Georgia State University

About: Georgia State University is a education organization based out in Atlanta, Georgia, United States. It is known for research contribution in the topics: Population & Poison control. The organization has 13988 authors who have published 35895 publications receiving 1164332 citations. The organization is also known as: GSU & Georgia State.

Genome-wide association study of glioma subtypes identifies specific differences in genetic susceptibility to glioblastoma and non-glioblastoma tumors

Abstract: Genome-wide association studies (GWAS) have transformed our understanding of glioma susceptibility, but individual studies have had limited power to identify risk loci. We performed a meta-analysis of existing GWAS and two new GWAS, which totaled 12,496 cases and 18,190 controls. We identified five new loci for glioblastoma (GBM) at 1p31.3 (rs12752552; P = 2.04 × 10-9, odds ratio (OR) = 1.22), 11q14.1 (rs11233250; P = 9.95 × 10-10, OR = 1.24), 16p13.3 (rs2562152; P = 1.93 × 10-8, OR = 1.21), 16q12.1 (rs10852606; P = 1.29 × 10-11, OR = 1.18) and 22q13.1 (rs2235573; P = 1.76 × 10-10, OR = 1.15), as well as eight loci for non-GBM tumors at 1q32.1 (rs4252707; P = 3.34 × 10-9, OR = 1.19), 1q44 (rs12076373; P = 2.63 × 10-10, OR = 1.23), 2q33.3 (rs7572263; P = 2.18 × 10-10, OR = 1.20), 3p14.1 (rs11706832; P = 7.66 × 10-9, OR = 1.15), 10q24.33 (rs11598018; P = 3.39 × 10-8, OR = 1.14), 11q21 (rs7107785; P = 3.87 × 10-10, OR = 1.16), 14q12 (rs10131032; P = 5.07 × 10-11, OR = 1.33) and 16p13.3 (rs3751667; P = 2.61 × 10-9, OR = 1.18). These data substantiate that genetic susceptibility to GBM and non-GBM tumors are highly distinct, which likely reflects different etiology.

Design of HIV protease inhibitors targeting protein backbone: an effective strategy for combating drug resistance.

Abstract: The discovery of human immunodeficiency virus (HIV) protease inhibitors (PIs) and their utilization in highly active antiretroviral therapy (HAART) have been a major turning point in the management of HIV/acquired immune-deficiency syndrome (AIDS). However, despite the successes in disease management and the decrease of HIV/AIDS-related mortality, several drawbacks continue to hamper first-generation protease inhibitor therapies. The rapid emergence of drug resistance has become the most urgent concern because it renders current treatments ineffective and therefore compels the scientific community to continue efforts in the design of inhibitors that can efficiently combat drug resistance. The present line of research focuses on the presumption that an inhibitor that can maximize interactions in the HIV-1 protease active site, particularly with the enzyme backbone atoms, will likely retain these interactions with mutant enzymes. Our structure-based design of HIV PIs specifically targeting the protein backbone has led to exceedingly potent inhibitors with superb resistance profiles. We initially introduced new structural templates, particulary nonpeptidic conformationally constrained P 2 ligands that would efficiently mimic peptide binding in the S 2 subsite of the protease and provide enhanced bioavailability to the inhibitor. Cyclic ether derived ligands appeared as privileged structural features and allowed us to obtain a series of potent PIs. Following our structure-based design approach, we developed a high-affinity 3( R),3a( R),6a( R)-bis-tetrahydrofuranylurethane (bis-THF) ligand that maximizes hydrogen bonding and hyrophobic interactions in the protease S 2 subsite. Combination of this ligand with a range of different isosteres led to a series of exceedingly potent inhibitors. Darunavir, initially TMC-114, which combines the bis-THF ligand with a sulfonamide isostere, directly resulted from this line of research. This inhibitor displayed unprecedented enzyme inhibitory potency ( K i = 16 pM) and antiviral activity (IC 90 = 4.1 nM). Most importantly, it consistently retained is potency against highly drug-resistant HIV strains. Darunavir's IC 50 remained in the low nanomolar range against highly mutated HIV strains that displayed resistance to most available PIs. Our detailed crystal structure analyses of darunavir-bound protease complexes clearly demonstrated extensive hydrogen bonding between the inhibitor and the protease backbone. Most strikingly, these analyses provided ample evidence of the unique contribution of the bis-THF as a P 2-ligand. With numerous hydrogen bonds, bis-THF was shown to closely and tightly bind to the backbone atoms of the S 2 subsite of the protease. Such tight interactions were consistently observed with mutant proteases and might therefore account for the unusually high resistance profile of darunavir. Optimization attempts of the backbone binding in other subsites of the enzyme, through rational modifications of the isostere or tailor made P 2 ligands, led to equally impressive inhibitors with excellent resistance profiles. The concept of targeting the protein backbone in current structure-based drug design may offer a reliable strategy for combating drug resistance.

Fundamental properties of stars using asteroseismology from Kepler and CoRoT and interferometry from the CHARA Array

Abstract: We present results of a long-baseline interferometry campaign using the PAVO beam combiner at the CHARA Array to measure the angular sizes of five main-sequence stars, one subgiant and four red giant stars for which solar-like oscillations have been detected by either Kepler or CoRoT. By combining interferometric angular diameters, Hipparcos parallaxes, asteroseismic densities, bolometric fluxes, and high-resolution spectroscopy, we derive a full set of near-model-independent fundamental properties for the sample. We first use these properties to test asteroseismic scaling relations for the frequency of maximum power (?max) and the large frequency separation (??). We find excellent agreement within the observational uncertainties, and empirically show that simple estimates of asteroseismic radii for main-sequence stars are accurate to 4%. We furthermore find good agreement of our measured effective temperatures with spectroscopic and photometric estimates with mean deviations for stars between T eff = 4600-6200 K of ?22 ? 32 K (with a scatter of 97?K) and ?58 ? 31 K (with a scatter of 93?K), respectively. Finally, we present a first comparison with evolutionary models, and find differences between observed and theoretical properties for the metal-rich main-sequence star HD?173701. We conclude that the constraints presented in this study will have strong potential for testing stellar model physics, in particular when combined with detailed modeling of individual oscillation frequencies.