Evidence Favoring Molybdenum−Carbon Bond Formation in Xanthine Oxidase Action: \u3csup\u3e17\u3c/sup\u3eO- and \u3csup\u3e13\u3c/sup\u3eC-ENDOR and Kinetic Studies

The reaction mechanism of the molybdoenzyme xanthine oxidase has been further investigated by 13C and 17O ENDOR of molybdenum(V) species and by kinetic studies of exchange of oxygen isotopes. Three EPR signal-giving species were studied:  (i) Very Rapid, a transient intermediate in substrate turnover, (ii) Inhibited, the product of an inhibitory side reaction with aldehyde substrates, and (iii) Alloxanthine, a species formed by reaction of reduced enzyme with the inhibitor, alloxanthine. The Very Rapid signal was developed either with [8-13C]xanthine or with 2-oxo-6-methylpurine using enzyme equilibrated with [17O]H2O. The Inhibited signal was developed with 2H13C2HO and the Alloxanthine signal by using [17O]H2O. Estimates of Mo−C distances were made, from the anisotropic components of the 13C-couplings, by corrected dipolar coupling calculations and by back-calculation from assumed possible structures. Estimated distances in the Inhibited and Very Rapid species were about 1.9 and less than 2.4 Å, respectively. A Mo−C bond in the Inhibited species is very strongly suggested, presumably associated with side-on bonding to molybdenum of the carbonyl of the aldehyde substrate. For the Very Rapid species, a Mo−C bond is highly likely. Coupling from a strongly coupled 17O, not in the form of an oxo group, and no coupling from other oxygens was detected in the Very Rapid species. No coupled oxygens were detected in the Alloxanthine species. That the coupled oxygen of the Very Rapid species is the one that appears in the product uric acid molecule was confirmed by new kinetic data. It is concluded that this oxygen of the Very Rapid species does not, as frequently assumed, originate from the oxo group of the oxidized enzyme. A new turnover mechanism is proposed, not involving direct participation of the oxo ligand group, and based on that of Coucouvanis et al. [Coucouvanis, D., Toupadakis, A., Lane, J. D., Koo, S. M., Kim, C. G., Hadjikyriacou, A. (1991) J. Am. Chem. Soc. 113, 5271−5282]. It involves formal addition of the elements of the substrate (e.g., xanthine) across the MoS double bond, to give a Mo(VI) species. This is followed by attack of a “buried” water molecule (in the vicinity of molybdenum and perhaps a ligand of it) on the bound substrate carbon, to give an intermediate that on intramolecular one-electron oxidation gives the Very Rapid species. The latter, in keeping with the 13C, 17O, and 33S couplings, is presumed to have the 8-CO group of the uric acid product molecule bonded side-on to molybdenum, with the sulfido molybdenum ligand retained, as in the oxidized enzyme

Phase ordering in bulk uniaxial nematic liquid crystals

The phase-ordering kinetics of a bulk uniaxial nematic liquid crystal is addressed using techniques that have been successfully applied to describe ordering in the O(n) model. The method involves constructing an appropriate mapping between the order-parameter tensor and a Gaussian auxiliary field. The mapping accounts both for the geometry of the director about the dominant charge 1/2 string defects and biaxiality near the string cores. At late-times t following a quench, there exists a scaling regime where the bulk nematic liquid crystal and the three-dimensional O(2) model are found to be isomorphic, within the Gaussian approximation. As a consequence, the scaling function for order-parameter correlations in the nematic liquid crystal is exactly that of the O(2) model, and the length characteristic of the strings grows as $t^{1/2}$. These results are in accord with experiment and simulation. Related models dealing with thin films and monopole defects in the bulk are presented and discussed.Comment: 21 pages, 3 figures, REVTeX, submitted to Phys. Rev.

Phase-ordering dynamics of the Gay-Berne nematic liquid crystal

Phase-ordering dynamics in nematic liquid crystals has been the subject of much active investigation in recent years in theory, experiments and simulations. With a rapid quench from the isotropic to nematic phase a large number of topological defects are formed and dominate the subsequent equilibration process. We present here the results of a molecular dynamics simulation of the Gay-Berne model of liquid crystals after such a quench in a system with 65536 molecules. Twist disclination lines as well as type-1 lines and monopoles were observed. Evidence of dynamical scaling was found in the behavior of the spatial correlation function and the density of disclination lines. However, the behavior of the structure factor provides a more sensitive measure of scaling, and we observed a crossover from a defect dominated regime at small values of the wavevector to a thermal fluctuation dominated regime at large wavevector.Comment: 18 pages, 16 figures, animations available at http://www.physics.brown.edu/Users/faculty/pelcovits/lc/coarsening.htm

Phase diagram of a Heisenberg spin-Peierls model with quantum phonons

Using a new version of the density-matrix renormalization group we determine the phase diagram of a model of an antiferromagnetic Heisenberg spin chain where the spins interact with quantum phonons. A quantum phase transition from a gapless spin-fluid state to a gapped dimerized phase occurs at a non-zero value of the spin-phonon coupling. The transition is in the same universality class as that of a frustrated spin chain, which the model maps to in the anti-adiabatic limit. We argue that realistic modeling of known spin-Peierls materials should include the effects of quantum phonons.Comment: RevTeX, 5 pages, 3 eps figures included using epsf. Improved theories in adiabatic and non-adiabatic regimes give better agreement with DMRG. This version accepted in Physical Review Letter

Aging and Holography

Aging phenomena are examples of `non-equilibrium criticality' and can be exemplified by systems with Galilean and scaling symmetries but no time translation invariance. We realize aging holographically using a deformation of a non-relativistic version of gauge/gravity duality. Correlation functions of scalar operators are computed using holographic real-time techniques, and agree with field theory expectations. At least in this setup, general aging phenomena are reproduced holographically by complexifying the bulk space-time geometry, even in Lorentzian signature.Comment: 1 pdf figur

Usefulness of baseline lipids and C-reactive protein in women receiving menopausal hormone therapy as predictors of treatment-related coronary events.

Blood lipids and high-sensitivity C-reactive protein (hs-CRP) are altered by hormone therapy. The goal of the present study was to determine whether lipids and hs-CRP have predictive value for hormone therapy benefit or risk for coronary heart disease events in postmenopausal women without previous cardiovascular disease. A nested case-control study was performed in the Women\u27s Health Initiative hormone trials. Baseline lipids and hs-CRP were obtained from 271 incident patients with coronary heart disease (cases) and 707 controls. In a combined trial analysis, favorable lipid status at baseline tended to predict better coronary heart disease outcomes when using conjugated equine estrogen (CEE) with or without medroxyprogesterone acetate (MPA). Women with a low-density lipoprotein (LDL)/high-density lipoprotein (HDL) cholesterol ratioor =2.5 had increased risk of coronary heart disease (odds ratio 1.73, 95% confidence interval 1.18 to 2.53, p for interaction = 0.02). Low hs-CRP added marginally to the value of LDL/HDL rati

Cost-effectiveness of stent-retriever thrombectomy in combination with IV t-PA compared with IV t-PA alone for acute ischemic stroke in the UK.

Objective: To evaluate the cost-effectiveness of neurothrombectomy with a stent retriever (Solitaire**Solitaire Revascularization Device is a registered trademark of Medtronic (Irvine, CA). View all notes Revascularization Device) in treating acute ischemic stroke patients from the UK healthcare provider perspective. Methods: A Markov model was developed to simulate health outcomes and costs of two therapies over a lifetime time horizon: stent-retriever thrombectomy in combination with intravenous tissue-type plasminogen activator (IV t-PA), and IV t-PA alone. The model incorporated an acute phase (0–90 days) and a rest of life phase (90+ days). Health states were defined by the modified Rankin Scale score. During the rest of life phase, patients remained in the same health state until a recurrent stroke or death. Clinical effectiveness and safety data were taken from the SWIFT PRIME study. Resource use and health state utilities were informed by published data. Results: Combined stent-retriever thrombectomy and IV t-PA led to improved quality-of-life and increased life expectancy compared to IV t-PA alone. The higher treatment costs associated with the use of stent-retriever thrombectomy were offset by long-term cost savings due to improved patient health status, leading to overall cost savings of £33 190 per patient and a net benefit of £79 402. Deterministic and probabilistic sensitivity analyses demonstrated that the results were robust to a wide range of parameter inputs. Limitations: The acute and long-term costs resource use data were taken from a study based on a patient population that was older and may have had additional comorbidities than the SWIFT PRIME population, resulting in costs that may not be representative of the cohort within this model. In addition, the estimates may not reflect stroke care today as no current evidence is available; however, the cost estimates were deemed reasonable by clinical opinion. Conclusions: Combined stent-retriever neurothrombectomy and IV t-PA is a cost-effective treatment for acute ischemic stroke compared with IV t-PA alone