Generalized linear mixed models were fit to examine associations between environmental variables and both outcomes, adjusting for demographic covariates. Results: Overall, in the fully adjusted models, greenness was positively associated with MVPA and LVPA (odds ratios [ORs] = 1.15, 95% confidence interval [CI] = 1.03, 1.30 and 1.25, 95% CI = 1.12, 1.41, respectively). In contrast, street density and LUM were negatively associated with MVPA (ORs = 0.69, 95% CI = 0.67, 0.71 and 0.87, 95% CI = 0.78, 0.97, respectively) and LVPA (ORs = 0.79, 95% CI = 0.77, 0.81 and 0.81, 95% CI = 0.74, 0.90, respectively). Negative associations of population density and walkability with both outcomes reached statistical significance, yet the effect sizes were small. Conclusions: Concurrent monitoring of activity with accelerometers and GPS units allowed us to investigate relationships between objectively measured built environment around GPS points and minute-by-minute PA. Negative relationships between street density and LUM and PA contrast evidence from most built environment studies in adults. However, direct comparisons should be made with caution since most previous studies have focused on spatially fixed buffers around home locations, rather than the precise locations where PA occurs

Elliptic curves of large rank and small conductor

For r=6,7,...,11 we find an elliptic curve E/Q of rank at least r and the smallest conductor known, improving on the previous records by factors ranging from 1.0136 (for r=6) to over 100 (for r=10 and r=11). We describe our search methods, and tabulate, for each r=5,6,...,11, the five curves of lowest conductor, and (except for r=11) also the five of lowest absolute discriminant, that we found.Comment: 16 pages, including tables and one .eps figure; to appear in the Proceedings of ANTS-6 (June 2004, Burlington, VT). Revised somewhat after comments by J.Silverman on the previous draft, and again to get the correct page break

Inequalities in the distribution of COVID-19-related financial difficulties for Australian families with young children

BACKGROUND: We examine (1) the frequency of financial difficulties in Australian families with young children (0-8 years) in the early and later phases of the pandemic; (2) the extent to which parents' pre-pandemic socio-economic disadvantage (SED) predicted financial difficulties; and (3) whether grandparent intergenerational SED further amplified this risk. METHOD: Data: Australian Temperament Project (ATP; established 1983, N = 2443) and ATP Generation 3 study (ATPG3; established 2012; N = 702), of which 74% (N = 553) completed a COVID-specific module in the early (May-September 2020) and/or later (October-December 2021) phases of the pandemic. OUTCOMES: Parent-reported loss of employment/reduced income, difficulty paying for essentials, and financial strain. EXPOSURES: Pre-pandemic parent and grandparent education and occupation. ANALYSIS: Logistic regressions, estimated via generalized estimating equations, were used to examine associations between the pre-pandemic SED of parents and grandparents and their interaction with financial difficulties, adjusting for potential confounders. RESULTS: At both pandemic time points, a third of parents reported adverse financial impacts (early: 34%, 95% confidence interval [CI] = 30-38; later: 32%, 95% CI = 28-36). Each standard deviation increase in the parents' pre-pandemic SED was associated with a 36% increase in the odds of reporting multiple financial difficulties (odds ratio [OR] = 1.36, 95% CI = 1.04-1.78). There was little evidence of an interaction between the SED of parents and grandparents. CONCLUSIONS: Financial impacts related to the COVID-19 pandemic were common and, irrespective of grandparent SED, disproportionately borne by parents with higher pre-pandemic SED. Given the well-established relationship between disadvantage and child health and development, sustained and well-targeted government supports will be critical to minimizing adverse impacts in years to come

Identification of families in need of support : correlates of adverse childhood experiences in the right@home sustained nurse home visiting program

Background Little is known about the efficacy of pregnancy screening tools using non-sensitive sociodemographic questions to identify the possible presence of as yet undiagnosed disease in individuals and later adverse childhood events disclosure. Objectives The study aims were to: 1) record the prevalence of risk disclosed by families during receipt of a sustained nurse home visiting program; and 2) explore patterns of relationships between the disclosed risks for their child having adverse experiences and the antenatal screening tool, which used non-sensitive demographic questions. Design Retrospective, observational study. Participants and methods Data about the participants in the intervention arm of the Australian right@home trial, which is scaffolded on the Maternal Early Childhood Sustained Home-visiting model, collected between 2013 and 2017 were used. Screening data from the 10-item antenatal survey of non-sensitive demographic risk factors and disclosed risks recorded by the nurse in audited case files during the subsequent 2 year intervention were examined (n = 348). Prevalence of disclosed risks for their child having adverse experiences were analysed in 2019 using multiple response frequencies. Phi correlations were conducted to test associations between screening factors and disclosed risks. Results Among the 348 intervention participants whose files were audited, 300 were noted by nurses to have disclosed risks during the intervention, with an average of four disclosures. The most prevalent maternal disclosures were depression or anxiety (57.8%). Mental health issues were the most prevalent partner and family disclosures. Screening tool questions on maternal smoking in pregnancy, not living with another adult, poverty and self-reporting anxious mood were significantly associated with a number of disclosed risks for their child having adverse experiences. Conclusions These findings suggest that a non-sensitive sociodemographic screening tool may help to identify families at higher risk for adverse childhood experiences for whom support from a sustained nurse home visiting program may be beneficial