Employing Modular Polyketide Synthase Ketoreductases as Biocatalysts in the Preparative Chemoenzymatic Syntheses of Diketide Chiral Building Blocks

SummaryChiral building blocks are valuable intermediates in the syntheses of natural products and pharmaceuticals. A scalable chemoenzymatic route to chiral diketides has been developed that includes the general synthesis of α-substituted, β-ketoacyl N-acetylcysteamine thioesters followed by a biocatalytic cycle in which a glucose-fueled NADPH-regeneration system drives reductions catalyzed by isolated modular polyketide synthase (PKS) ketoreductases (KRs). To identify KRs that operate as active, stereospecific biocatalysts, 11 isolated KRs were incubated with 5 diketides and their products were analyzed by chiral chromatography. KRs that naturally reduce small polyketide intermediates were the most active and stereospecific toward the panel of diketides. Several biocatalytic reactions were scaled up to yield more than 100 mg of product. These syntheses demonstrate the ability of PKS enzymes to economically and greenly generate diverse chiral building blocks on a preparative scale

The Grizzly, November 14, 1980

Campus Life Committee Discusses Greek Societies • McDonald\u27s Opening Soon • Field Hockey Heading For Nationals • Frats Get Together for Clean-up • Ursinus News In Brief: Honors for Ursinus faculty member; College presents Rafferty art exhibit • Policy Unveiled for Gym • Elephant Man Seen As Statement On Human Behavior • Talented Student Performances • ProTheatre Opens • Aging Is Topic At College Forum • Coffeehouse Sings The Right Tune • En Garde, Ursinus! • Delta Pi Defeats Marines In Football • Disappointing Weekend For Volleyball • Harriers Take MAC Title • Demas, Rho To Meet In Hockey Finals • Grizzlies Win Behind Solid Offense Efforthttps://digitalcommons.ursinus.edu/grizzlynews/1047/thumbnail.jp

Considering the Influence of Coronary Motion on Artery‑Specific Biomechanics Using Fluid–Structure Interaction Simulation

The endothelium in the coronary arteries is subject to wall shear stress and vessel wall strain, which influences the biology of the arterial wall. This study presents vessel-specific fluid–structure interaction (FSI) models of three coronary arteries, using directly measured experimental geometries and boundary conditions. FSI models are used to provide a more physiologically complete representation of vessel biomechanics, and have been extended to include coronary bending to investigate its effect on shear and strain. FSI both without- and with-bending resulted in significant changes in all computed shear stress metrics compared to CFD (p = 0.0001). Inclusion of bending within the FSI model produced highly significant changes in Time Averaged Wall Shear Stress (TAWSS) + 9.8% LAD, + 8.8% LCx, − 2.0% RCA; Oscillatory Shear Index (OSI) + 208% LAD, 0% LCx, + 2600% RCA; and transverse wall Shear Stress (tSS) + 180% LAD, + 150% LCx and + 200% RCA (all p \u3c 0.0001). Vessel wall strain was homogenous in all directions without-bending but became highly anisotropic under bending. Changes in median cyclic strain magnitude were seen for all three vessels in every direction. Changes shown in the magnitude and distribution of shear stress and wall strain suggest that bending should be considered on a vessel-specific basis in analyses of coronary artery biomechanics

Determination of freedom-from-rabies for small Indian mongoose populations in the United States Virgin Islands, 2019–2020

Mongooses, a nonnative species, are a known reservoir of rabies virus in the Caribbean region. A cross-sectional study of mongooses at 41 field sites on the US Virgin Islands of St. Croix, St. John, and St. Thomas captured 312 mongooses (32% capture rate). We determined the absence of rabies virus by antigen testing and rabies virus exposure by antibody testing in mongoose populations on all three islands. USVI is the first Caribbean state to determine freedom-from-rabies for its mongoose populations with a scientifically-led robust cross-sectional study. Ongoing surveillance activities will determine if other domestic and wildlife populations in USVI are rabies-free

Insights on uranium uptake mechanisms by ion exchange resins with chelating functionalities: Chelation vs. anion exchange

X-ray absorption fine structure analysis has been successfully used to determine the coordination environment and therefore uptake mechanism towards the uranyl cation for a selection of commercially available ion exchange resins in non-saline and saline conditions ([Cl−] = 22.7 g L−1, 0.64 M) similar to those found in sea water. The resins tested were Purolite S985, S910 and S957, Dowex M4195, Ps-EDA, Ps-DETA and Ps-PEHA, which contain polyamine, amidoxime, mixed sulfonic/phosphonic acid, bispicolylamine, ethylenediamine, diethylenetriamine and pentaethylenehexamine functional groups, respectively. Purolite S910 and S957 were both found to extract the uranyl cation through a chelation mechanism. The uranium coordination environment on uranyl loaded Purolite S910 was found to be either tetra- or hexa-coordinate in the equatorial plane, with a 2:1 ratio of amidoxime:uranium in the fit suggesting either monodentate or η2 coordination by two amidoxime groups. The uranium environment for uranyl loaded Purolite S957 was found to be tetra-coordinate in the equatorial plane, with both sulfonic and phosphonic acid groups being involved in sorption. The presence of chloride in the loading solution had no effect on the uranyl coordination environment observed on any of the resins. In contrast, Dowex M4195, Purolite S985, Ps-EDA, Ps-DETA and Ps-PEHA exhibited an anion exchange mechanism for uranyl uptake as the corresponding extended X-ray absorption fine structure (EXAFS) data best fit a [UO2(SO4)3]4− structure

The effect of contaminants on the application of polyamine functionalised ion exchange resins for uranium extraction from sulfate based mining process waters

Three in-house produced polyamine functionalised ion exchange resins and Purolite S985 (a commercial ion exchange resin) have been assessed for their ability to extract UO22+ from a variety of aqueous matrices applicable to current and potential future uranium mining processes. The uptake of common contaminant species in uranium processing liquors at variable acid concentrations has been assessed, with Al3+ and MoO42− showing the most extraction, with AsO43−, Eu3+ and Fe3+ showing extractions >10% at low [H+]. Extraction of MoO42−, AsO43−, Eu3+ and Fe3+ was seen to decrease with increasing [H+]. The impact of increasing [Cl−] on UO22+ and Fe3+ extraction has been determined. Fe3+ showed low extractions by all resins, with no dependence on [Cl−]. In contrast, increasing suppression of UO22+ uptake was seen with increasing [Cl−] up to 80 g L−1, with extraction remaining constant beyond this [Cl−]. At high [Cl−] (>50 g L−1) Purolite S985 was seen to remove UO22+ from solution more effectively than all synthesised polyamine resins. The presence of Fe3+ in solution was seen to suppress UO22+ uptake by around 10% when [Fe3+]/[UO22+] increased from 0 to 2. Fe3+ extraction by all studied resins was promoted by the presence of UO22+ in solution. This was most prevalent with Purolite S985, with an extraction of 30% for [Fe3+]/[UO22+] = 2 by Purolite S985. All resins were tested using a process water from a uranium mine and have shown an ability to selectively extract UO22+ from such solutions, with the best synthetic resin recovering 15.7% more uranium than Purolite S985

Whole-Genome Sequencing Uncovers Two Loci for Coronary Artery Calcification and Identifies Arse as a Regulator of Vascular Calcification

Coronary artery calcification (CAC) is a measure of atherosclerosis and a well-established predictor of coronary artery disease (CAD) events. Here we describe a genome-wide association study (GWAS) of CAC in 22,400 participants from multiple ancestral groups. We confirmed associations with four known loci and identified two additional loci associated with CAC (ARSE and MMP16), with evidence of significant associations in replication analyses for both novel loci. Functional assays of ARSE and MMP16 in human vascular smooth muscle cells (VSMCs) demonstrate that ARSE is a promoter of VSMC calcification and VSMC phenotype switching from a contractile to a calcifying or osteogenic phenotype. Furthermore, we show that the association of variants near ARSE with reduced CAC is likely explained by reduced ARSE expression with the G allele of enhancer variant rs5982944. Our study highlights ARSE as an important contributor to atherosclerotic vascular calcification, and a potential drug target for vascular calcific disease

Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci

Introduction: Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. Methods: A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: “Some College” (yes/no, for any education beyond high school) and “Graduated College” (yes/no, for completing a 4-year college degree). Genome-wide significant (p &lt; 5 × 10−8) and suggestive (p &lt; 1 × 10−6) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals). Results: In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (FOXP1, MBOAT4, SKP2, STIM1, STX4), brain (BRI3, FILIP1, FOXP1, LINC00290, LMTK2, MBOAT4, MYO6, SENP6, SRGAP3, STIM1, TMEM167A, TMEM30A), and liver (BRI3, FOXP1) biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue. Discussion: Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.</p