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PubMedDate not supplied

Range of motion of the wrist: implications for designing computer input devices for the elderly.

PURPOSE: The purpose of this study was to report normative values of the amplitude of joint wrist motions and grip strength for older age groups. METHOD: Volunteers. (N = 147) were divided into four age groups, 60-69, 70-79, 80-89 and 90+ years, with a total of 62 men and 85 women. Maximum range motion values were obtained for wrist flexion, extension and ulnar deviation. In addition, grip strength measures were obtained for each participant. RESULTS: In general, the strength and ROM values for the oldest participants in this study were lower than those of the younger age group (age 60 to 69) and significantly lower than those published for subjects between 25 and 54 years of age. Furthermore, across all age groups males were significantly stronger than females. However, females tended to have greater ROM than males, particularly for wrist extension and ulnar deviations. Joint ROM and grip strength declined significantly with age for both males and females. Comparisons with published data for younger subjects (age 25-35) indicate that a 60-69 year old male, will on average experience a decline in wrist flexion, extension and ulnar deviation of 12%, 41%, and 22% respectively. By age 90, an individual may be expected to have ROM values that are only approximately 60% of an average 30 year old individual. CONCLUSION: The results suggest that the ageing population (particularly men) may face greater difficulty using an input device such as a mouse that relies on motions of the wrist. In addition, the reduced ROM of the wrist may put the elderly at greater risk of developing cumulative trauma disorders. The implications of these findings for the design of input devices are discussed.

Adult↗
PubMed2006

Computational design of proteins stereochemically optimized in size, stability, and folding speed.

Artificial proteins potentially barrier-free in the folding kinetics are approached computationally under the guidance of protein-folding theories. The smallest and fastest folding globular protein triple-helix-bundle (THB) is so modified as to minimize or eliminate its presumed barriers in folding speed. As the barriers may reside in the ordering of either secondary or tertiary structure, the elements of both secondary and tertiary structure in the protein are targeted for prenucleation with suitable stereochemically constrained amino acid residues. The required elements of topology and sequence for the THB are optimized independently; first the topology is optimized with simulated annealing in polypeptides of highly simplified alphabet; next, the sequence in side chains is optimized using the standard inverse design methods. The resultant three best-adapted THBs, variable in topology and distinctive in sequences, are assessed by comparing them with a few benchmark proteins. The results of mainly molecular dynamics (MD) comparisons, undertaken in explicit water at different temperatures, show that the designed sequences are favorably placed against the chosen benchmarks as THB proteins potentially thermostable in the native folds. Folding simulation experiments with MD establish that the designed sequences are rapid in the folding of individual helices, but not in the evolution of tertiary structure; energetic cum topological frustrations remain but could be the artifacts of the starting conformations that were chosen in the THBs in the folding simulations. Overall, a practical high-throughput approach for de novo protein design has been developed that may have fruitful application for any type of tertiary structure.

Amino Acid Sequence↗
PubMed2003

17-beta-Hydroxysteroid dehydrogenase type 1: computational design of active site inhibitors targeted to the Rossmann fold.

17-beta-Hydroxysteroid dehydrogenase type 1 (17betaHSD1), also called estradiol dehydrogenase, catalyzes the NADPH-dependent reduction of the weak estrogen, estrone, into the more potent estrogen, 17-beta-estradiol. 17betaHSD1 is an attractive drug target in hormone-sensitive breast cancer. Past efforts to develop selective inhibitors of 17betaHSD1 have focused on design of substrate analogs. It is challenging to develop steroid analogs that are devoid of any undesired biological activity. 17betaHSD1 is a member of the short-chain dehydrogenase/reductase (SDR) superfamily that includes many hydroxysteroid dehydrogenases. Members of the SDR family bind NAD(P)(H) in a motif that is a modified Rossmann fold. We demonstrated previously that the Rossmann folds of classical dehydrogenases can be selectively inhibited by derivatives and analogs of the natural product gossypol. In this study, we have addressed the question whether the modified Rossmann fold in 17betaHSD1 is a target for identification of lead compounds for structure-based drug design. 17betaHSD1 was purified from human placenta. 17betaHSD1 is inhibited by derivatives of gossypol with dissociation constants as low as 2 microM. Inhibition is competitive with the binding of cofactor. Molecular modeling studies using the published coordinates of human 17betaHSD1 suggest that these inhibitors occupy the modified Rossmann fold at the nicotinamide end of the dinucleotide-binding site, extending towards the substrate site. A computational approach was used to design potential new inhibitors of 17betaHSD1. The results suggest not only that derivatives of gossypol represent attractive lead compounds for structure-based drug design but also suggest that appropriate incorporation of a substrate analog into the design of these Rossmann fold inhibitors may provide pan-active site inhibitors that span the cofactor and substrate site, potentially offering specificity and increased potency.

17-Hydroxysteroid Dehydrogenases↗
PubMed2002

Computational simulations of stress shielding and bone resorption around existing and computer-designed orthopaedic screws.

Failure of an orthopaedic fixation due to stress shielding and consequent screw loosening is a major concern among surgeons: the loosened screws could not only interfere with the healing process but also endanger adjacent anatomical structures. In this study, the effect of the screw's engineering design (dimensions, profile shape and material properties) on the load sharing with adjacent bone and consequent bone resorption was tested, using a set of two-dimensional computational (finite element) models. An algorithm simulating local bone adaptation to strain energy density (SED) mechanical stimuli was developed and used to evaluate the biomechanical performances of different commercial screws. Two new designs, a 'graded-stiffness' composite screw, with a reduced-stiffness titanium core and outer polymeric threads, and an active-compression hollow screw that generates compressive stresses on the surrounding bone, were also evaluated. A dimensionless set of stress transfer parameters (STPs) were utilised for ranking the performances of the different screws according to the expected screw-bone load sharing and its evolution with adaptation of the surrounding tissue. The results indicated that commercial wide (6 mm thread diameter) trapezoidal and rectangular screw profiles have superior biomechanical compatibility with bone (i.e. predicted to be stable after 2 years). The graded-stiffness and active-compression screws provided the best biomechanical performances: bone loading around them was predicted to decrease by no more than 15% after 3 years, compared with a decrease of 55-70% in bone loading around commercially available screws. Computer simulations of bone adaptation around orthopaedic screws are demonstrated to be effective means for objective and quantitative evaluation of the biomechanical aspects of implant-tissue compatibility.

Bone Resorption↗
PubMed2002

Influence of laptop computer design and working position on physical exposure variables.

OBJECTIVE: To evaluate the impact of two laptop designs (with or without palm rest) and two work situations (on desk or lap) on neck and upper limb posture, muscle activity and productivity. DESIGN AND METHODS: Eight healthy subjects performed a standardized typing task of 15 min duration. During the last 5 min of each test, the neck, upper arm and trunk postures were captured by a three-dimensional video system, wrist motion was measured by a biaxial electrogoniometer and muscle activity of four neck and upper limb muscles was recorded. RESULTS: Only minor differences in postures, wrist positions and productivity were observed when comparing the two laptop designs in the same situation. Larger differences were found when comparing the two situations (desk or lap). In the desk situation, the subjects bent their heads forward less, had less backward trunk inclination and wrist extension, but more elevation of the upper arm. Higher electromyographic (EMG) levels in the trapezius and deltoid muscles and lower EMG levels in the wrist extensors were also found in the desk situation. CONCLUSIONS: Our findings do not favor one particular laptop design because only small differences in physical exposure were found. However, the workstation set up influenced the physical exposure variables, and was pinpointed as the main determinant to be considered when doing laptop work even-though no ideal situation was found. Greater physical (muscular and articular) constraints seem to be imposed to the shoulder region in the desk situation whereas the head-neck and wrist segments appear to be more stressed in the lap situation. RELEVANCE: Laptop computers are often used although the physical exposure in laptop work and the impact of different laptop designs have not been systematically assessed. A better understanding of these factors may help formulate some recommendations for laptop users.

Adult↗
PubMed1992

Computer-designed inlays after 5 years in situ: clinical performance and scanning electron microscopic evaluation.

Eight mesio-occlusodistal adhesive inlays, fabricated from ceramic blocks using a computer-aided design/machining method, were reexamined after 5 years of clinical service. The inlays wre evaluated according to modified US Public Health Service criteria. The results indicated excellent clinical performance, with eight Alfa ratings for wear, recurrent caries, and color match, and five Alfa and three Bravo for marginal discoloration and marginal integrity. Under scanning electron microscope, 81.0% of the tooth-cement interfaces and 84.1% of the cement-inlay interfaces were rated continuous at the occlusal margin. Axially, 73.6% of the tooth-cement interfaces and 87.0% of the cement-inlay interfaces were rated continuous. Although this long-term investigation revealed good clinical performance of the inlays, improvements in the ceramic structure and its properties, the cavosurface design, and the luting composite resin were recently introduced to further optimize quality.

Ceramics↗
PubMed2005

Molecular Dynamics Simulation of WSK-3, a Computationally Designed, Water-Soluble Variant of the Integral Membrane Protein KcsA.

Poor solubility and low expression levels often make membrane proteins difficult to study. An alternative to the use of detergents to solubilize these aggregation-prone proteins is the partial redesign of the sequence so as to confer water solubility. Recently, computationally assisted membrane protein solubilization (CAMPS) has been reported, where exposed hydrophobic residues on a protein's surface are computationally redesigned. Herein, the structure and fluctuations of a designed, water-soluble variant of KcsA (WSK-3) were studied using molecular dynamics simulations. The root mean square deviation of the protein from its starting structure, where the backbone coordinates are those of KcsA, was 1.8 angstroms. The structure of salt bridges involved in structural specificity and solubility were examined. The preferred configuration of ions and water in the selectivity filter of WSK-3 was consistent with the reported preferences for KcsA. The structure of the selectivity filter was maintained, which is consistent with WSK-3 having an affinity for agitoxin2 comparable to that of wild-type KcsA. In contrast to KcsA, the central cavity's side chains were observed to reorient, allowing water diffusion through the side of the cavity wall. These simulations provide an atomistic analysis of the CAMPS strategy and its implications for further investigations of membrane proteins.

Bacterial Proteins↗
PubMed2006

Bone regeneration on computer-designed nano-fibrous scaffolds.

The ability to control architectural features in tissue engineering scaffolds is critical to the success of neo-tissue regeneration. In this work, reverse solid freeform fabrication and thermal phase separation of poly(L-lactic acid) (PLLA) solutions were used to create three-dimensional nano-fibrous (NF) scaffolds with complex geometries on the macro- and micro-scales. This approach allows for the fabrication of NF matrices while having precise control of internal pore size and structure, as well as external scaffold shape including architectures generated from computed-tomography scans and histological sections. In vitro cell cultivation experiments with MC3T3-E1 pre-osteoblasts were performed on NF scaffolds and on similarly designed solid-walled (SW) scaffolds that did not have nano-fibers. Proliferation studies showed significantly more cells on NF scaffolds after 7 d. In differentiation studies, the NF scaffolds displayed more uniform matrix and mineral production throughout. Real-time PCR also showed significantly higher expression of osteocalcin and bone sialoprotein mRNAs after 2 and 6 weeks in the NF scaffolds. Expression of type I collagen mRNA was lower in NF scaffolds which possibly indicates quicker differentiation on the NF substrate. In summary, we controlled the geometry of NF PLLA scaffolds at multiple size scales, and the in vitro results showed that these NF scaffolds were advantageous to control scaffolds for bone tissue engineering.

3T3 Cells↗
PubMed2005

Computational design of antiviral RNA interference strategies that resist human immunodeficiency virus escape.

Recently developed antiviral strategies based upon RNA interference (RNAi), which harnesses an innate cellular system for the targeted down-regulation of gene expression, appear highly promising and offer alternative approaches to conventional highly active antiretroviral therapy or efforts to develop an AIDS vaccine. However, RNAi is faced with several challenges that must be overcome to fully realize its promise. Specifically, it degrades target RNA in a highly sequence-specific manner and is thus susceptible to viral mutational escape, and there are also challenges in delivery systems to induce RNAi. To aid in the development of anti-human immunodeficiency virus (anti-HIV) RNAi therapies, we have developed a novel stochastic computational model that simulates in molecular-level detail the propagation of an HIV infection in cells expressing RNAi. The model provides quantitative predictions on how targeting multiple locations in the HIV genome, while keeping the overall RNAi strength constant, significantly improves efficacy. Furthermore, it demonstrates that delivery systems must be highly efficient to preclude leaving reservoirs of unprotected cells where the virus can propagate, mutate, and eventually overwhelm the entire system. It also predicts how therapeutic success depends upon a relationship between RNAi strength and delivery efficiency and uniformity. Finally, targeting an essential viral element, in this case the HIV TAR region, can be highly successful if the RNAi target sequence is correctly selected. In addition to providing specific predictions for how to optimize a clinical therapy, this system may also serve as a future tool for investigating more fundamental questions of viral evolution.

Computational Biology↗
PubMed2003

Computational design of variant TNF molecules: a novel methodology for inhibition of proinflammatory cascades.

Site-directed mutagenesis of tumor necrosis factor (TNF) based on prediction of the interaction of specific residues with TNF receptors generated dominant-negative constructs, in which single- or double-amino acid changes result in decreased receptor binding and cellular activation. These dominant-negatives not only provide a novel manner to block the proinflammatory effects of TNF, but also can be used as a tool to examine ligand-receptor interactions and their importance in signaling. Because these TNF mutant molecules are smaller than those used for conventional anti-TNF therapies, such as etanercept or infliximab, they are likely to achieve greater tissue concentrations and may provide enhanced therapeutic effect. However, the immunogenicity, as well as efficacy, of the dominant-negative TNF constructs must be more completely examined.

Computational Biology↗
PubMed2006

Computational design of a new hydrogen bond network and at least a 300-fold specificity switch at a protein-protein interface.

The redesign of protein-protein interactions is a stringent test of our understanding of molecular recognition and specificity. Previously we engineered a modest specificity switch into the colicin E7 DNase-Im7 immunity protein complex by identifying mutations that are disruptive in the native complex, but can be compensated by mutations on the interacting partner. Here we extend the approach by systematically sampling alternate rigid body orientations to optimize the interactions in a binding mode specific manner. Using this protocol we designed a de novo hydrogen bond network at the DNase-immunity protein interface and confirmed the design with X-ray crystallographic analysis. Subsequent design of the second shell of interactions guided by insights from the crystal structure on tightly bound water molecules, conformational strain, and packing defects yielded new binding partners that exhibited specificities of at least 300-fold between the cognate and the non-cognate complexes. This multi-step approach should be applicable to the design of polar protein-protein interactions and contribute to the re-engineering of regulatory networks mediated by protein-protein interactions.

Bacterial Proteins↗
PubMed1995

Computer design of T-cell agonist or antagonist glycopeptides: the effect of sugar identity and anomeric configuration on MHC binding.

The improved chemical and biological properties of synthetic glycopeptides over peptides suggest their use as T cell agonists or antagonists. Recently, we prepared glycopeptide analogues of major T helper cell epitopic peptides corresponding to rabies virus proteins, and experimentally characterized their ability to bind to MHC class II proteins and stimulate T cell clones to rabies virus. In the current study, we investigated these MHC: peptide interactions by molecular modeling. We obtained structural support for our finding concerning the anomeric specificity of MHC with binding. While alpha-linked glycopeptides can bind to MHC without major alterations in the spatial arrangements and hydrogen bonding pattern of class II-peptide binding, the binding of beta-linked glycopeptides is considerably less favorable due to steric and columbic conflicts. Depending on where the saccharides are positioned along the peptide sequence, the MHC: glycopeptide complex may or may not produce the surface profile required for successful T cell receptor interaction. Application of this approach to other antigenic stimuli offers a good model to "dial in" the necessary sugar identity, length and anomeric configuration, as well as promising amino acid mutation sites, for successful design of T cell agonist or antagonist glycopeptides.

Amino Acid Sequence↗
PubMed2004

Computational design of reduced metabolic networks.

Cellular functions are based on thousands of chemical reactions and transport processes, most of them being catalysed and regulated by specific proteins. Systematic gene knockouts have provided evidence that this complex reaction network possesses considerable redundancy, that is, alternative routes exist along which signals and metabolic fluxes may be directed to accomplish an identical output behaviour. This property is of particular importance in cases where parts of the reaction network are transiently or permanently impaired, for example, due to an infection or genetic alterations. Here we present a computational concept to determine enzyme-reduced metabolic networks that are still sufficient to accomplish a given set of cellular functions. Our approach consists of defining an objective function that expresses the compromise that has to be made between successive reduction of the network by omission of enzymes and its decreasing thermodynamic and kinetic feasibility. Optimisation of this objective function results in a linear mixed-integer program. With increasing weight given to the reduction of the number of enzymes, the total flux in the network increases and some of the reactions have to proceed in thermodynamically unfavourable directions. The approach was applied to two metabolic schemes: the energy and redox metabolism of red blood cells and the carbon metabolism of Methylobacterium extorquens. For these two example networks, we determined various variants of reduced networks differing in the number and types of disabled enzymes and disconnected reactions. Using a comprehensive kinetic model of the erythrocyte metabolism, we assess the kinetic feasibility of enzyme-reduced subnetworks. The number of enzymes predicted to be indispensable amounts to 14 (out of 28) for the erythrocyte scheme and 13 (out of 77) for the bacterium scheme, the largest group of enzymes predicted to be simultaneously dispensable amounts to 3 and 37 for these two systems. Our approach might contribute to identifying potential target enzymes for rational drug design, to rationalising gene-expression profiles of metabolic enzymes and to designing synthetic networks with highly specialised metabolic functions.

Computational Biology↗
PubMed1991

The computational design of test compounds with potentially specific biological activity: histamine-H2 agonists derived from 5-HT/H2 antagonists.

The previously proposed models for the recognition and activation of 5-HT and histamine-H2 receptors, which were employed to explain the antagonist activity of LSD at both of these receptors, as well as the selective antagonism for H2 receptors by SKF-10856 and 9,10-dihydro-LSD, are used herein to design a compound to test the H2-receptor model. The design strategy attempts to construct a compound with potentially selective H2 agonism. The design scheme maintains features which were previously used to explain selective recognition of SKF-10856 and 9,10-dihydro-LSD as well as reintroduces the chemical features proposed to be responsible for H2 activation. The existence of the H2 recognition and activation features in the proposed compound is verified, in a previously proposed model, by computational studies of the molecular electrostatic potentials and shifts in the tautomeric preference.

Drug Design↗