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Results for “Process optimization”

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PubMed1993

Intrinsic nature of the three-dimensional structure of proteins as determined by distance geometry with good sampling properties.

A protocol for distance geometry calculation is shown to have excellent sampling properties in the determination of three-dimensional structures of proteins from nuclear magnetic resonance (NMR) data. This protocol uses a simulated annealing optimization employing mass-weighted molecular dynamics in four-dimensional space (Havel, T.F. (1991) Prog. Biophys. Mol. Biol., 56, 43-78). It attains an extremely large radius of convergence, allowing a random coil conformation to be used as the initial estimate for the succeeding optimization process. Computations are performed with four systems of simulated distance data as tests of the protocol, using an unconstrained L-alanine 30mer and three different types of proteins, bovine pancreatic trypsin inhibitor, the alpha-amylase inhibitor Tendamistat, and the N-terminal domain of the 434-repressor. The test of the unconstrained polypeptide confirms that the sampled conformational space is that of the statistical random coil. In the larger and more complicated systems of the three proteins, the protocol gives complete convergence of the optimization without any trace of initial structure dependence. As a result of an exhaustive conformational sampling by the protocol, the intrinsic nature of the structures generated with distance restraints derived from NMR data has been revealed. When the sampled structures are compared with the corresponding X-ray structures, we find that the averages of the sampled structures always show a certain pattern of discrepancy from the X-ray structure. This discrepancy is due to the short distance nature of the distance restraints, and correlates with the characteristic shape of the protein molecule.

Animals↗

PubMed2000

Novel inhibitors of DNA gyrase: 3D structure based biased needle screening, hit validation by biophysical methods, and 3D guided optimization. A promising alternative to random screening.

Random screening provided no suitable lead structures in a search for novel inhibitors of the bacterial enzyme DNA gyrase. Therefore, an alternative approach had to be developed. Relying on the detailed 3D structural information of the targeted ATP binding site, our approach combines as key techniques (1) an in silico screening for potential low molecular weight inhibitors, (2) a biased high throughput DNA gyrase screen, (3) validation of the screening hits by biophysical methods, and (4) a 3D guided optimization process. When the in silico screening was performed, the initial data set containing 350 000 compounds could be reduced to 3000 molecules. Testing these 3000 selected compounds in the DNA gyrase assay provided 150 hits clustered in 14 classes. Seven classes could be validated as true, novel DNA gyrase inhibitors that act by binding to the ATP binding site located on subunit B: phenols, 2-amino-triazines, 4-amino-pyrimidines, 2-amino-pyrimidines, pyrrolopyrimidines, indazoles, and 2-hydroxymethyl-indoles. The 3D guided optimization provided highly potent DNA gyrase inhibitors, e. g., the 3,4-disubstituted indazole 23 being a 10 times more potent DNA gyrase inhibitor than novobiocin (3).

Anti-Infective Agents↗

PubMed1999

Optimal stoichiometric designs of ATP-producing systems as determined by an evolutionary algorithm.

The design of metabolic pathways is thought to be the result of an optimization process such that the structure of contemporary metabolic routes maximizes a particular objective function. Recently, it has been shown that some essential stoichiometric properties of glycolysis can be explained on the basis of the requirement for a high ATP production rate. Because the number of stoichiometrically feasible designs increases strongly with the number of reactions involved, a systematic analysis of all the possibilities turns out to be inaccessible beyond a certain system size. We present, therefore, an alternative approach to compute in a more efficient way the optimal design of glycolysis interacting with an external ATP-consuming reaction. The algorithm is based on the laws of evolution by natural selection, and may be viewed as a particular version of evolutionary algorithms. The following conclusions are derived: (a) evolutionary algorithms are very useful search strategies in determining optimal stoichiometries of metabolic pathways. (b) Essential topological features of the glycolytic network may be explained on the basis of flux optimization. (c) There is a strong interrelation between the optimal stoichiometries and the thermodynamic and kinetic properties of the participating reactions. (d) Some subsequences of reactions in optimal pathways are strongly conserved at variation of system parameters, which may be understood by applying principles of metabolic control analysis.

Adenosine Triphosphatases↗

PubMed1995

Optimization of intensity-modulated 3D conformal treatment plans based on biological indices.

To overcome the limitations of the intensity modulation optimization techniques based on dose criteria, we introduce a method for optimizing intensity distributions in which we employ an objective function based on biological indices. The objective function also includes constraints on dose and dose-volume combinations to ensure that the results are consistent with the physician's judgement. We apply a variant of the steepest-descent method to optimize the objective function. The method is three-dimensional and incorporates scattered radiation in the optimization process using an iterative scheme employing the pencil beam convolution method. Previously we had shown that the inverse technique of obtaining optimum intensity distributions, for which the objectives are defined in terms of a desired uniform dose to the target volume and desired upper limits of dose to normal organs, produces satisfactory approximations of the desired dose distributions for prostate plans. However, for lung, the performance of this technique was considerably inferior. Our conclusion was that, in general, it is not sufficient to specify the objectives of optimization purely in terms of a desired pattern of dose and that the objectives should also incorporate biology, perhaps in the form of biological indices. We demonstrate that the biology-based approach produces lung plans that are superior to those produced when only dose-based objectives are used. For the treatment of prostate, the two methods produce comparable dose distributions.

Adenocarcinoma↗

PubMed2003

A two-stage interval-stochastic programming model for waste management under uncertainty.

This study introduces a two-stage interval-stochastic programming (TISP) model for the planning of solid-waste management systems under uncertainty. The model is derived by incorporating the concept of two-stage stochastic programming within an interval-parameter optimization framework. The approach has the advantage that policy determined by the authorities, and uncertain information expressed as intervals and probability distributions, can be effectively communicated into the optimization processes and resulting solutions. In the modeling formulation, penalties are imposed when policies expressed as allowable waste-loading levels are violated. In its solution algorithm, the TISP model is converted into two deterministic submodels, which correspond to the lower and upper bounds for the desired objective-function value. Interval solutions, which are stable in the given decision space with associated levels of system-failure risk, can then be obtained by solving the two submodels sequentially. Two special characteristics of the proposed approach make it unique compared with other optimization techniques that deal with uncertainties. First, the TISP model provides a linkage to predefined policies determined by authorities that have to be respected when a modeling effort is undertaken; second, it furnishes the reflection of uncertainties presented as both probabilities and intervals. The developed model is applied to a hypothetical case study of regional solid-waste management. The results indicate that reasonable solutions have been generated. They provide desired waste-flow patterns with minimized system costs and maximized system feasibility. The solutions present as stable interval solutions with different risk levels in violating the waste-loading criterion and can be used for generating decision alternatives.

Environment↗

PubMed1999

Eye movements reflect impaired face processing in patients with schizophrenia.

BACKGROUND: Impaired processing of faces in patients with schizophrenia may underlie aspects of disturbance in their social interaction. This study examined patterns of eye fixation in subjects with schizophrenia and non-psychiatric controls, while processing a high resolution picture of a neutral face and a nonbiological complex geometric stimulus. METHODS: Ten-second sequences of eye movement were recorded video-oculographically (50 samples/sec) while subjects were "free-viewing" the stimuli. An essential element of the study was customized software that ensured stimulus presentation on a video display only after subjects were fixated upon a centre-screen cue, so that all subjects began stimulus processing from the same point. RESULTS: Compared with the control group, subjects with schizophrenia exhibited reduced scanpath lengths and a tendency toward fewer fixations for the face stimulus. They also showed an initial relative right spatial hemineglect (for the first voluntary fixation) when viewing the Rey figure, but not when viewing the face stimulus. Overall, there were no significant differences between the schizophrenia and control groups in the lateral distribution of subsequent fixations for either stimulus. CONCLUSIONS: Disturbed spatial and temporal patterns of eye movement in some people with schizophrenia may reflect sub-optimal processing of face stimuli, that may predispose these individuals to dysfunctional interpretation of facial communication cues.

Adult↗

PubMedDate not supplied

Separation and determination of beta-lactoglobulin variants A and B in cow's milk by capillary free zone electrophoresis.

beta-Lactoglobulin is a whey protein that can be present in at least two genetic variant forms that determine milk composition and product functionality. A free zone capillary electrophoresis (CZE) method was optimized to separate, identify, and quantify beta-lactoglobulin (beta-Lg) A and B variants in milk. Whey proteins were prepared by casein precipitation at pH 4.6. The experimental conditions such as sample preparation, injection size, pH, voltage, and capillary length and temperature were determined after a univariate optimization process. alpha-Lactoalbumin (alpha-La), beta-Lg A, and beta-Lg B were separated in an uncoated capillary using 0.05 M borate buffer containing 0.1% Tween 20 (Sigma Chemical Co., St. Louis, MO, U.S.A.) at pH 8.0 by applying 25 kV. Repeatability was excellent, since variation coefficients for migration times and peak areas were <0.98 and <1.33%, respectively. Identification of the individual proteins was confirmed by spiking with commercially purified standards. Linearity of the method was demonstrated by constructing calibration curves that followed linear relationships with highly significant (p < 0.01) correlation coefficients. Optimized conditions were used for phenotyping and quantifying beta-Lg in milk collected from Holstein cows. The concentration ranges of the individual beta-Lg A and B variants determined in the AA and BB phenotypes were 5.9-6.02 and 3.43-5.48 mg/mL, respectively. In the AB phenotypes, the range was 1.05-5.46 mg/mL for beta-Lg B and 0.37-4.05 mg/mL for beta-Lg A. The frequency of beta-Lg AA, BB, and AB phenotypes were 0.03, 0.10, and 0.86, respectively. The quantitative determination of beta-Lg variants may be useful in establishing statistical correlations between genetic polymorphism of this protein and milk composition.

Animals↗

PubMed1994

Glutathione disulfide variability in normal human blood.

A prevailing opinion is that glutathione disulfide (GSSG) levels in human blood are very low, but many studies have reported variable results. Therefore, our objective was to determine valid processing conditions for GSSG measurement and apply them to normal human blood samples. Reproducibility and stability of GSSG were demonstrated in acid extracts of a single sample of fresh whole blood by repetitive measurements during a 6-h period in which the %CVs were < 10. In contrast, in normal subjects tested repeatedly over several years, GSSG values ranging from < 2 to 166 nmol per 10(10) red blood cells were obtained and the overall %CV was 46. Lower GSSG values were obtained in hemolysates and ultrafiltrates. Thus, these results indicate that blood GSSG concentrations differ due to biological variation using optimal processing conditions.

Adult↗

PubMed2001

[Cornea bank of Lyon: from quality diagnosis to ISO 9001 certification].

The tissue and cell bank of the HCL (Hospices Civils de Lyon) has, since 10 June 1999, consisted of two sections with related activities: cell culture for the Skin Substitutes Laboratory (Laboratoire des Substituts Cutanés, LSC) and preservation of corneas at 31 degrees C for the Cornea Bank. As the LSC had been ISO 9001 certified since March 1997 our aim, since merger, was to raise the Cornea Bank to the same level of quality as the LSC, so as to coincide with the renewal of the LSC certificate in February 2000. The methods we used (project, quality control, analysis and process optimization) led us to receive official certification only nine months after the merger. The procedure started with a program of quality control at the Cornea Bank from February 1999 onwards, in order to list the work and equipment required, evaluate its documentation system and what was needed to incorporate this new activity into the existing system of quality assurance at the LSC. On the 7th March 2000, the Tissue and Cell Bank of the HCL obtained an ISO 9001 certificate for its combined functions. As well as achieving our objectives and the strong points highlighted by the auditor during the renewal process, this quality assessment revealed many advantages: improvements in the conservation of corneas, economies in staff replacement and reductions in both the cost of maintaining quality, the cost of the corneas themselves, etc. The decree 'Banque' no. 99-741 of 30th August 1999, which put in place the system of authorization of tissue banks in France, demands quality control. Our application for certification which started in early 1999 had anticipated this regulation. This helped us enormously when compiling the dossier accompanying the official request and was an essential element in obtaining the favourable response of the ASSAPS on 21 June 2000.

Certification↗

PubMed2002

Optimization of the isoelectric precipitation method to obtain protein isolates from amaranth (Amaranthus cruentus) seeds.

This research was conducted to evaluate the effect of extraction pH (7.8-9.2) and precipitation pH (4.3-5.7) on four selected quality attributes of protein isolates from amaranth seeds (Amaranthus cruentus) such as protein content (PC), whiteness index (WI), enthalpy of transition (EN), and denaturation temperature (DT). Ten different treatments involving extraction and precipitation pH combinations were analyzed by a central composite design; the experimental data were fitted by a second-order model using a least-squares method for each one of the four dependent variables. Response surface methodology was used for the optimization process; in addition, a common optimum value for the four dependent variables was obtained utilizing the desirability method. A confirmatory test showed that the generated regression equations could adequately predict performance of this isoelectric precipitation method. The results indicate that extraction pH and precipitation pH showed an important effect on PC, WI, and EN. However, the different combinations did not significantly affect the DT. Values of 9.2 and 8.0 for extraction pH and 5.7 for precipitation pH produced the best overall result for all responses. Finally, the results have shown that it is possible to obtain protein isolates from A. cruentus seeds at optimized values of extraction pH and precipitation pH, which presented a high protein content and good physicochemical properties.

Amaranthus↗

PubMed1996

[Experimental orthopedic surgery: the practical aspects and management].

The funds to grant for a scientific research project are more and more interesting public and private administrations. A quantitative analysis of experimental research prices in all its phases is mandatory for an optimization process. The aim of this paper is to define practical and economical aspects of the experimental 'in vivo' models designed for the validation of biomaterials, with particular respect to the managerial bookkeeping of consumer goods, based on the experience of our Institute. Some tables were realized in order to quantify the resources needed to perform experimental 'in vivo' models. These tables represent a reliable tool for a continuous monitoring of managerial costs for the current year and for an accurate budget planning for the future years considering the experimental projects in progress and the planned researches. A business organization of public research facilities may lead to an optimization of costs and an easier national and international funds achievement increasing, also, the partnership with private appointers.

Animals↗

PubMed1997

Tandem repeats of T helper epitopes enhance immunogenicity of fusion proteins by promoting processing and presentation.

Empirical findings have shown that recombinant chimeric proteins may be made more immunogenic if T helper epitopes are incorporated as tandem repeats. In the present study we investigated the mechanisms responsible for the enhanced immunogenicity of fusion proteins composed of the heat-stable enterotoxin of enterotoxigenic E. coli (STa) linked to multiple copies of the ovalbumin323-339 T helper epitope (ova) and a connecting dimer of an Ig-binding region of Staphylococcus aureus protein A (ZZ), which were previously shown to stimulate strong anti-STa titres in mice. We used B cell and macrophage cell lines as APC and IL-2 production by ova-specific T cells as our read-out system. Fusion proteins containing four repeated T helper epitopes were found to be the most immunogenic and resulted in 50-fold higher IL-2 production than constructs with a single T helper epitope. Under limiting APC conditions the construct with four epitopes was the best inducer of IL-2, indicating that this construct was most effectively processed by the APC. Analysis of IL-2R alpha expression by flow cytometry confirmed that four copies gave the highest frequency of activated T cells in culture, indicating a direct correlation between ability to activate T cells and IL-2 production in culture. Also in vivo, the fusion protein with four epitopes exhibited the strongest T cell priming effect. Moreover, both in vitro and in vivo, the ZZ construct was found to serve as an efficient means for targeting of the fusion proteins to B cells, thereby allowing access to the Ig receptor uptake pathway for Ag. The present study provides direct evidence that fusion proteins can be constructed to optimize processing in the individual APC and enhance activation of clonal T cells.

Animals↗

PubMed2003

Method development in high-performance liquid chromatography for high-throughput profiling and metabonomic studies of biofluid samples.

"Metabonomics" has in the past decade demonstrated enormous potential in furthering the understanding of, for example, disease processes, toxicological mechanisms, and biomarker discovery. The same principles can also provide a systematic and comprehensive approach to the study of food ingredient impact on consumer health. However, "metabonomic" methodology requires the development of rapid, advanced analytical tools to comprehensively profile biofluid metabolites within consumers. Until now, NMR spectroscopy has been used for this purpose almost exclusively. Chromatographic techniques and in particular HPLC, have not been exploited accordingly. The main drawbacks of chromatography are the long analysis time, instabilities in the sample fingerprint and the rigorous sample preparation required. This contribution addresses these problems in the quest to develop generic methods for high-throughput profiling using HPLC. After a careful optimization process, stable fingerprints of biofluid samples can be obtained using standard HPLC equipment. A method using a short monolithic column and a rapid gradient with a high flow-rate has been developed that allowed rapid and detailed profiling of larger numbers of urine samples. The method can be easily translated into a slow, shallow-gradient high-resolution method for identification of interesting peaks by LC-MS/NMR. A similar approach has been applied for cell culture media samples. Due to the much higher protein content of such samples non-porous polymer-based small particle columns yielded the best results. The study clearly shows that HPLC can be used in metabonomic fingerprinting studies.

Body Fluids↗

PubMed1995

N-acyl-2-substituted-1,3-thiazolidines, a new class of non-narcotic antitussive agents: studies leading to the discovery of ethyl 2-[(2-methoxyphenoxy)methyl]-beta-oxothiazolidine-3-propanoate.

The synthesis of a novel class of antitussive agents is described. The compounds were examined for antitussive activity in guinea pig after cough induction by electrical or chemical stimulation. Ethyl 2-[(2-methoxyphenoxy)methyl]-beta-oxothiazolidine-3-propanoate (BBR 2173, moguisteine, 7) and other structurally related compounds showed a significant level of activity, comparable to that of codeine and dextromethorphan. The compounds presented in this paper are characterized by the N-acyl-2-substituted-1,3-thiazolidine moiety, which is a novel entry in the field of antitussive agents. The serendipitous discovery of the role played by the thiazolidine moiety in determining the antitussive effect promoted extensive investigations on these structures. This optimization process on N-acyl-2-substituted-1,3-thiazolidines led to the initial identification of 2-[(2-methoxypheoxy)methyl]-3-[2-(acetylthio)acetyl]- 1,3-thiazolidine (18a) as an interesting lead compound. The careful study of the rapid and very complicated metabolism of 18a provided further insights for the design of newer related derivatives. The observation that the metabolic oxidation on the lateral chain's sulfur of 18a to sulfoxide maintained the antitussive properties suggested the introduction of isosteric functional groups with respect to the sulfoxide moiety. Subsequent structural modifications showed that hydrolyzable malonic residues in the 3-position of the thiazolidine ring were able to assure high antitussive activity. This optimization ultimately led to the selection of moguisteine (7) as the most effective and safest representative of the series. Moguisteine is completely devoid of unwanted side effects (such as sedation and addiction), and its activity was demonstrated also in clinical studies.

Animals↗

PubMed1996

Evaluating sol-gel ceramic thin films for metal implant applications. I. Processing and structure of zirconia films on Ti-6AI-4V.

Thin ceramic films or coatings over metallic bone-interfacing implant surfaces have the potential to improve implant performance with respect to implant fixation, wear, or corrosion. In this study, zirconia (ZrO2) thin films formed on Ti-6AI-4V using a polymeric alkoxide-based solgel process were investigated. ZrO2 films of uniform thickness on the order of 100 nm were obtained by dip coating Ti-6AI-4V samples into a zirconium propoxide containing solution using a substrate withdrawal speed ranging from 2 to 8 cm/min and a sol of nominal viscosity approximately 6 cps. These films were essentially free of surface macrodefects but had random submicron "pinholes." X-ray diffraction studies suggested that the films were at least partially crystalline, with some "metastable" cubic and/or tetragonal phases after annealing for 1 h at 500 degrees C. The demonstrated reproducibility of this approach for producing good quality ZrO2 films on Ti-6AI-4V warrants further studies to optimize processing conditions for implant applications.

Alloys↗

PubMed2002

Sulfur polymer solidification/stabilization of elemental mercury waste.

Elemental mercury, contaminated with radionuclides, presents a waste disposal problem throughout the Department of Energy complex. In this paper we describe a new process to immobilize elemental mercury wastes, including those contaminated with radionuclides, in a form that is non-dispersible, will meet EPA leaching criteria, and has low mercury vapor pressure. In this stabilization and solidification process, elemental mercury is combined with an excess of powdered sulfur polymer cement (SPC) and sulfide additives in a mixing vessel and heated to approximately 40 degrees C for several hours, until all of the mercury is converted into mercuric sulfide (HgS). Additional SPC is then added and the temperature of the mixture raised to 135 degrees C, resulting in a molten liquid which is poured into a mold where it cools and solidifies. The final treated waste was characterized by powder X-ray diffraction and found to be a mixture of the hexagonal and orthorhombic forms of mercuric sulfide. The Toxicity Characteristic Leaching Procedure was used to assess mercury releases, which for the optimized process averaged 25.8 microg/l, with some samples being well below the new EPA Universal Treatment Standard of 25 microg/l. Longer term leach tests were also conducted, indicating that the leaching process was dominated by diffusion. Values for the effective diffusion coefficient averaged 7.6x10(-18) cm2/s. Concentrations of mercury vapor from treated waste in equilibrium static headspace tests averaged 0.6 mg/m3.

Diffusion↗

PubMed2001

The contribution of combinatorial chemistry to lead generation: an interim analysis.

In the process of finding new drug candidates medicinal chemists nowadays have a variety of options to choose from, one is to apply combinatorial chemistry techniques. Since the early 1990's synthetic and analytical methods as well as new technologies have been growing rapidly in the area of combinatorial chemistry. Applying these techniques have resulted in the production of large numbers of compounds. A trend is observed towards smaller libraries of compounds with more drug-like properties. An analysis is made to establish the contribution of combinatorial chemistry in providing new lead candidates for (pre)clinical development towards new pharmaceutical products. Ten representative examples are given to describe the impact of ombinatorial chemistry on different levels of the lead discovery and optimization process. Furthermore, reports on combinatorial chemistry products that are already in (pre)clinical development were traced back to their source. The interim analysis showed only limited success of combinatorial chemistry approaches in terms of delivering leads. Second generation libraries appear more drug-like and focussed and may result in more compounds entering clinical studies in the future.

Combinatorial Chemistry Techniques↗

PubMed1980

[Correlative neuropsychology & neurobiology by evoked potentials in central nervous aging process (author's transl)].

Evoked potentials (VEP, SEP) in 40 elderly patients, who were in different states of vitality and aged from 71 to 95, were recorded and analysed. Specific neuronal activity of the cortex on the one hand and neuropsychological and clinical parameters on the other hand should be correlated. No correlation between SEP and the results of neuropsychological assessment had been suggested, and there was not any. Regular VEP correlate significantly with both, prompt time of reaction and a good psychological performance in the reduced Wechsler Adult Intelligence Scale (WAIS). The results do not provide a neurophysiological parameter of intellectual faculties. Regular VEP and SEP, however, mean that the visual and somatosensory cortex and subcortex has not been impaired to any extent. In other words normal VEP and SEP suggest normal mental and motor ability. This, "state of vitality" and neurobiological items as "mental flexibility" and "sensomotor flexibility" operationalised and defined may be related to recorded function of the neuron, respectively. Basically, the results seem to confirm that a specific optimated process, which has been succeeded in a human ecological relation between "activity and performance", and intact neuronal function does appear, even if the primary spectrum of adaption that is caused by aging might be narrowed and easy to be disturbed altogether.

Aged↗