Biomedical subjects

Yoh Iwasa

Publications and source records attributed to Yoh Iwasa.

60 records · Page 4Linked to original sources

PubMed2003

Patterns of cell division and the risk of cancer.

Epidermal and intestinal tissues divide throughout life to replace lost surface cells. These renewing tissues have long-lived basal stem cell lineages that divide many times, each division producing one stem cell and one transit cell. The transit cell divides a limited number of times, producing cells that move up from the basal layer and eventually slough off from the surface. If mutation rates are the same in stem and transit divisions, we show that minimal cancer risk is obtained by using the fewest possible stem divisions subject to the constraints imposed by the need to renew the tissue. In this case, stem cells are a necessary risk imposed by the constraints of tissue architecture. Cairns suggested that stem cells may have lower mutation rates than transit cells do. We develop a mathematical model to study the consequences of different stem and transit mutation rates. Our model shows that stem cell mutation rates two or three orders of magnitude less than transit mutation rates may favor relatively more stem divisions and fewer transit divisions, perhaps explaining how renewing tissues allocate cell divisions between long stem and short transit lineages.

Cell Division↗

PubMed2002

Optimal defense strategy: storage vs. new production.

If hosts produce defense proteins after they are infected by pathogens, it may take hours to days before defense becomes fully active. By producing defense proteins beforehand, and storing them until infection, the host can cope with pathogens with a short time delay. However, producing and storing defense proteins require energy, and the activated defense proteins often cause harm to the host's body as well as to pathogens. Here, we study the optimal strategy for a host who chooses the amount of stored defense proteins, the activation of the stored proteins upon infection, and the new production of the proteins. The optimal strategy is the one that minimizes the sum of the harm by pathogens and the cost of defense. The host chooses the storage size of defense proteins based on the probability distribution of the magnitude of pathogen infection. When the infection size is predictable, all the stored proteins are to be activated upon infection. The optimal strategy is to have no storage and to rely entirely on new production if the expected infection size n(0) is small, but to have a big storage without new production if n(0) is large. The transition from the "new production" phase to "storage" phase occurs at a smaller n(0) when storage cost is small, activation cost is large, pathogen toxicity is large, pathogen growth is fast, the defense is effective, the delay is long, and the infection is more likely. On the other hand, the storage size to produce for a large n(0) decreases with three cost parameters and the defense effectiveness, increases with the likelihood of infection, the toxicity and the growth rate of pathogens, and it is independent of the time delay. When infection size is much smaller than the expected size, some of the stored proteins may stay unused.

Animals↗

PubMed2002

Comparative study of circadian clock models, in search of processes promoting oscillation.

We study simple models for circadian rhythm, and examine the condition in which the equilibrium is unstable, generating a sustained oscillation. In the models, a clock gene(s) is transcribed to produce mRNAs, which are translated to produce proteins that suppress the transcription of the clock gene(s). First, using a Lyapunov function, we prove under very general conditions that two-variable models cannot generate a stable oscillation, implying that additional structures are needed for the model to generate a sustainable rhythm. By comparing several models of different complexities using the Routh-Hurwitz criteria of stability, we show that a sustained oscillation is more likely to occur if the cell is compartmentalized and the proteins need to be transported from the cytosol to the nucleus, if the proteins have to be modified before entering the nucleus, if the kinetics of transcription inhibition or the transport to the nucleus have cooperativity with a nonlinear dependence on the substrate concentration, or if the products of two clock genes form a heterodimer that suppresses both of their own genes. We discuss the implications of these results.

Animals↗

PubMed2002

Directionality of stripes formed by anisotropic reaction-diffusion models.

Turing mechanism explains the formation of striped patterns in a uniform field in which two substances interact locally and diffuse randomly. In a twin paper, to explain the directionality of stripes on fish skin in closely related species, we studied the effect of anisotropic diffusion of the two substances on the direction of stripes, in the cases in which both substances have high diffusivity in the same direction. In this paper, we study the direction of stripes in more general situations in which the diffusive direction may differ between the two substances. We derive a formula for the direction of stripes, based on a heuristic argument of unstable modes of deviation from the uniform steady state. We confirm the accuracy of the formula by computer simulations. When the diffusive direction is different between two substances, the directions of stripes in the spatial pattern change smoothly with the magnitude of anisotropy of two substances. When the diffusive direction of the two substances is the same, the stripes are formed either parallel or perpendicular to the common diffusive direction, depending on the relative magnitude of the anisotropy. The transition between these two phases occurs sharply.

Animals↗

PubMed2002

Saturation of enzyme kinetics in circadian clock models.

From the mathematical study of simple models for circadian rhythm, the authors identified a clear effect of saturation in the enzyme kinetics on the promotion or suppression of a sustained oscillation. In the models, a clock gene (per gene) is transcribed to produce mRNAs, which are translated to produce proteins in the cytosol which are then transported to the nucleus and suppress the transcription of the gene. The negative feedback loop with a long time delay creates sustained oscillation. All the enzymatic reactions (e.g., degradation, translation, and modification) are assumed to be of Michaelis-Menten type. The reaction rate increases with the amount of substrate but saturates when it is very large. The authors prove mathematically that the saturation in any of the reactions included in the feedback loop (in-loop reaction steps) suppresses the oscillation, whereas the saturation of both degradation steps and the back transport of the protein to cytosol (branch reaction steps) makes the oscillation more likely to occur. In the experimental measurements of enzyme kinetics and in published circadian clock simulators, in-loop reaction steps have a small saturation index whereas branch reaction steps have a large saturation index.

Animals↗

PubMed2002

Extinction risk to herring gull populations from DDT exposure.

The impact of toxic chemicals on wild animals and plants can be quantified in terms of the enhanced risk of population extinction. To illustrate the method, we estimated it for herring gull (Larus argentatus) populations in Long Island (NY, USA) exposed to DDT (p,p'-dichlorodiphenyltrichloroethane) and its metabolites (abbreviated as DDTs) with a strong biomagnification effect. The method is based on a formula of the mean time to population extinction derived for a stochastic differential equation (the canonical model). The intrinsic rate of natural population growth was estimated from the doubling time of an exponentially growing population and the intensity of the environmental fluctuation from the magnitude of population size fluctuation. The effect of exposure to DDTs in reducing the population growth rate was evaluated based on an age-structured population model by assuming that age-specific fertilities (including chick survivorship) are density dependent and sensitive to DDTs exposure but age-specific survivorships are not. The results are expressed in terms of the risk equivalent-the decrease in the carrying capacity K that causes the same enhancement of extinction risk as chemical exposure at a given level. The high concentration reported in Long Island in the 1960s corresponds to the equivalent loss of carrying capacity by 42.5% when K is 100 (the number of breeding females), and coefficient of variation (CV) = 0.2 (sigma2 = 0.0298) [corrected]. Risk equivalent allows us to compare different risk factors and is useful in mitigation banking.

Animals↗