Jonathan Tang | Lawrence Berkeley National Laboratory (original) (raw)

Papers by Jonathan Tang

Robust predictive models are essential to manage the risk of radiation-induced carcinogenesis. Ch... more Robust predictive models are essential to manage the risk of radiation-induced carcinogenesis. Chronic exposure to cosmic rays in the context of the complex deep space environment may place astronauts at high cancer risk. To estimate this risk, it is critical to understand how radiation-induced cellular stress impacts cell fate decisions and how this in turn alters the risk of carcinogenesis. Exposure to the heavy ion component of cosmic rays triggers a multitude of cellular changes, depending on the rate of exposure , the type of damage incurred and individual susceptibility. Heterogeneity in dose, dose rate, radiation quality, energy and particle flux contribute to the complexity of risk assessment. To unravel the impact of each of these factors, it is critical to identify sensitive biomarkers that can serve as inputs for robust modeling of individual risk of cancer or other long-term health consequences of exposure. Limitations in sensitivity of biomarkers to dose and dose rate, and the complexity of longitudinal monitoring, are some of the factors that increase uncertainties in the output from risk prediction models. Here, we critically evaluate candidate early and late biomarkers of radiation exposure and discuss their usefulness in predicting cell fate decisions. Some of the biomarkers we have reviewed include complex clustered DNA damage, persistent DNA repair foci, reactive oxygen species, chromosome aberrations and inflammation. Other biomarkers discussed, often assayed for at longer points post exposure, include mutations, chromosome aberrations, reactive oxygen species and telomere length changes. We discuss the relationship of biomarkers to different potential cell fates, including proliferation, apoptosis, senescence, and loss of stemness, which can propagate genomic instability and alter tissue composition and the underlying mRNA signatures that contribute to cell fate decisions. Our goal is to highlight factors that are important in choosing biomarkers and to evaluate the potential for biomarkers to inform models of post exposure cancer risk. Because cellular stress response pathways to space radiation and environmental carcinogens share common nodes, biomarker-driven risk models may be broadly applicable for estimating risks for other carcinogens.

Cancer Metastasis - Biology and Treatment, 2014

The constant damage of DNA in human cells is considered the main cause of aging and cancer. In th... more The constant damage of DNA in human cells is considered the main cause of aging and cancer. In this review, we discuss the most lethal form of DNA damage, the DNA double strand break (DSB), and how it relates to cancer. DSB sensor proteins in the nucleus detect DNA breaks within minutes following damage. These proteins are now routinely labeled by immunocytochemistry, and access to high throughput fluorescence microscopy and robotics open the door to rapid measurement of DSB levels in individuals. This method, often referred as the DSB foci assay, leads to images showing small bright spots at the site of each damage in the nucleus. We first discuss how energy consumption in the cell leads to detectable baseline levels of foci per cell measured in peripheral blood lymphocytes. Mathematical kinetics are then described to infer both genetic defects in DNA repair and environmental factors influencing these levels. We emphasize ionizing radiation, which is the principal environmental factor that increases DSB levels. Mathematical models associating a mutation probability for each DSB have been used to explain the dose dependence of cancer incidence observed after exposure to high doses of radiation. The main assumption in these models is that high mutation frequency can eventually lead to tumor suppressor gene deletion or oncogene amplification. We conclude by suggesting that the growing stream of genetic and phenotypic measurements related to DNA repair and DNA damage will lead to more accurate predictive tools for cancer risk and individualized cancer prevention.

Journal of Radiation Research, 2014

This review focuses on recent experimental and modeling studies that attempt to define the physio... more This review focuses on recent experimental and modeling studies that attempt to define the physiological context in which high linear energy transfer (LET) radiation increases epithelial cancer risk and the efficiency with which it does so. Radiation carcinogenesis is a two-compartment problem: ionizing radiation can alter genomic sequence as a result of damage due to targeted effects (TE) from the interaction of energy and DNA; it can also alter phenotype and multicellular interactions that contribute to cancer by poorly understood nontargeted effects (NTE). Rather than being secondary to DNA damage and mutations that can initiate cancer, radiation NTE create the critical context in which to promote cancer. Systems biology modeling using comprehensive experimental data that integrates different levels of biological organization and time-scales is a means of identifying the key processes underlying the carcinogenic potential of high-LET radiation. We hypothesize that inflammation is a key process, and thus cancer susceptibility will depend on specific genetic predisposition to the type and duration of this response. Systems genetics using novel mouse models can be used to identify such determinants of susceptibility to cancer in radiation sensitive tissues following high-LET radiation. Improved understanding of radiation carcinogenesis achieved by defining the relative contribution of NTE carcinogenic effects and identifying the genetic determinants of the high-LET cancer susceptibility will help reduce uncertainties in radiation risk assessment.

Cancer research, 2014

Traditionally, the kinetics of DNA repair have been estimated using immunocytochemistry by labeli... more Traditionally, the kinetics of DNA repair have been estimated using immunocytochemistry by labeling proteins involved in the DNA damage response (DDR) with fluorescent markers in a fixed cell assay. However, detailed knowledge of DDR dynamics across multiple cell generations cannot be obtained using a limited number of fixed cell time-points. Here we report on the dynamics of 53BP1 radiation induced foci (RIF) across multiple cell generations using live cell imaging of non-malignant human mammary epithelial cells (MCF10A) expressing histone H2B-GFP and the DNA repair protein 53BP1-mCherry. Using automatic extraction of RIF imaging features and linear programming techniques, we were able to characterize detailed RIF kinetics for 24 hours before and 24 hours after exposure to low and high doses of ionizing radiation. High-content-analysis at the single cell level over hundreds of cells allows us to quantify precisely the dose dependence of 53BP1 protein production, RIF nuclear localization and RIF movement after exposure to X-ray. Using elastic registration techniques based on the nuclear pattern of individual cells, we could describe the motion of individual RIF precisely within the nucleus. We show that DNA repair occurs in a limited number of large domains, within which multiple small RIFs form, merge and/or resolve with random motion following normal diffusion law. Large foci formation is shown to be mainly happening through the merging of smaller RIF rather than through growth of an individual focus. We estimate repair domain sizes of 7.5 to 11 µm2 with a maximum number of ~15 domains per MCF10A cell. This work also highlights DDR which are specific to doses larger than 1 Gy such as rapid 53BP1 protein increase in the nucleus and foci diffusion rates that are significantly faster than for spontaneous foci movement. We hypothesize that RIF merging reflects a "stressed" DNA repair process that has been taken outside physiological conditions when too many DSB occur at once. High doses of ionizing radiation lead to RIF merging into repair domains which in turn increases DSB proximity and misrepair. Such finding may therefore be critical to explain the supralinear dose dependence for chromosomal rearrangement and cell death measured after exposure to ionizing radiation.

Stem Cells, 2014

Children exposed to ionizing radiation have a substantially greater breast cancer risk than adult... more Children exposed to ionizing radiation have a substantially greater breast cancer risk than adults; the mechanism for this strong age dependence is not known. Here we show that pubertal mammary glands exposed to sparsely or densely ionizing radiation exhibit enrichment of mammary stem cell and Notch pathways, increased mammary repopulating activity indicative of more stem cells, and propensity to develop estrogen receptor (ER) negative tumors thought to arise from stem cells. We developed a mammary lineage agent-based model (ABM) to evaluate cell inactivation, self-renewal or dedifferentiation via epithelial-mesenchymal transition (EMT) as mechanisms by which radiation could increase stem cells. ABM rejected cell inactivation and predicted increased self-renewal would only affect juveniles while dedifferentiation could act in both juveniles and adults. To further test self-renewal versus dedifferentiation, we used the MCF10A human mammary epithelial cell line, which recapitulates ductal morphogenesis in humanized fat pads, undergoes EMT in response to radiation and transforming growth factor β (TGFβ), and contains rare stem-like cells that are Let-7c negative or express both basal and luminal cytokeratins. ABM simulation of population dynamics of double cytokeratin cells supported increased self-renewal in irradiated MCF10A treated with TGFβ. Radiation-induced Notch concomitant with TGFβ was necessary for increased self-renewal of Let-7c negative MCF10A cells but not for EMT, indicating that these are independent processes. Consistent with these data, irradiating adult mice did not increase mammary repopulating activity or ER-negative tumors. These studies suggest that irradiation during puberty transiently increases stem cell self-renewal, which increases susceptibility to developing ER-negative breast cancer. Stem Cells 2013

Cancer Research, 2014

Densely ionizing radiation, which is present in the space radiation environment and used in radia... more Densely ionizing radiation, which is present in the space radiation environment and used in radiation oncology, has potentially greater carcinogenic effect compared to sparsely ionizing radiation that is prevalent on earth. Here we used a radiation chimera in which mice were exposed to densely ionizing 350 MeV/amu Si-particles, gamma-radiation, or sham-irradiated and transplanted 3 days later with syngeneic Trp53 null mammary fragments. Trp53 null tumors arising in mice densely irradiated had a shorter median time to appearance and grew faster once detected compared to those in sham-irradiated or gamma-irradiated mice. Tumors were further classified by markers keratin 8/18 (K18, KRT18), keratin 14 (K14, KRT18) and estrogen receptor (ER, ESR1) and expression profiling. Most tumors arising in sham irradiated hosts were comprised of both K18 and K14 positive cells (K14/18) while those tumors arising in irradiated hosts expressed mostly K18. Keratin staining was significantly associated with ER status. K14/18 tumors were predominantly ER positive while K18 tumors were predominantly ER negative. Genes differentially expressed in K18 tumors compared to K14/18 tumor were associated with ERBB2 and KRAS, metastasis and loss of E-cadherin. Although K18 tumors tended to grow faster and be more metastatic than K14/18 tumors, K18 tumors in particle-irradiated mice grew significantly larger compared to controls and were more metastatic compared to sham-irradiated mice. An expression profile that distinguished K18 tumors arising in particle-irradiated compared sham-irradiated mice was enriched in mammary stem cell, stroma, and Notch signaling genes. These data suggest that the carcinogenic effects of densely ionizing radiation is mediated by the microenvironment, which elicits more aggressive tumors compared to similar tumors arising in sham-irradiated hosts.

International Journal of Genomics, 2015

Long noncoding RNAs (lncRNAs) are emerging as key regulators of diverse cell functions and proces... more Long noncoding RNAs (lncRNAs) are emerging as key regulators of diverse cell functions and processes. However, the relevance of lncRNAs in the cell and tissue response to ionizing radiation has not yet been characterized. Here we used microarray profiling to determine lncRNA and mRNA expression in mammary glands of BALB/c and SPRET/EiJ mice after low-dose ionizing radiation (LDIR) exposure. We found that unirradiated mammary tissues of these strains differed significantly in baseline expressions of 290 lncRNAs. LDIR exposure (10 cGy) induced a significant change in the expression of many lncRNAs. The vast majority of lncRNAs identified to be differentially expressed after LDIR in either BALB/c or SPRET/EiJ had a significantly correlated expression pattern with at least one LDIR responsive mRNA. Functional analysis revealed that the response to LDIR in BALB/c mice is highly dynamic with enrichment for genes involved in tissue injury, inflammatory responses, and mammary gland development at 2, 4, and 8 weeks after LDIR, respectively. Our study demonstrates that genetic background strongly influences the expression of lncRNAs and their response to radiation and that lncRNAs may coordinate the tissue response to LDIR exposure via regulation of coding mRNAs.

Radiation Research, 2014

In contrast to the classic view of static DNA double-strand breaks (DSBs) being repaired at the s... more In contrast to the classic view of static DNA double-strand breaks (DSBs) being repaired at the site of damage, we hypothesize that DSBs move and merge with each other over large distances (μm). As X-ray dose increases, the probability of having DSB clusters increases as does the probability of misrepair and cell death. Experimental work characterizing the X-ray dose dependence of radiation-induced foci (RIF) in nonmalignant human mammary epithelial cells (MCF10A) is used here to validate a DSB clustering model. We then use the principles of the local effect model (LEM) to predict the yield of DSBs at the submicron level. Two mechanisms for DSB clustering namely random coalescence of DSBs versus active movement of DSBs into repair domains are compared and tested. Simulations that best predicted both RIF dose dependence and cell survival after X-ray irradiation favored the repair domain hypothesis, suggesting the nucleus is divided into an array of regularly spaced repair domains of ∼1.55 μm sides. Applying the same approach to high-linear energy transfer (LET) ion tracks, we are able to predict experimental RIF/μm along tracks with an overall relative error of 12%, for LET ranging between 30-350 keV/μm and for three different ions. Finally, cell death was predicted by assuming an exponential dependence on the total number of DSBs and of all possible combinations of paired DSBs within each simulated RIF. Relative biological effectiveness (RBE) predictions for cell survival of MCF10A exposed to high-LET showed an LET dependence that matches previous experimental results for similar cell types. Overall, this work suggests that microdosimetric properties of ion tracks at the submicron level are sufficient to explain both RIF data and survival curves for any LET, similarly to the LEM assumption. Conversely, high-LET death mechanism does not have to infer linear-quadratic dose formalism as done in the LEM. In addition, the size of repair domains derived in our model are based on experimental RIF and are three times larger than the hypothetical LEM voxel used to fit survival curves. Our model is therefore an alternative to previous approaches that provides a testable biological mechanism (i.e., RIF). In addition, we propose that DSB pairing will help develop more accurate alternatives to the linear cancer risk model (LNT) currently used for regulating exposure to very low levels of ionizing radiation.

Journal of Radiation Research, 2014

This review focuses on recent experimental and modeling studies that attempt to define the physio... more This review focuses on recent experimental and modeling studies that attempt to define the physiological context in which high linear energy transfer (LET) radiation increases epithelial cancer risk and the efficiency with which it does so. Radiation carcinogenesis is a two-compartment problem: ionizing radiation can alter genomic sequence as a result of damage due to targeted effects (TE) from the interaction of energy and DNA; it can also alter phenotype and multicellular interactions that contribute to cancer by poorly understood non-targeted effects (NTE). Rather than being secondary to DNA damage and mutations that can initiate cancer, radiation NTE create the critical context in which to promote cancer. Systems biology modeling using comprehensive experimental data that integrates different levels of biological organization and time-scales is a means of identifying the key processes underlying the carcinogenic potential of high-LET radiation. We hypothesize that inflammation is a key process, and thus cancer susceptibility will depend on specific genetic predisposition to the type and duration of this response. Systems genetics using novel mouse models can be used to identify such determinants of susceptibility to cancer in radiation sensitive tissues following high-LET radiation. Improved understanding of radiation carcinogenesis achieved by defining the relative contribution of NTE carcinogenic effects and identifying the genetic determinants of the high-LET cancer susceptibility will help reduce uncertainties in radiation risk assessment.

Mutation Research, 2013

Repair of double strand breaks (DSBs) is essential for cell survival and genome integrity. While ... more Repair of double strand breaks (DSBs) is essential for cell survival and genome integrity. While much is known about the molecular mechanisms involved in DSB repair and checkpoint activation, the roles of nuclear dynamics of radiation-induced foci (RIF) in DNA repair are just beginning to emerge. Here, we summarize results from recent studies that point to distinct features of these dynamics in two different chromatin environments: heterochromatin and euchromatin. We also discuss how nuclear architecture and chromatin components might control these dynamics, and the need of novel quantification methods for a better description and interpretation of these phenomena. These studies are expected to provide new biomarkers for radiation risk and new strategies for cancer detection and treatment.

PLoS Biology, 2012

CENP-A (CID in flies) is the histone H3 variant essential for centromere specification, kinetocho... more CENP-A (CID in flies) is the histone H3 variant essential for centromere specification, kinetochore formation, and chromosome segregation during cell division. Recent studies have elucidated major cell cycle mechanisms and factors critical for CENP-A incorporation in mitosis, predominantly in cultured cells. However, we do not understand the roles, regulation, and cell cycle timing of CENP-A assembly in somatic tissues in multicellular organisms and in meiosis, the specialized cell division cycle that gives rise to haploid gametes. Here we investigate the timing and requirements for CID assembly in mitotic tissues and male and female meiosis in Drosophila melanogaster, using fixed and live imaging combined with genetic approaches. We find that CID assembly initiates at late telophase and continues during G1 phase in somatic tissues in the organism, later than the metaphase assembly observed in cultured cells. Furthermore, CID assembly occurs at two distinct cell cycle phases during male meiosis: prophase of meiosis I and after exit from meiosis II, in spermatids. CID assembly in prophase I is also conserved in female meiosis. Interestingly, we observe a novel decrease in CID levels after the end of meiosis I and before meiosis II, which correlates temporally with changes in kinetochore organization and orientation. We also demonstrate that CID is retained on mature sperm despite the gross chromatin remodeling that occurs during protamine exchange. Finally, we show that the centromere proteins CAL1 and CENP-C are both required for CID assembly in meiosis and normal progression through spermatogenesis. We conclude that the cell cycle timing of CID assembly in meiosis is different from mitosis and that the efficient propagation of CID through meiotic divisions and on sperm is likely to be important for centromere specification in the developing zygote.

Pharmaceutical Research, 2009

We provide a rationale for and describe examples of synthetic modeling and simulation (M&S) of bi... more We provide a rationale for and describe examples of synthetic modeling and simulation (M&S) of biological systems. We explain how synthetic methods are distinct from familiar inductive methods. Synthetic M&S is a means to better understand the mechanisms that generate normal and disease-related phenomena observed in research, and how compounds of interest interact with them to alter phenomena. An objective is to build better, working hypotheses of plausible mechanisms. A synthetic model is an extant hypothesis: execution produces an observable mechanism and phenomena. Mobile objects representing compounds carry information enabling components to distinguish between them and react accordingly when different compounds are studied simultaneously. We argue that the familiar inductive approaches contribute to the general inefficiencies being experienced by pharmaceutical R&D, and that use of synthetic approaches accelerates and improves R&D decision-making and thus the drug development process. A reason is that synthetic models encourage and facilitate abductive scientific reasoning, a primary means of knowledge creation and creative cognition. When synthetic models are executed, we observe different aspects of knowledge in action from different perspectives. These models can be tuned to reflect differences in experimental conditions and individuals, making translational research more concrete while moving us closer to personalized medicine.

Integrative Biology, 2011

We introduce an agent-based model of epithelial cell morphogenesis to explore the complex interpl... more We introduce an agent-based model of epithelial cell morphogenesis to explore the complex interplay between apoptosis, proliferation, and polarization. By varying the activity levels of these mechanisms we derived phenotypic transition maps of normal and aberrant morphogenesis. These maps identify homeostatic ranges and morphologic stability conditions. The agent-based model was parameterized and validated using novel high-content image analysis of mammary acini morphogenesis in vitro with focus on time-dependent cell densities, proliferation and death rates, as well as acini morphologies. Model simulations reveal apoptosis being necessary and sufficient for initiating lumen formation, but cell polarization being the pivotal mechanism for maintaining physiological epithelium morphology and acini sphericity. Furthermore, simulations highlight that acinus growth arrest in normal acini can be achieved by controlling the fraction of proliferating cells. Interestingly, our simulations reveal a synergism between polarization and apoptosis in enhancing growth arrest. After validating the model with experimental data from a normal human breast line (MCF10A), the system was challenged to predict the growth of MCF10A where AKT-1 was overexpressed, leading to reduced apoptosis. As previously reported, this led to non growth-arrested acini, with very large sizes and partially filled lumen. However, surprisingly, image analysis revealed a much lower nuclear density than observed for normal acini. The growth kinetics indicates that these acini grew faster than the cells comprising it. The in silico model could not replicate this behavior, contradicting the classic paradigm that ductal carcinoma in situ is only the result of high proliferation and low apoptosis. Our simulations suggest that overexpression of AKT-1 must also perturb cell–cell and cell–ECM communication, reminding us that extracellular context can dictate cellular behavior.

PLoS Computational Biology, 2010

The LFA-1 integrin plays a pivotal role in sustained leukocyte adhesion to the endothelial surfac... more The LFA-1 integrin plays a pivotal role in sustained leukocyte adhesion to the endothelial surface, which is a precondition for leukocyte recruitment into inflammation sites. Strong correlative evidence implicates LFA-1 clustering as being essential for sustained adhesion, and it may also facilitate rebinding events with its ligand ICAM-1. We cannot challenge those hypotheses directly because it is infeasible to measure either process during leukocyte adhesion following rolling. The alternative approach undertaken was to challenge the hypothesized mechanisms by experimenting on validated, working counterparts: simulations in which diffusible, LFA1 objects on the surfaces of quasi-autonomous leukocytes interact with simulated, diffusible, ICAM1 objects on endothelial surfaces during simulated adhesion following rolling. We used object-oriented, agent-based methods to build and execute multi-level, multi-attribute analogues of leukocytes and endothelial surfaces. Validation was achieved across different experimental conditions, in vitro, ex vivo, and in vivo, at both the individual cell and population levels. Because those mechanisms exhibit all of the characteristics of biological mechanisms, they can stand as a concrete, working theory about detailed events occurring at the leukocyte–surface interface during leukocyte rolling and adhesion experiments. We challenged mechanistic hypotheses by conducting experiments in which the consequences of multiple mechanistic events were tracked. We quantified rebinding events between individual components under different conditions, and the role of LFA1 clustering in sustaining leukocyte–surface adhesion and in improving adhesion efficiency. Early during simulations ICAM1 rebinding (to LFA1) but not LFA1 rebinding (to ICAM1) was enhanced by clustering. Later, clustering caused both types of rebinding events to increase. We discovered that clustering was not necessary to achieve adhesion as long as LFA1 and ICAM1 object densities were above a critical level. Importantly, at low densities LFA1 clustering enabled improved efficiency: adhesion exhibited measurable, cell level positive cooperativity.

Pharmaceutical Research, 2009

BMC Systems Biology, 2007

We present a multilevel, agent based, in silico model that represents the dynamics of rolling, ac... more We present a multilevel, agent based, in silico model that represents the dynamics of rolling, activation, and adhesion of individual leukocytes in vitro. Object-oriented software components were designed, verified, plugged together, and then operated in ways that represent the molecular and cellular mechanisms believed responsible for leukocyte rolling and adhesion. The result is an in silico analogue of an experimental in vitro system. The experimentally measured, phenotypic attributes of the analogue were compared and contrasted to those of leukocytes in vitro from three different experimental conditions. The individual in silico dynamics of "rolling" on simulated P-selectin, and separately on simulated VCAM-1, were an acceptable match to individual in vitro distance-time and velocity-time measurements. The analogues are also able to represent the transition from rolling to adhesion on P-selectin and VCAM-1 in the presence of GRO-α chemokine. The individual in silico and in vitro behavioral similarities translated successfully to population level measures. These behavioral similarities were enabled in part by subdividing the functionality of the analogue's surface into 600 independent, "cell"-controlled, equally capable modules of comparable functionality. The overlap in phenotypic attributes of our analogue with those of leukocytes in vitro confirm the considerable potential of our model for studying the key events that determine the behavioral outcome of individual leukocytes during rolling, activation, and adhesion. Our results provide an important foundation and framework for future in silico research into plausible causal links between well-documented, subcellular molecular level events and the variety of systemic phenotypic attributes that distinguish normal leukocyte adhesion from abnormal disease-associated adhesion.

Journal of Critical Care, 2007

Journal of Critical Care, Volume 22, Issue 4, Pages 341, December 2007, Authors:Jonathan Tang; C.... more Journal of Critical Care, Volume 22, Issue 4, Pages 341, December 2007, Authors:Jonathan Tang; C. Anthony Hunt.

Cancer Metastasis - Biology and Treatment, 2014

Journal of Radiation Research, 2014

Cancer research, 2014

Stem Cells, 2014

Cancer Research, 2014

International Journal of Genomics, 2015

Radiation Research, 2014

Journal of Radiation Research, 2014

This review focuses on recent experimental and modeling studies that attempt to define the physio... more This review focuses on recent experimental and modeling studies that attempt to define the physiological context in which high linear energy transfer (LET) radiation increases epithelial cancer risk and the efficiency with which it does so. Radiation carcinogenesis is a two-compartment problem: ionizing radiation can alter genomic sequence as a result of damage due to targeted effects (TE) from the interaction of energy and DNA; it can also alter phenotype and multicellular interactions that contribute to cancer by poorly understood non-targeted effects (NTE). Rather than being secondary to DNA damage and mutations that can initiate cancer, radiation NTE create the critical context in which to promote cancer. Systems biology modeling using comprehensive experimental data that integrates different levels of biological organization and time-scales is a means of identifying the key processes underlying the carcinogenic potential of high-LET radiation. We hypothesize that inflammation is a key process, and thus cancer susceptibility will depend on specific genetic predisposition to the type and duration of this response. Systems genetics using novel mouse models can be used to identify such determinants of susceptibility to cancer in radiation sensitive tissues following high-LET radiation. Improved understanding of radiation carcinogenesis achieved by defining the relative contribution of NTE carcinogenic effects and identifying the genetic determinants of the high-LET cancer susceptibility will help reduce uncertainties in radiation risk assessment.

Mutation Research, 2013

PLoS Biology, 2012

Pharmaceutical Research, 2009

Integrative Biology, 2011

PLoS Computational Biology, 2010

Pharmaceutical Research, 2009

BMC Systems Biology, 2007

Journal of Critical Care, 2007