Journal of Theoretical Biology

Published by Elsevier
Online ISSN: 1095-8541
Print ISSN: 0022-5193
The meaning of the word efficiency in ecology is compared with the basic English usage and with its technical usage in physics and economics. Three distinct kinds of technical efficiencies are identified on the basis of the aim or goal toward which the efficiency is addressed. Efficiency-I is the traditional thermodynamic efficiency, redefined with the goal of delayed production of entropy. Efficiency-II is commonplace in social, economic and ecological situations and is characterized by the goal of selfish use, or maximum power input. Efficiency-III governs systems of many parts, particularly ecosystems described in four dimensions, and is characterized by integration and survival. Efficiency-III also characterizes organisms, vis-à-vis their components. “Ecological efficiency” as commonly used to relate different trophic levels is found to be an unacceptable compound of efficiencies I and II.
Replicating genetically modified adenoviruses have shown promise as a new treatment approach against cancer. Recombinant adenoviruses replicate only in cancer cells which contain certain mutations, such as the loss of functional p53, as is the case in the virus ONYX-015. The successful entry of the viral particle into target cells is strongly dependent on the presence of the main receptor for adenovirus, the coxsackie- and adenovirus receptor (CAR). This receptor is frequently down-regulated in highly malignant cells, rendering this population less vulnerable to viral attack. It has been shown that the use of MEK inhibitors can up-regulate CAR expression, resulting in enhanced adenovirus entry into the cells. However, inhibition of MEK results in G1 cell cycle arrest, rendering infected cells temporarily unable to produce virus. This forces a tradeoff. While drug mediated up-regulation of CAR enhances virus entry into cancer cells, the consequent cell cycle arrest inhibits production of new virus particles and the replication of the virus. Optimal control-based schedules of MEK inhibitor application should increase the efficacy of this treatment, maximizing the overall tumor toxicity by exploiting the dynamics of CAR expression and viral production. We introduce a mathematical model of these dynamics and show simple optimal control based strategies which motivate this approach.
A novel knowledge-based method is developed to virtually screen potential HLA-A*0201 binders from large-scale peptide candidates. This method utilizes the information from both the crystal structures and experimental affinities of various peptides bound with HLA-A*0201 to construct a single-position mutation free energy profile for accurately characterizing HLA-A*0201-peptide interaction and for effectively predicting the binding affinities of peptides to HLA-A*0201. We employ this method to analyze physicochemical properties and structural implication underlying the specific recognition and association between the HLA-A*0201 and a large panel of peptide segments generated from the herpes simplex virus type 1 (HSV-1) genome, and to evaluate the binding potencies of these peptide candidates to HLA-A*0201. As a result, 288 out of 38,020 candidates are predicted as the potential high-affinity binders of HLA-A*0201, from which three most promising peptides are picked out for further development of potent vaccines against HSV-1. In addition, we also demonstrate that this newly proposed method can successfully identify 8 known binders and 3 known nonbinders from the glycoproteins D and K of HSV-1.
The pandemic H1N1/09 influenza virus differs from seasonal influenza in its greater prevalence among younger individuals. It is well known that younger individuals interact with one another and society as a whole more than older individuals, suggesting that this could account for the skewed prevalence. However, the observed skewed disease prevalence could also be due to a lesser biological vulnerability (cross-immunity or partial immunity) in the older generation. We develop an age-structured, compartmental mathematical model to quantify the degree to which the skewed disease prevalence among younger individuals is due to a lesser biological vulnerability in the older generation. The model incorporates synthetic data regarding sociological interaction between different age groups generated from the simulation software EpiSims, which allows a clear distinction of the sociological and biological susceptibility effects on the transmission rate of the disease. After fitting the model to available data, we quantify the degree of biological susceptibility of five age groups in the population of the United States. Our model indicates that individuals over the age of 60 are 1/15 as susceptible to H1N1/09 influenza as those under 30 years of age. The key feature in the model is separating social contact factors of disease transmission from biological ones.
A mathematical model of the action of a photosystem II herbicide 3-(3',4'-dichlorophenyl)-1, 1-dimenthylurea, DCMU, in plant leaves upon an external application is presented. The diffusion of DCMU in a plant tissue is described with the help of Fick's laws and the following reaction of the herbicide with the QB-binding site of photosystem II by the mass action theory. The model is used for a description of the effect of the herbicide on chlorophyll fluorescence induction (the O-J-I-P curve) measured with spring barley primary leaves submerged in the herbicide solution. The increase of the J step during the herbicide action is ascribed to an increase of the number of photosystem II centres with bound herbicide molecules and malfunctioning in the electron transport to the plastoquinone pool. The experimental data were fitted with the help of the mathematical model. Values of the diffusion coefficient and the second order rate constant of the reaction of the herbicide with photosystem II, obtained by the fitting procedure, are discussed.Copyright 1998 Academic Press Limited
The conformations of 2S,3R-2-(N-formyl)amino-l,3-dihydroxy-Δ31-pentene, a model compound of sphingomyelin, have been studied both by the classical potential function and by the INDO molecular orbital method. The results suggest that the preferred conformation of sphingomyelin in the membrane is such that the olefinic double bond of the γ-hydrocarbon chain and the planar amide group of the β-chain are parallel and stack in an antiparallel manner with dihedral angles β1′(C3-C2-N21-C21) = −100 ° and γ1(C2-C3-C31-C32) = −100 °.
A mathematical account is given of the processes governing the time courses of calcium ions (Ca2+), inositol 1,4,5-trisphosphate (IP(3)) and phosphatidylinositol 4,5-bisphosphate (PIP(2)) in single cells following the application of external agonist to metabotropic receptors. A model is constructed that incorporates the regulation of metabotropic receptor activity, the G-protein cascade and the Ca2+ dynamics in the cytosol. It is subsequently used to reproduce observations on the extent of desensitization and sequestration of the P(2)Y(2) receptor following its activation by uridine triphosphate (UTP). The theory predicts the dependence on agonist concentration of the change in the number of receptors in the membrane as well as the time course of disappearance of receptors from the plasmalemma, upon exposure to agonist. In addition, the extent of activation and desensitization of the receptor, using the calcium transients in cells initiated by exposure to agonist, is also predicted. Model predictions show the significance of membrane PIP(2) depletion and resupply on the time course of IP(3) and Ca2+ levels. Results of the modelling also reveal the importance of receptor recycling and PIP(2) resupply for maintaining Ca2+ and IP(3) levels during sustained application of agonist.
Regulation of the human menstrual cycle is a frequency dependent process controlled in part by the pulsatile release of gonadotropin releasing hormone (GnRH) from the hypothalamus. The binding of GnRH to gonadotroph cells in the pituitary stimulates inositol 1,4,5-trisphosphate (IP3) mediated release of calcium from the endoplasmic reticulum, resulting in calcium oscillations and the secretion of luteinizing hormone (LH). A sudden increase in serum LH concentrations known as the LH surge triggers ovulation. Here we model the intracellular calcium dynamics of gonadotroph cells by adapting the model of Li and Rinzel (J. Theor. Biol. 166 (1994) 461) to include the desensitization of IP3 receptors to IP3. Allowing the resensitization rate of these receptors to vary over the course of the cycle suffices to explain the LH surge in both the normal menstrual cycle, and in the treatment of Kallmann's syndrome (a condition where endogenous production of GnRH is absent).
Considerable insight into intracellular responses has been obtained through the development of whole cell models that are based on molecular mechanisms, e.g., single channel kinetics of the inositol 1,4,5-trisphosphate ( ) receptor channel. However, a limitation of most whole cell models to date is the assumption that receptor channels ( s) are globally coupled by a “continuously stirred” bulk cytosolic [ ], when in fact open s experience elevated “domain” concentrations. Here we present a -compartment whole cell model of local and global responses mediated by diffusely distributed s, each represented by a four-state Markov chain. Two of these compartments correspond to bulk cytosolic and luminal concentrations, and the remaining compartments represent time-dependent cytosolic and luminal domains associated with each . Using this Monte Carlo model as a starting point, we present an alternative formulation that solves a system of advection–reaction equations for the probability density of cytosolic and luminal domain [ ] jointly distributed with state. When these equations are coupled to ordinary differential equations for the bulk cytosolic and luminal [ ], a realistic but minimal model of whole cell dynamics is produced that accounts for the influence of local signaling on channel gating and global responses. The probability density approach is benchmarked and validated by comparison to Monte Carlo simulations, and the two methods are shown to agree when the number of channels is large (i.e., physiologically realistic). Using the probability density approach, we show that the time scale of domain formation and collapse (both cytosolic and luminal) may influence global oscillations, and we derive two reduced models of global dynamics that account for the influence of local signaling on global dynamics when there is a separation of time scales between the stochastic gating of s and the dynamics of domain .
We propose a molecular model for InsP3-sensitive Ca2+ oscillations based on the allosteric properties of the InsP3 receptor/Ca2+ channel. Our model interprets the cooperatively towards InsP3 saturation, of calcium efflux from intravesicular stores as well as the absence of cooperativity in the binding process of InsP3 on the receptor. It takes into account quantitatively the two antagonist, concentration-dependent effects (fast activator and slow inhibitor) that cytosolic Ca2+ exerts on the InsP3 receptor/Ca2+ channel. Assuming that a single pool of releasable Ca2+ exists in the endoplasmic reticulum, the model leads to cytosolic and intravesicular oscillations in Ca2+ at fixed InsP3 concentration. Activation of the receptor by cytosolic calcium is essential for the triggering of oscillations whereas the slow Ca2+ inhibition effect is irrelevant in this respect, although this regulation loop might prevent the system from entering the unstable domain in absence of a true agonist stimulation. Activating cytosolic Ca2+ and InsP3 have quite distinct functions for the induction of Ca2+ release: cytosolic Ca2+ triggers oscillations whereas InsP3 only brings the receptor into a potentially oscillatory regime. Hence, the increasing slope of Ca2+ spiking is constitutively independent from the intensity of the hormonal stimuli in our model, in accord with experimental observations. Comparisons with other existing models are given and additional possible coupling mechanisms are discussed in order to explain particular facts (such as possible oscillations of InsP3) which do not depend on the intrinsic properties of the oscillator.
The charge relay hypothesis generated a large number of theoretical and experimental studies that tested the ideas involved. Opinion based upon theoretical and experimental studies is divided on the prediction, although there are many experimental data which do not support the hypothesis. The essential feature is the proton transfer from the histidine imidazole to the aspartate. Thus, we have performed the detailed calculations of the proton transfer from His 57 to Asp 102 including the environment of the couple in protonated bovine pancreatic β-trypsin. The charge state of the His 57-Asp 102 couple is greatly influenced by the environment of the enzyme around it. In this paper, it is shown that the proton between His 57 and Asp 102 is covalently bonded to the His 57 imidazole in the protonated β-trypsin. Our MO calculations, which support the neutral-pK-histidine theory as the results, do not support the charge relay mechanism.
The stochastic fluctuations in the initial phase of a one substrate one product enzyme system have been calculated for an actual enzyme reaction, using the model of Heyde & Heyde (1969). The experimental data are for the reaction catalysed by triose phosphate isomerase. It is shown that for this system the stochastic fluctuations in free enzyme, enzyme-substrate or enzyme-product complex, substrate and product are negligible. Using a more general stochastic model it is shown that stochastic fluctuations will in general be negligible for such systems except at the beginning of the transient phase.
Over the past two decades there has been increasing interest in the development of an objective, or formalized “medical logic”, and many authors have employed classical symbolic logic as a part of their approach. On the other hand, it has become clear that certain patterns of reasoning which are commonplace in evaluating patients clinicopathologically are awkward to handle in classical symbolic logic. The present paper proposes an extension of classical symbolic logic which addresses three problems in medical reasoning: (i) the problem of provisional diagnosis, (ii) the problem of inaccessible data, and (iii) the problem of the adequate discharge summary. It is proved mathematically that with a suitably constructed logic, the system “complains” until all questions involving threats to the patient's health are either answered or shown to be unanswerable because of inaccessibility of data. To illustrate this method, the cause of death was studied in 108 patients who had been autopsied at The Johns Hopkins Hospital after coronary artery bypass surgery. The analysis disclosed that 46% of patients suffered a fatal complication which could be attributed to events in the perioperative period; in 15% of patients the cause of death was unexplained by the analysis. Computerized symbolic logic analysis is a useful supplement to intuitive reasoning in assigning cause of death to patients with complex medical histories.
Ecologists have long been searching for mechanisms of species coexistence, particularly since G.E. Hutchinson raised the 'paradox of the plankton'. A promising approach to solve this paradox and to explain the coexistence of many species with strong niche overlap is to consider over-compensatory density regulation with its ability to generate endogenous population fluctuations. Previous work has analysed the role of over-compensation in coexistence based on analytical approaches. Using a spatially explicit time-discrete simulation model, we systematically explore the dynamics and conditions for coexistence of two species. We go beyond the analytically accessible range of models by studying the whole range of density regulation from under- to very strong over-compensation and consider the impact of spatial structure and temporal disturbances. In particular, we investigate how coexistence can emerge in different types of population growth models. We show that two strong competitors are able to coexist if at least one species exhibits over-compensation. Analysing the time series of population dynamics reveals how the differential responses to density fluctuations of the two competitors lead to coexistence: The over-compensator generates density fluctuations but is the inferior competitor at strong amplitudes of those fluctuations; the competitor, therefore, becomes frequent and dampens the over-compensator's amplitudes, but it becomes inferior under dampened fluctuations. These species interactions cause a dynamic alternation of community states with long-term persistence of both species. We show that a variety of population growth models is able to reproduce this coexistence although the particular parameter ranges differ among the models. Spatial structure influences the probability of coexistence but coexistence is maintained for a broad range of dispersal parameters. The flexibility and robustness of coexistence through over-compensation emphasize the importance of nonlinear density dependence for species interactions, and they also highlight the potential of applying more flexible models than the classical Lotka-Volterra equations in community ecology.
Zero-order ultrasensitivity (ZOU) is a long known and interesting phenomenon in enzyme networks. Here, a substrate is reversibly modified by two antagonistic enzymes (a 'push-pull' system) and the fraction in modified state undergoes a sharp switching from near-zero to near-unity at a critical value of the ratio of the enzyme concentrations, under saturation conditions. ZOU and its extensions have been studied for several decades now, ever since the seminal paper of Goldbeter and Koshland (1981); however, a complete probabilistic treatment, important for the study of fluctuations in finite populations, is still lacking. In this paper, we study ZOU using a modular approach, akin to the total quasi-steady state approximation (tQSSA). This approach leads to a set of Fokker-Planck (drift-diffusion) equations for the probability distributions of the intermediate enzyme-bound complexes, as well as the modified/unmodified fractions of substrate molecules. We obtain explicit expressions for various average fractions and their fluctuations in the linear noise approximation (LNA). The emergence of a 'critical point' for the switching transition is rigorously established. New analytical results are derived for the average and variance of the fractional substrate concentration in various chemical states in the near-critical regime. For the total fraction in the modified state, the variance is shown to be a maximum near the critical point and decays algebraically away from it, similar to a second-order phase transition. The new analytical results are compared with existing ones as well as detailed numerical simulations using a Gillespie algorithm.
Ribosomal phosphoprotein P1 (RPP1) is acidic phosphoprotein which in association with neutral phosphoprotein P0 and acidic phosphoprotein P2 forms ribosomal P protein complex as (P1)2-P0-(P2)2. P protein is known to be immunogenic and has important role in protein translation. 3D structure of P1 is not known. We have built an ab-initio model of RPP1 of Plasmodium falciparum using I-TASSER. Stereochemical stability of structure was checked using PROCHECK and the normality of the local environment of amino acids was checked using WHATIF. Comparison between known protein structures in PDB database and model protein was done using Dali server. Molecular dynamic simulation study and virtual screening of RPP1 was carried out. Three dimensional model structure of RPP1 was generated and model validation studies proved the model to be steriochemically significant. RPP1 structure was found to be stable at room temperature in water environment demonstrated by 30ns molecular dynamic simulation study. Dali superimposition showed 69% superimposition to known 3D structures in PDB. Further virtual screening and docking studies promoted good interaction of ligands Ecgonine, Prazepam and Ethyl loflazepate with RPP1. The work provides insight for molecular understanding of RPP1 of Plasmodium falciparum and can be used for development of antimalarial drugs.
Sugar rearrangement in the pentose phosphate cycle for transformation of six pentoses into five hexoses is analysed by abstraction to a mathematical model consisting of the resolution of a logical mathematical game of optimization. In the model, the problem is to arrive at five boxes containing six balls each, having started with six boxes containing five balls each, where boxes simulate the sugars and balls simulate the carbons in each. This is achieved by means of transferring two or three balls from any box to any other in each step, according to transketolase and transaldolase (or aldolase) mechanisms which account for sugar interconversions in the living cell. A hypothesis of simplicity is imposed in order to arrive at the objective with the least number of steps and with the least number of balls in the intermediary boxes. A symmetrical solution is obtained, demonstrating that this is the simplest solution, which is the procedure carried out by biological systems. The same treatment is applied for sugar rearrangement in the non-oxidative phase of the Calvin cycle in photosynthesis and the analysis of the "L-type" of pentose phosphate cycle is also treated, obtaining similar solutions in both cases, which allow us to make some physiological reflections.
This Corrigendum has been withdrawn at the request of the authors. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at
The present paper aims at exploring the elongation of the PrP106-126 fibril under acid environments through molecular dynamics simulation. It shows that influenced by the edge strands of the fibril, single PrP106-126 peptide forms beta-sheet and becomes a new element of the fibril. Under acidic condition, single PrP106-126 fragment presents a much larger variety of conformations than it does under neural condition. However, acidic condition does not largely affect the stability of the PrP106-126 fibril. Consequently, the speed of the fibril elongation can be dramatically increased by lowering the pH value of the solution. The pH values are adjusted by either altering the protonation state of the residues or adding hydronium ions or hydroxyl ions.
The differing inheritance patterns of cytoplasmic genes and the sex chromosomes from the Mendelian autosomal patterns can be used to divide the genome into fractions whose defining rule is that the fitness of all genes in a set is maximized in the same way. Each set will be selected to modify the phenotype of the organism in a way which maximally propagates the genes comprising the set, and hence in ways inconsistent with the other sets which comprise the total genome. The coexistence of such multiple sets in the same genome creates intragenomic conflict. Evidence is presented in which the fitness of cytoplasmic and other non-autosomal genetic sets are increased at the expense of the autosomal genetic set. The relationship of such intragenomic conflict to the evolution of anisogamy, dioecy, skewed sex ratios, differential male mortality, systems of sex determination, and altruism is discussed.
This paper analyzes the evolutionary dynamics of a locus controlling the degree of female mating preference in a temporally fluctuating environment. Preference for mating with males with respect to their genotypes at a locus that is subject to temporally varying natural selection pressure is considered first. With weak selection and free recombination between the choice locus and the selected locus, preference for mating with heterozygotes appears to be favored. With strong selection, preference for homozygous mates may be favored. In each case, choice alleles may increase from very low initial frequencies to near fixation, in contrast to previous models of mate choice in varying environments. Linkages between the two loci has complex effects on the strength and direction of selection for mate choice. Preference for mating with males with the currently fitter genotypes at the locus under natural selection is also modelled. Provided that the environmental period is not too short, a rare allele conferring such preference may be favored and spread to fixation. Strong natural selection, tight linkage and a short environmental period may produce polymorphism for the level of mate choice.
It is proposed that chi-square statistic be employed in constructing periodograms for the analysis of hourly time series data obtained in studies of circadian rhythmicity. We show that even for relatively short (10 day) time series, the integral-valued chi-square periodogram can distinguish circadian-periodic from random series at a level of significance of about 0·01. In addition, we describe the effects of serial correlation and examine the resolving power of the method for two periodic components in the circadian range. We suggest how the method can be most profitably employed in the analysis of event-recorder data for detection of rhythmicity in the range 14 to 34 h., and for the estimation of period to ±0·2 h.
By means of a population genetical model, we study the evolution of segregation distortion. Most models of segregation distortion focus on a single distorter allele. In contrast, we consider the competition between a large number of distorters. Motivated by systems as the t complex of the house mouse or the Sd complex of Drosophila melanogaster, we assume that there is some "complementation" between distorter alleles, i.e. that the fitness of individuals heterozygous for two distorter alleles is higher than the fitness of homozygous individuals. In the presence of complementation, the most efficient distorter allele with the highest segregation ratio often does not outcompete less efficient distorters. In fact, our results show that coexistence of a large number of distorter alleles is more typical than the competitive exclusion of less efficient distorters by a single superior allele. We first consider the analytically tractable system where all distorters show the same amount of complementation. In this case, all distorters with a segregation ratio higher than a certain critical value will persist, resulting in a polymorphic population where the average segregation ratio is only slightly larger than 0.5. If the degree of complementation varies, there may be more than one stable equilibrium, and the outcome of competition may depend on the initial conditions. Motivated by empirical examples, we also consider the case that the distorting ability of an allele is negatively related to its effects on individual fitness. Interestingly, the outcome of competition depends crucially on details of such a trade-off. We conclude that verbal arguments are insufficient to predict the evolution of segregation distortion.
The state of activity and condensation of the sex chromosomes in gametocytes is frequently different from that found in somatic cells. For example, whereas the X chromosomes of XY males are euchromatic and active in somatic cells, they are usually condensed and inactive at the onset of meiosis; in the somatic cells of female mammals, one X chromosome is heterochromatic and inactive, but both X chromosomes are euchromatic and active early in meiosis. In species in which the female is the heterogametic sex (ZZ males and ZW females), the W chromosome, which is often seen as a condensed chromatin body in somatic cells, becomes euchromatic in early oocytes. We describe an hypothesis which can explain these changes in the activity and condensation of sex chromosomes in gametocytes. It is based on the fact that normal chromosome pairing seems to be essential for the survival of sex cells; chromosomal anomalies resulting in incomplete pairing during meiosis usually result in gametogenic loss. We argue that the changes seen in the sex chromosomes reflect the need to avoid pairing failure during meiosis. Pairing normally requires structural and conformational homology of the two chromosomes, but when the regions is avoided when these regions become heterochromatinized. This hypothesis provides an explanation for the changes found in gametocytes both in species with male heterogamety and those with female heterogamety. It also suggests possible reasons for the frequent origin of large supernumerary chromosomes from sex chromosomes, and for the reported lack of dosage compensation in species with female heterogamety.
An hypothesis is presented by which gamete specialization resolves a conflict between the function and replication of mitochondria. The function of mitochondria is to synthesize ATP by oxidative phosphorylation, which is coupled to respiratory electron transport. This requires a mitochondrial genetic system. However, "incorrect" electron transfers produce free radicals that cause mutation, and the frequency of these events is increased by mutation. Mitochondrial function is therefore detrimental to the fidelity of mitochondrial replication. Damage to somatic mitochondrial DNA may accumulate within, and indeed determine, the life span of individual organisms. Motility of one gamete is required for fertilization, and requires ATP. It is proposed that male gametes maximize energy production for motility by sacrificing mitochondrial DNA to electron transfer and its mutagenic by-products, while female gametes, which are non-motile, repress mitochondrial oxidative phosphorylation, thus protecting mitochondrial DNA for faithful transmission between generations. Male gametes then make no contribution to the mitochondrial genome of the zygote: mitochondria are maternally inherited. This testable hypothesis may help to explain the evolution of separate sexes and a number of their characteristics. Maternal inheritance of chloroplasts may be explained in a similar way, and contribute to the maintenance of separate sexes in plants.
Social and cultural habits of human populations affect the biological evolution of the agents of infectious diseases. Measles and similar diseases have evolved in the Old World and cannot have existed in their present form before the rise of the great river valley civilizations. It is suggested that increased virulence of measles in white and indigenous communities in America 1500-1800 may be due to a rare strain of the virus, which was selected during transfer from Europe. The release of viruses for biological pest control has provided new material for the study of the co-evolution of host-parasite systems, which has upset the dogma "evolution tends to avirulence". It is pointed out that this issue is closely related to the group selection debate among ethologists, i.e. to the problem: how can group selection overcome individual selection? A model is proposed in which differential growth of two strains of a parasite within the host and their transmission to new hosts is considered. It is supposed that transmission stages excreted by infectious hosts enter a common pool where they are mixed before infecting new hosts. Under these conditions, selection of the slower strain is possible only if the mean size of parasite inoculum is very small, i.e. if the density of transmission stages in the environment is low. The impact of this result on host pathology depends on the relation between virulence and transmission efficiency of the parasite.
We explore the use of [15N,13C]leucine tracer to estimate whole-body fractional rates of a fast-turning-over protein pool employing synthetic data. The kinetics of [15N,13C]leucine tracer are simplified compared with those of traditional leucine tracers and benefit from irreversible transamination to [13C]alpha-ketoisocaproaic acid (KIC) resulting in a simplified model structure. A three-compartment model of [15N,13C]leucine kinetics was proposed and evaluated using data generated by a Reference Model (based on a model by Cobelli et al.). The results suggest that fractional turnover rates of a fast-turning-over protein pool can be estimated with a low but acceptable precision during a six-hour constant intravenous infusion of [15N,13C]leucine with frequent sampling of plasma tracer-to-tracee ratio (TTR) of [15N,13C]leucine. We conclude that [15N,13C]leucine may be useful for the measurement of protein kinetics and its full potential should be explored in clinical studies with compartmental data analysis.
Leishmania major causes cutaneous form of Leishmaniasis affecting 21 million people in developing countries. Overuse of the chemotherapeutics against leishmaniasis has resulted in the development of drug resistance in the parasite. To surmount this emerging threat we have attempted to target the surface molecules. GlycosylPhosphatidylInositol is one such molecule that is present abundantly and thus our work revolves around the enzyme mannosyltransferase (GPI 14), an enzyme essential to add mannose on the glycosylphosphatidyl. It has been targeted for drug discovery on account of growing resistance to miltefosine in L.major. This paper serves as the first attempt to detect GPI 14 gene in L.major supported with modeling and molecular dynamic analysis of complete three dimensional structure of GPI 14. The functional analysis revealed multiple transmembrane regions in GPI 14 and a close phylogenetic relation with Trypanosoma species and Schistosoma mansoni with highest bootstrap values. The protein model obtained was subjected to minimization for 14ns simulation. Eight derivatives of N-4-(-5(trifluromethyl)-1-methyl-1 H benzo[d]imidazole-2 yl) phenyl) were docked onto GPI 14. The contact frequency of GPI 14 with the docked compounds suggested the inhibition of mannosylation proposing the druggability for leishmaniasis therapy.
The occurrence frequencies of bases A, C, G and T, denoted by a, c, g and t, respectively, in 1487 human protein coding sequences have been calculated and analyzed. The analysis has been performed by a diagrammatic method presented recently, in which each coding sequence is represented by a point in 3-D space. The distribution of points gives the observer an overall and intuitive picture of the base frequencies. The distance between a point and the origin of the co-ordinate, which corresponds to the case of a = c = g = t = 1/4, is called the radical distance. The radical distribution of 1487 points in 3-D space has been found to be normal, with the center basically coinciding with the origin of the co-ordinate. We have found that among 1487 coding sequences, an empirical rule a2 + c2 + g2 + t2 < 1/3 holds for 1486 sequences. The only sequence in which the above rule does not hold is the one coding for the human parathymosin protein. The composition of amino acids and the structural class of this protein has been studied in some detail.
The codon usages for 1490 human proteins have been published by Wada et al. (1990). Based on these data, the frequencies of occurrence of 20 amino acids for each of the 1490 proteins have been calculated according to the genetic codes. Proteins are generally classified into five folding types, i.e. the alpha, beta, alpha + beta, alpha/beta and zeta (irregular) types. The folding type of a protein is correlated to its amino acid composition. By means of three methods established by different investigators, the folding type for each of the 1490 human proteins has been predicted. It has been demonstrated that the accuracy of prediction for the 1490 human proteins is at least 80% by examining the predicted results of some structurally known proteins with these methods. There are only six proteins for which there is uncertainty about their folding types as completely inconsistent results were obtained when predicted with the three different methods. For the remaining 1484 human proteins the numbers of alpha, beta, alpha + beta, alpha/beta, and zeta folding type proteins were found to be 128, 235, 169, 933 and 19, respectively, suggesting that the alpha/beta type proteins would predominate in this set of human proteins. The occurrence frequencies of bases in the first, second and third codon position for each folding type of protein have been calculated. It is shown that the folding type of a protein is strongly dependent on the ratio of frequency of base G in the first codon position with that in the second codon position. The biological implication of the results has been discussed.
Here, we consider a noisy, bistable, single neuron model in the presence of periodic external modulation. The modulation induces a correlated switching between states driven by the noise. The information flow through the system, from the modulation, or signal, to the output switching events, leads to a succession of strong peaks in the power spectrum. The signal-to-noise ratio (SNR) obtained from this power spectrum is a measure of the information content in the neuron response. With increasing noise intensity, the SNR passes through a maximum: an effect which has been called stochastic resonance, and which was first advanced as a possible explanation of the observed periodicity in the recurrences of the Earth's ice ages. We treat the problem within the framework of a recently developed approximate theory, valid in the limits of weak noise intensity, weak periodic forcing and low forcing frequency, for both additive and multiplicative noise. Moreover, we have constructed an analog simulator of the neuron which demonstrates the stochastic resonance effect, and with which we have measured the SNRs for comparison with the theoretical results. Our model should be of interest in situations where a single inherently noisy neuron is the receptor of a periodic signal, which is itself noisy, either from the network or from an external source.
Genetic recombination has important consequences, including the familiar rules of Mendelian genetics. Here we present a new argument for the evolutionary function of recombination based on the hypothesis that meiotic drive systems continually arise to threaten the fairness of meiosis. These drive systems act at the expense of the fitness of the organism as a whole for the benefit of the genes involved. We show that genes increasing crossing over are favoured, in the process of breaking up drive systems and reducing the fitness loss to organisms.
Data and arguments are given in favour of the hypothesis that the primitive tRNA molecule may have originated from a direct duplication event involving one of the two halves of the tRNA molecule. It seems that a molecule capable of assuming a hairpin structure was involved as a precursor in this duplication. The two halves of the present tRNAs could, therefore, be considered as paralogous.
If regeneration were adaptive, it would have arisen autonomously by natural selection from non-regenerative antecedents. Unless each episode coincidentally reinvented the same method of regeneration independently, one would expect the various lineages to differ basically from each other, which they do not. On the other hand, if regeneration were inherent to metazoan life, a derivative of embryogenesis, its various expressions should be as much like each other as they resemble the development of embryonic appendage buds, which they do. It follows that the uneven distribution of regeneration must have been due to its extinction here and there, not as a negative adaptation by natural selection but as a pleiotropic epiphenomenon linked to more useful adaptations with which it was incompatible. In vertebrate evolution, these adaptations have included the transition from aquatic to terrestrial habitats and the modification of poikilothermic to homeothermic metabolism. The former advance rendered the regeneration of weight-bearing limbs impractical; the latter favored rapid wound healing and scar formation which effectively precluded blastema formation. If the latent capacity for regeneration persists in non-regenerative appendages, as would seem to be the case, then the restoration of its overt expression should be possible if the mechanisms of its inhibition could be discovered and eventually rendered ineffectual.
An important goal of cardiac revascularization is to improve the left ventricular ejection fraction, which is an important clinical determinant of the long-term outcome for patients with coronary artery disease. Regional myocardium function improvement may be expected from revascularization when viable myocardium is detected using non-invasive cardiac imaging. However, the quantitative relation between regional myocardial function recovery and global heart function improvement has not been determined and there is no tool to predict the amount of ejection fraction improvement prior to revascularization. A 16 segment biomechanical model of the left ventricle is proposed to establish the relationship between the ejection fraction improvement and the viable segments detected by echocardiography. With the assumption that the viable segments would potentially improve contractility after revascularization, the ejection fraction improvement is estimated for all possible wall motion score improvement in viable segments. The model shows that the ejection fraction improvement is linearly related to the contractility in the normal segments and a weighted sum of the numbers of viable segments that recover to normal or hypokinetic contractility. The predictive value of the model is illustrated for a group of patients reported in the literature. The model predictions of the post-revascularization ejection fraction are very close to the follow-up data with a very strong correlation (R2 = 0.92). By predicting the ejection fraction improvement, the model may provide a tool for evaluating the efficacy of revascularization and for selecting patients who would benefit from revascularization.
A new key-string segmentation algorithm for identification of alpha satellite DNAs and higher-order repeat (HOR) units was introduced and exemplified. Starting with an initial key string, we determine the dominant key string and HOR. Our key-string algorithm was used to scan the recent GenBank data for human alpha satellite DNA sequence AC017075.8 (193 277 bp) from the centromeric region of chromosome 7. The sequence was computationally segmented into one HOR domain (super-repeat domain) and two non-HOR domains. Dominant key-string GTTTCT provided segmentation in terms of alpha monomers. The HOR is tandemly repeated in 54 copies in the super-repeat (HOR) domain. Five insertions and three deletions in the HOR structure associated with a dominant key string were identified. Concensus HOR was constructed. Divergence of individual HOR copies from concensus amounts to 0.7% on the average, while divergence between 16 monomer variants within each HOR is on the average 20%. In the front and back domain, 199 monomer variants were identified that are not organized in HOR and diverge by 20-40%.
Theoretical evaluation of the content of oligonucleotide triplets AAA, CCC, and UAU in 16S rRNAs of anoxygenic phototrophic bacteria (genera Chlorobium; Chloroflexus; Chromatium: Rhodopseudomonas) and nitrifying bacteria (genera Nitrosococcus, Nitrosomonas, Nitrosolobus, Nitrosovibrio, Nitrospira, Nitrospina, Nitrobacter) showed that the number of the AAA, CCC or UAU triplets in 16S rRNAs specifically corresponds to the genus and species of bacteria. The ratio of AAA and CCC triplet numbers in the sequences of 16S rRNA (AAA/CCC) of anoxygenic phototrophic bacteria was within the range of 0.61 to 2.03, and the ratio of AAA and UAU (AAA/UAU) triplet numbers in the sequence of 16S rRNA was within the range of 2.88 to 12.00. The regions of any genus within the AAA/CCC and AAA/UAU axes did not overlap. The combination of the numbers of nucleotide triplets in 16S rRNA is genus-specific character. The similar data were obtained in the study of a physiological group of nitrifying bacteria. The range of AAA/UAU ratio was from 1.8 to 9.0, and range of AAA/CCC was from 0.9 to 2.6 for this taxon. The number of triplets in 16S rRNAs of the studied taxa was genus- and species-specific character. The biological significance of these data is the evidence that not only the sequence but the number of nucleotide triplets in 16S rRNAs reflects the phylogeny of corresponding taxa.
The relation between the number of some trinucleotides in the sequence of 16S rRNA gene and pathogenicity of bacterial species from the genera of Bacillus and Clostridium was revealed. The species of genus Bacillus, which are pathogenic for humans, mammals and insects, have an increased number of AAA and TAT triplets in 16S rRNA gene. Theoretically, these species, B. anthracis and B. cereus for example, may be detected in the specimen by the higher ratio of AAA plus TAT triplets to the number of GGG triplet. Species of genus Clostridium, which are pathogenic for humans and mammals, have a maximum ratio of AAA and TAT triplet numbers. This ratio was higher than 2.6 for pathogenic species and lower than 2.2 for saprophytic ones. These theoretical data may open a new way for detecting pathogenic bacteria through the determination of triplet numbers in the sequences of 16S rRNA or rRNA. However, the mechanism of evolutionary relation between the number of AAA and TAT triplets in the sequence of 16S rRNA gene and the pathogenicity of bacterial species is not known.
Three different but related comprehensive statistical analyses of amino acid sequences in proteins are described. The goal in each case is to search for evidence of significant sequence structure in individual proteins relative to a purely random arrangement of the amino acid residues and to attempt to relate any significant structure uncovered to the secondary and/or tertiary configuration of the protein.In the first of these analyses, which is reviewed briefly in an appendix, amino acids are divided into subgroups according to a variety of side chain physical properties (e.g. polarity, hydrophobicity). Deviations from randomness are expressed in terms of correlation indices ϱij(c) which are composition normalized doublet frequencies. Here i and j denote membership in a particular group for the physical property chosen and c denotes the “lag”, that is the number of residues along the chain separating the doublet.The other more refined analyses are described in some detail. For both of these each amino acid in a given protein is replaced by its appropriate value on a continuous physical property scale. Six such scales are employed: bulkiness, polarity, RF, pI, pK1 and hydrophobicity. The resulting amino acid index sequences are treated as discrete series and are analyzed first by means of serial correlation methods and subsequently by employing spectral analysis techniques. Periodicities exhibited in these series are evaluated statistically and speculations are made concerning the connection between such structure and protein configuration.Although more than forty individual proteins whose primary sequences are known have been analyzed by these methods, results for the cytochrome c series, the hemoglobins and lysozyme are emphasized in the present paper. In the case of the cytochrome c family of proteins several relationships between primary sequence structure and “evolutionary order” are discussed. In addition, the results of several homogeneity studies are described in which the sequence structure of various portions of a given protein chain are compared.
Conditions are analyzed under which natural selection favors an individual to help another species at a cost to its own reproduction. Traditional models for the evolution of altruism between species focus on the genetic relatedness between the original donor and the recipients of return benefits from the mutualistic partner species. A more general model is analyzed here that focuses on the synergistic effects between partner species caused by genetic variability. The model shows that the spread of altruism is enhanced by spatial correlations between species in the genetic tendency to give aid to partners. These spatial correlations between species are similar to the kin selection coefficients of relatedness that determine the course of social evolution within species. The model also shows that natural selection and ecological dynamics can create genetic correlations between neighbors of different species, even when the initial spatial distributions of the species are uncorrelated. Genetic correlations between species may play an important role in the origin and maintenance of altruism between species.
A model is presented for the distribution of protein molecules between the cells in a microbial population during steady-state growth. A general expression is derived under the sole assumption that each protein molecule has equal probability of joining either daughter cell at cell division, i.e. a binomial partitioning. With reasonable assumptions about transcription and translation probabilities a specific protein distribution is described. The main result is that this distribution is very broad, especially for small protein numbers; it is definitely not a Poisson distribution. The case of repressor proteins, which have one strong binding site on the chromosome, is treated separately. As a specific example, the distribution of β-galactosidase is described, also in regard to the influence from the statistical fluctuations in the distribution of the lac repressors.
This article reports the preliminary results of a search for patterns in the strand asymmetry and local self-similarity in mammalian nuclear DNA. The study provides the basis for statistical investigations of larger-scale DNA structure, which may be correlated with genetic mechanisms or with gene function.
We have used a microcomputer program to test eukaryotic mRNA 5'-leader sequences for complementarity to the 3'-terminus of 18S rRNA. No mismatched bases, bulge loops, or viral mRNA's were utilized. At least one-fourth of the more than 200 mRNA's studied were found to have two distinct regions of complementarity which resulted in an ability to bind to two separate rRNA regions (GAAGG and UUUGG). The analysis of 60 mRNAs with these dual sites resulted in a consensus structure that was a mean distance of 11.75 bases 5' from the initiator AUG and had an average predicted interstrand binding strength of delta G = -13.40 kcal. These characteristics compare favorably to those observed for the prokaryotic 16S rRNA-mRNA Shine and Dalgarno bond.
Top-cited authors
Stuart A. Kauffman
  • Institute for Systems Biology, Seattle WA United States
Kuo-Chen Chou
  • Gordon Life Science Institute
Denise E Kirschner
  • University of Michigan
Martin A Nowak
  • Harvard University
Simeone Marino
  • University of Michigan