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Biomedical subjects

D C Krakauer

Publications and source records attributed to D C Krakauer.

At least 19 recordsLinked to original sources
PubMed2001

Selective imitation for a private sign system.

A distinctive feature of all human languages is the diverse and arbitrary nature of the sign (signifier). This can be interpreted as stating that the mapping between signals and referents is established by convention rather than by functional constraints. This property of the sign provides for a great deal of linguistic flexibility and is a key component of symbolic communication. Game theoretic models to describe signal imitation are investigated with a view to understanding how non-arbitrary (indexical) animal-style signals might 'evolve' culturally into diverse, arbitrary signs. I explore the evolutionary hypothesis that private, arbitrary signs emerge as a result of selective imitation within a socially structured population. Once arbitrary signs have emerged, they contribute towards greater assortative interactions among individuals using a shared sign system. In natural populations, the models for imitation will very often be close kin. Hence, kinship provides one mechanism for the creation of true symbols. An imitation-structured population can support many more sign systems than an equivalent non-structured population and is one in which symbols become the dominant force in assortative interactions.

Animal Communication↗
PubMed2000

Error, population structure and the origin of diverse sign systems.

Evolutionary models of communication are used to shed some light on the selective pressures involved in the evolution of simple referential signals, and the constraints hindering the emergence of signs. Error-prone communication results from errors in transmission (in which individuals learn the wrong associations) and communication (in which signs are mistaken for one another). We demonstrate how both classes of errors are required to generate diversity and subsequently impose limits on the sign repertoire within a population. We then explore the influence of geographic structuring of a population on the evolution of a shared sign system and the importance of such structure for the maintenance of sign diversity. Deceit tends to erode conventional signs systems thereby reducing signal diversity, we demonstrate that population structure can act as a hedge against deceit, thereby ensuring the persistence of sign systems.

Animals↗
PubMed2000

Mapping the parameters of prion-induced neuropathology.

We present a theoretical framework that enables us to dissect out the parametric dependencies of the pathogenesis of prion diseases. We are able to determine the influence of both host-dependent factors (connectivity, cell density, protein synthesis rate, and cell death) and strain-dependent factors (cell tropism, virulence, and replication rate). We use a model based on a linked system of differential equations on a lattice to explore how the regional distribution of central nervous system pathology in Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome, and fatal familial insomnia relates to each of these factors. The model then is used to make qualitative predictions about the pathology for two possible hypothetical triggers of neuronal loss in prion diseases. Pathological progression in overexpressing mouse models has been shown to depend on the site of initial infection. The model allows us to compare the pathologies resulting from different inoculation routes.

Apoptosis↗
PubMed2000

Defining CTL-induced pathology: implications for HIV.

The relationship between virus and host cells is multifactorial and nonlinear. This indicates that the effect of an immune response on infection can lead to several different outcomes. These include severe immunopathology. We seek to define properties of CTL-induced pathology in viral infections and examine the implications for HIV disease progression. We find that CTL-induced pathology is observed if the rate of viral replication is fast relative to the CTL responsiveness of the host. Theoretical predictions are consistent with empirical data on LCMV infection. These conditions are also sufficient to induce pathology in HIV infection. However, the absence of HIV-specific CTL can result in an equivalent depletion of the CD4 T cell pool as a consequence of the short life span of activated T cells. A mathematical model describing the evolution of HIV coreceptor usage in the context of lytic and nonlytic CD8 cell responses might account for the relatively long time span required to result in disease. Viral evolution toward parameter ranges allowing CTL-induced pathology is difficult to achieve. It requires the emergence of fast viral replication together with escape from nonlytic CTL responses. However, according to the model, fast viral replication can result in the evolution of virus strains that are susceptible to chemokine-mediated inhibition of viral replication.

Biological Evolution↗
PubMed2000

Models of experimental evolution: the role of genetic chance and selective necessity.

We present a theoretical framework within which to analyze the results of experimental evolution. Rapidly evolving organisms such as viruses, bacteria, and protozoa can be induced to adapt to laboratory conditions on very short human time scales. Artificial adaptive radiation is characterized by a list of common observations; we offer a framework in which many of these repeated questions and patterns can be characterized analytically. We allow for stochasticity by including rare mutations and bottleneck effects, demonstrating how these increase variability in the evolutionary trajectory. When the product Np, the population size times the per locus error rate, is small, the rate of evolution is limited by the chance occurrence of beneficial mutations; when Np is large and selective pressure is strong, the rate-limiting step is the waiting time while existing beneficial mutations sweep through the population. We derive the rate of divergence (substitution rate) and rate of fitness increase for the case when Np is large and illustrate our approach with an application to an experimental data set. A minimal assumption of independent additive fitness contributions provides a good fit to the experimental evolution of the bacteriophage phiX174.

Animals↗
PubMed2000

Stability and evolution of overlapping genes.

When the same sequence of nucleotides codes for regions of more than one functional polypeptide, this sequence contains overlapping genes. Overlap is most common in rapidly evolving genomes with high mutation rates such as viruses, bacteria, and mitochondria. Overlap is thought to be important as: (1) a means of compressing a maximum amount of information into short sequences of structural genes; and (2) as a mechanism for regulating gene expression through translational coupling of functionally related polypeptides. The stability of overlapping codes is examined in relation to the information cost of overlap and the mutation rate of the genome. The degree of overlap in a given population will tend to become monomorphic. Evolution toward partial overlap of genes is shown to depend on a convex cost function of overlap. Overlap does not evolve when expression of overlapping genes is mutually exclusive and produced by rare mutations to the wild-type genome. Assuming overlap increases coupling between functionally related genes, the conditions favoring overlap are explored in relation to the kinetics of gene activation and decay. Coupling is most effective for genes in which the gene overlapping at its 5' end (leading gene) decays rapidly, while the gene overlapping at the 3' end (induced gene) decays slowly. If gene expression can feedback on itself (autocatalysis), then high rates of activation favor overlap.

Evolution, Molecular↗
PubMed1999

An error limit for the evolution of language.

On the evolutionary trajectory that led to human language there must have been a transition from a fairly limited to an essentially unlimited communication system. The structure of modern human languages reveals at least two steps that are required for such a transition: in all languages (i) a small number of phonemes are used to generate a large number of words; and (ii) a large number of words are used to a produce an unlimited number of sentences. The first (and simpler) step is the topic of the current paper. We study the evolution of communication in the presence of errors and show that this limits the number of objects (or concepts) that can be described by a simple communication system. The evolutionary optimum is achieved by using only a small number of signals to describe a few valuable concepts. Adding more signals does not increase the fitness of a language. This represents an error limit for the evolution of communication. We show that this error limit can be overcome by combining signals (phonemes) into words. The transition from an analogue to a digital system was a necessary step toward the evolution of human language.

Biological Evolution↗
PubMed1999

The evolutionary language game.

We explore how evolutionary game dynamics have to be modified to accomodate a mathematical framework for the evolution of language. In particular, we are interested in the evolution of vocabulary, that is associations between signals and objects. We assume that successful communication contributes to biological fitness: individuals who communicate well leave more offspring. Children inherit from their parents a strategy for language learning (a language acquisition device). We consider three mechanisms whereby language is passed from one generation to the next: (i) parental learning: children learn the language of their parents; (ii) role model learning: children learn the language of individuals with a high payoff; and (iii) random learning: children learn the language of randomly chosen individuals. We show that parental and role model learning outperform random learning. Then we introduce mistakes in language learning and study how this process changes language over time. Mistakes increase the overall efficacy of parental and role model learning: in a world with errors evolutionary adaptation is more efficient. Our model also provides a simple explanation why homonomy is common while synonymy is rare.

Biological Evolution↗
PubMed1999

The evolution of language.

The emergence of language was a defining moment in the evolution of modern humans. It was an innovation that changed radically the character of human society. Here, we provide an approach to language evolution based on evolutionary game theory. We explore the ways in which protolanguages can evolve in a nonlinguistic society and how specific signals can become associated with specific objects. We assume that early in the evolution of language, errors in signaling and perception would be common. We model the probability of misunderstanding a signal and show that this limits the number of objects that can be described by a protolanguage. This "error limit" is not overcome by employing more sounds but by combining a small set of more easily distinguishable sounds into words. The process of "word formation" enables a language to encode an essentially unlimited number of objects. Next, we analyze how words can be combined into sentences and specify the conditions for the evolution of very simple grammatical rules. We argue that grammar originated as a simplified rule system that evolved by natural selection to reduce mistakes in communication. Our theory provides a systematic approach for thinking about the origin and evolution of human language.

Biological Evolution↗
PubMed1999

T-cell induced pathogenesis in HIV: bystander effects and latent infection.

The progress of HIV is accompanied by the infection and decline of the population of CD4+ cells. This reduction in cells results from both cytolytic influences of the virus and virus-specific cytotoxic T-cell (CTL) responses. We seek to characterize the extent of CD4+ reduction caused by HIV-specific CTLs at equilibrium. Here we show that intermediate levels of cytotoxic killing of infected cells can be inferior to both strong and weak or absent immune responses. We further show that the deleterious effects of the CTL response are made worse by a slow immune response. Bystander effects in which uninfected cells are thought to be eliminated by non-specific CTL activation lead to small or negligible reductions in uninfected CD4+ cells. Latently infected cells containing pro-viral DNA and which become activated at a constant rate ensure that the immune response is more effective for a larger range of CTL activities and reduces T-cell associated pathology.

Apoptosis↗
PubMed1999

Evolutionary preservation of redundant duplicated genes.

Gene duplication events produce both perfect and imperfect copies of genes. Perfect copies are said to be functionally redundant when knockout of one gene produces no 'scoreable', phenotypic effects. Preserving identical, duplicate copies of genes is problematic as all copies are prone to accumulate neutral mutations as pseudogenes, or more rarely, evolve into new genes with novel functions. We summarise theoretical treatments for the invasion and subsequent evolutionary modification of functionally redundant genes. We then consider the preservation of functionally identical copies of a gene over evolutionary time. We present several models for conserving redundancy: asymmetric mutation, asymmetric efficacy, pleiotropy, developmental buffering, allelic competition and regulatory asymmetries. In all cases, some form of symmetry breaking is required to maintain functional redundancy indefinitely.

Animals↗
PubMed1998

The spatial dynamics of prion disease.

An important component of the latency period of the transmissible spongiform encephalopathies (prion diseases) can be attributed to delays during the propagation of the infectious prion isoform, PrPSc, through peripheral nervous tissues. A growing body of data report that the host prion protein, PrPC, is required in both peripheral and central nervous tissues for susceptibility to infection. We introduce a mathematical model, which treats the PrPSc as a mobile infectious pathogen, and show how peripheral delays can be understood in terms of the intercellular dispersal properties of the PrPSc strain, its decay rate, and its efficiency at transforming the PrPC. It has been observed that when two pathogenic strains co-infect a host, the presence of the first inoculated strain can slow down, or stop completely, the spread of the second strain. This is thought to result from a reduced concentration of host protein available for conversion by the second strain. Our model can explain the mechanisms of such interstrain competition and the time-course of the increased delay. The model provides a link between those data suggesting a role for a continuous chain of PrP-expressing tissue linking peripheral sites to the brain, and data on prion strain competition.

Animals↗
PubMed1998

Spatial scales of desert locust gregarization.

Central to swarm formation in migratory locusts is a crowding-induced change from a "solitarious" to a "gregarious" phenotype. This change can occur within the lifetime of a single locust and accrues across generations. It represents an extreme example of phenotypic plasticity. We present computer simulations and a laboratory experiment that show how differences in resource distributions, conspicuous only at small spatial scales, can have significant effects on phase change at the population level; local spatial concentration of resource induces gregarization. Simulations also show that populations inhabiting a locally concentrated resource tend to change phase rapidly and synchronously in response to altered population densities. Our results show why information about the structure of resource at small spatial scales should become key components in monitoring and control strategies.

Journal Article↗
PubMed1998

The paradoxical dynamics of prion disease latency.

A salient characteristic of the prion diseases--including Creutzfeldt-Jakob disease and bovine spongiform encephalopathy in cattle--is an extended asymptomatic incubation period followed by a rapid and often fatal clinical phase. We present a kinetic model of progression of infection based upon the existence of a bottleneck in the natural protein pathways within the cell. The model can reconcile the different time-scales of the pre-clinical and clinical phases, and is able to account for the dependency of the duration of the incubation period on several important governing factors, including the inoculum size, the phenotype of the host, and the phenotype of the pathogenic form of the prion protein. Our results suggest that saturation events--first of the rate of pathogenic transformation (an auto-catalysis ceiling), and subsequently of the bottleneck in the protein pathways--could be fundamental in determining the dynamics of infection.

Genetic Predisposition to Disease↗
PubMed1998

Prion's progress: patterns and rates of molecular evolution in relation to spongiform disease.

Modification of the cellular prion protein has been correlated with the acquisition of several neurodegenerative diseases, including kuru, scrapie, bovine spongiform encephalopathy (BSE), and Creutzfeldt-Jakob disease (CJD). Sequence conservation and amino acid identity are known to influence the efficacy of interspecific transmission. We analyzed patterns of interspecific genetic variation with a view toward identifying features related to disease transmission. The reconstructed gene trees and amino acid tree were compared with the species tree, and all discordances observed were related to the species barrier of disease transmission. The rates of synonymous substitution, nonsynonymous substitution, and nucleotide content were determined for the protein-coding gene. Substitutions implicated in each of the prion diseases were found to occur in regions of the protein that are least variable across all species-opposite to the pattern of variability expected from interaction with an infectious pathogen. Amino acid residues related to the species barrier form a single cluster associated with the first alpha-helical domain of the protein. Residues related to sporadic and hereditary human prion disease form two separate clusters, associated with the second and third alpha-helical domains. Taken together, these results are consistent with the view that prion diseases arise from accidents in protein folding, rather than infection with an undiscovered virus-like particle. We speculate that the differences in disease phenotype between transmissable and hereditary forms could result from interactions between different parts of the protein during propagation.

Animals↗
PubMed1998

Effect of immune activation on the dynamics of human immunodeficiency virus replication and on the distribution of viral quasispecies.

Virus replication in a human immunodeficiency virus (HIV)-infected individual, as determined by the steady-state level of plasma viremia, reflects a complex balance of viral and host factors. We have previously demonstrated that immunization of HIV-infected individuals with the common recall antigen, tetanus toxoid, disrupts this steady state, resulting in transient bursts of plasma viremia after immunization. The present study defines the viral genetic basis for the transient bursts in viremia after immune activation. Tetanus immunization was associated with dramatic and generally reversible shifts in the composition of plasma viral quasispecies. The viral bursts in most cases reflected a nonspecific increase in viral replication secondary to an expanded pool of susceptible CD4(+) T cells. An exception to this was in a patient who harbored viruses of differing tropisms (syncytium inducing and non-syncytium inducing [NSI]). In this situation, immunization appeared to select for the replication of NSI viruses. In one of three patients, the data suggested that immune activation resulted in the appearance in plasma of virus induced from latently infected cells. These findings illustrate certain mechanisms whereby antigenic stimulation may influence the dynamics of HIV replication, including the relative expression of different viral variants.

Amino Acid Sequence↗