Remodelling of the natural product fumagillol employing a reaction discovery approach

In the search for new biologically active molecules, diversity-oriented synthetic strategies break through the limitation of traditional library synthesis by sampling new chemical space. Many natural products can be regarded as intriguing starting points for diversity-oriented synthesis, wherein stereochemically rich core structures may be reorganized into chemotypes that are distinctly different from the parent structure. Ideally, to be suited to library applications, such transformations should be general and involve few steps. With this objective in mind, the highly oxygenated natural product fumagillol has been successfully remodelled in several ways using a reaction-discovery-based approach. In reactions with amines, excellent regiocontrol in a bis-epoxide opening/cyclization sequence can be obtained by size-dependent interaction of an appropriate catalyst with the parent molecule, forming either perhydroisoindole or perhydroisoquinoline products. Perhydroisoindoles can be further remodelled by cascade processes to afford either morpholinone or bridged 4,1-benzoxazepine-containing structures.P50 GM067041 - NIGMS NIH HHS; P50 GM067041-07 - NIGMS NIH HHS; P50 GM067041-08 - NIGMS NIH HHS; P50 GM067041-09 - NIGMS NIH HH

The Peierls substitution in an engineered lattice potential

Artificial gauge fields open new possibilities to realize quantum many-body systems with ultracold atoms, by engineering Hamiltonians usually associated with electronic systems. In the presence of a periodic potential, artificial gauge fields may bring ultracold atoms closer to the quantum Hall regime. Here, we describe a one-dimensional lattice derived purely from effective Zeeman-shifts resulting from a combination of Raman coupling and radiofrequency magnetic fields. In this lattice, the tunneling matrix element is generally complex. We control both the amplitude and the phase of this tunneling parameter, experimentally realizing the Peierls substitution for ultracold neutral atoms.Comment: 6 pages, 5 figure

Combining polynomial chaos expansions and genetic algorithm for the coupling of electrophysiological models

The number of computational models in cardiac research has grown over the last decades. Every year new models with di erent assumptions appear in the literature dealing with di erences in interspecies cardiac properties. Generally, these new models update the physiological knowledge using new equations which reect better the molecular basis of process. New equations require the fi tting of parameters to previously known experimental data or even, in some cases, simulated data. This work studies and proposes a new method of parameter adjustment based on Polynomial Chaos and Genetic Algorithm to nd the best values for the parameters upon changes in the formulation of ionic channels. It minimizes the search space and the computational cost combining it with a Sensitivity Analysis. We use the analysis of di ferent models of L-type calcium channels to see that by reducing the number of parameters, the quality of the Genetic Algorithm dramatically improves. In addition, we test whether the use of the Polynomial Chaos Expansions improves the process of the Genetic Algorithm search. We conclude that it reduces the Genetic Algorithm execution in an order of 103 times in the case studied here, maintaining the quality of the results. We conclude that polynomial chaos expansions can improve and reduce the cost of parameter adjustment in the development of new models.Peer ReviewedPostprint (author's final draft

Identification of Acidic pH-Dependent Ligands of Pentameric C-reactive Protein

C-reactive protein (CRP) is a phylogenetically conserved protein; in humans, it is present in the plasma and at sites of inflammation. At physiological pH, native pentameric CRP exhibits calcium-dependent binding specificity for phosphocholine. In this study, we determined the binding specificities of CRP at acidic pH, a characteristic of inflammatory sites. We investigated the binding of fluid-phase CRP to six immobilized proteins: complement factor H, oxidized low-density lipoprotein, complement C3b, IgG, amyloid β, and BSA immobilized on microtiter plates. At pH 7.0, CRP did not bind to any of these proteins, but, at pH ranging from 5.2 to 4.6, CRP bound to all six proteins. Acidic pH did not monomerize CRP but modified the pentameric structure, as determined by gel filtration, 1-anilinonaphthalene-8-sulfonic acid-binding fluorescence, and phosphocholine-binding assays. Some modifications in CRP were reversible at pH 7.0, for example, the phosphocholine-binding activity of CRP, which was reduced at acidic pH, was restored after pH neutralization. For efficient binding of acidic pH-treated CRP to immobilized proteins, it was necessary that the immobilized proteins, except factor H, were also exposed to acidic pH. Because immobilization of proteins on microtiter plates and exposure of immobilized proteins to acidic pH alter the conformation of immobilized proteins, our findings suggest that conformationally altered proteins form a CRP-ligand in acidic environment, regardless of the identity of the protein. This ligand binding specificity of CRP in its acidic pH-induced pentameric state has implications for toxic conditions involving protein misfolding in acidic environments and favors the conservation of CRP throughout evolution

Resistance Training and Milk-Substitution Enhance Body Composition and Bone Health in Adolescent Girls

Background: Increased soft-drink consumption has contributed to poor calcium intake with 90% of adolescent girls consuming less than the RDA for calcium. Purpose/objectives: The purpose of this investigation was to determine the independent and additive effects of two interventions (milk and resistance training) on nutrient adequacy, body composition, and bone health in adolescent girls. Methods: The experimental design consisted of four experimental groups of adolescent girls 14–17 years of age: (1) Milk + resistance training [MRT]; n = 15; (2) Resistance training only [RT]; n = 15; (3) Milk only [M] n = 20; (4) Control [C] n = 16. A few significant differences were observed at baseline between the groups for subject characteristics. Testing was performed pre and post-12 week training period for all groups. Milk was provided (3, 8 oz servings) for both the MRT and the M groups. The MRT group and the RT groups performed a supervised periodized resistance training program consisting of supervised one-hour exercise sessions 3 d/wk (M, W, F) for 12 wk. Baseline dietary data was collected utilizing the NUT-P-FFQ and/or a 120 item FFQ developed by the Fred Hutchinson Cancer Research Center (Seattle, Washington). Body composition was measured in the morning after an overnight fast using dual-energy X-ray absorptiometry (DXA) with a total body scanner (ProdigyTM, Lunar Corporation, Madison, WI). A whole body scan for bone density and lumbar spine scans were performed on all subjects. Maximal strength of the upper and lower body was assessed via a one-repetition maximum (1-RM) squat and bench press exercise protocols. Significance was set at P ≤ 0.05. Results: Significant differences in nutrient intakes between groups generally reflected the nutrient composition of milk with greater intakes of protein and improved nutrient adequacy for several B vitamins, vitamin A, vitamin D, calcium, magnesium, phosphorus, potassium, and zinc. Mean calcium intake was 758 and 1581 mg/d, in the non-milk and milk groups, respectively, with 100% of girls in the milk groups consuming \u3e RDA of 1300 mg/d. There were no effects of milk on body composition or muscle performance, but resistance training had a main effect and significantly increased body mass, lean body mass, muscle strength, and muscle endurance. There was a main effect of milk and resistance training on several measures of bone mineral density (BMD). Changes in whole body BMD in the M, RT, MRT, and CON were 0.45, 0.52, 1.32, and −0.19%, respectively (P \u3c 0.01). Conclusions: Over the course of 12 weeks the effects of 1300 mg/d of calcium in the form of fluid milk combined with a heavy resistance training program resulted in the additive effects of greater nutrient adequacy and BMD in adolescent girls. While further studies are needed, combining increased milk consumption with resistance training appears to optimize bone health in adolescent girls