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Biomedical subjects

Yoh Iwasa

Publications and source records attributed to Yoh Iwasa.

At least 37 records · Page 2Linked to original sources
PubMed2005

Extinction risk of a meta-population: aggregation approach.

Aggregation of variables of a complex mathematical model with realistic structure gives a simplified model which is more suitable than the original one when the amount of data for parameter estimation is limited. Here we explore use of a formula derived for a single unstructured population (canonical model) in predicting the extinction time for a population living in multiple habitats. In particular we focus multiple populations each following logistic growth with demographic and environmental stochasticities, and examine how the mean extinction time depends on the migration and environmental correlation. When migration rate and/or environmental correlation are very large or very small, we may express the mean extinction time exactly using the formula with properly modified parameters. When parameters are of intermediate magnitude, we generate a Monte Carlo time series of the population size for the realistic structured model, estimate the "effective parameters" by fitting the time series to the canonical model, and then calculate the mean extinction time using the formula for a single population. The mean extinction time predicted by the formula was close to those obtained from direct computer simulation of structured models. We conclude that the formula for an unstructured single-population model has good approximation capability and can be applicable in estimating the extinction risk of the structured meta-population model for a limited data set.

Animals↗
PubMed2005

Virus evolution within patients increases pathogenicity.

Viruses like the human immunodeficiency virus (HIV), the hepatitis B virus (HBV), the hepatitis C virus (HCV) and many others undergo numerous rounds of inaccurate reproduction within an infected host. The resulting viral quasispecies is heterogeneous and sensitive to any selection pressure. Here we extend earlier work by showing that for a wide class of models describing the interaction between the virus population and the immune system, virus evolution has a well-defined direction toward increased pathogenicity. In particular, we study virus-induced impairment of the immune response and certain cross-reactive stimulation of specific immune responses. For eight different mathematical models, we show that virus evolution reduces the equilibrium abundance of uninfected cells and increases the rate at which uninfected cells are infected. Thus, in general, virus evolution makes things worse. An idea for combating HIV infection, however, is constructing a virus mutant that could outcompete the existing infection without being pathogenic itself.

Antigens, Viral↗
PubMed2005

Can chromosomal instability initiate tumorigenesis?

Cancers result from the accumulation of inherited and somatic mutations in oncogenes and tumor suppressor genes. These genes encode proteins that function in growth regulatory and differentiation pathways. Mutations in those genes increase the net reproductive rate of cells. Chromosomal instability (CIN) is a feature of most human cancers. Mutations in CIN genes increase the rate at which whole chromosomes or large parts of chromosomes are lost or gained during cell division. CIN causes an imbalance in chromosome number (aneuploidy) and an enhanced rate of loss of heterozygosity, which is an important mechanism of inactivating tumor suppressor genes. A crucial question of cancer biology is whether CIN is an early event and thus a driving force of tumorigenesis. Here we discuss mathematical models of situations where inactivation of one or two tumor suppressor genes is required for tumorigenesis. If two tumor suppressor genes have to be inactivated in rate-limiting steps, then CIN is likely to emerge before the inactivation of the first tumor suppressor gene.

Animals↗
PubMed2005

Dynamics of colorectal cancer.

Colorectal cancer results from an accumulation of mutations in tumor suppressor genes and oncogenes. An additional defining characteristic of colorectal cancer is its genetic instability. Two main types of genetic instability have been identified. Microsatellite instability leads to an increased point mutation rate, whereas chromosomal instability refers to an enhanced rate of accumulating gross chromosomal aberrations. All colon cancer cell lines are genetically unstable. An interesting question is whether genetic instability arises early in tumorigenesis. An early emergence of genetic instability could drive most of the somatic evolution of cancer. Here, we review mathematical models of colorectal tumorigenesis and discuss the role of genetic instability.

Colorectal Neoplasms↗
PubMed2004

Temperature compensation in circadian clock models.

Circadian clock of organisms has a free-running period that does not change much with ambient temperature. This property "temperature compensation" is studied when the rate of all reaction steps increase with temperature in the biochemical network generating the rhythm. The period becomes shorter when all the rate parameters are enhanced by the same factor. However, the period becomes longer as degradation rate of proteins and/or transcription rate of the clock gene increase (their elasticity is positive). This holds for a wide range of models, including N-variable model, and PER-TIM double oscillator model, provided that (1) branch reactions (e.g. degradation of proteins or mRNAs) are strongly saturated, and that (2) the cooperativity of transcription inhibition by nuclear proteins is not very large. A strong temperature sensitivity of degradation of PER proteins and/or temperature-sensitive alternative splicing of per gene, known for Drosophila, can be mechanisms for the temperature compensation of circadian clock.

Alternative Splicing↗
PubMed2004

Optimal growth pattern of defensive organs: the diversity of shell growth among mollusks.

Mollusks show a diversity of shell growth patterns. We develop a model for the dynamic resource allocation to defense organs and analyze it with the Pontryagin maximum principle. A typical optimal growth schedule is composed of the initial phase of soft-body growth without shell followed by a simultaneous growth of shell and soft body and finally the reproductive phase without growth (simultaneous shell growth). If the defensible predation risk is low or if the cost of defense is high, the optimal strategy is to have no shell (shell-less growth). If defensible predation pressure or general mortality differs before and after maturation, an additional three strategies, characteristic of the exclusive growth of shell or soft body, can be optimal (sequential shell growth, additional body-expansion growth, and additional callus-building growth). These optimal strategies are in accord with the patterns observed for mollusks. In particular, the growth strategies with exclusive growth phase of external shells are preferred when durophagous predation pressure after maturation is higher than that before maturation. This result explains the observation that many tropical gastropods with thickened shell lips spend their vulnerable juvenile phase in sheltered habitats.

Animals↗
PubMed2004

Population genetics of tumor suppressor genes.

Cancer emerges when a single cell receives multiple mutations. For example, the inactivation of both alleles of a tumor suppressor gene (TSG) can imply a net reproductive advantage of the cell and might lead to clonal expansion. In this paper, we calculate the probability as a function of time that a population of cells has generated at least one cell with two inactivated alleles of a TSG. Different kinetic laws hold for small and large populations. The inactivation of the first allele can either be neutral or lead to a selective advantage or disadvantage. The inactivation of the first and of the second allele can occur at equal or different rates. Our calculations provide insights into basic aspects of population genetics determining cancer initiation and progression.

Alleles↗
PubMed2004

How should we define goodness?--reputation dynamics in indirect reciprocity.

Theory of indirect reciprocity is important in explaining cooperation between humans. Since a partner of a social interaction often changes, an individual should assess his partner by using social information such as reputation and make decisions whether to help him or not. To those who have 'good' social reputation does a player give aid as reciprocation, whereas he has to refuse to help those who have 'bad' reputation. Otherwise benefits of altruism is easily exploited by them. Little has been known, however, about the definition of 'goodness' in reputation. What kind of actions are and should be regarded as good and what kind of actions bad? And what sort of goodness enables sustaining exchange of altruism? We herein challenge this question with an evolutionary perspective. We generalize social reputation as 'Honor-score' (H-score) and examine the conditions under which individuals in a group stably maintain cooperative relationships based on indirect reciprocity. We examine the condition for evolutionarily stable strategies (ESSs) over 4096 possible cases exhaustively. Mathematical analysis reveals that only eight cases called 'leading eight' are crucial to the evolution of indirect reciprocity. Each in the leading eight shares two common characteristics: (i) cooperation with good persons is regarded as good while defection against them is regarded as bad, and (ii) defection against bad persons should be regarded as a good behavior because it works as sanction. Our results give one solution to the definition of goodness from an evolutionary viewpoint. In addition, we believe that the formalism of reputation dynamics gives general insights into the way social information is generated, handled, and transmitted in animal societies.

Altruism↗
PubMed2004

On the emergence of multifocal cancers.

Several tumors can exist as multiple lesions within a tissue. The lesions may either arise independently, or they may be monoclonal. The importance of multiple lesions for tumor staging, progression, and treatment is subject to debate. Here we use mathematical models to analyze the emergence of multiple, clonally related lesions within a single tissue. We refer to them as multi-focal cancers. We find that multifocal cancers can arise through a dynamical interplay between tumor promoting and inhibiting factors. This requires that tumor promoters act locally, while tumor inhibitors act over a longer range. An example of such factors may be angiogenesis promoters and inhibitors. The model further suggests that multifocal cancers represent an intermediate stage in cancer progression as the tumor evolves away from inhibition and towards promotion. Different patterns of progression can be distinguished: (i) If tumor inhibition is strong, the initial growth occurs as a unifocal and self contained lesion; progression occurs through bifurcation of the lesion and this gives rise to multiple lesions. As the tumor continues to evolve and pushes the balance between inhibition and promotion further towards promotion, the multiple lesions eventually give rise to a single large mass which can invade the entire tissue. (ii) If tumor inhibition is weaker upon initiation, growth can occur as a single lesion without the occurrence of multiple lesions, until the entire tissue is invaded. The model suggests that the sum of the tumor sizes across all lesions is the best characteristic which correlates with the stage and metastatic potential of the tumor.

Journal Article↗
PubMed2004

Multiple-year optimization of conservation effort and monitoring effort for a fluctuating population.

We consider optimal conservation strategies for an endangered population. We assume that juvenile survival is affected by unpredictable environmental fluctuation and can be improved by costly conservation effort. The initial population size is not accurately known at the time that the conservation effort level is chosen, but the uncertainty of its estimate can be reduced by a costly monitoring effort. In a previous paper, we analysed the optimal management strategy that minimizes a weighted sum of extinction probability and economic costs when only a single year is considered. Here we examine the case in which the conservation period lasts for several years by dynamic programming with incompletely observed process states. We study the optimal levels of the conservation and the monitoring efforts, and their dependence on the length of the conservation period and other parameters. The main conclusions are: (1) The optimal conservation effort in the first year depends on the accuracy of the information on the population size in the first year, but is almost independent of the accuracy of the information in later years. (2) When the risk of population extinction is small, the optimal conservation effort increases with the uncertainty of the population size. In contrast when the population is endangered, the optimal conservation effort decreases with the uncertainty of the population size. (3) The optimal conservation and monitoring efforts both increase with the length of the conservation period, provided that the population is relatively safe. However, if the population is endangered, both types of effort become smaller when the conservation period increases.

Animals↗
PubMed2004

Forest gap dynamics and the Ising model.

The vegetation height in forest ecosystems is spatially heterogeneous. Canopy gaps (sites with low vegetation) are formed by treefalls, and they recover to canopy sites (with high vegetation) either by growth of small trees or by branch extension of surrounding trees. The dynamics of canopy gaps have been studied using a spatial Markov chain with nearest neighbor interaction. (1) If the canopy recovery rate is constant and if the gap formation rate for a site increases exponentially with the number of neighboring gap sites, the equilibrium distribution is the same as the one generated by the Ising model in statistical mechanics. Here, we extend the equivalence to the situation in which both the gap formation and canopy recovery depend on the neighborhood, as shown in recent forest data. (2) We develop a statistical test of whether a given spatial pattern is a random sample from the Ising model. The test is based on the conditional probability of configurations on a partial lattice. We apply the method to vegetation height data from the Ogawa forest reserve, Japan, measured on a 5x5 m grid in 1976, 1981, 1986, and 1991. The spatial pattern of the original forest data deviates significantly from the Ising model. We examine whether a larger sampling distance or the removal of the effects of the topography can reduce this deviation.

Ecosystem↗
PubMed2004

Some basic properties of immune selection.

We analyze models for the evolutionary dynamics of viral or other infectious agents within a host. We study how the invasion of a new strain affects the composition and diversity of the viral population. We show that--under strain-specific immunity--the equilibrium abundance of uninfected cells declines during viral evolution. In addition, for cytotoxic immunity the absolute force of infection, and for non-cytotoxic immunity the absolute cellular virulence increases during viral evolution. We prove global stability by means of Lyapunov functions. These unidirectional trends of virus evolution under immune selection do not hold for general cross-reactive immune responses, which introduce frequency-dependent selection among viral strains. Therefore, appropriate cross-reactive immunity can lead to a viral evolution within a host which limits the extent of the disease.

Animals↗
PubMed2004

Evolutionary dynamics of tumor suppressor gene inactivation.

Tumor suppressor genes (TSGs) are important gatekeepers that protect against somatic evolution of cancer. Losing both alleles of a TSG in a single cell represents a step toward cancer. We study how the kinetics of TSG inactivation depends on the population size of cells and the mutation rates for the first and second hit. We calculate the probability as function of time that at least one cell has been generated with two inactivated alleles of a TSG. We find three different kinetic laws: in small, intermediate, and large populations, it takes, respectively, two, one, and zero rate-limiting steps to inactivate a TSG. We also study the effect of chromosomal and other genetic instabilities. Small lesions without genetic instability can take a very long time to inactivate the next TSG, whereas the same lesions with genetic instability pose a much greater risk for cancer progression.

Alleles↗
PubMed2004

Dynamic optimization of host defense, immune memory, and post-infection pathogen levels in mammals.

When attacked by pathogens, higher vertebrates produce specific immune cells that fight against them. We here studied the host's optimal schedule of specific immune cell production. The damage caused by the pathogen increases with the pathogen amount in the host integrated over time. On the other hand, there is also a cost incurred by the production of specific immune cells, not only in terms of the energy needed to produce and maintain the cells, but also with respect to damages sustained by the host's body as a result of immune activity. The optimal strategy of the host is the one that minimizes the total cost, defined as a weighted sum of the damage caused by pathogens and the costs caused by the specific immune cells. The problem is solved by using Pontryagin's maximum principle and dynamic programming. The optimal defense schedule is typically as follows: In the initial phase after infection, immune cells are produced at the fastest possible rate. The amount of pathogen increases temporarily but is eventually suppressed. When the pathogen amount is suppressed to a sufficiently low level, the immune cell number decreases and converges to a low steady level, which is maintained by alternately switching between fastest production and no production. We examine the effect of time delay required to have fully active immune cells by comparing cases with different number of rate limiting steps before producing immune cells. We examine the effect of the duration of time (time delay) required before full-scale production of active immune cells by comparing cases with different numbers of rate-limiting steps before immune-cell production. We also discuss the role of immune memory based on the results of the optimal immune reaction.

Animals↗
PubMed2004

Linear model of colon cancer initiation.

Cancer results if regulatory mechanisms of cell birth and death are disrupted. Colorectal tumorigenesis is initiated by somatic or inherited mutations in the APC tumor suppressor gene pathway. Several additional genetic hits in other tumor suppressor genes and oncogenes drive the progression from polyps to malignant, invasive cancer. The majority of colorectal cancers present chromosomal instability, CIN, which is caused by mutations in genes that are required to maintain chromosomal stability. A major question in cancer genetics is whether CIN is an early event and thus a driving force of tumor progression. We present a new mathematical model of colon cancer initiation assuming a linear flow from stem cells to differentiated cells to apoptosis. We study the consequences of mutations in different cell types and calculate the conditions for CIN to precede APC inactivation. We find that early emergence of CIN is very likely in colorectal tumorigenesis.

Cell Transformation, Neoplastic↗
PubMed2004

Coexistence of a sexual and an unisexual form stabilized by parasites.

An unisexual species (either parthenogenetic or gynogenetic form) often coexists sympatrically with a closely related anisogamous sexual species, forming a unisexual complex. This is puzzling because, all else being equal, a sexual population with the two-fold cost of sex (or the cost of producing males) cannot coexist with a unisexual population. This suggests that some ecological processes are at work to make possible the coexistence of the unisexual complex. Field and laboratory studies suggest that parasitism in a gynogenetic complex of the Japanese crucian carp (Carassius auratus) may play an important role in realizing the coexistence by giving frequency-dependent benefit to sexual population. Here, we study the simple dynamics of host-parasite interactions in which non-specific immune reaction of a sexual host is more effective than that of an unisexual host. We simply assume that the infective individuals are sterile. Stable coexistence of a unisexual species with their sexual relative is possible if pathogens are virulent and if the susceptibility of the unisexual form is more than twice as high as that of the sexual form. The coexistence is more difficult, when the fertility of males is relatively low in gynogenetic complexes. This implies that the coexistence of gynogenetic complexes is more difficult than that of parthenogenetic complexes in which parthenogenesis has no constraint on males. We conclude that parasitism is a promising candidate mechanism for the coexistence of unisexual complexes.

Animals↗
PubMed2004

Evolutionary dynamics of invasion and escape.

Whenever life wants to invade a new habitat or escape from a lethal selection pressure, some mutations may be necessary to yield sustainable replication. We imagine situations like (i) a parasite infecting a new host, (ii) a species trying to invade a new ecological niche, (iii) cancer cells escaping from chemotherapy, (iv) viruses or microbes evading anti-microbial therapy, and also (v) the repeated attempts of combinatorial chemistry in the very beginning of life to produce self-replicating molecules. All such seemingly unrelated situations have a common structure in terms of Darwinian dynamics: a replicator with a basic reproductive ratio less than one attempts to find some mutations that allow indefinite survival. We develop a general theory, based on multitype branching processes, to describe the evolutionary dynamics of invasion and escape.

Animals↗