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Interactome networks

2007-11-27 , Vidal, Marc

For over half a century it has been conjectured that macromolecules form complex networks of functionally interacting components, and that the molecular mechanisms underlying most biological processes correspond to particular steady states adopted by such cellular networks. However, until recently, systems-level theoretical conjectures remained largely unappreciated, mainly because of lack of supporting experimental data. To generate the information necessary to eventually address how complex cellular networks relate to biology, we initiated, at the scale of the whole proteome, an integrated approach for modeling protein-protein interaction or "interactome" networks. Our main questions are: How are interactome networks organized at the scale of the whole cell? How can we uncover local and global features underlying this organization, and how are interactome networks modified in human disease, such as cancer?

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Relating Cellular to Molecular Specificity – the Recognition Mechanism of Hox Proteins and Cadherins

2007-10-23 , Honig, Barry

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The Effect of Surface Curvature and a Gel Liner Interface on Performance Properties of the Tekscan Socket System

2007-04-25 , Schrock, Lara

The presence of mechanical loads at the limb socket interface is considered an initiating cause of tissue breakdown and ulceration. Historically, prosthetists have relied on past experience, patient feedback, and indirect indications of load to gauge socket fit. The clinical measurement of interface pressures has the potential to provide quantitative, objective information to help in the evaluation of prosthetic fit. Tests of the Tekscan F-Socket system have been performed over flat and curved surfaces, but not using axial load and the presence of a gel liner to more closely simulate a clinical setting. This study investigates how drift and cyclic drift errors of the F-Socket system are affected by surface curvature and the presence of a gel liner interface. For drift, a known constant axial load was applied by a servo-hydraulic testing machine for 20 minutes. Samples were taken at 1, 5, 10, 15, and 20 minutes. For cyclic drift, load was alternated in a known range at 0.5Hz for 10 minutes. Samples were taken at 1, 5, and 10 minutes. These tests were performed under four conditions: flat rigid, flat with liner, round rigid, and round with liner. It was found that drift error was significantly affected by the curvature of the model, but not by the presence of a gel liner. It was also found that cyclic drift was not affected by the curvature of the model, but was by the presence of a gel liner. Further study should be done with other curvatures, other liners, and other sensor properties such as hysteresis and accuracy.

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The Capacity of the Prosthetic Profession to Provide Lower Extremity Prosthetic Limbs within the State of Georgia

2007-04-18 , Curran, Andrew

Due to an aging population and a rise in conditions known to increase the risk of amputation, demand for prosthetic services is thought to be increasing nation wide. 20% of certified practitioners will reach retirement age within the next ten years. A recent National Commission on Orthotic and Prosthetic Education (NCOPE) study highlights the need to substantially increase the number of educational programs and the number of graduates becoming certified to meet the demand for services. The purpose of this study was to investigate the current capacity of the prosthetic profession in the state of Georgia to provide services. Palmetto GBA ,the Durable Medical Equipment Regional Carrier (DMERC) for Medicare Region C. was asked to identify the number of times the "Base" L-Codes for lower limb prostheses were submitted for billing in the years 2000 and 2004. Total sales was then estimated by extrapolating the Medicare information assuming Medicare sales represent 58% of total sales. The number of Georgia based American Board for Certification (ABC) and Board for Orthotist / Prosthetist Certification (BOC) certified prosthetists was solicited from their respective certifying agencies. The data collected represents the only estimate of lower limb prostheses fabricated in GA in 2000 and 2004. The data also represents the only estimate of prostheses fabricated per practitioner, and the only study to capture services rendered beyond Medicare beneficiaries.

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Hybrid Experiments: Linking Real-Time Simulations to In Vitro Electrophysiology Experiments

2007-10-30 , Butera, Robert J.

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From Systems Biology to Systems Analytics: Seeing More by Looking at Less

2007-10-09 , Mizaikoff, Boris

Systematic analysis of interactions between molecules and biological entities requires the development and application of experimental tools and analytical methods to quantitatively measure and image molecular events, molecular pathways, and molecular signals at the level of individual cells, ensembles of small biological entities and entire organisms with the required molecular selectivity, sensitivity, and temporal/spatial resolution. While it is evident that current analytical techniques are frequently limited to averaged measurements or ex-situ analysis, the analytical challenges for in-situ multi-parametric characterization of living biological entities such as cells, microbes, bacteria or ensembles thereof remain significant. Hence, in analogy and complementary to Systems Biology concerned with deciphering complex molecular processes and their relation to biological functionalities, we view Systems Analytics as the toolbox enabling the quantitative determination of multiple molecular parameters to elucidate these interactions and relations. From the analytic chemistry point of view, we may describe individual cells as a measurement compartment with spatial/volume dimensions in the μm-nm/μL-nL range, and quantitative molecular dimensions in the mM-nM domain. The spatial dimensionality of molecular events within or at cellular compartments (e.g. vesicular processes) or at the cell surface (e.g. exo-or endocytosis) along with the magnitude of the local species concentration determine the need for quantitative analytical measurements at the micro- and nanoscale. We will discuss the diversity of measurement challenges at these compartments, which include the small dimensions of the involved samples and volumes, the complex and frequently changing background matrix, the sensitivity and/or discriminatory power of in-situ analytical techniques, and their temporal and/or spatial resolution to quantitatively monitor dynamic processes associated with cellular functions. In turn, individual optical/spectroscopic, electrochemical, and surface sensitive analytical techniques have already demonstrated their potential at the macro- and microscopic level, i.e. identifying which molecular species are present, their concentration, their location, and — ideally - the kinetics, dynamics of the involved molecular processes. In contrast to approaches utilizing individual analytical techniques, the development of generic multifunctional analytical platforms orchestrates a suite of complementary measurement techniques to cooperatively investigate complex biological systems, complemented by the development of (bio)sensing chemistries, synthetic molecular receptors, multivariate evaluation techniques, and micro/nanofabrication for functional system miniaturization. Thereby, we capitalize on the benefits of several analytical techniques addressing the conformational, electrochemical, and spectroscopic properties of the sample leading toward simultaneous rather than the classical sequential information acquisition process, aiming at maximizing the synchronicity between multiple methods in the temporal and spatial domain.

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Upper Extremity Robotic Therapy for Individuals with Spinal Cord Injury

2007-04-25 , Bui, Tina

Cervical injury causes tetraplegia in about half of spinal cord injury (SCI) cases and results in impaired hand function. Despite their different etiologies, both SCI and stroke subjects have demonstrated recovery by similar mechanisms of cortical reorganization. This suggests that interventions used after stroke may also be effective after SCI. With the current technology available, robotic devices are being used to provide safe and intensive rehabilitation to people with motor impairment after stroke. The main objective of this study is to assess the safety, comfort, ease of use, fit and therapeutic value of robotic therapy in a SCI clinic. This study investigates the hypothesis that a robotic device used to deliver elbow flexion and extension exercises will be accepted by the subject and lead to improved strength in the treated limb of SCI subjects.

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Refinement of reduced protein models with all-atom force fields - Ph.D. Defense

2007-10-30 , Wróblewska, Liliana

The goal of the following thesis research was to develop a systematic approach for the refinement of low-resolution protein models, as a part of the protein structure prediction procedure. Significant progress has been made in the field of protein structure prediction and the contemporary methods are able to assemble correct topology for a large fraction of protein domains. But such approximate models are often not detailed enough for some important applications, including studies of reaction mechanisms, functional annotation, drug design or virtual ligand screening. The development of a method that could bring those structures closer to the native is then of great importance. The minimal requirements for a potential that can refine protein structures is the existence of a correlation between the energy with native similarity and the scoring of the native structure as being lowest in energy. Extensive tests of the contemporary all-atom physics-based force fields were conducted to assess their applicability for refinement. The tests revealed flatness of such potentials and enabled the identification of the key problems in the current approaches. Guided by these results, the optimization of the AMBER (ff03) force field was performed that aimed at creating a funnel shape of the potential, with the native structure at the global minimum. Such shape should facilitate the conformational search during refinement and drive it towards the native conformation. Adjusting the relative weights of particular energy components, and adding an explicit hydrogen bond potential significantly improved the average correlation coefficient of the energy with native similarity (from 0.25 for the original ff03 potential to 0.65 for the optimized force field). The fraction of proteins for which the native structure had lowest energy increased from 0.22 to 0.90. The new, optimized potential was subsequently used to refine protein models of various native-similarity. The test employed 47 proteins and 100 decoy structures per protein. When the lowest energy structure from each trajectory was compared with the starting decoy, we observed structural improvement for 70% of the models on average. Such an unprecedented result of a systematic refinement is extremely promising in the context of high-resolution structure prediction.

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A Method of Prototype Evaluation for Assistive Mobility in Animals: Intervention for a Congenitally Malformed Dog – a Case Study

2007-04-25 , Forest, Tiffany

Several studies report successful fittings of tripedal quadruped animals with prosthetic devices, but very few report fittings of bipedal quadrupeds. None of these studies report how the animals were trained to use their assistive devices or how the device was developed. The research focus of this project was to develop a method to train animals to use assistive devices and measure their mobility in order to determine the success or failure of prototype design. The overall goal of the assistive devices for a bilateral front limb deficient dog was to increase the animal’s mobility. After eight prototype designs over the course of 10 weeks, a design suitable for a timed up and go test was achieved. The test revealed an increase in mobility.

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Stiffness properties of prosthetic feet under cross-slope conditions

2007-04-18 , Zeller, Sean

As an integral component after lower extremity amputation, prosthetic feet assist the body in forward progression, weight bearing stability and shock absorption. A Key element of weight bearing stability is the foot’s interaction with non-flat surfaces. Cross-slopes are encountered in daily activities from wheelchair ramps, to crossing uneven streets. Some prosthetic feet have been designed to accommodate such terrain. The objective of this study is to evaluate the stiffness of a representative sample of prosthetic feet when placed on a cross slope and use these results to discuss their potential as a classification tool. 15 prosthetic feet were acquired representing all available types of prosthetic feet. A servo-hydraulic testing machine was used for quasi-static loading of prosthetic feet under various conditions; Flat surface, medial slopes 7.5 deg., 15 deg., and lateral slopes 7.5 deg., 15 deg. Feet were cyclically loaded on two separate days to evaluate repeatability. 400 N was selected as a reference point for today’s discussion; it represents 50% of our hypothetical user’s body weight and coincides with the force applied to the foot during quiet standing. A one way ANOVA test was used in addition to correlation data to assess variance across two separate test dates. A significant difference was not noted between trial days. It was observed that for nearly all feet, the lateral border experienced greater changes in stiffness compared to the medial border when encountering a cross-slope. Feet showed a range of stiffness; at 400 N, the stiffness observed in the feet ranged from 54.6 N/mm to 236.2 N/mm. Feet also showed a significant range in the magnitude of change from stiffness on flat surfaces’ the change in stiffness ranged from 158 N/mm to 122 N/mm. While prosthetic feet designed and marketed to accommodate uneven terrain tended to have a significant reduction in stiffness compared to other feet, this did not necessarily produce a less overall stiffness. High variation was seen between feet of the same family in their interaction with cross-slopes. Laboratory tests can be used to classify prosthetic feet and clarify differences between feet. These results have implications for prosthetic foot prescription, reimbursement, research and development, although should be interpreted alongside clinical research to fully understand their implications.

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