PocketMatch: A new algorithm to compare binding sites in protein structures

Recognizing similarities and deriving relationships among protein molecules is a fundamental requirement in present-day biology. Similarities can be present at various levels which can be detected through comparison of protein sequences or their structural folds. In some cases similarities obscure at these levels could be present merely in the substructures at their binding sites. Inferring functional similarities between protein molecules by comparing their binding sites is still largely exploratory and not as yet a routine protocol. One of the main reasons for this is the limitation in the choice of appropriate analytical tools that can compare binding sites with high sensitivity. To benefit from the enormous amount of structural data that is being rapidly accumulated, it is essential to have high throughput tools that enable large scale binding site comparison. Results: Here we present a new algorithm PocketMatch for comparison of binding sites in a frame invariant manner. Each binding site is represented by 90 lists of sorted distances capturing shape and chemical nature of the site. The sorted arrays are then aligned using an incremental alignment method and scored to obtain PMScores for pairs of sites. A comprehensive sensitivity analysis and an extensive validation of the algorithm have been carried out. A comparison with other site matching algorithms is also presented. Perturbation studies where the geometry of a given site was retained but the residue types were changed randomly, indicated that chance similarities were virtually non-existent. Our analysis also demonstrates that shape information alone is insufficient to discriminate between diverse binding sites, unless combined with chemical nature of amino acids. Conclusion: A new algorithm has been developed to compare binding sites in accurate, efficient and high-throughput manner. Though the representation used is conceptually simplistic, we demonstrate that along with the new alignment strategy used, it is sufficient to enable binding comparison with high sensitivity. Novel methodology has also been presented for validating the algorithm for accuracy and sensitivity with respect to geometry and chemical nature of the site. The method is also fast and takes about 1/250(th) second for one comparison on a single processor. A parallel version on BlueGene has also been implemented.

Maximal regularity for second order non-autonomous Cauchy problems

We consider some non-autonomous second order Cauchy problems of the form u + B(t)(u) over dot + A(t)u = f (t is an element of [0, T]), u(0) = (u) over dot(0) = 0. We assume that the first order problem (u) over dot + B(t)u = f (t is an element of [0, T]), u(0) = 0, has L-p-maximal regularity. Then we establish L-p-maximal regularity of the second order problem in situations when the domains of B(t(1)) and A(t(2)) always coincide, or when A(t) = kappa B(t).

Probing the Neutral Edge Modes in Transport across a Point Contact via Thermal Effects in the Read-Rezayi Non-Abelian Quantum Hall States

Non-Abelian quantum Hall states are characterized by the simultaneous appearance of charge and neutral gapless edge modes, with the structure of the latter being intricately related to the existence of bulk quasiparticle excitations obeying non-Abelian statistics. Here we propose a scenario for detecting the neutral modes by having two point contacts in series separated by a distance set by the thermal equilibration length of the charge mode. We show that by using the first point contact as a heating device, the excess charge noise measured at the second point contact carries a nontrivial signature of the presence of the neutral mode. We also obtain explicit expressions for the thermal conductance and corresponding Lorentz number for transport across a quantum point contact between two edges held at different temperatures and chemical potentials.

Collision-Geometry-Based Pulsed Guidance Law for Exoatmospheric Interception

No abstract is available.

A follow up MRI-based geometry and computational fluid dynamics study of carotid bifurcation

Cardiovascular disease is the leading causes of death in the developed world. Wall shear stress (WSS) is associated with the initiation and progression of atherogenesis. This study combined the recent advances in MR imaging and computational fluid dynamics (CFD) and evaluated the patient-specific carotid bifurcation. The patient was followed up for 3 years. The geometry changes (tortuosity, curvature, ICA/CCA area ratios, central to the cross-sectional curvature, maximum stenosis) and the CFD factors (Velocity distribute, Wall Shear Stress (WSS) and Oscillatory Shear Index (OSI)) were compared at different time points.The carotid stenosis was a slight increase in the central to the cross-sectional curvature, and it was minor and variable curvature changes for carotid centerline. The OSI distribution presents ahigh-values in the same region where carotid stenosis and normal border, indicating complex flow and recirculation.The significant geometric changes observed during the follow-up may also cause significant changes in bifurcation hemodynamics.

MRI-based fatigue analysis predicts plaque vulnerability: A study comparing symptomatic and asymptomatic individuals

BACKGROUND: Rupture of atheromatous plaque in the carotid artery often leads to thrombosis and subsequent stroke. The mechanism of plaque rupture is not entirely clear but is thought to be a multi-factorial process involving thinning and weakening of the fibrous cap and biomechanical stress as the trigger leading to plaque rupture. As the cardiovascular system is a classic fatigue environment, the weakening of plaque leading to rupture may be a fatigue process, which is a symptomatically quiescent but potentially progressive failure process. In this study, we used a fatigue analysis based on in vivo magnetic resonance imaging (MRI) to investigate the rupture initiation location, crack propagation path and fatigue life within plaques of asymptomatic and symptomatic individuals. METHODS: Forty non-consecutive subjects (20 symptomatic and 20 asymptomatic) underwent high-resolution multi-sequence in vivo MRI of the carotid bifurcation. Fatigue analysis was performed based on the plaque geometry derived from in vivo MRI of the carotid artery at the point of maximum stenosis. Paris’ Law in fracture mechanics is adopted to determine the fatigue crack growth rate. Incremental crack propagation was dynamically simulated based on stress distributions. Plaque initiation location, crack propagation path and fatigue cycle of symptomatic and asymptomatic individuals were compared. RESULTS: Cracks were often found to begin at the lumen wall at areas of stress concentration. The preferred rupture direction was radial from the lumen center. The crack initially advanced slowly but accelerated as it developed, depending on plaque morphology. The fatigue cycles of symptomatic plaques were significantly less than those in the asymptomatic group (2.3 ± 0.9 vs 3.1 ± 0.7 (x106); p = 0.003). CONCLUSIONS: The number of cycles to rupture in symptomatic patients was higher than those predicted in asymptomatic patients by fatigue analysis, suggesting the possibility that plaques with a less fatigue life may be more prone to be symptomatic and rupture. If further validated by large-scale longitudinal studies, fatigue analysis based on high resolution in vivo MRI could potentially act as a useful tool for risk assessment of carotid atheroma.

Utility of magnetic resonance imaging-based finite element analysis for the biomechanical stress analysis of hemorrhagic and non-hemorrhagic carotid plaques

Background: Biomechanical stress analysis has been used for plaque vulnerability assessment. The presence of plaque hemorrhage (PH) is a feature of plaque vulnerability and is associated with thromboembolic ischemic events. The purpose of the present study was to use finite element analysis (FEA) to compare the stress profiles of hemorrhagic and non-hemorrhagic profiles. Methods and Results: Forty-five consecutive patients who had suffered a cerebrovascular ischemic event with an underlying carotid artery disease underwent high-resolution magnetic resonance imaging (MRI) of their symptomatic carotid artery in a 1.5-T MRI system. Axial images were manually segmented for various plaque components and used for FEA. Maximum critical stress (M-CstressSL) for each slice was determined. Within a plaque, the maximum M-CstressSL for each slice of a plaque was selected to represent the maximum critical stress of that plaque (M-CstressPL) and used to compare hemorrhagic and non-hemorrhagic plaques. A total of 62% of plaques had hemorrhage. It was observed that plaques with hemorrhage had significantly higher stress (M-CstressPL) than plaques without PH (median [interquartile range]: 315 kPa [247-434] vs. 200 kPa [171-282], P=0.003). Conclusions: Hemorrhagic plaques have higher biomechanical stresses than non-hemorrhagic plaques. MRI-based FEA seems to have the potential to assess plaque vulnerability.

Stress analysis of carotid atheroma in transient ischemic attack patients: Evidence for extreme stress-induced plaque rupture

Plaque rupture has been considered to be the result of its structural failure. The aim of this study is to suggest a possible link between higher stresses and rupture sites observed from in vivo magnetic resonance imaging (MRI) of transient ischemic attack (TIA) patients, by using stress analysis methods. Three patients, who had recently suffered a TIA, underwent in vivo multi-spectral MR imaging. Based on plaque geometries reconstructed from the post-rupture status, six pre-rupture plaque models were generated for each patient dataset with different reconstructions of rupture sites to bridge the gap of fibrous cap from original MRI images. Stress analysis by fluid structure interaction simulation was performed on the models, followed by analysis of local stress concentration distribution and plaque rupture sites. Furthermore, the sensitivity of stress analysis to the pre-rupture plaque geometry reconstruction was examined. Local stress concentrations were found to be located at the plaque rupture sites for the three subjects studied. In the total of 18 models created, the locations of the stress concentration regions were similar in 17 models in which rupture sites were always associated with high stresses. The local stress concentration region moved from circumferential center to the shoulder region (slightly away from the rupture site) for a case with a thick fibrous cap. Plaque wall stress level in the rupture locations was found to be much higher than the value in non-rupture locations. The good correlation between local stress concentrations and plaque rupture sites, and generally higher plaque wall stress level in rupture locations in the subjects studied could provide indirect evidence for the extreme stress-induced plaque rupture hypothesis. Local stress concentration in the plaque region could be one of the factors contributing to plaque rupture.

Study of tracheal collapsibility, compliance and stress by considering its asymmetric geometry

The shape of tracheal cartilage has been widely treated as symmetric in analytical and numerical models. However, according to both histological images and in vivo medical image, tracheal cartilage is of highly asymmetric shape. Taking the cartilage as symmetric structure will induce bias in calculation of the collapse behavior, as well as compliance and muscular stress. However, this has been rarely discussed. In this paper, tracheal collapse is represented by considering its asymmetric shape. For comparison, the symmetric shape, which is reconstructed by half of the cartilage, is also presented. A comparison of cross-sectional area, compliance of airway and stress in the muscular membrane, determined by asymmetric shape and symmetric shape is made. The result indicates that the symmetric assumption brings a small error, around 5% in predicting the cross-sectional area under loading conditions. The relative error of compliance is more than 10%. Particularly when the pressure is close to zero, the error could be more than 50%. The model considering the symmetric shape results in a significant difference in predicting stress in muscular membrane by either under- or over-estimating it. In conclusion, tracheal cartilage should not be treated as a symmetric structure. The results obtained in this study are helpful in evaluating the error induced by the assumption in geometry.

Invasive and non-invasive modalities of imaging carotid stenosis

Despite recent therapeutic advances, acute ischemic complications of atherosclerosis remain the primary cause of morbidity and mortality in Western countries, with carotid atherosclerotic disease one of the major preventable causes of stroke. As the impact of this disease challenges our healthcare systems, we are becoming aware that factors influencing this disease are more complex than previously realized. In current clinical practice, risk stratification relies primarily on evaluation of the degree of luminal stenosis and patient symptomatology. Adequate investigation and optimal imaging are important factors that affect the quality of a carotid endarterectomy (CEA) service and are fundamental to patient selection. Digital subtraction angiography is still perceived as the most accurate imaging modality for carotid stenosis and historically has been the cornerstone of most of the major CEA trials but concerns regarding potential neurological complications have generated substantial interest in non-invasive modalities, such as contrast-enhanced magnetic resonance angiography. The purpose of this review is to give an overview to the vascular specialist of the current imaging modalities in clinical practice to identify patients with carotid stenosis. Advantages and disadvantages of each technique are outlined. Finally, limitations of assessing luminal stenosis in general are discussed. This article will not cover imaging of carotid atheroma morphology, function and other emerging imaging modalities of assessing plaque risk, which look beyond simple luminal measurements.

Synthesis, crystal structures and protease activity of amino acid Schiff base iron(III) complexes

Iron(III) complexes, (NHEt3)[Fe(III)(sal-met)(2)] and (NHEt3)[Fe(III)(sal-phe)(2)], of amino acid Schiffbase ligands, viz., N-salicylidene-L-methionine and N-salicylidene L-phenylalanine, have been prepared and their binding to bovine serum albumin (BSA) and photo-induced BSA cleavage activity have been investigated. The complexes are structurally characterized by single crystal X-ray crystallography. The crystal Structures of the discrete mononuclear rnonoanionic complexes show FeN2O4 octahedral coordination geometry in which the tridentate dianionic amino acid Schiff base ligand binds through phenolate and carboxylate oxygen and imine nitrogen atoms. The imine nitrogen atoms are trans to each other. The Fe-O and Fe-N bond distances range between 1.9 and 2.1 angstrom. The sal-met complex has two pendant thiomethyl groups. The high-spin iron(III) complexes (mu(eff) similar to 5.9 mu(B)) exhibit quasi-reversible Fe(III)/Fe(II) redox process near -0.6 V vs. SCE in water. These complexes display a visible electronic hand near 480 nm in tris-HCl buffer assignable to the phenolate-to-iron(III) charge transfer transition. The water soluble complexes bind to BSA giving binding constant values of similar to 10(5) M-1. The Complexes show non-specific oxidative cleavage of BSA protein on photo-irradiation with UV-A light of 365 nm.

Influence of non-stoichiometric defects on nonlinear absorption and refraction in Nd:Zn co-doped lithium niobate

Nonlinear absorption and refraction phenomena in stoichiometric lithium niobate (SLN) pure and co-doped with Zn and Nd, and congruent lithium niobate (CLN) were investigated using Z-scan technique. Femtosecond laser pulses from Ti:Sapphire laser (800 nm, 110 fs pulse width and 1 kHz repetition rate) were utilized for the experiment. The process responsible for nonlinear behavior of the samples was identified to be three photon absorption (3PA). This is in agreement with the band gap energies of the samples obtained from the linear absorption cut off and the slope of the plot of Ln(1 − TOA) vs. Ln(I0) using Sutherland’s theory (s = 2.1, for 3PA). The nonlinear refractive index (n2) of Zn doped samples was found to be lower than that of pure samples. Our experiments show that there exists a correlation between the nonlinear properties and the stoichiometry of the samples. The values of n2 fall into the same range as those obtained for the materials of similar band gap.

Fluid-structure interaction study on human arterial plaque with patient specific geometry and boundary conditions

Atherosclerotic plaque rupture has been extensively considered as the leading cause of death in western countries. It is believed that high stresses within plaque can be an important factor on triggering the rupture of the plaque. Stress analysis in the coronary and carotid arteries with plaque have been developed by many researchers from 2D to 3-D models, from structure analysis only to the Fluid-Structure Interaction (FSI) models[1].

In vivo non-invasive high resolution MR-based method for the determination of the elastic modulus of arterial vessels

The mechanical properties of arterial walls have long been recognized to play an essential role in the development and progression of cardiovascular disease (CVD). Early detection of variations in the elastic modulus of arteries would help in monitoring patients at high cardiovascular risk stratifying them according to risk. An in vivo, non-invasive, high resolution MR-phase-contrast based method for the estimation of the time-dependent elastic modulus of healthy arteries was developed, validated in vitro by means of a thin walled silicon rubber tube integrated into an existing MR-compatible flow simulator and used on healthy volunteers. A comparison of the elastic modulus of the silicon tube measured from the MRI-based technique with direct measurements confirmed the method's capability. The repeatability of the method was assessed. Viscoelastic and inertial effects characterizing the dynamic response of arteries in vivo emerged from the comparison of the pressure waveform and the area variation curve over a period. For all the volunteers who took part in the study the elastic modulus was found to be in the range 50-250 kPa, to increase during the rising part of the cycle, and to decrease with decreasing pressure during the downstroke of systole and subsequent diastole.

Does PGA external stenting reduce compliance mismatch in venous grafts?

Background: Autogenous vein grafting is widely used in regular bypassing procedures. Due to its mismatch with the host artery in both mechanical property and geometry, the graft often over expands under high arterial blood pressure and forms a step-depth where eddy flow develops, thus causing restenosis, fibrous graft wall, etc. External stents, such as sheaths being used to cuff the graft, have been introduced to eliminate these mismatches and increase the patency. Although histological and immunochemical studies have shown some positive effects of the external stent, the mechanical mismatch under the protection of an external stent remains poorly analyzed. Methods: In this study, the jugular veins taken from hypercholesterolemic rabbits were transplanted into the carotid arteries, and non-woven polyglycolic acid (PGA) fabric was used to fabricate the external stents to study the effect of the biodegradable external stent. Eight weeks after the operation, the grafts were harvested to perform mechanical tests and histological examinations. An arc tangent function was suggested to describe the relationship between pressure and cross-sectional area to analyse the compliance of the graft. Results: The results from the mechanical tests indicated that grafts either with or without external stents displayed large compliance in the low-pressure range and were almost inextensible in the high-pressure range. This was very different from the behavior of the arteries or veins in vivo. The data from histological tests showed that, with external stents, collagen fibers were more compact, whilst those in the graft without protection were looser and thicker. No elastic fiber was found in either kind of grafts. Furthermore, grafts without protection were over-expanded which resulted in much bigger cross-sectional areas. Conclusion: The PGA external extent contributes little to the reduction of the mechanical mismatch between the graft and its host artery while remodeling develops. For the geometric mismatch, it reduces the cross-section area, therefore matching with the host artery much better. Although there are some positive effects, conclusively the PGA is not an ideal material for external stent.