Online Fitness Training Programs

The Warrior Zero Body Weight Challenge

The Warrior zero body weight challenge was created by Helder Gomes, he is a service-connected disabled veteran. He has been a victim of body slowing down and energy stripped off, he has used the techniques and now is sharing with you to assist you as well. He has also experienced the working of other programs and has testified that they were actually doing more harm than good, so if you are thinking of other programs, don't. Filled with a decade of research information, the product has been used widely by various clients and has proven to work, it can, therefore, be trusted and used. It is an operational fitness program that will get you the lean muscles and body shape you have hoped for, without signing up for expensive membership programs at the gym or using fancy types equipment. This fitness operator shows the men over forty years how to keep active and eliminate weakness. This will also teach you how to build combat-ready conditioning at any age. This secret training method is used by the most dangerous men there exists. In the program; you will find thirteen weeks of precision fitness system operator programming that is strategically designed to help you eliminate, weakness and build a stable body. And each week you are guaranteed a result that will leave you in shock! How to get through the defined exercise performance from start to finish. Read more...

The Warrior Zero Body Weight Challenge Summary

Rating:

4.8 stars out of 17 votes

Contents: Ebooks, Video Course
Author: Helder Gomes
Official Website: thewarriorzeroproject.com
Price: $37.00

Access Now

My The Warrior Zero Body Weight Challenge Review

Highly Recommended

The writer has done a thorough research even about the obscure and minor details related to the subject area. And also facts weren’t just dumped, but presented in an interesting manner.

I give this ebook my highest rating, 10/10 and personally recommend it.

Exercise And Fitness Training

Many programs include regular exercise and fitness training. This may range from written or verbal advice on posture, body mechanics, ergonomics, and recommended exercise routines through to specific exercises and techniques targeted at movement and exercise integrated with the patient's physical strength and deficits and with their

Fitness landscapebased models and search strategies

The concept of fitness is defined in more detail below, but can generally be regarded as the molecular property of interest, such as affinity towards a given receptor. This section focuses on the three arenas in which fitness landscape structure has relevance to molecular diversity techniques (i) library design, in which methods of biasing the initial library can be evaluated based on landscape structure (ii) mutation and recombination, for which protocol parameters can be determined from landscape properties and (iii) variant search strategies such as pooling, in which there is no mutation but directed expansion of a subset of the library towards a sequence subspace. For laboratory protocols using random, unbiased library design and no mutation, models of the type described above are completely appropriate. Landscape models are much more abstract than the laboratory technique-based models. As extensive as theory about evolution and optimization on fitness landscapes has become, there...

Effects of Resistance Associated Loss of Viral Fitness on Virus Pathogenicity and on Disease Profile

Since fitness is defined in terms of replicative potential, one could predict that loss of viral fitness would result in a reduction in the rate of infection of CD4+ cells, leading to lower amounts of circulating virus and to a reduction in the rate of CD4+ cell depletion, whatever its mechanism. However, even in patients in which viruses with significant loss of viral fitness was documented, the amounts of circulating virus were high, reflecting their strong level of resistance. In parallel, mostly in patients escaping combinations of drugs including protease inhibitors, the number of peripheral CD4+ cells appeared to be discordant with the high viral load. Indeed, a significant proportion of patients escaping therapy with at least one protease inhibitor displayed a continued improvement in the number of their circulating CD4+ cells, paralleled by a continued clinical improvement, in spite of high amounts of plasma virus (Deeks et al., 1999 Kaufmann et al., 1998 Piketty et al.,...

Fitness Functions

Fitness values must reflect the relative quality of the individual solutions for the problem being optimized in order to be useful in directing the evolutionary search toward more promising solutions. Functions for calculating such values must therefore be written specifically for each problem. Some problems naturally suggest their own fitness functions. For example, a conformational search method that seeks the global minimum energy conformation can naturally use the energies of the population members to describe their relative fitnesses. Calculation of fitness values often consumes a majority of the time devoted to solving problems by EAs. Optimization or parallel implementation of fitness functions can therefore provide a significant gain in speed. There is, of course, no requirement that fitness values be determined computationally. Novel implementations of genetic algorithms in combinatorial chemistry actually used experimentally determined biological assay results as fitness...

History and Biological Motivation

The past 30 years have seen the independent development of three biologically motivated computational problem-solving methods 1-3 grouped together under the term, evolutionary algorithms (EAs). The three parent methods share a biological foundation, the basic principles of Darwinian evolution 4 , but differ in their computational implementation of these evolutionary principles 5 , The shared biological foundation of EAs includes treatment of proposed problem solutions as members of a population that vary in adaptation to their environment, or fitness. These population members are subjected to selection pressure, and survivors breed offspring by the application of genetic operations that may include mutation, crossover (also called recombination), or both. Optimization proceeds for a number of generations after which fitter population members have evolved from the original population. A general scheme for EAs is demonstrated in Fig. 1. The three parent methods that follow this general...

Evolutionary Operators 1221 Mutation

The child is selected randomly from one parent or the other. A second type of crossover is to select a point in the gene, and create the child using the information from one parent prior to that point, and data from the second parent after that point. This type of crossover is called one-point crossover. A final type of crossover is to use multiple crossover points. These three types of crossover are shown in Fig. 5. The suitability of crossover to assist in optimization problems relies on the presence of patterns in the genotype which always result in phenotypes having relatively high fitness values. In the previously defined example, such a pattern might be a particular set of distance offsets that move the molecule into a pocket in the receptor. Crossover of a parent having this optimal pattern of distance offsets with another parent can result in a child that retains this beneficial set of distance offsets and has values for other parameters that result in a better overall fitness...

Implementation Issues and Representative Applications of EAs in Drug Design

The prior sections have outlined the historical background and biological motivation of the three parent types of EAs. This type of description was not meant to imply that all implementations should strictly adhere to any one of these standards . A recent overview of genetic methods by Luke makes two key points 21 . First, particular choices for the representation, evolutionary operators, selection and fitness function should be adapted to the problem rather than forcing the problem into the mold of a particular EA implementation. The second key point from Luke's overview is that not all problems are suited to solution by EAs. It is also important to note that many reports have now been made on effective combinations of EAs with other search or optimization methods.

Nutritionrelated Other Health Benefits Of Seaweed

In addition to the above discussed nutrients, diverse amount of phenolic molecules has been identified from seaweed and is classified under different groups of phytochemicals. Those molecules virtually do not play the roles of nutrients and proven to have different bioactive properties associated with enhancing physical fitness to refrain from diseases or to exert therapeutic effects against certain illnesses. However, the medicinal effects of such molecules are not discussed in this chapter. Non-communicable diseases such as diabetes, obesity, and cardiovascular dieses have a strong relationship with dietary habits and nutritional profiles of the food. Therefore, next few sections of this chapter address the nutrition-related several health effects of seaweed fiber, other than previously mentioned, and its contribution to enhance digestive health.

Problem Suitability for EA Implementation

A theoretical comparison by Wolpert and Macready has shown that no algorithm is capable of outperforming any other algorithm over all problems 23 , Any algorithm which clearly outperforms others on a particular problem will suffer in comparison to other algorithms when confronted with a different type of problem. Wolpert and Macready have termed this the No Free Lunch Theorem . This performance issue has also been demonstrated in an area relevant to computer-aided drug design for the specific problem of selecting maximally dissimilar molecules from a database 24 , The similarity of a molecule to others in the database, in both the problem-specific algorithm and the GA, was measured by comparison of the molecule to the centroid of the database. The GA implementation used the inverse of this similarity measure as the fitness value, and represented sets of molecules as a list of integers, each integer referring to a specific compound in the database. It also included a knowledge-enhanced...

Multidimensional combinatorial library optimization

Gillet et al. 15 proposed to solve such problems by a genetic algorithm (GA) 20 . Other GA applications in library design have been used in lead optimization 16-17 , in library mixture optimization 18 , and for the selection of preferable compounds from a large virtual library (i.e., 'cherry picking') 19 . Genetic algorithms optimize a population of individuals (possible solutions) by improving their 'fitness', i.e., the adaption to the problem, by applying principles of the natural evolution like 'mutation' and 'crossover'. The implementation used here is based on the Genesis program 21 . The individuals in a population are different 15 x 15 sub-libraries out of the virtual library described above. Their fitness is the weighted sum of the percentage of compounds with a crop protection score greater than 0.3, of a diversity index, and of the reciprocal prices of the starting materials. The GA was run with a population size of 50, a maximum number of generations of 200, a mutation rate...

Evolutionary Methods for Structure Optimization

EAs (and in particular GAs) nowadays are very popular methods for finding the optimal geometry of a molecular structure with respect either to agreement with experimental data, such as NMR-derived distance constraints, or internal energy. These two types of problem form the bulk of all EA applications in this area, and they will be treated in more detail in the next paragraphs. Several other applications also deserve a mention. Structure optimization with respect to complementarity to an active site (e.g., 39, 40 ) belongs to the domain of molecular docking and will be dealt with in Chapter 3. Another problem is tackled in 41 , where a small set of diverse conformers is sought. The fitness of a solution is given by a measure of the difference with all other solutions in the population. The algorithm is initiated from a 3-D structure, and a population is generated by applying random mutations to this structure.

Satisfying Constraints from Experiments

A different approach is taken in 48 , where distance constraints derived from NMR spectroscopy are used in the evaluation function. A GA, called DGi2, was used as a front-end for the distance geometry program DGII 49 , The upper and lower bounds for a set of 58 distance restraints were coded in the strings. Each member of the population was the starting point for a distance geometry calculation, and the fitness of this member was given by the number of distance constraint violations. It was shown that for cyclosporin A, a cyclic undecapeptide notorious for its difficult sampling properties, the GA led to a significant improvement in the sampling behavior of the distance geometry algorithm. In other applications, the agreement with experimentally obtained distance constraints is used as a fitness function for oligopeptides 50 , RNA stem-loop structures 28 and DNA oligonucleotides 18, 47, 51 . Pearlman 52 uses a genetic algorithm to derive an ensemble of structures that best fits NMR...

Age and Exercise Induced ROS

Age could be a factor in eccentric-exercise induced oxidative stress because of the potential for more ROS produced from a mitochondrial respiratory chain that is known to functionally decline with age (Trounce et al., 1989). On the other hand, antioxidant activity tends to increase with age (Leeuwenburgh et al, 1994). An age-related increase in antioxidant activity may not meet the age-related oxidant activity produced by defective, leaky mitochondria. An additional consideration is the compromised immune system of older adults. Phagocytic response to muscle damage caused by eccentric exercise may be inadequate in older compared with younger individuals, and result in oxidative damage to DNA and the accumulation of harmful by-products in around the muscle. Sacheck et al. (2003) compared biomarkers of oxidative stress and muscle damage in old and young individuals following eccentric exercise. They found that fitness level was more important than age, in determining protection against...

Risk factors for occurrence

Although results of epidemiological studies are not necessarily consistent, factors that have been reported to be associated with low back pain are age, physical fitness, and strength of back and abdominal muscles. There seems to be no association between low back pain and other individual factors such as gender, length, weight, Body Mass Index, flexibility mobility and structural deformities of the spine. Physical fitness

Testing and Evaluating Docking Methods

In a typical test, the ligand and the protein in a complexed structure are separated, the ligand is randomly translated, re-oriented and conformationally changed, and then docked back into the protein. With stochastic search methods, the ligand is docked several times, giving different results that are dependent on the random number generator and its seed value(s). These docked structures are ranked by score, energy or free energy. Some methods perform conformational clustering, before ranking the clusters by fitness. For each docked structure, the RMSD of the atomic positions in the docked structure from the corresponding atoms in the crystallographic structure is then calculated. Ideally, this should be small, say 1.0 A or less. The most important criterion is that all the observed

Evolutionary Algorithms for Protein Ligand Docking

The genetic algorithm is modeled closely on biological evolution, and it mimics many features observed in Nature. The simulation is composed of series of generations. Each generation is composed of a population of individuals, which in molecular docking are various candidate protein-ligand complexes. At each generation, a population of parents gives rise to a new population of offspring. Typically, a selection method is applied, and parents must compete with one another so that only the individuals with the best fitness give rise to offspring in the next generation. In molecular docking, the fitness is the total score, enthalpy or free energy of interaction of the ligand with the protein it is evaluated using a fitness function. The iterative process of evolution continues until some termination criterion is met the maximum number of generations, the maximum number of fitness function evaluations, or convergence of the population. Evolutionary algorithm-based docking methods use...

Overview of a Genetic Algorithm

The basic operation of a GA is illustrated in Fig. 1. A GA operates on a population in which each member is usually a fixed length string that represents a potential solution to the given problem. Each population member is assigned a fitness according to how well it satisfies the solution requirements. The GA then enters a breeding phase where individuals or parents are chosen to reproduce, generating offspring (or children). Evolutionary pressure is applied by basing the selection of parents on the fitness scores so that fitter members have a greater chance of being selected than less fit members. The selection method is usually roulette wheel selection, a process in which each individual is assigned to a sector of a roulette wheel, with the size of the sector proportional to the fitness of the individual. The size of the sector corresponds to the probability of the individual being selected, thus, fitter individuals have a higher chance of being selected. The standard genetic...

Insert children into population Test for convergence

The basic GA outlined here can be adapted easily to solve problems in different domains with the development of a GA to solve a particular problem involving consideration of the following the encoding scheme used to represent the problem space within a population of individuals the fitness function used to evaluate the goodness of an individual the selection criterion used to choose parents for breeding the particular genetic operators that are used to produce offspring and the termination condition for the algorithm.

Applications of EAs to Pharmacophore Mapping

Payne and Glen 49 reported the first use of a GA for the alignment of flexible molecules. Constraints are defined as a set of pharmacophore features and distance constraints previously calculated from a template molecule, and the GA attempts to find an optimum superposition of the molecules with respect to the constraints. A chromosome of the GA encodes the conformation of each molecule to be aligned as torsional rotations and parameters that control the conformations of rings. The chromosome is divided into sections, with each section describing the conformation of a different molecule in the set. The GA is initialized with a random population of chromosomes, each representing a different conformation for each molecule. A chromosome is scored by applying the appropriate conformational changes to the original molecules and then least-squares fitting the molecules to the constraints. The fitness function measures the RMS difference between the point properties of the target molecule...

Applications of EAs to Receptor Modeling

The aim of the GERM (Genetically Evolved Receptor Models) program 58, 59 is to build an atomic-level model of a receptor site based on a small set of known structure-activity relationships. First, a set of compounds with experimentally determined activities are superimposed in low-energy conformations. An initial model of the receptor site is then constructed by placing 40-60 atoms on a grid around the surface of the superimposed active compounds. The atom types consist of 14 typical protein atoms and a null atom type to correspond to no atom at all at a given position. A GA is used to alter and optimize the atom types of the receptor site in order to maximize the correlation between drug-receptor binding calculated using molecular mechanics and measured drug activity. The chromosomes of the GA encode potential receptor models as bit strings each bit corresponds to a grid point placed around the superimposed ligands together with pseudoreceptor atom assignments. The genetic operators...

Molecular Surface Shape

Protein molecular surfaces are generally observed in terms of cavities, protrusions, and flatness. These abstract molecular surface shapes are important for identifying unique and functionally important regions (Li et al. 2008). In the same paper mentioned in the previous section of relative ASA (Jones, Thornton 1997a Jones, Thornton 1997b) it was found that PPI sites are geometrically flat in general. The flatness of a surface patch is defined as the least square fitness of a plane to atoms of residues in the patch. Jones and Thornton examined another geometrical measure, named protrusion. The protrusion is defined as the average protrusion of each residue in the patch from the surface of the protein. Thus, intuitively, the flatness indicates an overall geometrical shape of the surface of a patch and the protrusion indicates local ruggedness of the patch.

Early Studies Of Ketogenic Diet Efficacy

Because epilepsy was supposedly caused by overindulgences of some sort by its victims, the early twentieth-century solution of fasting and prayer evolved, with the initial practitioners comprising a team of a physical fitness guru, Bernarr Macfadden, and an osteopath, Hugh Conklin (4). In 1921 H. R. Geyelin, a physician, published results of his protocol for the treatment of unclassified patients with convulsive episodes who, in general, were markedly improved after fasting for 3 wk and in some cases remained so when normal dietary allowances were reinstituted (5).

The Emergence of Drug Resistant TB

Will restore whatever fitness costs they incur by acquiring drug resistance, and, ultimately, these strains will emerge in the developed world again. The pace of our discovery efforts has been too slow we are now approaching a situation where we will have lost all of the achievements of the past. We will need to develop entirely new regimens, and we urgently need to consider the mistakes that were made 40 years ago and devise a strategy to avoid repeating them.

Box 111 Evidence of treatments for adult fibromyalgia syndrome

Multicomponent treatment (MT) programs There is no internationally accepted definition of mul-ticomponent therapy. The existing systematic reviews on MT agree that MT should include at least one educational or other psychologic therapy and at least one exercise therapy 67, 78 . The German FMS guideline group meta-analyzed 9 14 RCT, with 1119 subjects with a median treatment time of 24 hours included in the meta-analysis. There is strong evidence that MT reduces pain (SMD -0.37, 95 CI -0.62 to -0.13), fatigue (WMD -0.85, 95 CI -1.50 to -0.20), depressive symptoms (SMD -0.67, 95 CI -1.08 to -0.26) and limitations of HRQOL (SMD -0.59, 95 CI -0.90 to -0.27) and improves self-efficacy pain (SMD 0.54, 95 CI 0.26-0.82) and physical fitness (SMD 0.30, 95 CI 0.02-0.57) post treatment. There is no evidence of the efficacy of MT on pain, fatigue, sleep disturbances, depressive symptoms, HRQOL and self-efficacy pain in the long term. There is strong evidence that the positive effects on physical...

Laboratory techniquebased models and search strategies

At present, many popular applied molecular evolution protocols do not involve mutation or recombination. The laboratory technique-based models presented in this section are of this type. Incorporating mutation requires fitness landscape models or some other means of relating molecular properties to particular sequences. The more abstract models reviewed later allow for mutation and recombination and are based heavily on landscape structure. The models in the present section are based on affinity distribution p(Ka), the probability that a ligand chosen at random from the library has affinity Ka.

Evolutionary dynamics

In a space of particle numbers or concentrations, called the concentration space. Population dynamics of evolution experiments deals with selection of the 'fittest' genotype currently present in the population. It can be visualized as a hill-climbing process on a fitness landscape in the sense of Darwin's selection principle of survival of the fittest. Fitness is optimized and an optimal state of the population is approached. When many genotypes share identical (optimal) fitness values, populations may drift between different optimal solutions in a random walk-like manner. In the limit of (infinitely) large populations, selection kinetics of polynucleotides is properly modeled by the concept of molecular quasispecies that accounts explicitly for the influence of mutation 8 . Depending on both fitness differences and mutation rates, two different scenarios of replication-mutation kinetics are observed. At sufficiently large fitness differences or small enough mutation rates,...

Field Based Similarity Searching

The target structure for the similarity search is assumed to be held stationary, and a chromosome in the GA encodes the rotations and translations that are to be applied to the current database structure to align it with the target structure. The fitness function is the value of the Gaussian similarity coefficient resulting from the particular alignment encoded within a chromosome, and the GA hence moves the The algorithm was initially developed to align molecules on the basis of the molecular electrostatic potential 9 , but it has since been modified so that it can additionally encompass hydrophobic and steric fields 5 the resulting program, called FBSS (Field-Based Similarity Searching) thus permits the calculation of all three types of similarity by the same basic procedure. Alignments may be made based on a single field-type, or on any combination of the three types of field here, we report the results when all three types were combined. During the...

Evolutionary biotechnology

The theory of molecular evolution and the in vitro evolution experiments suggest practical applications to the design of biopolymer molecules as they were proposed already in the 1980s 4 . The basic principles of the so-called 'irrational design' of biomol-ecules are indeed identical with Darwin's natural law of variation and selection. Molecular properties are improved iteratively in selection cycles in order to achieve an optimal match with the predefined target function. The process is sketched in Fig. 5. Every selection cycle consists of three phases amplification, diversification, and selection. In these experiments, the fitness of genotypes is tantamount to their probability to enter the next selection round.

An Evolution Strategy for Systematic Search in Chemical Space

There is no general best optimization or search technique. In a smooth fitness landscape, advanced steepest descent or gradient search represent a reasonable choice to find the global optimum, and several variations of this technique have been described to facilitate navigation in a landscape with some few local optima 30 .Typically, virtual screening is confronted with a high-dimensional search space and convoluted fitness functions that easily lead to a rugged fitness landscape. Robust approximation algorithms must be employed to find practicable solutions here 26,31 , Stochastic search methods sometimes provide answers that are provably close to optimal in these cases. In fact, several systematic investigations demonstrated that a simple stochastic search technique may be comparable or sometimes superior to sophisticated gradient techniques, depending on the structure of fitness landscape or the associated error surface 32,33 . Special types of stochastic search methods, namely...

Mixed Viral Infections

According to the Darwinian definition of fitness, which applies to a selective advantage in conditions of reproductive competition between several variants, one would assume that all fitness assays should be competitive. Indeed, many authors have used culture systems in which mixtures of two or more viral variants are used to infect a population of target cells. In these systems, HIV infection leads to massive production of viral particles in the culture supernatant, reflecting exponential propagation of the infection in the culture following several cycles of virus replication. Virus from this initial peak production is used to inoculate a new culture, and after several such passages, the balance of virus populations is assessed by sequencing cell-associated viral DNA or supernatant viral RNA. Virus fitness is then calculated based on the rate of replacement of one variant by another along these several passages (Harrigan et al., 1998 Martinez-Picado et al., 1999 Tachedjian et al.,...

A cartoon representation of landscapes that map sequence to function

Before expanding on how in vitro selection experiments can be used to help define evolutionary landscapes, an explication of landscapes should be provided. A fitness landscape is a surface that is generated by graphing points in a sequence space to their corresponding fitnesses (i.e., plotting the fitness function 25 ). A nucleic acid sequence space would therefore be the set of all possible unique sequences of length N, and would contain 4N points. Such sequence spaces 26 can best be represented by a multidimensional Boolean polyhedron (Fig. 2), where each vertex would represent one sequence. Relationships between sequences within such a space can be determined by calculating their Hamming distance (h), a metric that assesses the number of sites at which two sequences differ 27 . Hence, given the four-letter alphabet for RNA, a sequence of length N would have 3N nearest neighbors with h 1. These nearest neighbors would extend in many dimensions, and all sequences would be...

Single Cycle Replication Assays

Assuming that the rate of infection of HIV target cells by a virus variant can be reflected by the number of cells infected after a single round of replication, single-cycle assay systems have been developed for the study of HIV fitness. In these systems, virus is produced following transfection of a molecular clone and used to infect target cells in which an indicator gene is turned on by the infection. In some assays, the indicator gene is carried by the viral genome itself. In other assays, the indicator gene is present but silent in target cells, and its expression can be turned on by production of the HIV transactivator Tat following successful infection of the cell (Carron de la Carriere et al., 1999 Mammano et al., 1998 Zennou et al., 1998). The main advantage of such assays is their simplicity and their speed the rate of infection can be usually measured in less than 2 days. Their other advantage is related to the fact that since there is only one cycle of replication, there...

Evolutionary Methods for Compound Selection

Genetic algorithms have been used to select molecules exhibiting structural similarities to a given target molecule, such as a known drug, from large virtual libraries. In this case, the fitness function is a description of molecular similarity to the target. Using GAs for the generation of diversity, one may also choose a molecular property and select molecules that are different with respect to that property. For example, selecting molecules to have dissimilar and unique molecular weights would facilitate, for example, the deconvo-lution of combinatorial library mixtures by mass spectroscopy. The analysis of the diversity of combinatorial libraries appears to be more amenable to computational methods than that of general molecule collections due to the well-defined closed chemical space of the former. The optimal design of combinatorial compound libraries was the aim of a recent application reported by Brown and Martin 36 , A GA was designed that is useful in selecting optimal...

Computer Aided Evolutionary Chemistry

A combination of GAs and neural networks was used for the design of signal peptidase I cleavage sites 54, 55 , Here, simulated molecular evolution exploits the rules of peptide sequence space. A neural network was trained with a set of protein sequences that are known cleavage sites for the peptidase. The trained network was used afterwards as a fitness function to predict new leader peptidase substrate sequences such as FFFFGWYGWA-RE. These proposed artificial cleavage sites were then cloned in Escherichia coli within a fusion protein that turned out to be processed by the secretory proteases as predicted. The first example of GA-driven selection and synthesis of nonpeptidic molecules was applied to thrombin inhibitors 7 . Using 10 isonitriles, 40 aldehydes, 10 amines and 40 carboxylic acids, 160 000 Ugi four-component reaction combinations are possible. Whereas in the initial population, the best reaction product exhibited an IC50 of about 300 ftM, a thrombin inhibitor with a...

Resistance to Nucleoside Analogs

Nucleoside analogs are an essential component of HIV therapy. The antiviral effect of these agents is the consequence of their incorporation into the nascent viral DNA chain, where they act as chain terminators, due to the absence of a 3' hydroxyl group. Because wild-type RTs lack efficient 3' exonuclease activity, they cannot efficiently remove incorporated nucleoside analogs, explaining in part the exquisite sensitivity of retroviruses to such compounds. The mechanisms of HIV resistance to nucleoside analogs, although they are not fully understood, can involve two basic processes excision of the newly incorporated chain terminators (the main mechanism for HIV resistance to AZT and probably to d4T) and reduced incorporation of the nucleoside analog triphosphate (a mechanism best documented for resistance to 3TC). Whatever the basic mechanisms involved in resistance, they imply modifications in key enzyme structures, therefore some loss of drug-free viral fitness should be expected...

Resistance to Other Nucleoside Analogs

Apart from AZT, the impact of resistance on HIV fitness has been examined mainly for two other nucleoside analogs, didanosine (ddl) and lamivudine (3TC). These studies mainly focused on two mutations that appeared to be selectively associated with resistance to either of these two nucleoside analogs, L74V (conferring resistance to ddl) and M184V (conferring resistance to 3TC). Mutation L74V, once considered a signature of resistance to ddl, was in fact mostly observed when ddl was used in monoth-erapy. This mutation confers only low-level resistance to ddl (usually less than a 10-fold increase in IC50 compared with a reference virus strain) and appears to counteract resistance to AZT of mutants carrying typical AZT-resistance genotypes. Therefore, it is now seldom observed in patients receiving combined antiretroviral therapy. Nonetheless, using mixed culture experiments, this mutation has been clearly shown to reduce the replicative potential of HIV (Sharma and Crumpacker, 1997)....

Nonnucleoside RT Inhibitors NNRTI

Nonnucleoside RT inhibitors are noncompetitive, allosteric inhibitors of HIV-1 RT. These molecules display a high affinity for a virtual hydrophobic pocket situated close to the active site of the enzyme (Kohlstaedt et al., 1992). After occupation of the pocket, the mobility of some of the domains of HIV RT is impeded, thereby blocking DNA polymerization. Mutations that confer resistance to these compounds result in amino acid substitutions that change the physical properties of the hydrophobic pocket. Although extensive cross-resistance to most NNRTIs have been described in viruses selected for resistance to any one of these compounds, the number and the positions of the mutations required for resistance often differ from one compound to another resistance to nevirapine can be achieved with a single Y181C substitution (Richman et al., 1994), resistance to efavirenz and delavirdine is most often characterized by combinations of mutations that include K103N. Recently, it has been shown...

Pyrophosphate Analogs

The principal molecule that is representative of this category, foscarnet, has not proven active in vivo and displays high toxicity. Nevertheless, foscarnet is active against HIV in culture and RT mutations that confer HIV resistance to foscarnet, affecting residues 88 and 89 of RT (Tachedjian etal., 1995), have been shown to significantly affect virus fitness in the absence of drug (Tachedjian et al., 1998).

Crystal Structure Prediction using GAs

The initial population comprises 2M candidate structures ( adults ) and is generated at random. The quality of each candidate structure is then assessed using the cost function (fitness function) described below. Pairs of parent structures are then chosen (either by tournament selection or based on their fitness) to participate in the crossing (mating) operation, which involves the exchange of random pieces of the strings representing each of the parent structures. The mutation operation is performed by randomly changing some digits in the binary code from 0 to 1 or from 1 to 0 for certain candidate structures. The GA approach is elitist as the best N members of any given generation are allowed to pass into the succeeding generation. In addition, randomly generated foreign structures are admitted at each cycle to ensure population diversity. difficult to generate may suggest that an alternative fitness function could be advantageous in the case of structures based on distinct...

A11b13c15d16e12f17 A13b14c11d10e11f14 A16b18c5d4e11f18

evaluate fitness of all initial individuals of population evaluate P (t) test for termination criterion (time, fitness, etc.) perturb the mated population stochastically mutate P' (t) evaluate its new fitness evaluate P' (t) select the survivors from actual fitness P survive P,P' (t)

Resistance to Protease Inhibitors

Early reports on viruses selected for resistance to protease inhibitors in tissue culture have emphasized the effect of resistance on the drug-free fitness of HIV. Some of these mutations, such as R8Q or V32I, which dramatically reduce HIV fitness, are not frequently observed in treated patients. However, many viruses with single or combined resistance mutations in the protease are clearly less fit than wild type, as shown in a variety of assay systems (Borman et al., 1996 Croteau et al., 1997 el-Farrash et al., 1994 Ho et al., 1994 Kaplan et al., 1994 Kuroda et al., 1995 Martinez-Picado et al., 1999 Zennou et al., 1998). Reduced performance is most prominent in enzymatic assays, where loss of enzymatic activity amounting to more than 80 has been described for mutations commonly observed in vivo (Gulnick et al., 1995 Ridky et al., 1998 Sardana et al., 1994). In culture assays, including single-cycle systems, the loss of fitness of PI-resistant viruses is generally markedly more...

General Principles of HIV1 Entry

In addition, the external surfaces of CXCR4 have been noted to be more electronegative compared with CCR5, and in general the V3 loop of X4 viral strains has a more positive charge than the V3 loop of CCR5 using isolates. Basic amino acids at position 11 or 25 of the V3 loop are usually associated with X4 isolates (66). However, changes in V3 during the process of CCR5 to CXCR4 coreceptor switching may result in the generation of less-fit viral intermediates, and it has been shown that gain-of-fitness mutations in or near V1 V2 were able to compensate for the deleterious effects of V3 loop alterations on virus viability, although they did not confer CXCR4 use (51,52), and this suggests that the appearance and establishment of functional X4 variants during the course of infection may be a multistep process (reviewed in ref. 50).

Mechanisms of NRTI Inhibition

Eventually become the dominant quasispecies. The time required for this selection to occur is dependent on factors such as mutant frequency at the time of treatment initiation, the replication fitness of the mutant, and the magnitude of the selective pressure (potency of the drug).

Physical therapy rest versus exercise

Available evidence suggests that range of motion, strengthening, and aerobic conditioning exercises are safe for patients with RA and improve muscle strength, cardiovascular fitness, and probably physical function. They do not seem to exacerbate joint symptoms. Preliminary evidence also suggests aerobic weight-bearing exercise may help prevent corticosteroid-associated osteoporosis.76 III , 77 III , 78 III

Automated Procedures which Incorporate GAs

Zimmerman and Montelione 11 reviewed and compared progress in the development of semi- and fully automated approaches to protein resonance assignments up to 1995. Wehrens et al. 33 treated the sequential assignment as a subset selection problem. In reference to the difficulties relating to the combinatorial explosion, consider that there are N spin systems identified and these systems are to be mapped to M positions in the protein sequence (assume N M in most cases). The size of the search space is therefore N (N-M)L This number can become too large for systematic and exhaustive searches. To solve this problem, a GA with a specially developed subset encoding along with specifically designed crossover and mutation operators was used. The candidate solutions were represented as a permutation of the N possible elements and only the first M elements are evaluated in the fitness function. The fitness function used in this work was basically the count of how many valid pattern combinations...

Algorithm Types in Protein Folding

In a GA, a number of searches are performed in parallel and information is exchanged between them. It is expected that this information exchange can increase the search efficiency by a larger factor than the number of parallel processes, and this has been demonstrated in some instances 16 . GAs may be described in the following way (Fig. 1). An initial population of trial solutions is established, usually represented by strings. Mutations are introduced independently into each string these are operations within a single search trajectory, analogous to those of a traditional Monte Carlo procedure 8 , In the canonical GA, a mutation constitutes changing a single bit in the string describing a solution. Theoretically, there is no reason why more general operators could not be used. After some number of mutations has been performed, new strings are created by crossover operations two members of the population are selected, a break point in each of the strings is chosen, and two new...

Coevolutionary Approaches

The most commonly used method of self-adaptation is simply to encode the EA parameters of interest (termed strategy parameters), such as the size of the mutation step made, into the encoded solution. These can then be operated on and allowed to co-evolve (hopefully) effective values alongside the solution's decision variables. This approach was proposed independently by the ES 23 and EP 24 communities. The driving force for developing these techniques was the observation that, given a population of competing solutions, the solutions with strategy parameters that produce children with increased fitness will have a better chance of having their material (including the choice of strategy parameters) passed on to later generations. This is a consequence of the fitter children having a head start on the children of the other solutions with less suitable strategy parameters. This results in an implicit selection pressure upon the strategy parameters that should drive them towards...

Adaptive And Maladaptive Aspects Of Immunologic Allyinduced Depression

It is also possible that many of the depressive symptoms associated with disease and immune activation are not adaptive in terms of the individual rather, they are adaptive for the population. Sociobiologists argue that complex social behaviors may be selected for, in the course of evolution, even though the effect of the behavior on its bearer is to reduce its own personal fitness (Wilson, 1975). For example, an animal that utters a loud alarm call is drawing attention to itself, increasing the likelihood that it will be captured by the predator. Theories of inclusive fitness and kin selection provide convincing evidence for the adaptive value of such altruistic behaviors (Wilson, 1975). A similar phenomenon may explain the behavioral effects of infectious diseases, because such diseases may be transmitted from the individual to its kins and family members, thus reducing the individual's inclusive fitness (i.e., the net genetic representation in succeeding generations, including...

What is a Good Solution

As noted earlier (section 12.3.1), the fitness function is itself a source of domain knowledge as it can be regarded as a specification of what is a desirable solution. However, for real-world problems it is not necessarily straightforward to set out a priori what constitutes a desirable solution Instances of how this can occur will now be discussed, and interactivity will be shown to be a possible solution to this issue, as well as to the more general problem of how to exploit the CAMD practitioner's knowledge to the full.

Citius Altius Fortius Acceleration by Highthroughput and Ultrahighthroughput Techniques

(mutants) with improved fitness from smaller populations of closely related variants within a species. Selection pressure favors a subset of variants of such a quasispecies over competing variants and confers a higher replication rate to these variants, which eventually leads to a shift of the quasispe-cies towards a distinct phenotype. Our understanding that mutations can improve an organism's phenotype gained increasing acceptance in the decades following the work of Johann Gregor Mendel (18221884). However, in vitro mutagenesis of proteins (through their respective genes) was only made possible after the structure of DNA was discovered, the genetic code determined and basic DNA manipulation technologies became available. From computer simulations as well as experimental data it has been derived that the fastest evolving species in nature are those that replicate their genome with a mutation rate near the error threshold. This has been shown for RNA viruses, which are known for...

Constrained and Multi Objective Problems

In the field of CAMD, a good example of a multi-objective optimization problem is the search for the 3-D maximum common substructure (MCS) among two or more molecular structures 44 . In this type of search, two generally contradictory parameters contribute to the fitness function the size of the MCS, and the closeness of the geometric fit. In other words, it is generally observed that as the size of the proposed MCS (expressed as the number of atoms it comprises) increases, the quality of the geometric fit between the two structures (expressed as RMS distance in A) decreases. The challenge is to find an optimum that accounts for both criteria. Consequently, Handschuh et al. 44 employed Pareto optimality in their GA fitness function for molecular MCS determination and superposition. In this way, they were able to select good results from the resulting Pareto sets of solutions.

Critical Issues in TB Drug Development 51 Cell Penetration

The complex, lipid-rich envelope of MTb acts as a permeation barrier to a broad range of therapeutic agents and has likely contributed to both the fitness and the success of the pathogen (Fig. 33). The plasma membrane (PM) forms the innermost region of the cell envelope and is a typical lipid bilayer, structurally and functionally similar to the PM of other eubacteria. External to the PM is the peptidoglycan sacculus. This contains repeating units of N-acetylglucosamine and

Bioactivity profiling

The chromosomes of the GA are integer strings that map directly to the weights. The standard genetic operators of crossover and mutation are used to generate child chromosomes. The fitness function of the GA measures the extent to which the weights contained in a chromosome can be used to discriminate between two classes of molecules, merged within the training set. Each molecule in the training set is scored by summing weights over all the features where the weight for an individual feature is determined by the value of that feature within the molecule. The molecules are then ranked according to decreasing score and the fitness function is calculated as the average ranked position of molecules in the preferred set (for example, the set of active compounds). Thus the GA attempts to shift the distribution of scores in one class of molecules relative to the other class in order that maximum separation between the two distributions is achieved.

Library design in product space

That is, SELECT can be used to design combinatorial subsets that are by definition synthetically efficient and that are optimised with respect to diversity and other user-defined properties. The diversity of libraries designed using SELECT can be measured using different descriptors, for example, Daylight 14 and UNITY 26 fingerprints and Molconn-Z parameters 27 , and different diversity metrics, for example, the sum-of-pairwise dissimilarities and average nearest neighbour distance. SELECT 25 is based on a genetic algorithm and uses a multi-objective fitness function that allows many properties to be optimised simultaneously with diversity. Thus, the physi-cochemical property profiles of libraries can be optimised in the design of diverse and 'drug-like' libraries. SELECT can also be used to design libraries that complement existing libraries and to explore different library configurations.

Design of diverse and druglike libraries

An important advantage of performing library design in product space is the ability to optimise the properties of individual molecules within the library simultaneously with the diversity of the library. SELECT has been designed with a multi-component fitness function whereby the physicochemical property profiles of the libraries can be optimised with respect to the profile of the same property in some reference collection, for example a 'drug-like' profile as found in WDI. In the following experiments we have compared the physicochemical property profiles of diverse libraries selected by analysing reactant space with the profiles of the same physicochemical properties in libraries selected from product space that are optimised on property and diversity, simultaneously. The property profiles we have investigated are the distribution of rotatable bonds and molecular weight, although the methods are applicable to any rapidly computable molecular property. In each case, the profile is...

What are the Outcomes of Changing Carbon Nitrogen Budgets

Protein complex in suboptimal as well as optimal growth conditions is rarely undertaken, and reproductive fitness (not, perhaps, of major concern to crop breeders) has been even more neglected. Much of this work has been carried out on Nicotiana spp., for which the leaf is the harvested organ for the major cultivated species Nicotiana tabacum, and the leaf protein content is not a major commercial consideration except insofar as a decreased N demand for chloroplast components in leaves may permit more N to contribute to synthesis of the alkaloid nicotine which is synthesized in the roots and is transported to the leaves in the xylem.

Applications of EAs to De Novo Design

Westhead et al. 37 developed a GA to refine a set of structures that had been generated using the de novo design program PRO_LIGAND. The set of structures output from PRO_LIGAND forms the initial population of the GA. As in the Chemical Genesis program described earlier, the GA operates directly on the molecules themselves. The molecules are evaluated using graph theory routines that fit the molecules onto interaction sites within the receptor site and the fitness function involves a weighted sum of the number of interaction sites hit, together with some physical properties of the molecules themselves such as the numbers of rings and rotatable bonds. The interaction sites include hydrogen bond donors, hydrogen bond acceptors, aliphatic lipophilic and aromatic lipophilic sites. The population is evolved by using roulette wheel parent selection and the genetic operators crossover and mutation. Crossover is implemented by cutting the two parents across a single bond and reconnecting the...

Fasting A Precursor To The Ketogenic Diet

Hugh Conklin

It was not until the early twentieth century that medical use of the ketogenic diet emerged as a strategy to mimic the biochemical effects of fasting (or starvation) (Fig. 2). Guelpa and Marie, both French physicians, authored the first scientific report on the value of fasting in epilepsy (6). They reported that seizures were less severe during treatment, but no details were given. In the United States, contemporary accounts of fasting were also recorded early in the twentieth century (Table 1) the first was a report on a patient of an osteopathic physician, Dr. Hugh W. Conklin, of Battle Creek, Michigan, and the second concerned Bernarr Macfadden (7,8). Macfadden was a physical fitness guru cultist and publishing genius of the early part of the 20th century (9). He called the medical profession an organized fraud and said that people who followed his rules could live to age 120. At age 31 (in 1899), he established his first magazine, Phys-

Second Generation Antipsychotics

Monitoring of patients receiving psychotropic medications for weight and metabolic parameters is crucial. The report from the Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes Consensus Panel contains valuable advice for appropriate and prudent monitoring 45 . The most frequently assessed parameter in the recommendations is weight. At a minimum it is obtained at baseline, monthly for the first 3 months, and then quarterly. However, monitoring weight at each and every patient visit will allow the clinician to catch a problem early, before substantial weight gain has set in, and underscore to both the patient and the clinician the importance of physical fitness. Additionally, patients and or caregivers can be educated about monitoring weight and report back to the clinician.

Generation of Molecular Alignments

The MPHIL and FBSS programs described above involve the alignment of rigid 3-D chemical structures in both cases, the principal aim of the work has been to identify an efficient matching criterion that permits large numbers of such alignments to be evaluated (either in the repeated invocations of the clique-detection procedure in MPHIL, or in the matching of the target structure with each of the database structures in FBSS). In this section, we describe a further alignment procedure called GASP (Genetic Algorithm Superimposition Program) that has been designed for the detailed processing of sets of flexible 3-D structures, with the aim of providing an effective method for the generation of putative pharmacophoric patterns. The fitness function that has been developed is far more complex than those discussed previously, and we hence focus upon this aspect of the program, rather than upon the results obtained when it is implemented (as with some of the previous GAs in this chapter)....

Principles And Guidelines For Prophylaxis And Chemotherapy Of Malaria

Isolates of P. falciparum from patients in highly endemic areas contain many parasite clones with different drug-resistance phenotypes. A patient with severe malaria may have 1012 parasites, so it is easy to understand how mutations conferring resistance can arise in virtually every patient and double mutations can arise occasionally. Therefore, drugs or drug combinations must not be susceptible to single-point-mutation resistance. Intense chloroquine use for decades preceded development of resistance to this agent, likely because multiple mutations are necessary to confer resistance. Resistance also can be promoted by free radicals generated by atovaquone treatment in the mitochondria of the parasite this is thought to promote development of resistance to this drug. Drugs with a long t122 are more likely to select out resistant parasites. On a population level, the fitness of resistant parasites is an important parameter if mutation causes a reduced ability to survive or grow, the...

Structure of Chemical Space and the Principle of Strong Causality

It is not sufficient to generate offspring around a parent structure in a systematic way. To enable a systematic search in chemical space, both the ordering of chemical space and the corresponding fitness landscape must be strongly related. This means that small steps in chemical space must be correlated with small changes in predicted fitness or experimentally determined bioactivity (Principle of Strong Causality 34 ). Otherwise the whole concept of optimization by evolutionary search will be corrupted. Very likely it will be impossible to perform a systematic exploration of high-dimensional chemical space if a small structural modification of a molecule induces drastic fitness deviations between the parent and the offspring. There are several reports in the literature on seemingly small structural variations of active compounds leading to even complete loss of activity. For example, exchange of the phenolic hydroxy groups of isoproterenol with chlorine results in the conversion of...

Current Superpositioning Techniques for Aligning 3D Pharmacophores and Molecules

A well-known pharmacophore elucidation program using such an approach is GASP33,67 that was developed by Jones and co-workers in the mid-1990s and is marketed by Tripos. The program is based on a genetic algorithm, i.e., a non-deterministic method that simulates evolution by randomly mutating chromosomes of a certain population. In terms of pharmacophore pattern matching, each chromosome represents a potential flexible pharmacophore by encoding all bond angles and by listing all feature mappings to a manually-selected reference compound. In each run, chromosomes are selected that score best, according to some crucial fitness function, and those are then mutated by applying random torsional rotations to cover conformational space on-the-fly. GALAHAD,32'35'68 developed at the University of Sheffield, Novo Nordisk, and Biovitrum, and also marketed by the company Tripos, uses a modified genetic algorithm reducing bias towards a single template (base) molecule and introduces partial...

Effect of HPA Axis on the Reproductive Axis

Synthesis and 3) infusion of stress levels of cortisol can produce inhibition of LH pulse amplitude but not frequency, which is blocked by RU486, a glucocorticoid receptor antagonist (Breen et al. 2004 Debus et al. 2002). Finally, a recent study of exercise-induced reproductive abnormalities in adolescent girls concluded that in active adolescents, increased cortisol concentration may. . . precede gonadotropin changes seen with higher levels of fitness (Kasa-Vubu et al. 2004, p. 1). These data suggest that cortisol, in addition to central CRH, may also play a role in LH disruption.

Clustering and Classification

The division of data sets into separate clusters is described in a number of publications. In all cases, the number of clusters is assumed to be known. For large data sets, Lucasius et al. describe a c-medoid clustering method, in which the GA is used to pick the cluster centers 68 . The fitness criterion consists of the minimization of the sum over all clusters

Contact Sports and Oxidative Stress

Levels that were almost twice as high as well-trained following a match. Both football and rugby athletes experience oxidative stress as a result of their sports. While the high fitness level of professional and well-trained athletes helps to control oxidative stress, there still is variability in oxidative stress biomarkers among athletes. Nevertheless, the intensity of force produced by muscles, trauma, and metabolic demands of football and rugby can overwhelm endogenous defenses.

Selection Algorithms

EAs implement selection mechanisms through algorithms that choose particular parents to be used in generating offspring. GAs are usually implemented with stochastic selection methods. One of these methods is roulette wheel selection (also called proportional selection). All members of a population are assigned a segment on a wheel, with each segment having a size in proportion to the fitness of its associated population member. Random positions on the wheel are chosen, and the population member occupying that space becomes a parent. This process is repeated as needed. This selection method can result in premature convergence to a local optimum if there is a candidate solution with a fitness that is greatly superior to that of other population members. This problem can be avoided by using a candidate's rank rather than its actual fitness to determine the size of its space on the wheel. Tournament selection relies on competitions between randomly selected population members for...

Energy Minimization

Parallellization using island or migration models is reported to improve results, mainly by making it easier for the algorithm to maintain a diverse population 51, 56, 62, 63 . Niching, where the population is divided into subsets of more or less similar individuals, is also used for this purpose. A popular niching technique is sharing, where the fitness of individuals in the same niche is lowered when the niche is overpopulated. Measuring the degree of similarity in the population (also called convergence) is not always straightforward. Torsion angles of -179 and 179 degrees are of course quite close, so simply looking at differences or variances may lead to wrong conclusions. In 21 , a simple criterion is defined for the measurement of similarity in a population defined by strings of torsion

The Targets

Our perceptions of these emergent pharmacological attributes are recorded as measured responses exhibited by other complex biological systems, or even as sensations within ourselves. The latter comprise the emergent states that we call health, fitness or well-being - in other words, the mission of medicine and drug research (Testa, 1996). At this organismic level of emergence we do not have a continual sense of the cellular or subcellular phenomena antecedent to the measurements and awareness of the health state. These antecedents, these ingredients of emergence experience dissolvence as they become part of the manifold of changes in tissues and organs that collectively constitute our state of health. These processes of dissolvence are prerequisite to the emergence of action, i.e. the functioning of the complex. By limiting the choices of states of the ingredients within the complex there is created a number of possible states of the complex. Options of action and reaction are...

The evidence base

Because pain has multiple and widespread effects on patients, I expected to find multiple treatment targets and measurement tools across the 25 trials analyzed. In total, over 200 separate measurement tools were employed in these trials. For clarity, all these measurement tools were classified into a domain of measurement. These were pain experience, mood affect, cognitive coping and appraisal, pain behavior, biological physical fitness, social role functioning, and use of healthcare systems. Not all trials had measurement tools in each domain, and some trials used numerous measures within a domain. The most psychometrically sound measure used in each domain was selected for analysis.

Published Methods

One of the first reports used the well-tested negative-spheres description from the DOCK program 17 for assigning a fitness, later on adding a GA procedure for docking ligands flexibly 26 . The DOCK method fills the protein active site with spheres, and then roughly docks the ligand by matching atoms with centers of the spheres. This required an alternate formulation of the genome, to allow control of this matching process by the values in each gene. A bit string was used to represent the matching of a set of ligand atoms to receptor spheres, thus defining ligand position and orientation. A traditional bit string was used to assign the torsion angle values of the rotatable bonds in the ligand. The GA optimized the position orientation matching and torsion angles simultaneously. The GA method was of comparable speed to DOCK when the ligands were treated rigidly, but slower when it allowed for ligand flexibility. Although no positional RMSD values were given for the GA docking results,...

Discussion

The fitness function is another crucial component of an EA, and the particular fitness function that is applied depends on the problem domain. For example, in receptor binding, the fitness function generally attempts to estimate the strength of drug-receptor binding. In other cases, the fitness function measures how well a molecule fits a pharmacophore hypothesis, or how similar it is to some known target compound. Fitness functions have also been developed that measure how well the evolving molecules fit a QSAR or QSPR. One of the attractive features of EAs in general is that it is relatively easy to incorporate multiple objectives within the fitness function. For example, in designing potential drug candidates, factors such as synthetic feasibility, chemical stability and properties of absorption, distribution, metabolism, and excretion (ADME) are important, as well as binding affinity. Many approaches encode multiple objectives using a weighted fitness function with a weight...

Genetic Algorithms

The fitness of each chromosome is evaluated based on a numerical function, which reflects the quality of each candidate solution. The next step, reproduction, creates new chromosomes from the existing generation. Through the selection operator, better chromosomes can proliferate preferentially. With crossover, each chromosome has an opportunity to exchange information with the others via a mating procedure. Finally, fitter offspring may appear in the next generation if beneficial mutations take place. As the system gathers more knowledge about the underlying parameter space, the collective search, which may appear to be random at first, begins to gain focus and moves towards more optimal regions. The reproductive cycle is repeated until a predefined number of generations, a specified convergence criterion or a target fitness score is attained.

New Gene Pool

Later, Rogers and Hopfinger published a paper that described a type of GA, termed genetic function approximation (GFA), to select descriptors. The GA was coupled with a standard multiple linear regression (MLR) method to derive QSAR models 27 , GFA is a conventional GA with crossover and mutation operators, and its reproduction strategy is shown in Fig. 3. The calculation began with a population of 300 randomly chosen sets of descriptors, and it took typically 3000-10 000 genetic operations to reach convergence. GFA incorporates the lack of fit (LOF) error measure as its fitness criterion

Curve Fitting

Choy and Sanctuary describe a genetic algorithm (GA) for fitting one-dimensional nuclear magnetic resonance (NMR) signals with a scaled squared error between the experimental and calculated spectrum as the fitness function 11 . The estimated parameters were peak damping factor and frequency peak amplitude and phase were then obtained by simple regression. A priori knowledge can be introduced by imposing constraints on the parameter values. It was shown using simulated noisy spectra that the GA performed better than an iterative maximum likelihood method proposed by the same authors, although execution times were longer. (For more applications of EAs in NMR, see Chapter 10.) In the area of X-ray spectroscopy, several groups have used GAs to solve crystal structures from powder diffraction data. The aim in this case is to find parameters describing both the structure of a molecule and its orientation in the unit cell. Shankland et al. use a X2 error value as the fitness function, based...

Spectroscopy

Examples of feature selection in spectroscopic calibration can be found in quantitative applications of IR spectroscopy 41-43 as well as qualitative ones 44 , mass spectrometry 45 and UV-Visible spectroscopy 46 . Jouan-Rimbaud et al. showed that a G A for wavelength selection sometimes includes uninformative variables if a fitness function is used that is based solely on a predictive sum-of-squares 47 , Therefore, they proposed performing a forward stepwise selection from the final best solution found by the GA. Other op tions are to use a fitness function which chooses the smallest set of wavelengths that yields a model with a predictive power better than a prespecified threshold 45 , or a fitness function which incorporates in some way the number of selected wavelengths 48 . Both have their disadvantages in the first case, one must specify a threshold value (and, in practice, will have to try several values before a suitable one is found) in the second case, the form of the fitness...

Miscellaneous

Zupan and Novic use the correlation between the biological activity predicted by a neural network and experimental values as the fitness function in a GA for the selection of the 15 most useful variables out of a set of 120 for defining molecular structure 58 , Hou et al. apply a GA to select a subset from 24 features with which to predict the biological activity of two groups of HIV-1 inhibitors 59 , An application in quality control is described in 60 , where the subset of product quality variables retaining most of the information contained in the original set is sought.

Object Selection

In the context of high-throughput biological screening, a different approach can be taken. In such an application, a subset of molecules is selected in which each molecule is representative of a number of similar species. An approach to select an optimal subset for such cases is described in 64 , where representative subsets of 100, 300, and 500 molecules were selected from a superset of 5000. The 281 original variables, chemical and physical descriptors, were summarized in 58 principal components prior to subset selection. A fitness function based on the product-moment correlation coefficient appeared to work well. In comparison with other methods, such as clustering, or using a maximum dissimilarity criterion, GAs are suitable for the selection of subsets that preserve local information 65 , Subsets retaining more global information are obtained by other approaches such as the maximum dissimilarity method, while the most representative subsets were obtained by clustering methods....

Step

Evolution of a potential thrombin inhibitor by TOPAS, showing 12 subsequent parent structures of an evolutionary design experiment. NAPAP served as the template structure, and the Tanimoto index was used as fitness measure. An example of a TOPAS design experiment aiming at the generation of a NAPAP-like structure is shown in Figure 8.16. The Tanimoto index was used as the fitness measure. Initially, a random structure was generated from the stock of -24000 available building blocks ( parent of the first generation). The Tanimoto similarity to NAPAP was 0.31 reflecting a great dissimilarity, as expected. In each of the following generations, 100 variants were systematically generated by TOPAS, and the best of each generation was selected as the parent for the subsequent generation. Following this scheme, novel molecules were assembled which exhibited a significantly increased fitness (Figure 8.17). After only 12 optimization cycles the process converged at a high fitness...

Summary and Outlook

Kauffman, Adaptive Walks with Noisy Fitness Measurements, Mol. Diversity 1995, 1, 53-68. 31 M. Forrest, M. Mitchell, Relative Building-block Fitness and the Building-block Hypothesis, in D. Whitley (Ed.), Foundations of Genetic Algorithms 2, Morgan Kaufmann, San Mateo, CA, 1993, pp. 109-126.

Resistance to AZT

Resistance to AZT is commonly encountered in treated HIV-infected patients, mainly because AZT was the first available antiviral with some activity against HIV. Resistance to AZT is easy to identify from the RT genotype, which usually bears characteristic amino acid substitutions M41L, D67N, K70R, L210W, T215Y, and K219Q (Larder and Kemp, 1989). The first HIV-1 variants clearly identified as AZT-resistant carried mutations M41L and T215Y. In spite of a strong resistance phenotype, these viruses appeared to replicate normally in culture in the absence of drug. In vivo, reports of transmission of AZT-resistant viruses to treatment-naive patients in which resistance mutations were maintained for long time periods in the absence of AZT treatment also indicated that HIV resistance to AZT was achieved at the expense of minimal, if any, loss of viral fitness (Yerly et al., 1998). Some authors even proposed that following selection for high-level resistance to AZT, HIV may become more fit...

A3b5c16d12e17f2

The good search power of GAs is believed to originate from the building-block hypothesis 8-11 . This model assumes that the combination of fit building blocks, or genes, or schemes of genes on the chromosome yields higher-order schemes of even better fitness. In the light of the above discussion on the properties of the S AR space, this hypothesis is equivalent to a continuous behavior. For the above example in Figure 9.4, building block A1 appears in the chromosome with rank one and four, and B4 with one and five. It is therefore meaningful to assume that the combination A1B4 is a scheme of higher order. C8 appears with rank three and four, so A1B4C8 could therefore be part of an even better peptide. The task of the genetic operators is to observe such schemes and to propose new chromosomes using these schemes. Thus, in a typical implementation of GAs, the probability of applying a genetic operator towards a given chromosome depends on its rank or fitness . For fitter chromosomes,...

Methodology

In the GA approach for indexing powder diffraction data, each member of the population is a set of trial lattice parameters (a, b, c, a, , y) (or a subset of these parameters, depending on the crystal system), and the population evolves through mating, mutation and natural selection. The fitness of each set of trial lattice parameters depends on its value of R , and the linear fitness function F(Rwp) 1 - (Rwp - Rmin) (Rmax - Rmin) has been used in our work so far. As before, Rmin and Rmax denote the lowest and highest values of Rwp in the current population, and are updated for each new generation of the population. Our strategy for carrying out the GA calculation is similar to that implemented in our GA technique for structure solution (see section 9.2.2).

Concluding Remarks

Although several other approaches may also be used for global optimization (including, for example, Monte Carlo and simulated annealing methods), it is not advantageous at this stage to enter a detailed general comparison between these approaches and GAs, as the relative merits depend critically on the particular problem at hand and details of the particular implementation of each approach. Nevertheless, it is worthwhile to highlight the fact that GAs operate in an intrinsically parallel manner, with many different regions of parameter space (corresponding to different members of the population) investigated simultaneously. Furthermore, information on these different regions of parameter space is passed actively between individual members of the population by the mating procedure, promoting efficient convergence towards the global minimum. The implicit parallel nature of GAs makes them efficient and robust vehicles for optimization, and particularly advantageous for optimization...

Market Wire

Market Wire is more focused on technology than the other wires. To browse the latest press releases by topic, such as alternative medicine, biotechnology, fitness, healthcare, legal, nutrition, and pharmaceuticals, access Market Wire's Medical Health channel at Or simply go to Market Wire's home page at http www.marketwire.com mw home, type colloidal silver (or synonyms) into the search box, and click on Search News. As this service is technology oriented, you may wish to use it when searching for press releases covering diagnostic procedures or tests.

United Atom Models

Sun et al. 29 used a description of a protein molecule that consisted of a full backbone together with one virtual atom per side chain. A potential of mean force derived from known protein structures was used to assess the fitness of trial conformations. An additional constraint was the experimental radius of gyration. A library of peptide fragment conformations two to five residues long, constructed from known protein structures, was used to construct initial conformations and to perform mutational changes. A population size of 90 was used. Low final root mean square deviations from the experimental structure were reported. The significance of these results is difficult to assess, as the fragments were selected from the library on the basis of sequence similarity and the library contained the two larger structures that were successfully reproduced. This would presumably introduce a strong bias towards the expected structure. Nonetheless, the method presented is interesting and worthy...

Self Adaptation

Most research on self-adaptation has emerged from the ES and EP communities, and has thus been primarily concerned with the mutation operator, which is the main variational operator for these two classes of EA. The motivation for developing self-adaptive techniques was the realization that, given a population of real-valued vectors, the optimization performance of the algorithm can be improved by applying perturbations of different magnitude to each of the variables in the vector, in other words, each dimension of the search. This is particularly so when the variables have different units of dimension, for example, pressure and temperature 22 , To try to determine a priori optimal values for these mutational step sizes is virtually impossible, especially as the optimal values may alter during the course of a search as the algorithm traverses the fitness landscape. The two main approaches towards self-adaptation seek to counter this problem by allowing the mutational step sizes to...

Interactive EAs

This approach takes a user-as-fitness-function approach that substitutes the fitness function for a user-assigned score in an admittedly ad hoc manner. Though this is in the spirit of what we are trying to achieve, Tuson et al. 46 raise a number of objections. First of all, most realistic optimization problems will require on the order of thousands of function evaluations and this is clearly infeasible for a human expert to perform. For instance, Gehlhaar et al. typically use 70 000 fitness function evaluations for each docking run with AGDOCK 31 . In addition to this scalability problem, Biles' approach ignores the fact that it is usually possible to construct a reasonably close model of what a good solution is, thereby reducing the human effort required. Finally, even a partial attempt at formalizing the goal knowledge can be a useful exercise in promoting a better understanding of the problem being solved. Therefore, a future issue in using interactive EAs for real-world problems...

Parallel Algorithms

In the execution of an EA, it is invariably the fitness evaluation step that is the most computationally expensive. However, the fact that this step is decoupled from the rest of the algorithm makes EAs highly amenable to parallelization, creating a parallel EA. Some of the various kinds of parallel EA have been classified by Cantu-Paz 49 . For the purposes of this chapter, two types of parallel EA are of particular interest. The first type is what Cantu-Paz terms coarse-grained parallelism. In this formalism, the population is divided into a small number of subpopulations that are kept relatively isolated from one another, evolving on separate processors or machines. The optional introduction of a migration operator permits the exchange of individuals between subpopulations at specified intervals. At least two models of coarse-grained parallelism are possible the first is termed the island model and the second is known as the stepping stone or ring model (Fig. 2). Both partition the...

NMR Pulse Shapes

Freeman and coworkers have reported that a GA approach leads quickly to acceptable pulse shapes 77, 78 , Simple examples were used to demonstrate the idea. Pulse shaping functions are used for gene encoding, and instead of defining an objective function to evaluate the fitness of the candidate solutions, the operator intervenes and chooses the most promising chromosomes as parents for the next generation. After some generations, pulse trains that are suitable for specific purposes can be generated. It was concluded that the genetic evolution approach could be successfully used for NMR pulse shaping. Moreover, insight can be obtained by noting how the various shaping functions influence the excitation spectrum.

Crf3301b

Recombinant viruses may have certain advantages over the parental strain, including modifications in tropism and replication efficiency ( viral fitness''). Under selection pressure imposed by antiretroviral drugs, recombination between strains with different drug sensitivity resulted in new HIV-1 variants with dual or multiple drug resistance (Moutouh et al., 1996). The

Phylogeny of TAS2Rs

When the TAS2R genes of other primates were cloned and their sequences analyzed (Parry et al. 2004 Wang et al. 2004 Fischer et al. 2005 Go et al. 2005), several points became clear. Firstly, compared with rodents, primate TAS2R genes experienced less selective constraint. Secondly, compared with other primates no significant loss in the number of functional TAS2R genes has been observed in humans. This is in contrast to the odorant receptor gene family and has been explained by reduced sensory needs specific for the olfactory system (Fischer et al. 2005). Thirdly, hallmarks of neutral evolution have been observed, including similar rates of synonymous and non-synonymous substitutions among rare polymorphisms, common polymorphisms and substitutions, segregation of pseudogene alleles within species and fixation of loss-of-function mutations (Wang et al. 2004 Fischer et al. 2005 Go et al. 2005). An interesting question is whether the observed ratio of non-synonymous to synonymous...

Cooh Hooc

Food, physical fitness, and aerobic capacity on HO activity, CO, and bilirubin need to be examined. Low serum bilirubin concentrations also could be due to the increased oxidative state or to low levels and activities of HO and BVR. Certainly, drugs which induce HO and drugs which decrease or increase serum bilirubin levels will enhance our understanding of the major protective factors in the heme catabolic pathway. It should be also noted that most of the information on serum bilirubin and disease have been derived from chronic studies. If bilirubin is an effective antioxidant and anti-inflammatory agent, it should have a role in amelioriating the acute medical conditions. Therefore, the effects of the heme catabolic pathway in acute medical conditions need to be examined in more detail.

Procurement

For computer systems in particular, the documentation produced by the vendor is critical in the verification of its fitness for purpose. A computer validation specialist is required to review these items. Additionally the specialist should work with the user to produce the user requirements. This is a critical document, upon which all further work is based. Never underestimate the amount of literature required to adequately underpin the validation of a complex computerised system. The vendor should have a quality system in place and the standard operating procedures, which are the visible expression of that system, may require review. Project specific documentation may include

Get Fit Get Healthy

Get Fit Get Healthy

Anyone who wants to experience better health and fitness... Discover Simple Techniques To Getting Fitter amp Healthier And Staying That Way, Starting Today! This Guide Will Show You Easy Ways To Get Fit And Get Healthy No Fluff, No Fillers...Just Useful Techniques You Can Start Using Today.

Get My Free Ebook