A quantum chemical study of the mechanism of action of Vitamin K epoxide reductase (VKOR) II. Transition states

A reaction path including transition states is generated for the Silverman mechanism [R.B. Silverman, Chemical model studies for the mechanism of Vitamin K epoxide reductase, J. Am. Chem. Soc. 103 (1981) 5939-5941] of action for Vitamin K epoxide reductase (VKOR) using quantum mechanical methods (B3LYP/6-311G**). VKOR, an essential enzyme in mammalian systems, acts to convert Vitamin K epoxide, formed by Vitamin K carboxylase, to its (initial) quinone form for cellular reuse. This study elaborates on a prior work that focused on the thermodynamics of VKOR [D.W. Deerfield II, C.H. Davis, T. Wymore, D.W. Stafford, L.G. Pedersen, Int. J. Quant. Chem. 106 (2006) 2944-2952]. The geometries of proposed model intermediates and transition states in the mechanism are energy optimized. We find that once a key disulfide bond is broken, the reaction proceeds largely downhill. An important step in the conversion of the epoxide back to the quinone form involves initial protonation of the epoxide oxygen. We find that the source of this proton is likely a free mercapto group rather than a water molecule. The results are consistent with the current view that the widely used drug Warfarin likely acts by blocking binding of Vitamin K at the VKOR active site and thereby effectively blocking the initiating step. These results will be useful for designing more complete QM/MM studies of the enzymatic pathway once three-dimensional structural data is determined and available for VKOR.     

Performance evaluation of a dental handpiece in simulation of clinical finishing using a novel 2DOF in vitro apparatus

This paper reports on the performance evaluation of a dental handpiece in simulation of clinical finishing using a novel two-degrees-of-freedom (2DOF) in vitro apparatus. The instrumented apparatus consisted of a two-dimensional computer-controlled coordinate worktable carrying a dental handpiece, a piezoelectric force dynamometer, and a high-speed data acquisition and signal conditioning system for simulating the clinical operations and monitoring the dental finishing processes. The performance of the dental handpiece was experimentally evaluated with respect to rotational speed, torque, and specific finishing energy under the applied clinical finishing conditions. The results show that the rotational speeds of the dental handpiece decreased by increasing either the depth of cut or the feed rate at a constant clinically applied air pressure and water flowrate. They also decreased when increasing both the tangential and normal finishing forces. The specific finishing energy decreased with an increase in either depth of cut or feed rate, while the finishing torque increased as either the depth of cut or the feed rate was increased. Implications of these results were to provide guidance for proper applications of dental handpieces in clinical practice.     

Prospective memory failures as an unexplored threat to patient safety: results from a pilot study using patient simulators to investigate the missed execution of intentions

This study investigated failures of prospective memory (PM) as a relevant but neglected error type in medicine. A patient simulator was used to investigate PM failures. The influence of subjective importance (high, low) and type of intention (educational, internal, external) on the (missed) execution of intention was investigated in a 2 x 2 design. The effects on missed executions by importance (high < low) and type of intention (educational < external < internal) were hypothesized. Of 73 valid intentions in 40 prepared simulator scenarios 19 (26%) were missed overall. A total of 64% of unimportant and 80% of important intentions were executed 79% of educational 67% of external and 72% of internal intentions were executed. Neither difference was statistically significant using chi(2) tests. Interaction was significant for missed executions (p = 0.025; n = 19; df = 2; chi(2) = 7.41) and for executions (p = 0.002; n = 54; df = 2; chi(2) = 12.50). Despite low statistical support and some methodological limitations, it was possible to show that PM failures are relevant to patient safety and that patient simulators are a suitable but so far unused tool for their investigation.     

Migration of human and mouse primordial germ cells and colonization of the developing ovary: an ultrastructural and cytochemical study

This review is an account of the origin and migratory events of primordial germ cells until their settlement in the gonad before sexual differentiation in the human as well as mice. In this context, the morphodynamic characteristics of the migration of the primordial germ cells, the macromolecular characteristics of the extracellular matrix of the migratory pathway, and the factors involved in the germ cell guidance have been analyzed and discussed in the light of recent advances in this field, by means of immunocytochemical procedures. The events prior to gonadal morphogenesis and the origin of the somatic cell content of the human gonadal primordium have been also analyzed. In particular, evidences are presented showing that cells derived from the coelomic epithelium and mesenchyme are at the origin of the somatic components of the gonadal primordium, and that a mesonephric cell contribution to the generation of somatic cell components of the genital ridge in humans should be discarded due to the morphological stability of the different nephric structures during the period preceding the sexual differentiation of the gonad.     

MCMC data association and sparse factorization updating for real time multitarget tracking with merged and multiple measurements

In several multitarget tracking applications, a target may return more than one measurement per target and interacting targets may return multiple merged measurements between targets. Existing algorithms for tracking and data association, initially applied to radar tracking, do not adequately address these types of measurements. Here, we introduce a probabilistic model for interacting targets that addresses both types of measurements simultaneously. We provide an algorithm for approximate inference in this model using a Markov chain Monte Carlo (MCMC)-based auxiliary variable particle filter. We Rao-Blackwellize the Markov chain to eliminate sampling over the continuous state space of the targets. A major contribution of this work is the use of sparse least squares updating and downdating techniques, which significantly reduce the computational cost per iteration of the Markov chain. Also, when combined with a simple heuristic, they enable the algorithm to correctly focus computation on interacting targets. We include experimental results on a challenging simulation sequence. We test the accuracy of the algorithm using two sensor modalities, video, and laser range data. We also show the algorithm exhibits real time performance on a conventional PC     

Oscillatory networks: pattern recognition without a superposition catastrophe

Using an oscillatory network model that combines classical network models with phase dynamics, we demonstrate how the superposition catastrophe of pattern recognition may be avoided in the context of phase models. The model is designed to meet two requirements: on and off states should correspond, respectively, to high and low phase velocities, and patterns should be retrieved in coherent mode. Nonoverlapping patterns can be simultaneously active with mutually different phases. For overlapping patterns, competition can be used to reduce coherence to a subset of patterns. The model thereby solves the superposition problem.