A study of the effect of radiation on megakaryocytopoiesis using a mathematical model

Mathematical modelling used in analysing the postirradiation changes in megakaryocytopoiesis permitted to determine the level of radiation-induced injury in each experiment conducted and to show that megakaryocytopoiesis regulation followed the same mechanism after irradiation as it does normally and after the effect of hydroxyurea and anti-thrombocyte serum. The analysis has demonstrated that after the stem cell death induced by ionizing radiation, the regeneration can be provided by the committed cells, and the level of regeneration is determined by the maturity of precursors.     

Proliferation of peripheral lymphocytes to interleukin-2 and interleukin-4 after marrow transplantation.

Defects in the interleukin-2 (IL-2)-mediated T-lymphocyte activation/proliferation pathway have been implicated as contributing to the compromised immune function observed in patients following bone marrow transplantation (BMT). Since interleukin-4 (IL-4) is also involved in T-lymphocyte function, we have examined whether phytohemagglutinin (PHA)- or anti-CD3 (OKT3)-activated lymphocytes obtained from patients after allogeneic or autologous BMT are capable of proliferating in response to human recombinant IL-4, and compared these results to those obtained using human recombinant IL-2. Peripheral blood lymphocytes from marrow graft recipients were initially cultured for 3 days in the presence of PHA or OKT3. Such mitogen-activated lymphocytes exhibited little or no proliferation (as assessed by incorporation of [3H]-thymidine) following culture for an additional 3 days in the presence of IL-4 or IL-2. Results were similar for lymphocytes obtained from patients early (less than 4 months) after marrow grafting and those obtained from long-term marrow graft recipients with chronic graft-vs-host disease at the time of testing. In contrast, lymphocytes obtained from healthy individuals proliferated in response to IL-4, as well as to IL-2, following initial activation with PHA or OKT3. Immunofluorescence analysis showed that in normals equal numbers of CD4 and CD8 cells proliferated after stimulation with anti-CD3 antibody and IL-2. However, in BMT patients there was a predominant proliferation of CD8 cells using the same stimulator. These results indicate that defects in the IL-4-mediated T-lymphocyte activation/proliferation pathway may also contribute to the immunodeficiency observed following BMT.     

Evaluation of the effect of cardiotropic agents using a mathematical model of electromechanical coupling

An assessment of the ionic action mechanism of cardiotropic substances with the aid of a mathematical model for excitation-contraction coupling in myocardium is proved to be possible. The technique developed consists in the model parameter identification from the experimental data on electrical and mechanical activity of myocardial strip. The validity of the technique is tested using the known mechanism drugs. An example is given of analysis by the technique suggested of the action mechanism of diltiazem on the rat papillary muscle.     

A mathematical model of CO2 effect on cardiovascular regulation

The effect of changes in arterial CO2 tension on the cardiovascular system is analyzed by means of a mathematical model. The model is an extension of a previous one that already incorporated the main reflex and local mechanisms triggered by O2 changes. The new aspects covered by the model are the O2-CO2 interaction at the peripheral chemoreceptors, the effect of local CO2 changes on peripheral resistances, the direct central neural system (CNS) response to CO2, and the control of central chemoreceptors on ventilation and tidal volume. A statistical comparison between model simulation results and various experimental data has been performed. This comparison suggests that the model is able to simulate the acute cardiovascular response to changes in blood gas content in a variety of conditions (normoxic hypercapnia, hypercapnia during artificial ventilation, hypocapnic hypoxia, and hypercapnic hypoxia). The model ascribes the observed responses to the complex superimposition of many mechanisms simultaneously working (baroreflex, peripheral chemoreflex, CNS response, lung-stretch receptors, local gas tension effect), which may be differently activated depending on the specific stimulus under study. However, although some experiments can be reproduced using a single basal set of parameters, reproduction of other experiments requires a different combination of the mechanism strengths (particularly, a different strength of the local CO2 mechanism on peripheral resistances and of the CNS response to CO2). Starting from these results, some assumptions to explain the striking differences reported in the literature are presented. The model may represent a valid support for the interpretation of physiological data on acute cardiovascular regulation and may favor the synthesis of contradictory results into a single theoretical setting.     

Making sense of parameter estimation and model simulation in bioprocesses

Most articles that report fitted parameters for kinetic models do not include meaningful statistical information. This study demonstrates the importance of reporting a complete statistical analysis and shows a methodology to perform it, using functionalities implemented in computational tools. As an example, alginate production is studied in a batch stirred-tank fermenter and modeled using the kinetic model proposed by Klimek and Ollis (1980). The model parameters and their 95% confidence intervals are estimated by nonlinear regression. The significance of the parameters value is checked using a hypothesis test. The uncertainty of the parameters is propagated to the output model variables through prediction intervals, showing that the kinetic model of Klimek and Ollis (1980) can simulate with high certainty the dynamic of the alginate production process. Finally, the results obtained in other studies are compared to show how the lack of statistical analysis can hold back a deeper understanding about bioprocesses.     

Fermentation process diagnosis using a mathematical model

Summary Intriguing physiology of a solvent-producing strain ofClostridium acetobutylicum led to the synthesis of a mathematical model of the acetone-butanol fermentation process. The model presented is capable of describing the process dynamics and the culture behavior during a standard and a substandard acetone-butanol fermentation. In addition to the process kinetic parameters, the model includes the culture physiological parameters, such as the cellular membrane permeability and the number of membrane sites for active tansport of sugar. Computer process simulation studies for different culture conditions used the model, and quantitatively pointed out the importance of selected culture parameters that characterize the cell membrane behaviour and play an important role in the control of solvent synthesis by the cell. The theoretical predictions by the new model were confirmed by experimental determination of the cellular membrane permeability.     

Augmentation of antitumor effect by combined administration with interleukin-2 and sizofiran,a single glucan,on murine EL-4 lymphoma

The antitumor effect of the combined administration with recombinant human interleukin-2 (rIL-2) and sizofiran (SPG), a single glucan of Shizophyllum commune Fries, was studied in vivo in C57BL/6 mice intraperitoneally inoculated with EL-4 lymphoma. The effect was evaluated by a) comparing the survival time of the mice, b) analysis of the intraperitoneal cell population in Giemsa-stained specimens, c) surface marker analysis of peritoneal exudative cells with flow cytometry, d) cytotoxic assay of cells against EL-4 and Yac-1 lymphoma, and e) elimination of some cell populations by monoclonal antibodies, to identify the antitumor-effector cells showing cytotoxic activity. The survival of mice given both rIL-2 and SPG was significantly longer than the control mice or those given SPG alone or rIL-2 alone. It was demonstrated that the administration of SPG and/or rIL-2 to the EL-4 lymphoma-bearing mice activated immune-response cells in the peritoneal cavity such as T lymphocytes, NK cells, or macrophages, which might be effective in reducing lymphoma cells. The combination of rIL-2 and SPG administration appears to activate the antitumor- immune response at the tumor site more effectively than when either agent was administered alone.     

The effect of interfering substances on the disinfection process: a mathematical model

AIMS: To gain a greater understanding of the effect of interfering substances on the efficacy of disinfection. METHODS AND RESULTS: Current kinetic disinfection models were augmented by a term designed to quantify the deleterious effect of soils such as milk on the disinfection process of suspended organisms. The model was based on the assumption that inactivation by added soil occurred at a much faster rate than microbial inactivation. The new model, the fat-soil model, was also able to quantify the effect of changing the initial inoculum size (1 x 10(7)-5 x 10(7) ml(-1) of Staphylococcus aureus) on the outcome of the suspension tests. Addition of catalase to the disinfection of Escherichia coli by hydrogen peroxide, resulted in changes to the shape of the log survivor/time plots. These changes were modelled on the basis of changing biocide concentration commensurate with microbial inactivation. CONCLUSIONS: The reduction in efficacy of a disinfectant in the presence of an interfering substance can be quantified through the use of adaptations to current disinfection models. SIGNIFICANCE AND IMPACT OF THE STUDY: Understanding the effect of soil on disinfection efficacy allows us to understand the limitations of disinfectants and disinfection procedures. It also gives us a mechanism with which to investigate the soil tolerance of new biocides and formulations.     

Interaction of bovine uterine luminal protein with interleukin-2 and the interleukin-2 receptor of T lymphocytes

Bovine uterine luminal proteins (ULP) collected on Day 17 of pregnancy were tested for inhibition of binding of interleukin-2 (IL-2) to the IL-2 receptor (IL-2R) of bovine (CLC) and human (HLC) T lymphocytes and for binding to IL-2. Additional experiments assessed IL-2 binding to the p55 alpha chain (Tac protein) of the IL-2R of HLC. High- and low-molecular weight (Mr) ULP components (H-ULP greater than 248,000 Mr and L-ULP 21,000 Mr, respectively) inhibited (p less than 0.05 and 0.01, respectively) the binding of 125I-IL-2 to the IL-2R of CLC, whereas only H-ULP inhibited (p less than 0.05) binding to the IL-2R (presumably, the p75 beta chain) of HLC. H-ULP failed (p greater than 0.05) to bind to the p55 alpha chain of the IL-2R of HLC. For IL-2 binding, L-ULP failed (p greater than 0.05) to bind 125I-IL-2 in short (2 h)-term and long (45 h)-term experiments, whereas binding was evident (p less than 0.05) for H-ULP at 2 h of incubation. For H-ULP, mean (+/- SEM) percentages for bound and unbound 125I-IL-2 were 70.1 +/- 11.4 and 29.9 +/- 11.4, respectively. Further purification of H-ULP yielded a component (1.76 x 10(6) Mr) that bound 11.7% of 125I-IL-2 and inhibited (p less than 0.01) thymidine uptake and binding of 125I-IL-2 to the IL-2R of CLC. H-ULP-mediated suppression of lymphocyte proliferation may result from blocking IL-2R recognition of IL-2 as well as binding to IL-2, whereas suppression by L-ULP may predominantly result from blocking IL-2R.     

Making sense of the diverse ligand recognition by NKG2D

NKG2D recognizes multiple diverse ligands. Despite recent efforts in determining the crystal structures of NKG2D-ligand complexes, the principle governing this receptor-ligand recognition and hence the criteria for identifying unknown ligands of NKG2D remain central issues to be resolved. Here we compared the molecular recognition between NKG2D and three of the known ligands, UL16 binding protein (ULBP), MHC class I-like molecule, and retinoic acid early inducible gene as observed in the ligand-complexed crystal structures. The comparison shows that while the receptor uses a common interface region to bind the three diverse ligands, each ligand forms a distinct, but overlapping, set of hydrogen bonds, hydrophobic interactions, and salt bridges, illustrating the underlying principle of NKG2D-ligand recognition being the conservation in overall shape complementarity and binding energy while permitting variation in ligand sequence through induced fit recognition. To further test this hypothesis and to distinguish between diverse recognition and promiscuous ligand binding, four ULBP3 interface mutations, H21A, E76A, R82M, and D169A, were generated to each disrupt a single hydrogen bond or salt bridge. All mutant ULBP3 displayed reduced receptor binding, suggesting a specific, rather than promiscuous, receptor-ligand recognition. Mutants with severe loss of binding affect the receptor interactions that are mostly buried. Finally, a receptor-ligand recognition algorithm was developed to assist the identification of diverse NKG2D ligands based on evaluating the potential hydrogen bonds, hydrophobic interactions, and salt bridges at the receptor-ligand interface.     

A mathematical model describing the combined effect of exposure time and temperature of hot-water treatments on survival of gladiolus cormels

Gladiolus cormels of five cultivars were given hot-water treatments at 50.0°C, 52.5°C, 55.0°C or 57.5°C for different exposure times. Survival of cormels was determined. A mathematical model to describe the combined effect of exposure time and temperature on cormel death is presented. Consequences of these relationships for the practical application of hot-water treatments to control cormel-borne Fusarium oxysporum f.sp. gladioli are discussed.     

Analysis of a mathematical model of the effect of inhibitors on the growth of tumors

In this paper, we study a model of tumor growth in the presence of inhibitors. The tumor is assumed to be spherically symmetric and its boundary is an unknown function r=R(t). Within the tumor the concentration of nutrient and the concentration of inhibitor (drug) satisfy a system of reaction-diffusion equations. The important parameters are Lambda(0) (which depends on the tumor's parameters when no inhibitors are present), gamma which depends only on the specific properties of the inhibitor, and beta; which is the (normalized) external concentration of the inhibitor. In this paper, we give precise conditions under which there exist one dormant tumor, two dormant tumors, or none. We then prove that in the first case, the dormant tumor is globally asymptotically stable, and in the second case, if the radii of the dormant tumors are denoted by R(s)(-),R(s)(+) with R(s)(-)infinity)R(t)=R(s)(-), provided the initial radius R(0) is smaller than R(s)(+); if however R(0)R(s)(+) then the initial tumor in general grows unboundedly in time. The above analysis suggests an effective strategy for treatment of tumors.     

Making sense of cilia and flagella

Data reported at an international meeting on the sensory and motile functions of cilia, including the primary cilium found on most cells in the human body, have thrust this organelle to the forefront of studies on the cell biology of human disease.     

The effect of blood volume loss on cardiovascular response to lower body negative pressure using a mathematical model

Different mathematical models of varying complexity have been proposed in recent years to study the cardiovascular (CV) system. However, only a few of them specifically address the response to lower body negative pressure (LBNP), a stress that can be applied in weightlessness to predict changes in orthostatic tolerance. Also, the simulated results produced by these models agree only partially with experimental observations. In contrast, the model proposed by Melchior et al., and modified by Karam et al. is a simple representation of the CV system capable of accurately reproducing observed LBNP responses up to presyncopal levels. There are significant changes in LBNP response due to a loss of blood volume and other alterations that occur in weightlessness and related one-g conditions such as bedrest. A few days of bedrest can cause up to 15% blood volume loss (BVL), with consequent decreases in both stroke volume and cardiac output, and increases in heart rate, mean arterial pressure, and total peripheral resistance. These changes are more pronounced at higher levels of LBNP. This paper presents the results of a simulation study using our CV model to examine the effect of BVL on LBNP response.     

Synergistic effect of interleukin-15 and interleukin-12 on antitumor activity in a murine malignant pleurisy model

 Interleukin(IL)-15, which uses IL-2 receptor (R) β and γ chains for signal transduction, shares many of the biological activities of IL-2. We examined the effects of exogenous IL-15 on protection in a murine malignant pleurisy model using BALB/c mice and syngeneic MethA fibrosarcoma (MethA). Intrapleural administration of IL-15 significantly prolonged the survival time of mice after an intrapleural inoculation of MethA, whereas the same dose of IL-2 did not. The in vivo antitumor effect of IL-15 was synergistically enhanced by additive administration of IL-12. Combination therapy of IL-15 and IL-12 protected mice from death from bloody pleural fluid. Such treatment induced marked increases in the number of CD3^-IL-2Rβ⁺ cells corresponding to natural killer (NK) cells and the production of interferon γ (IFNγ) by T cells in the thoracic exudate cells (TEC). Administration of anti-IFNγ mAb partly inhibited the protective effect of a combination of IL-15 and IL-12. A tumor-neutralizing (Winn) assay revealed that the antitumor activity of effector cells in the TEC was abrogated by treatment with anti-CD8 mAb or anti-asialoGM1 Ab plus complement. Thus, treatment with IL-15 in combination with IL-12 may enhance the activities of NK and CD8⁺ T cells in the TEC, providing strong antitumor activity against the malignant pleurisy. These results suggest that IL-15 together with IL-12 may have potential for the immunotherapy of some types of malignant pleurisy. Received: 13 July 1999 / Accepted: 3 December 1999     

Differential modulation of interleukin-2-and interleukin-4-mediated early activation of normal human B lymphocytes by the caspase inhibitor zVAD-fmk

Caspases are a group of cysteine-related proteases that control the process of apoptosis and may also be involved in the control of lymphocyte activation. We show here that the broad-spectrum caspase inhibitor benzyloxycarbonyl (Cbz)-Val-Ala-Asp (Ome)-fluoromethylketone (zVAD-fmk) prevents the proliferation of resting human B tonsilar lymphocytes mediated by the B cell mitogen SAC or the combination of anti-mu Ab and IL-2. zVAD-fmk inhibits IL-2-induced phosphorylation of the retinoblastoma protein, and cyclin D2 expression. However, neither the IL-2-mediated proliferation of cycling activated B cells nor that of lymphoma cells were inhibited by zVAD-fmk, suggesting that only the early steps of SAC- or IL-2-mediated B cell activation were sensitive to the inhibitory properties of zVAD-fmk. Our data also demonstrated that the inhibitory effect of zVAD-fmk was not observed when B cells were activated with IL-4 in the presence of either anti-mu Ab or anti-CD40 Ab. Thus, our results suggest that caspase activation is required for the IL-2-mediated entry of primary B lymphocytes into the cell cycle and show that caspase activation plays different roles in IL-2- and IL-4-mediated B cell proliferation.     

A mathematical model of a crocodilian population using delay-differential equations

The crocodilia have multiple interesting characteristics that affect their population dynamics. They are among several reptile species which exhibit temperature-dependent sex determination (TSD) in which the temperature of egg incubation determines the sex of the hatchlings. Their life parameters, specifically birth and death rates, exhibit strong age-dependence. We develop delay-differential equation (DDE) models describing the evolution of a crocodilian population. In using the delay formulation, we are able to account for both the TSD and the age-dependence of the life parameters while maintaining some analytical tractability. In our single-delay model we also find an equilibrium point and prove its local asymptotic stability. We numerically solve the different models and investigate the effects of multiple delays on the age structure of the population as well as the sex ratio of the population. For all models we obtain very strong agreement with the age structure of crocodilian population data as reported in Smith and Webb (Aust. Wild. Res. 12, 541-554, 1985). We also obtain reasonable values for the sex ratio of the simulated population.