Uranium Mine Proposed Experimental Design for Natural Background Gross Gamma Exposure Rates, Post Remediation Final Status Survey Sampling Density, and Radiological Water Quality Modeling for a Worst-case Catastrophic Failure, Coles Hill, Virginia.

ABSTRACT: Completely randomized experimental design statistical modeling techniques were employed to analyze exposure rate measurements for evaluating hypothetical natural background post uranium mill operations at Coles Hill, Virginia uranium milling processes. The proposed Coles Hill Uranium Mine is situated upstream of the Banister River. This River is nearly homogenous throughout the reach length used in analysis and feeds into the mouth of Kerr Reservoir, Lake Gaston, which serves as the main drinking water source for cities in the Hampton Roads area including Norfolk, Virginia Beach, and Chesapeake. A critical scan value (=DCGLscan) was developed to flag anomalies of surface contamination during simulated post remediation final status surveys. The natural background was critical for meeting the Multi-Agency Radiation Survey and Site Investigation Manual guidance for post remediation final status surveys. The overarching null hypothesis suggested that the selected mean natural background is equal to the survey unit's mean natural background. Using SAS Procedures Shapiro-Wilk Test, ANOVA, and CR, it was decided the exposure rate data was normal, had no extreme outliers, and no collinearity between the number of samples (=treatment) and the areas (=block). Using the q-hyper (hypergeometric) distribution, the soil sampling density was decided for a final status survey unit. The most likely worst-case catastrophic failure analysis, 500-year event, such as the1969 Hurricane Camille of 69 centimeters of rain in Nelson County, Virginia was included in the model. The model showed impact was minimal at most to the Banister River's drinking water and likely less than the Virginia's Drinking Water Standards for gross alpha, 226Ra and 228Ra, and total uranium.

Identification of two HIV inhibitors that also inhibit human RNaseH2.

A total of 140,000 compounds were screened in a targetfree cell-based high throughput assay against HIV-1 infection, and a subset of 81 promising compounds was identified. Secondary screening of these 81 compounds revealed two putative human RNaseH2 inhibitors, RHI001 and RHI002, with IC50 value of 6.8 µM and 16 µM, respectively. RHI002 showed selective activity against human RNaseH2 while RHI001 inhibited HIV-RNaseH, E. coli RNaseH, and human RNaseH1 with IC50 value of 28.5 µM, 7.9 µM, and 31.7 µM, respectively. Kinetic analysis revealed that both inhibitors had non-competitive inhibitor-like properties. Because RNaseH2 is involved in the etiology of Aicardi-Goutier syndrome and has been suggested as an anticancer drug target, small molecule inhibitors modulating its activity would be useful for investigating the cellular function of this molecule.

A novel 3,4-dihydropyrimidin-2(1H)-one: HIV-1 replication inhibitors with improved metabolic stability.

Following the previous SAR of a novel dihydropyrimidinone scaffold as HIV-1 replication inhibitors a detailed study directed towards optimizing the metabolic stability of the ester functional group in the dihydropyrimidinone (DHPM) scaffold is described. Replacement of the ester moiety by thiazole ring significantly improved the metabolic stability while retaining antiviral activity against HIV-1 replication. These novel and potent DHPMs with bioisosteres could serve as advanced leads for further optimization.

Discovery of Phenylaminopyridine Derivatives as Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors.

We identified a novel class of aryl-substituted triazine compounds as potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) during a high-throughput screening campaign that evaluated more than 200000 compounds for antihuman immunodeficiency virus (HIV) activity using a cell-based full replication assay. Herein, we disclose the optimization of the antiviral activity in a cell-based assay system leading to the discovery of compound 27, which possessed excellent potency against wild-type HIV-1 (EC50 = 0.2 nM) as well as viruses bearing Y181C and K103N resistance mutations in the reverse transcriptase gene. The X-ray crystal structure of compound 27 complexed with wild-type reverse transcriptase confirmed the mode of action of this novel class of NNRTIs. Introduction of a chloro functional group in the pyrazole moiety dramatically improved hERG and CYP inhibition profiles, yielding highly promising leads for further development.