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The authors contribute to the existing literature on the determinants of legislative voting by offering a social network-based theory about the ways that legislators’ social relationships affect floor voting behaviour. It is argued that legislators establish contacts with both political friends and enemies, and that they use the information they receive from these contacts to increase their confidence in their own policy positions. Social contacts between political allies have greater value the more the two allies agree on policy issues, while social contacts between political adversaries have greater value the more the two adversaries disagree on policy issues. To test these propositions, we use social network analysis tools and demonstrate how to account for network dependence using a multilevel modelling approach.
Our goal in producing this book is to provide a broad overview of the most important approaches used in protein- and ligand-structure-based drug design. Beyond this we aim to illustrate how these approaches are currently being applied in drug discovery efforts. We hope this book will be a useful resource to practitioners in the field, as well as a good introduction for researchers or students who are new to the field. We believe it provides a snapshot of the most important trends and capabilities in the application of modeling and structural data in drug discovery.
Since the 1990s the role of structure and modeling in drug discovery has grown enormously. There have been remarkable scientific advances in both the experimental and computational fields that are the underpinnings of modern drug design. For example, x-ray capabilities have improved to the point that protein structures are now routinely available for a wide range of protein targets. One only need look at the exponential growth of the Protein Databank (RCSB) for evidence. Tremendous strides have been made in all aspects of protein structure determination, including crystallization, data acquisition, and structure refinement. Modeling has made similar gains. Recent years have brought more realistic force fields, new and more robust free-energy methods, computational models for absorption/distribution/metabolism/excretion (ADME)-toxicity, faster and better docking algorithms, automated 3D pharmacophore detection and searching, and very-large-scale quantum calculations.
Structure-based (SBDD) and ligand-based (LBDD) drug design are extremely important and active areas of research in both the academic and commercial realms. This book provides a complete snapshot of the field of computer-aided drug design and associated experimental approaches. Topics covered include X-ray crystallography, NMR, fragment-based drug design, free energy methods, docking and scoring, linear-scaling quantum calculations, QSAR, pharmacophore methods, computational ADME-Tox, and drug discovery case studies. A variety of authors from academic and commercial institutions all over the world have contributed to this book, which is illustrated with more than 200 images. This is the only book to cover the subject of structure and ligand-based drug design, and it provides the most up-to-date information on a wide range of topics for the practising computational chemist, medicinal chemist, or structural biologist. Professor Kenneth Merz has been selected as the recipient of the 2010 ACS Award for Computers in Chemical & Pharmaceutical Research that recognizes the advances he has made in the use of quantum mechanics to solve biological and drug discovery problems.
Novel material structures that combine magneto-optic (MO) and semiconductor devices have potential applications in monolithic microwave systems and optoelectronics. We have investigated the materials issues pertaining to the film structure, interface uniformity, and magnetic/MO properties of (BiDy)3(FeGa)5O12 (Bi-DyIG) thin films sputter deposited on Si and GaAs. The rapid thermally annealed films were polycrystalline with a nominal grain size of 20 nm. The magnetic and MO properties were strongly dependent on the type of substrate such that square hysteresis loops and coercivities of 0.1 to 0.9 kOe were observed for Bi-DyIG/Si structures while Bi-DyIG/GaAs structures showed much lower coercivity values (0.03 kOe). A comparison of the magnetic properties, microstructure and substrate composition was carried out with plan-view and cross-section transmission electron microscopy, as well as electron and x-ray diffraction. The results suggest that grain orientation effects, stress, and compositional inhomogeneity due to interfacial reactions or diffusion introduced by the substrate strongly influence the magnetic and MO properties of the films.
This study investigated biological correlates of depression in patients with idiopathic Parkinson's disease (PD). We tested the hypothesis that in patients with PD and depression, there was regional dysfunction involving brain areas previously implicated in functional imaging studies of patients with primary depression.
Using positron emission tomographic measurements of regional cerebral blood flow (rCBF), patterns of resting rCBF were measured in ten patiens with PD and major depression, and ten patients with PD alone. The results were compared with findings from ten patients with primary depression and ten normal controls, scanned using identical methods as part of an earlier study. Groups were matched for age, sex and symptom severity.
Bilateral decreases in rCBF were observed in anteromedial regions of the medial frontal cortex and the cingulate cortex (Brodmann's areas (BA) 9 and 32) in the depressed PD group, compared with those with PD alone and compared with normal controls. This regional disturbance overlapped that observed in patients with primary depression.
The findings indicate that the medial prefrontal cortex is a common area of neural dysfunction in the manifestation of both primary depression and depression in PD.
We describe the existence of the savant syndrome in association with Gilles de la Tourette's Syndrome (GTS). The presentation of savant abilities is typical of that previously described. Similarities between autism, the disorder most characteristically associated with savants, and GTS in terms of obsessionality are noted. Previously reported psychological studies of autistic savants are briefly reviewed and, together with evidence from neuroimaging in GTS, obsessive compulsive disorder (OCD), and autism, used to support a model of the underpinnings of savant skills.
Rapid tranquillisation – giving a psychotropic to control behavioural disturbances – is common in medical practice, yet few surveys describe its use in psychiatric populations. Over five months, 102 incidents, involving 60 patients, were retrospectively surveyed. Patients most often involved were young white men. The commonest diagnosis was affective disorder (manic phase) (39%) followed by schizophrenia (33%). Fifteen patients were involved in 57% of the incidents. The majority of incidents involved injury to people or damage to property. The most frequently used drugs were diazepam and haloperidol, alone or in combination. Droperidol, chlorpromazine, sodium amytal and paraldehyde were rarely used. Diazepam alone or in combination with haloperidol delivered intravenously was most rapidly effective and was associated with greatest staff satisfaction. Serious side-effects were rare.
Monodisperse and spherical titania powders were prepared by the hydrolysis of titanium tetraethoxide in ethanol with hydroxy-propyl cellulose(HPC) present during particle precipitation. The mean particle size decreased as the concentration of tLPC increased. The critical concentration of HPC for the in situ stabilization of titania powder suspensions was determined by a photographic method, and found to be independent of the molecular weight of HPC within the molecular range of 60,000 to 300,000. The amount of HPC adsorbed on the particle surface, determined by a colorimetric method using a UV-visible spectrophotometer, decreased with the increasing molecular weight of HPC. Suspension stability was confirmed by theoretical calculations based on experimental results.
The volatile products from the thermal reaction (414°C) of silane in excess acetylene are hydrogen, ethylene, vinylsilane, ethynylsilane, vinylethynylsilane (possibly divinylsilane) and ethynyl-divinylsilane (1,2). We have reexamined this reaction using a 3 C2 H2/1 SiH4 reaction mixture and have obtained product yield curves for these products versus percent silane loss. We have also found that product curves are unaffected when propylene at pressures equal to that of acetylene is also present. Since only trace quantities of propylsilane are produced in the presence of propylene, we can rule out reactions involving silyl radicals. Thus the SiH4−C2H2 reaction involves silylene and silene intermediates. The products can be explained by a mechanism similar to one proposed by Barton and Burns (3).