Shaowen Hu

MODELING THE ACUTE HEALTH EFFECTS OF ASTRONAUTS FROM EXPOSURE TO LARGE SOLAR PARTICLE EVENTS

Radiation exposure from Solar Particle Events (SPE) presents a significant health concern for astronauts for exploration missions outside the protection of the Earth’s magnetic field, which could impair their performance and result in the possibility of failure of the mission. Assessing the potential for early radiation effects under such adverse conditions is of prime importance. Here we apply a biologically based mathematical model that describes the dose- and time-dependent early human responses that constitute the prodromal syndromes to consider acute risks from SPEs. We examine the possible early effects on crews from exposure to some historically large solar events on lunar and/or Mars missions. The doses and dose rates of specific organs were calculated using the Baryon radiation transport (BRYNTRN) code and a computerized anatomical man model, while the hazard of the early radiation effects and performance reduction were calculated using the Radiation-Induced Performance Decrement (RIPD) code. Based on model assumptions we show that exposure to these historical events would cause moderate early health effects to crew members inside a typical spacecraft or during extra-vehicular activities, if effective shielding and medical countermeasure tactics were not provided. We also calculate possible even worse cases (double intensity, multiple occurrences in a short period of time, etc.) to estimate the severity, onset and duration of various types of early illness. Uncertainties in the calculation due to limited data on relative biological effectiveness and dose-rate modifying factors for protons and secondary radiation, and the identification of sensitive sites in critical organs are discussed.

A biomathematical model of lymphopoiesis following severe radiation accidents--potential use for dose assessment.

Abstract A biomathematical model of lymphopoiesis is described and used to analyze the lymphocyte changes observed in the blood of exposed victims in radiation accidents. The coarse-grained architecture of cellular replication and production and implicit cellular regulation mechanisms used in this model make it straightforward to incorporate various radiation conditions. Model simulations with reported absorbed doses as inputs are shown to qualitatively and quantitatively describe a wide range of accidental data in vastly different scenarios. In addition, the absolute lymphocyte counts and the depletion rate constants calculated by this model show good correlation with two widely recognized empirical methods for early dose assessment. This demonstrates the potential to use the biophysical model as an alternative method for the assessment of radiation injury in the case of large-scale radiation disaster. The physiological assumptions underlying the model are also discussed, which may provide a putative mechanism for some biodosimetric tools that use the peripheral blood cell counts as markers of radiation impairment.

Characterization of the radiation-damaged precursor cells in bone marrow based on modeling of the peripheral blood granulocytes response.

Bone marrow failure is the major cause of radiation lethality in mammals. Since bone marrow is distributed heterogeneously within trabecular spongiosa encased in a cortex of cortical bone, it is very difficult to measure the extent of the radiation damage directly. However, indirect consequences of damage to marrow, such as reductions in peripheral blood cell counts, are easily measured. In this paper, the authors investgate a mathematical model of the granulopoiesis system that provides quantitative relationships between reductions in peripheral blood cells and the bone marrow precursor cells following radiation exposure. A coarse-grained architecture of cellular replication and production as well as a mechanism for implicit regulation used in this model are discussed. The model is based on previous investigations of rodents. The authors test how well the model matches, in the principal dynamic regime of hematopoiesis, experimental data on large animals as well as empirical data on humans following radiation exposure. Due to its ability to infer, albeit indirectly, radiation damage to bone marrow, this model will provide a useful computational tool in radiation accident management, military operations involving nuclear warfare, radiation therapy, and space radiation risk assessment.

Analysis of the Lymphocytopoiesis Dynamics in Nonirradiated and Irradiated Humans: A Modeling Approach

In this work, a recently developed mathematical model of the lymphocytopoietic system in acutely irradiated humans was extended to predict the dynamics of this system both in nonirradiated and acutely/chronically irradiated humans. The mathematical implementation of this model is a system of nonlinear ordinary differential equations, whose variables and parameters have clear biological meaning. We demonstrate that the model is capable of reproducing the dynamic regimes that are typical for lymphocytopoiesis in nonirradiated individuals with a hematological disorder (cyclic lymphocytopenia) and in patients receiving allogeneic stem cell transplantation. The model is also capable of predicting the dynamics of the lymphocytopoietic system in humans exposed to acute and chronic irradiation over a wide range of doses and dose rates. Additionally, the “lethal” dose rate of chronic irradiation, evaluated in the framework of the lymphocytopoiesis model, agrees with the actual minimum dose rate of lethal chronic irradiation observed for humans.

HEMODOSE: A Biodosimetry Tool Based on Multi-type Blood Cell Counts.

AbstractPeripheral blood cell counts are important biomarkers of radiation exposure. In this work, a simplified compartmental modeling approach is applied to simulate the perturbation of the hematopoiesis system in humans after radiation exposure, and HemoDose software is reported to estimate individuals’ absorbed doses based on multi-type blood cell counts. Testing with patient data in some historical accidents indicates that either single or serial granulocyte, lymphocyte, leukocyte, and platelet counts after exposure can be robust indicators of the absorbed doses. In addition, such correlation exists not only in the early time window (1 or 2 d) but also in the late phase (up to 4 wk) after exposure, when the four types of cell counts are combined for analysis. These demonstrate the capability of HemoDose as a rapid point-of-care diagnostic or centralized high-throughput assay system for personnel exposed to unintended high doses of radiation, especially in large-scale nuclear/radiological disaster scenarios involving mass casualties.

Dynamics of acutely irradiated skin epidermal epithelium in swine: modeling studies.

AbstractA mathematical model, which describes the dynamics of acutely irradiated skin epidermal epithelium in swine, is developed. This model embodies the key mechanisms of regulation of skin epidermal epithelium and the principal stages of development of its cells (basal, prickle, and corneal). The model is implemented as a system of nonlinear ordinary differential equations, whose variables and parameters have clear biological meaning. The modeling results for the dose- and time-dependent changes in basal and prickle cell populations are in a good agreement with relevant experimental data. The correlation between the experimental data on the dynamics of moist reaction in acutely irradiated swine skin epidermal epithelium and the corresponding modeling results on the dynamics of corneal cells is revealed. Proceeding from this, the threshold level of corneal cells, which indicates the appearance of the moist reaction, is found. All this bears witness to the validity of employment of the developed model, after appropriate identification, in the investigation and prediction of radiation effects on skin epidermal epithelium in humans.

Modeling the Depressed Hematopoietic Cells for Immune System under Chronic Radiation

Although moderate dose (0.5 to 2 Gy) of ionizing radiation (IR) is well recognized to cause various disorders of the hematopoietic system (e.g., short-term effects like cytopenia, and long-term effects like leukemia), many quantitative aspects of the dynamics of the hematopoiesis response to long duration low dose rate IR still require additional investigation. Recently two cell kinetics models after acute radiation exposure are proposed to describe the perturbation of granulocytes and lymphocytes, respectively, in peripheral blood of various mammals. These two models are indeed built on a similar coarse-grained structure of hematopoietic system, thus they have the potential to form a unified model to characterize the mammalian hematopoietic system after various types of IR exposure. In this study we investigate the capability of the models to simulate the data of hematological measurements of the Techa River residents chronically exposed to IR in 1950-1956. Our modeling investigation indicates human hematopoietic precursor cells are more sensitive to chronic radiation than previously considered.

Radiation Dose Assessment by Using Lymphocyte Counts

Peripheral blood cell counts are important biomarkers of radiation exposure. With the successful application of a simplified compartmental modeling approach to simulate the perturbation of hematopoiesis system in humans after radiation exposure, we recently developed a HemoDose software program to estimate absorbed dose based on multi-type blood cell counts. Testing with patient data in some historical accidents indicates that either single or serial granulocyte, lymphocyte, leukocyte, or platelet counts after exposure can be robust indicators of the absorbed doses. In this work, the first week lymphocyte counts of five patients in the 2011 Bulgaria radiation accident are used to do serial points and single point calculations with HemoDose. Overall, the estimated doses are in good agreement with those evaluated with cytogenetic analysis in two independent laboratories. The program also confirms that calculation with individual reference counts can significantly increase the accuracy of this simple dose estimation algorithm. These results indicate that HemoDose can be employed as an easy-to-use and deployable biodosimetry tool for predicting the clinical severity, treatment, and survivability of exposed individuals and triaging those with minimum or no exposure, especially in a large-scale nuclear/radiological disaster scenario involving mass casualties.

Modelling the way Ku binds DNA

Ku plays a crucial role in the non-homologous end joining pathway to repair DNA double-strand breaks. In this study, we modelled the full-length Ku heterodimer from the truncated crystal structure and NMR structure, and conducted a series of docking and molecular dynamics simulations in an effort to probe the structural, dynamical and energetic features of each domain in free Ku and Ku-DNA complexes.

Computational studies on full-length Ku70 with DNA duplexes: base interactions and a helical path

AbstractThe Ku70/80 heterodimer is among the first responding proteins to recognize and bind the DNA double strand breaks (DSBs). Once Ku is loaded at the DSB, it works as a scaffold to recruit other repair factors in non-homologous end joining thereby facilitates the following repair processes. In this work, we characterized the detailed interactions and binding free energies between a Ku70 subunit and several DNA duplexes, by using some well-established computational methods. The results reveal that the structure of the protein may suffer certain contractions without the company of Ku80, and may experience large conformational changes in the presence of different DNA duplexes. Notably, we observe the closest interactions between Ku70 and DNA can be easily strengthened to form H-bonds with the bases in the minor groove, which is unexpected. However, this finding is supported by the presence of a similar bond between Ku80 and DNA in the published crystal structure (PDB code 1JEY). We suggest that these interactions are responsible for the observed pausing sites when Ku translocates along DNA and the subtle difference in binding with AT- and GC-rich DNA ends. Additionally, simulations indicate the inner surface of the ring encircling the DNA is not flat, but contains a delicate clamp like structure, which is ideal to grip the two strands of DNA in the minor groove and confine the movement of the duplex in a unique helical path. FigureH-bond network of R403 (a) and R254 (b) of Ku70 formed with nucleotide bases in the minor groove.