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PubMed1994

The rational design of amino acid sequences by artificial neural networks and simulated molecular evolution: de novo design of an idealized leader peptidase cleavage site.

A method for the rational design of locally encoded amino acid sequence features using artificial neural networks and a technique for simulating molecular evolution has been developed. De novo in machine design of Escherichia coli leader peptidase (SP1) cleavage sites serves as an example application. A modular neural network system that employs sequence descriptions in terms of physicochemical properties has been trained on the recognition of characteristic cleavage site features. It is used for sequence qualification in the design cycle, representing the sequence fitness function. Starting from a random sequence several cleavage site sequences were generated by a simulated molecular evolution technique. It is based on a simple genetic algorithm that takes the quality values calculated by the artificial neural network as a heuristic for inductive sequence optimization. Simulated in vivo mutation and selection allows the identification of predominant sequence positions in Escherichia coli signal peptide cleavage site regions (positions -2 and -6). Various amino acid distance maps are used to define metrics for the step size of mutations. Position-specific mutability values indicate sequence positions exposed to high or low selection pressure in the simulations. The use of several distance maps leads to different courses of optimization and to various idealized sequences. It is concluded that amino acid distances are context dependent. Furthermore, a method for identification of local optima during sequence optimization is presented.

Algorithms↗
PubMed1978

Internal mammary lymphoscintigraphy: a rational adjunct to the staging and management of breast carcinoma.

Radionuclide lymphoscintigraphy utilising the bilateral subcostal introduction into the posterior rectus sheath of a small volume of radiocolloid of suitable particle size (99mTc antimony colloid) has provided scintigraphic images of diagnostic quality of the parasternal nodes in 2328 patients with malignant disease. An evaluation of the use of this technique in 1072 patients with breast carcinoma underlines the value of a procedure which, utilised routinely, should alter conventional staging criteria and provide a more rational basis for the management of patients with breast carcinoma and assessment of end results.

Axilla↗
PubMed2002

Conversion of the dimeric D-amino acid oxidase from Rhodotorula gracilis to a monomeric form. A rational mutagenesis approach.

The relevance of the dimeric state for the structure/function relationships of Rhodotorula gracilis D-amino acid oxidase (RgDAAO) holoenzyme has been investigated by rational mutagenesis. Deletion of 14 amino acids in a surface loop (connecting beta-strands 12 and 13) transforms RgDAAO from a dimeric protein into a stable monomer. The mutant enzyme is still catalytically competent and retains its binding with the FAD coenzyme. Dimerization has been used by this flavoenzyme in evolution to achieve maximal activity, a tighter interaction between the protein moiety and the coenzyme, and higher thermal stability.

Amino Acid Sequence↗
PubMed2000

Novel approaches in the rational design of antifungal agents of low toxicity.

This paper presents an overview of studies on novel strategies for the rational design of antifungal agents of low toxicity and overcoming the multidrug resistance (MDR) of fungi. This goal was achieved both due to the introduction of a novel target, glucosamine-6-phosphate synthase, as well as to the recognition of molecular basis of selectivity of action of amphotericin B derivatives.

Antifungal Agents↗
PubMed1999

Biochemical aspects of egg hatch in endo- and ectoparasites: potential for rational drug design.

Control of parasites through rational drug design requires a thorough understanding of the parasite's lifecycle encompassing the biochemical and physiological processes which contribute to normal parasite homeostasis. The hatching of parasite eggs for example, represents an important process in the development of a parasitic infection. Previous studies in helminths have indicated that secreted enzymes often facilitate successful endoparasite egg hatch. In contrast, there are relatively few examples demonstrating a role for secreted enzymes in the egg hatching process of insects. An analysis of this process in the ectoparasite Lucilia cuprina suggests a role for secreted enzymes in the hatching of sheep blowfly eggs. Characterisation of the proteases collected at the time of egg hatch indicates the presence of serine proteases. Further purification and characterisation of these proteases may enable the design of specific inhibitors to interfere with the egg hatch process and therefore provide a novel means of control.

Animals↗
PubMed2003

Characterisation of reversed-phase liquid chromatographic columns by chromatographic tests. Rational column classification by a minimal number of column test parameters.

The European Pharmacopoeia (Ph. Eur.) and other official compendia give only a general description of the stationary phase in the description of a liquid chromatographic method. Therefore the selection of a column giving suitable selectivity presents difficulties. Earlier, a test procedure was proposed that allows to measure 36 chromatographic parameters which have been described for characterising stationary phases. This procedure was carried out on 69 reversed-phase liquid chromatography (RP-LC) columns. This paper focuses on the classification of RP-LC stationary phases based on chromatographic parameters. A chemometric study was conducted using 24 parameters that could be measured in a repeatable and reproducible way. Principal component analysis was used to classify the columns and to estimate the minimal number of parameters necessary for a rational classification. It is shown that after reducing the number of parameters from 24 to four or three, similar classifications were obtained. The column classifications were compared to the European Pharmacopoeia stationary phase description and to the column properties obtained from the manufacturers.

Chromatography, Liquid↗
PubMed2002

Rationalization of gene regulation by a eukaryotic transcription factor: calculation of regulatory region occupancy from predicted binding affinities.

DNA-binding proteins regulate gene expression by binding preferentially to a set of related sequences. In order to quantify the correlation between gene regulation and the presence of sequence motifs, the affinity of a transcription factor for each variant of the binding site must be known or predicted. In addition, the contribution of multiple binding sites to the regulation of a single gene must be modeled. To predict the affinity of the yeast Leu3 transcription factor for genomic-binding sites, we measured the in vitro equilibrium dissociation constants of 43 binding-site variants and established that the free energy of binding can be approximated as a sum of free energy contributions from each base-pair. This allows the prediction of an equilibrium dissociation constant for all potential binding sites in the genome and, therefore, their fractional occupancy at some assumed concentration of free Leu3. From the occupancy of individual sites, the probability that at least one site is occupied within a defined segment upstream of a gene was calculated for all genes in yeast. We find that this probability is substantially better correlated with regulation by Leu3 than is the number of binding sites. This is true whether the number of binding sites is based on a consensus site definition of the binding site or by enumeration of all variants that have a predicted K(d) value below some threshold. The occupancy calculation was best able to rationalize the Leu3-regulated gene set over a Leu3 concentration range that spans the K(d) values for the best sites.

Base Sequence↗
PubMed1997

Making a rational diagnosis of growth-hormone deficiency.

Growth hormone (GH) has been available for therapeutic use for more than 30 years, but there is still considerable debate about the best way to diagnose GH deficiency. This can be attributed to the existence of a variable degree of GH insufficiency in most cases and the fact that assays vary considerably between laboratories in terms of sensitivity and epitope specificity. These difficulties are compounded by the episodic nature of GH secretion and our reliance on a variety of provocative tests. A workshop and consensus report held in Portland, Oregon, in 1995 highlighted these issues and suggested a rational diagnostic approach that emphasizes good auxologic evidence, followed by assays of insulin-like growth factor I and insulin-like growth factor binding protein 3 to identify abnormalities in the GH axis. Actual assays of GH, during some provocative tests, are relegated to confirming that an identified abnormality in the GH-insulin-like growth factor axis is related to GH insufficiency rather than to GH resistance.

Epitopes↗
PubMed1998

Organizational considerations for an electronic curriculum. Part I: A rational nosology for concept management in dentistry.

STATEMENT OF PROBLEM: With the use of multimedia electronic knowledge as a tool in dental education, an overriding concern has centered on how to devise an organizational model that will accommodate the vast and diverse arrays of information involved, yet be sufficiently simple enough to provide students with a rational and consistent means of accessing the information they require. By adopting the natural history of the diseases dentists are called on to address as a common organizing principle, it becomes possible to link all concepts that relate to individual problem areas through a technique of retro-mapping. PURPOSE: The purpose of this article is to introduce learners to a cognitive "scaffolding" that will assist them in achieving a deeper cognitive dimension for problem solving.

Curriculum↗
PubMed1999

Rationalization of incisor shape: experimental-numerical analysis.

STATEMENT OF PROBLEM: Moving from the posterior segment in the anterior direction within the dental arch, the process of "incisivization" takes place. The occlusal table is gradually replaced by an incisal edge that has the function of cutting. PURPOSE: This study considers these genetically controlled changes by using strain gauge measurements and finite element analyses to rationalize the clinical and biologic advantages of incisal form. A direct clinical link in the common esthetic procedure of anterior veneering is expected. MATERIAL AND METHODS: Six maxillary incisors were mounted in a positioning device and equipped with 2 strain gauges bonded to the palatal surface: gauge 1 (G1) in the concavity and gauge 2 (G2) on the cingulum. A 50 N load was applied on the palatal side of the incisal edge, perpendicular to the long axis of the tooth. Displacement of the load tip and the palatal strain were recorded after successively removing one third, two thirds, and the total thickness of the facial enamel. The same experiment was reproduced with the finite element method (FEM). Four additional experimental designs were tested with the FEM by simulating the progressive thinning and elimination of palatal enamel and a thickened palatal lobe. Surface tangential stresses and local strain in the area corresponding to gauges 1 and 2 were calculated from the postprocessing files. RESULTS: The FEM was validated by experimental results considering both displacement of the load tip ( approximately 120 +/- 30 microm) and tangential surface strain at G1/G2. Recorded strains were always higher in the concavity when compared with the cingulum; high tensile strains were recorded at G1 after the total removal of the facial enamel. The entire facial surface was submitted to compressive forces. Subsequent compressive stresses were higher ( approximately 150 MPa) when facial enamel was thin or when the palatal enamel was removed. However, their absolute value never reached the elevated and potentially harmful tensile stresses measured in the palatal concavity, especially in the absence of facial enamel (272 MPa). Multiple experimental cracks were generated in the remaining palatal enamel as a consequence of stress redistribution. However, smooth and convex surfaces with local enamel bulk such as the cingulum, the marginal ridges, and the facial cervical third of the anatomic crown showed the lowest stress level. The optimal configuration with regard to the stress pattern was given by the modified natural tooth that exhibited thick palatal enamel and a mostly convex palatal surface. CONCLUSIONS: Palatal concavity that provides the incisor with its sharp incisal edge and cutting ability proved to be an area of stress concentration. This shortcoming can be compensated by specific areas that feature thick enamel such as the cingulum and the marginal ridges. When enamel is worn or removed from the facial surface, its replacement should be carried out by using materials with properties similar to enamel to restore the original biomechanical behavior of the tooth.

Compliance↗
PubMed1991

The paradox of the adventurous young and the cautious old: natural selection vs. rational calculation.

Younger people are more adventurous and less willing to reduce the risk to life. This seems to be fitness reducing since the gene cannot be passed on if one dies before leaving offsprings. However, due to the cumulative nature of knowledge and the complementarity of learning and adventurousness, it is shown in a simple model that it enhances fitness. Nevertheless, the higher willingness of the old to pay to reduce the risk to life may also be due to the rational calculation of expected utility maximization. A positive real rate of interest makes accumulation of wealth desirable and hence may make the dollar value of life increase dramatically until a fairly old age. Even if the lifetime earnings of everyone are the same and everyone can lend and borrow at the same rate of interest, the old may be willing to pay much more to reduce the risk to life.

Aging↗
PubMed2001

Toward a rational understanding of migraine trigger factors.

The typical migraine patient is exposed to a myriad of migraine triggers on a daily basis. These triggers potentially can act at various sites within the cerebral vasculature and the central nervous system to promote the development of migraine headache. The challenge to the physician is in the identification and avoidance of migraine trigger factors within patients suffering from migraine headache. Only through a rational approach to migraine trigger factors can physicians develop an appropriate treatment strategy for migraine patients.

Diagnosis, Differential↗
PubMed2001

Safety and rational use of the triptans.

The safety of the triptans has been established, with more than 8 million patients treating greater than 340 million attacks with sumatriptan alone. All triptans narrow coronary arteries by 10% to 20% at clinical doses and should not be administered to patients with coronary or cerebrovascular disease. Some triptans have the potential for significant drug-drug interactions (sumatriptan, rizatriptan, and zomitriptan and monoamine oxidase inhibitors; rizatriptan and propanolol; zolmitriptan and cimetidine; and eletriptan and CYP3A4 metabolized medications and p-glycoprotein pump inhibitors). Rational use of triptans should be governed by the use of these medications for patients with disability associated with migraine. Patients with greater than 10 days of at least 50% disability during 3 months have benefited from treating with triptans as their first-line treatment for acute attacks. When the decision has been made to treat with a triptan, the patient should be instructed to treat early in the attack, when the pain is at a mild phase. This approach increases the likelihood of achieving a pain-free response, with fewer adverse events and lower likelihood of the headache recurring.

Adverse Drug Reaction Reporting Systems↗
PubMed1983

Pharmacologic basis for developing rational drug regimens for elderly patients.

Changes in responsiveness with age have been observed for autonomic drugs (agonists as well as antagonists, analgesics, anticonvulsants, bronchodilators, hypoglycemics, corticosteroids, and virtually every other group of drugs). As indicated earlier, however, this review is not meant to present an exhaustive treatment of the area, but rather to focus attention on the factors that contribute to alterations in sensitivity. As a secondary aim, the review serves to focus attention on the problem of adverse drug reactions, particularly those related to the practice of polypharmacy, which compounds the problem through drug interactions. As indicated in the introduction, adverse drug reactions (undesired or unwanted effects of drugs) occur more frequently in the older patient than in the young one. In the elderly, this relates to increased use of drugs, polypharmacy, diminution in the function of organs which play a role in drug distribution and elimination, and poor patient compliance. Drugs which most often result in adverse reactions in the elderly have been listed by Lamy (Table 1). It is of significance that this list includes many drugs that are obtainable over the counter without prescription, such as aspirin and antacids. Because of the widespread practice of polypharmacy in the elderly, there is an increased potential for drug interactions. Examples of drugs and the mechanisms whereby interactions occur, which are of particular significance in geriatric therapeutics, are provided in Table 3. Since monographs summarizing drug interactions have been available for a number of years, it is somewhat surprising that the magnitude of the problem is still so great. It appears clear that the more we understand about the basic changes that occur in the physiology, biochemistry, and structure of an organism as it ages, and the more we learn about basic pharmacologic principles, the better we can combine the knowledge toward the development of rational therapeutic drug regimens for the geriatric patient. For more detailed discussion, the reader is referred to Caird et al., Kayne, Vestal, Lamy, and Poe and Holloway. A summary of the major principles in prescribing drugs for the elderly, quoted from Riley, is provided in Table 2.

Age Factors↗
PubMed2000

Balance function testing: a rational approach.

Recent advances in the area of balance function testing have left clinicians with a wide variety of diagnostic tests that provide insights into the function of the balance system. Laboratory tests used to evaluate the balance system include electronystagmography, rotational chair, and dynamic posturography. This article summarizes the currently available balance function testing protocols. A cost-effective and rational protocol for the application of these tests is provided.

Caloric Tests↗
PubMed1989

Lytic/"DPT" cocktail: time for rational and safe alternatives.

These therapeutic approaches to the premedication of children, in our opinion, offer a more rational, probably safer, and at least equally efficacious treatment regimen as the DPT/lytic cocktail. It is understood that controlled, double-blind comparative clinical trials in children are needed of these or other potential premedicant regimens for specific pediatric procedures (e.g., cardiac catheterization, CT scans, bone marrow aspiration, gastrointestinal endoscopy, pleural taps, etc.) to establish the premedication treatment(s) with the greatest benefit-to-risk ratio. Until these data are available, we must maintain prudence in the selection (design) of premedicant regimens and carefully monitor all children receiving these "cocktails."

Child↗
PubMedDate not supplied

Rational use of drugs against Plasmodium falciparum.

Recent studies on resistance to blood schizontocides in Plasmodium falciparum give a rational basis for the use of artemisinins combined with arylaminoalcohols for the treatment of uncomplicated chloroquine-resistant malaria in Africa. In areas where such combinations are introduced, there is reason to believe that the continued use of chloroquine in the community will help protect the new drugs from resistance. In view of several laboratory studies, combinations of artemisinins with antifolates or chloroquine pose a risk of antagonistic interaction. This can be avoided by use of the artemisinin and the companion drug sequentially.

Animals↗
PubMed2000

Rational evolutionary design: the theory of in vitro protein evolution.

Directed evolution uses a combination of powerful search techniques to generate proteins with improved properties. Part of the success is due to the stochastic element of random mutagenesis; improvements can be made without a detailed description of the complex interactions that constitute function or stability. However, optimization is not a conglomeration of random processes. Rather, it requires both knowledge of the system that is being optimized and a logical series of techniques that best explores the pathways of evolution (Eigen et al., 1988). The weighing of parameters associated with mutation, recombination, and screening to achieve the maximum fitness improvement is the beginning of rational evolutionary design. The optimal mutation rate is strongly influenced by the finite number of mutants that can be screened. A smooth fitness landscape implies that many mutations can be accumulated without disrupting the fitness. This has the effect of lowering the required library size to sample a higher mutation rate. As the sequence ascends the fitness landscape, the optimal mutation rate decreases as the probability of discovering improved mutations also decreases. Highly coupled regions require that many mutations be simultaneously made to generate a positive mutant. Therefore, positive mutations are discovered at uncoupled positions as the fitness of the parent increases. The benefit of recombination is twofold: it combines good mutations and searches more sequence space in a meaningful way. Recombination is most beneficial when the number of mutants that can be screened is limited and the landscape is of an intermediate ruggedness. The structure of schema in proteins leads to the conclusion that many cut points are required. The number of parents and their sequence identity are determined by the balance between exploration and exploitation. Many disparate parents can explore more space, but at the risk of losing information. The required screening effort is related to the number of uphill paths, which decreases more rapidly for rugged landscapes. Noise in the fitness measurements causes a dramatic increase in the required mutant library size, thus implying a smaller optimal mutation rate. Because of strict limitations on the number of mutants that can be screened, there is motivation to optimize the content of the mutant library. By restricting mutations to regions of the gene that are expected to show improvement, a greater return can be made with the same number of mutants. Initial studies with subtilisin E have shown that structurally tolerant positions tend to be where positive activity mutants are made during directed evolution. Mutant fitness information is produced by the screening step that has the potential to provide insight into the structure of the fitness landscape, thus aiding the setting of experimental parameters. By analyzing the mutant fitness distribution and targeting specific regions of the sequence, in vitro evolution can be accelerated. However, when expediting the search, there is a trade-off between rapid improvement and the quality of the long-term solution. The benefit of neutrality has yet to be captured with in vitro protein evolution. Neutral theory predicts the punctuated emergence of novel structure and function, however, with current methods, the required time scale is not feasible. Utilizing neutral evolution to accelerate the discovery of new functional and structural solutions requires a theory that predicts the behavior of mutational pathways between networks. Because the transition from neutral to adaptive evolution requires a multi-mutational switch, increasing the mutation rate decreases the time required for a punctuated change to occur. By limiting the search to the less coupled region of the sequence (smooth portion of the fitness landscape), the required larger mutation rate can be tolerated. Advances in directed evolution will be achieved when the driving forces behind such proce

Evolution, Molecular↗