Tool For Refinement Research Articles

Os Precedentes da Corte Europeia de Direitos Humanos como Instrumento de Refinamento das Normas de Direitos Humanos: Decisão Judicial e Norma de Direito Fundamental Adscrita /Derivada

Essa pesquisa possui o objetivo de demonstrar importância das decisões dos Tribunais Internacionais, especificamente a Corte Europeia de direitos Humanos, para o refinamento das normas de direitos humanos/fundamentais. Para tanto, se dedicará, em um primeiro momento, a identificar o conceito semântico de norma jurídica, o que colocará a hermenêutica jurídica em evidência; bem como, pontuará a questão da abertura da identificação da norma em decorrência dos conteúdos ético-morais inseridos nos enunciados normativos que prescrevem direitos humanos/fundamentais. Em um segundo momento, apresentaremos aquilo que Robert Alexy denomina de norma de direito fundamental atribuída ou adstrita, o que permitirá identificar como normas de direitos fundamentais todas as manifestação legislativas ou jurisdicionais que guardem correntes de fundamentação com as normas primárias de direitos humanos/fundamentais. Com isso, analisaremos duas decisões do Tribunal Europeu de Direitos Humanos como instrumento de refinamento, delimitação e, mais, como mecanismo de efetiva concretização das normas de direitos humanos/fundamentais, a partir das correntes racionais de argumentação.

Stochastic nonlinear mixed effects: a metformin case study.

In nonlinear mixed effect (NLME) modeling, the intra-individual variability is a collection of errors due to assay sensitivity, dosing, sampling, as well as model misspecification. Utilizing stochastic differential equations (SDE) within the NLME framework allows the decoupling of the measurement errors from the model misspecification. This leads the SDE approach to be a novel tool for model refinement. Using Metformin clinical pharmacokinetic (PK) data, the process of model development through the use of SDEs in population PK modeling was done to study the dynamics of absorption rate. A base model was constructed and then refined by using the system noise terms of the SDEs to track model parameters and model misspecification. This provides the unique advantage of making no underlying assumptions about the structural model for the absorption process while quantifying insufficiencies in the current model. This article focuses on implementing the extended Kalman filter and unscented Kalman filter in an NLME framework for parameter estimation and model development, comparing the methodologies, and illustrating their challenges and utility. The Kalman filter algorithms were successfully implemented in NLME models using MATLAB with run time differences between the ODE and SDE methods comparable to the differences found by Kakhi for their stochastic deconvolution.

Deformable complex network for refining low-resolution X-ray structures.

In macromolecular X-ray crystallography, building more accurate atomic models based on lower resolution experimental diffraction data remains a great challenge. Previous studies have used a deformable elastic network (DEN) model to aid in low-resolution structural refinement. In this study, the development of a new refinement algorithm called the deformable complex network (DCN) is reported that combines a novel angular network-based restraint with the DEN model in the target function. Testing of DCN on a wide range of low-resolution structures demonstrated that it constantly leads to significantly improved structural models as judged by multiple refinement criteria, thus representing a new effective refinement tool for low-resolution structural determination.

SFESA: a web server for pairwise alignment refinement by secondary structure shifts.

BackgroundProtein sequence alignment is essential for a variety of tasks such as homology modeling and active site prediction. Alignment errors remain the main cause of low-quality structure models. A bioinformatics tool to refine alignments is needed to make protein alignments more accurate.ResultsWe developed the SFESA web server to refine pairwise protein sequence alignments. Compared to the previous version of SFESA, which required a set of 3D coordinates for a protein, the new server will search a sequence database for the closest homolog with an available 3D structure to be used as a template. For each alignment block defined by secondary structure elements in the template, SFESA evaluates alignment variants generated by local shifts and selects the best-scoring alignment variant. A scoring function that combines the sequence score of profile-profile comparison and the structure score of template-derived contact energy is used for evaluation of alignments. PROMALS pairwise alignments refined by SFESA are more accurate than those produced by current advanced alignment methods such as HHpred and CNFpred. In addition, SFESA also improves alignments generated by other software.ConclusionsSFESA is a web-based tool for alignment refinement, designed for researchers to compute, refine, and evaluate pairwise alignments with a combined sequence and structure scoring of alignment blocks. To our knowledge, the SFESA web server is the only tool that refines alignments by evaluating local shifts of secondary structure elements. The SFESA web server is available at http://prodata.swmed.edu/sfesa.

Microstructural Design of an AlMgSi Alloy via ECAP Processing: An Advanced SPD Manufacturing Technique for NC/UFG Materials

Severe plastic deformation (SPD) has received enormous interest over the last two decades as a method capable of producing fully dense and bulk ultra-fine grained (UFG) and nanocrystalline (NC) materials. Significant grain refinement obtained by SPD leads to improvement of mechanical, microstructural and physical properties. Compared to classical deformation processes, the big advantage of SPD manufacturing techniques, represented in particular by equal channel angular pressing (ECAP) is the lack of shape-change deformation and the consequent possibility to impart extremely large strain. In ECAP processing, the workpiece is pressed through a die in which two channels of equal cross-section intersect at an angle of ϕ and an additional angle of ψ define the arc of curvature at the outer point of intersection of the two channels. As a result of pressing, the sample theoretically deforms by simple shear and retains the same cross-sectional area to allow repeated pressings for several cycles. A commercial AlMgSi alloy was investigated in our study. The specimens were processed at room temperature for multiple passes, using three different ECAP dies. All samples (ECAP processed and as-received) were subjected to metallographic analysis and mechanical testing. Several correlations between the main processing parameters and the resulting microstructural aspect and mechanical features for the processed material were established. It was shown that severe plastic deformation by means of ECAP processing can be used in aluminum alloys microstructural design as an advanced tool for grain refinement in order to attain the desired microstructure and mechanical properties.

SU‐E‐T‐237: Deformable Image Registration and Deformed Dose Composite for Volumetric Evaluation of Multimodal Gynecological Cancer Treatments

Purpose:Radiotherapy plans for patients with cervical cancer treated with EBRT followed by HDR brachytherapy are optimized by constraining dose to organs at risk (OARs). Risk of treatment related toxicities is estimated based on the dose received to the hottest 2cc (D2cc) of the bladder, bowel, rectum, and sigmoid. To account for intrafractional variation in OAR volume and positioning, a dose deformation method is proposed for more accurate evaluation of dose distribution for these patients.Methods:Radiotherapy plans from five patients who received 50.4Gy pelvic EBRT followed by 30Gy in five fractions of HDR brachytherapy, using split‐ring and tandem applicators, were retrospectively evaluated using MIM Software version 6.0. Dose accumulation workflows were used for initial deformation of EBRT and HDR planning CTs onto a common HDR planning CT. The Reg Refine tool was applied with user‐specified local alignments to refine the deformation. Doses from the deformed images were transferred to the common planning CT. Deformed doses were scaled to the EQD2, following the linear‐quadratic BED model (considered α/β ratio for tumor as 10, and 3 for rest of the tissues), and then combined to create the dose composite. MIM composite doses were compared to the clinically‐reported plan assessments based upon the American Brachytherapy Society (ABS) guidelines for cervical HDR brachytherapy treatment.Results:Bladder D2cc exhibited significant reduction (−11.4%±3.85%, p< 0.02) when evaluated using MIM deformable dose composition. Differences observed for bowel, rectum, and sigmoid D2cc were not significant (−0.58±7.37%, −4.13%±13.7%, and 8.58%±4.71%, respectively and p>0.05 for all) relative to the calculated values used clinically.Conclusion:Application of deformable dose composite techniques may lead to more accurate total dose reporting and can allow for elevated dose to target structures with the assurance of not exceeding dose to OARs. Further study into deformable dose composition and correlation with clinical outcomes is warranted.

Statistical radii associated with amino acids to determine the contact map: fixing the structure of a type I cohesin domain in the Clostridium thermocellum cellulosome

We propose to improve and simplify protein refinement procedures through consideration of which pairs of amino acid residues should form native contacts. We first consider 11 330 proteins from the CATH database to determine statistical distributions of contacts associated with a given type of amino acid. The distributions are set across the distances between the α-C atoms that are in contact. Based on this data, we determine typical radii of effective spheres that can be placed on the α-C atoms in order to reconstruct the distribution of the contact lengths. This is done by checking for overlaps with enlarged van der Waals spheres associated with heavy atoms on other amino acids.The resulting contacts can be used to identify non-native contacts that may arise during the time evolution of structure-based models. Here, the radii are used to guide reconstruction of nine missing side chains in a type I cohesin domain with the Protein Data Bank code 1AOH. We first identify the likely missing contacts and then sculpt the corresponding side chains by standard refinement tools to achieve consistency with the expected contact map. One ambiguity in refinement is resolved by determining all-atom conformational energies.

Modeling Macromolecular Motions by X-Ray-Scattering-Constrained Molecular Dynamics

A fundamental problem for structural biology in combining solution x-ray scattering data with atomic resolution structures determined by crystallography is to find effective ways to model motions accessible to molecules outside the crystal environment. Motions can be derived when multiple conformations are experimentally observed or can be inferred through computational methods such as normal modes, molecular dynamics, and Monte Carlo-based techniques. Small-angle x-ray scattering (SAXS) is a complete, resolution-limited structural measurement of the solution state for macromolecules.

The solvent component of macromolecular crystals.

The mother liquor from which a biomolecular crystal is grown will contain water, buffer molecules, native ligands and cofactors, crystallization precipitants and additives, various metal ions, and often small-molecule ligands or inhibitors. On average, about half the volume of a biomolecular crystal consists of this mother liquor, whose components form the disordered bulk solvent. Its scattering contributions can be exploited in initial phasing and must be included in crystal structure refinement as a bulk-solvent model. Concomitantly, distinct electron density originating from ordered solvent components must be correctly identified and represented as part of the atomic crystal structure model. Herein, are reviewed (i) probabilistic bulk-solvent content estimates, (ii) the use of bulk-solvent density modification in phase improvement, (iii) bulk-solvent models and refinement of bulk-solvent contributions and (iv) modelling and validation of ordered solvent constituents. A brief summary is provided of current tools for bulk-solvent analysis and refinement, as well as of modelling, refinement and analysis of ordered solvent components, including small-molecule ligands.

Is the analysis of histamine and/or interleukin-4 release after isocyanate challenge useful in the identification of patients with IgE-mediated isocyanate asthma?

Isocyanates are a well-known and frequent cause of occupational asthma. The implementation of specific inhalation challenges (SICs) is the gold standard in asthma diagnosis supporting occupational case history, lung function testing, specific skin prick tests and the detection of specific IgE. However, the diagnosis is not always definitive. An interesting new approach, analyses of individual genetic susceptibilities, requires discrimination between a positive SIC reaction arising from IgE-mediated immune responses and one from other pathophysiological mechanisms. Hence, additional refinement tools would be helpful in defining sub-classes of occupational asthma and diagnosis. We used total IgE levels, specific IgE and SIC results for sub-classification of 27 symptomatic isocyanate workers studied. Some mutations in glutathione S-transferases (GSTs) are suspected either to enhance or to decrease the individual risk in the development of isocyanate asthma. Our patient groups were assessed for the point mutations GSTP1*I105V and GSTP1*A114V as well as deletions (null mutations) of GSTM1 and GSTT1. There seems to be a higher risk in developing IgE-mediated reactions when GSTM1 is deleted, while GSTT1 deletions were found more frequently in the SIC positive group. Blood samples taken before SIC, 30–60min and 24h after SIC, were analyzed for histamine and IL-4, classical markers for the IgE-mediated antigen-specific activation of basophils or mast cells. We suggest that the utility of histamine measurements might provide an additional useful marker reflecting isocyanate-induced cellular reactions (although the sampling times require optimization). The promising measurement of IL-4 is not feasible at present due to the lack of a reliable, validated assay.

Verification Method of Real-time System Based on Refinement Relation

With the continuous increase in the size and complexity of a real-time computer system, the use of formal verification methods in software development is also on the rise. The traditional formal verification method is not fully applicable to the development of actual system life cycle. Therefore, this paper presents a new real-time system verification method, It takes the deadlock timed Buchi automata as the medium, and translates the timed temporal logic into timed communicating sequential process language. The tock event is also joined, which can be directly used for the detection of refinement tool FDR. The method verifies the situation of deadlock. To establish the link between the conventional model checking and refinement model checking can well combine the advantages of both and improves system security and reliability.

Crystal structure determination and refinementviaSIR2014

SIR2014is the latest program of theSIRsuite for crystal structure solution of small, medium and large structures. A variety of phasing algorithms have been implemented, bothab initio(standard or modern direct methods, Patterson techniques,Vive la Différence) and non-ab initio(simulated annealing, molecular replacement). The program contains tools for crystal structure refinement and for the study of three-dimensional electron-density mapsviasuitable viewers.

Timing of operative management in patient with traumatic Central Cord syndrome

Objectives: Patients with traumatic central cord syndrome (TCCS) provide some of the most dramatic opportunities for neurological improvement when compared to other subgroups of SCI, particularly evident in young patients with TCCS. The purpose of this study is to review a series of patients with central cord syndrome and to corroborate the consensus about optimal treatment and surgical timing for decompression. Materials and Methods: Patients developing this suffering belong to two relative categories – the first group are relatively young patients with a high-energy injury that leads to fracture/subluxation or dislocation. The second category are older individuals who, due to a low-energy fall or cervical hyperextension injury present with TCCS that occurs in the presence of cervical spondylosis but without obvious injury to the spinal column. The main tool for refinement of the operative window was ASIA motor score. Results: Thirty-two patient were divided in two groups – patients with ASIA motor score less than or equal to 50 p. (mean – 42.4 p.) – 10, and patients with a score higher than 50 p. (mean – 67.45 p.) – 22. Patients with ASIA Mscores less than 50 p. were operated within 24 hours, but 2 patients from these – within 20 days. Patients with ASIA Mscore higher than 50 p. underwent decompression within 72 hours. All patients sustained improvement in neurological status with the exception of these two, who underwent late decompression. Discussion: These cases clearly demonstrate to what range should operative activity be targeted in patients with TCCS. Patients with ASIA Mscore 80 and above, with MRI fracture evidence and those who may have already experienced significant motor improvement between the time of injury and the moment of initial neurological evaluation, may undergo delayed surgical treatment. Conclusions: There was a recommendation based on low-quality evidence that early (as soon as feasible) surgical decompression for patients with TCCS and spondylosis should be recommended when their initial neurological impairment is significant.

Design, fabrication and testing of an apparatus for in-situ investigation of free dendritic growth under an applied electric field

Modification of dendritic growth of primary phase during solidification has been a continuous quest for materials researchers during last decades. Use of electric current during solidification has been recently proposed as a suitable tool for refinement and modification of dendritic microstructures. Mechanisms by which an electric field could affect a dendritic morphology are not entirely clear as it is difficult to study the solidification phenomena during cooling. This paper reports the design, fabrication and testing of an instrument for in-situ study of the dendritic growth of transparent model materials in the presence of an applied electric field. The system consists of an isothermal bath, a growth chamber and an optical and imaging system. The structure of the growth chamber is designed to allow the growth of only a single dendrite under the applied electric field. In contrast to some previously made instruments which use two orthogonally placed cameras to take care of dendrite tilting or rotation errors, in this research a mathematical approach for calculating the actual dimensions and growth velocity of the dendrite using only one camera was suggested. This greatly simplifies the structure of the instrument. Solidification of a transparent model material, i.e. a succinonitrile alloy, was investigated as a case study under different applied electric fields using the instrument. The results of the study showed a reduction in the dendrite tip velocity in the presence of the electric field.

Solving the wind farm layout optimization problem using random search algorithm

Wind farm (WF) layout optimization is to find the optimal positions of wind turbines (WTs) inside a WF, so as to maximize and/or minimize a single objective or multiple objectives, while satisfying certain constraints. In this work, a random search (RS) algorithm based on continuous formulation is presented, which starts from an initial feasible layout and then improves the layout iteratively in the feasible solution space. It was first proposed in our previous study and improved in this study by adding some adaptive mechanisms. It can serve both as a refinement tool to improve an initial design by expert guesses or other optimization methods, and as an optimization tool to find the optimal layout of WF with a certain number of WTs. A new strategy to evaluate layouts is also used, which can largely save the computation cost. This method is first applied to a widely studied ideal test problem, in which better results than the genetic algorithm (GA) and the old version of the RS algorithm are obtained. Second it is applied to the Horns Rev 1 WF, and the optimized layouts obtain a higher power production than its original layout, both for the real scenario and for two constructed scenarios. In this application, it is also found that in order to get consistent and reliable optimization results, up to 360 or more sectors for wind direction have to be used. Finally, considering the inevitable inter-annual variations in the wind conditions, the robustness of the optimized layouts against wind condition changes is analyzed, and the optimized layouts consistently show better performance in power production than the original layout, despite of considerable variations in wind direction and speed.

Tools for macromolecular model building and refinement into electron cryo-microscopy reconstructions.

The recent rapid development of single-particle electron cryo-microscopy (cryo-EM) now allows structures to be solved by this method at resolutions close to 3 Å. Here, a number of tools to facilitate the interpretation of EM reconstructions with stereochemically reasonable all-atom models are described. The BALBES database has been repurposed as a tool for identifying protein folds from density maps. Modifications to Coot, including new Jiggle Fit and morphing tools and improved handling of nucleic acids, enhance its functionality for interpreting EM maps. REFMAC has been modified for optimal fitting of atomic models into EM maps. As external structural information can enhance the reliability of the derived atomic models, stabilize refinement and reduce overfitting, ProSMART has been extended to generate interatomic distance restraints from nucleic acid reference structures, and a new tool, LIBG, has been developed to generate nucleic acid base-pair and parallel-plane restraints. Furthermore, restraint generation has been integrated with visualization and editing in Coot, and these restraints have been applied to both real-space refinement in Coot and reciprocal-space refinement in REFMAC.

Direct phasing of protein crystals with high solvent content.

An iterative transform method is proposed for solving the phase problem in protein crystallography. In each iteration, a weighted average electron-density map is constructed to define an estimated protein mask. Solvent flattening is then imposed through the hybrid input-output algorithm [Fienup (1982). Appl. Opt. 21, 2758-2769]. Starting from random initial phases, after thousands of iterations the mask evolves into the correct shape and the phases converge to the correct values with an average error of 30-40° for high-resolution data for several protein crystals with high solvent content. With the use of non-crystallographic symmetry, the method could potentially be extended to phase protein crystals with less than 50% solvent fraction. The new phasing algorithm can supplement and enhance the traditional refinement tools.

A simple method for the design of tension structures combining topological mapping and nonlinear structural analysis

When designing a tension structure the shape is not known at the beginning of the process. Form-finding methods allow the designer to obtain an initial shape from given boundary conditions. Several form-finding methods for tension structures are already available in the technical literature; all of them posses certain limitations and drawbacks and no single method is optimal for all problems. The engineer may select the proper combination of methods best suited to the designer’s needs. In this paper it is proposed a combined method to achieve satisfactory equilibrium configurations for fabric tension structures. The force density method (FDM) implemented with topological mapping (TM) is used as a search engine for the preliminary design, and a procedure that employs nonlinear structural analysis is proposed for final refinement of the initial equilibrium configuration hence allowing the use of the same analysis tool for both refinement of the solution and analysis under loading.

A three dimensional visualisation approach to protein heavy-atom structure reconstruction.

BackgroundA commonly recurring problem in structural protein studies, is the determination of all heavy atom positions from the knowledge of the central α-carbon coordinates.ResultsWe employ advances in virtual reality to address the problem. The outcome is a 3D visualisation based technique where all the heavy backbone and side chain atoms are treated on equal footing, in terms of the Cα coordinates. Each heavy atom is visualised on the surfaces of a different two-sphere, that is centered at another heavy backbone and side chain atoms. In particular, the rotamers are visible as clusters, that display a clear and strong dependence on the underlying backbone secondary structure.ConclusionsWe demonstrate that there is a clear interdependence between rotameric states and secondary structure. Our method easily detects those atoms in a crystallographic protein structure which are either outliers or have been likely misplaced, possibly due to radiation damage. Our approach forms a basis for the development of a new generation, visualization based side chain construction, validation and refinement tools. The heavy atom positions are identified in a manner which accounts for the secondary structure environment, leading to improved accuracy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12900-014-0027-8) contains supplementary material, which is available to authorized users.

Facilitating access to evidence: Primary Health Care Search Filter.

The evidence base developed by, and relevant to, primary health care (PHC) is rapidly increasing. With the wealth of literature available, searchers trying to find PHC-specific citations can feel overwhelmed. Flinders Filters and the Primary Health Care Research & Information Service collaborated to develop a search filter enabling efficient and effective retrieval of relevant PHC literature. Stage 1 involved developing a PHC Search Filter in the OvidSP Medline platform using a rigorous experimental methodology. The search filter was then translated for Web-based 'one-click searching' in PubMed during Stage 2. Stage 3 involved planning and implementing a mixed-methods evaluation. The search filter sensitivity was 77.0% with a post hoc relevance assessment of 78.3%. Four months after its launch, a mixed-methods study evaluated the PHC Search Filter. With 90 respondents, analysis of data from the online survey demonstrated overarching benefits, a positive response to the tool and directions for further refinement of the PHC Search Filter. Designing the PHC Search Filter followed an established method that ensures the tool offers a validated search strategy. Evaluation results suggest that the PHC Search Filter is a useful tool that is easy to navigate. Challenges for the Filter relate to access to full text articles, while challenges for the evaluation relate to the small sample size. The PHC Search Filter reduces the burden associated with literature searching, increases the value of the results that are received and provides a useful resource to improve the likelihood of incorporating relevant evidence into policy and practice.