John H. Gauthier

A general framework for modeling growth and division of mammalian cells

BackgroundModeling the cell-division cycle has been practiced for many years. As time has progressed, this work has gone from understanding the basic principles to addressing distinct biological problems, e.g., the nature of the restriction point, how checkpoints operate, the nonlinear dynamics of the cell cycle, the effect of localization, etc. Most models consist of coupled ordinary differential equations developed by the researchers, restricted to deal with the interactions of a limited number of molecules. In the future, cell-cycle modeling--and indeed all modeling of complex biologic processes--will increase in scope and detail.ResultsA framework for modeling complex cell-biologic processes is proposed here. The framework is based on two constructs: one describing the entire lifecycle of a molecule and the second describing the basic cellular machinery. Use of these constructs allows complex models to be built in a straightforward manner that fosters rigor and completeness. To demonstrate the framework, an example model of the mammalian cell cycle is presented that consists of several hundred differential equations of simple mass action kinetics. The model calculates energy usage, amino acid and nucleotide usage, membrane transport, RNA synthesis and destruction, and protein synthesis and destruction for 33 proteins to give an in-depth look at the cell cycle.ConclusionsThe framework presented here addresses how to develop increasingly descriptive models of complex cell-biologic processes. The example model of cellular growth and division constructed with the framework demonstrates that large structured models can be created with the framework, and these models can generate non-trivial descriptions of cellular processes. Predictions from the example model include those at both the molecular level--e.g., Wee1 spontaneously reactivates--and at the system level--e.g., pathways for timing-critical processes must shut down redundant pathways. A future effort is to automatically estimate parameter values that are insensitive to changes.

Exploring Human-Technology Interaction in Layered Security Military Applications

System-of-systems modeling has traditionally focused on physical systems rather than humans, but recent events have proved the necessity of considering the human in the loop. As technology becomes more complex and layered security continues to increase in importance, capturing humans and their interactions with technologies within the system-of-systems will be increasingly necessary. After an extensive job-task analysis, a novel type of system-of-systems simulation model has been created to capture the human-technology interactions on an extra-small forward operating base to better understand performance, key security drivers, and the robustness of the base. In addition to the model, an innovative framework for using detection theory to calculate d’ for individual elements of the layered security system, and for the entire security system as a whole, is under development.

Human performance modeling in system of systems analytics

The Department of Defense has identified that integrating the human element into large scale System of Systems (SoS) models is a significant challenge that remains unaddressed. Failure in doing so leads to significant limitations in our SoS analytical capabilities as human performance is a large contributor to the performance of a SoS. The primary challenge is that, in most SoS domains, the problems being analyzed are large in scale. Conversely, most Human Performance Modeling (HPM) initiatives look at integrating detailed cognitive models that capture fine grained details of human perception, decision making, and response with detailed systems models and simulations (e.g., Lebiere et al., 2003). It is not feasible to integrate such fine grained cognitive models with systems models and perform SoS scale analysis. This paper documents a capability that integrates HPM into a large scale SoS simulation toolset and demonstrates the utility of the toolset.

MODELING UNSATURATED-ZONE FLOW AT RAINIER MESA AS A POSSIBLE ANALOG FOR A FUTURE YUCCA MOUNTAIN

Rainier Mesa is structurally similar to Yucca Mountain, and receives precipitation similar to the estimated long-term average for Yucca Mountain. Tunnels through the unsaturated zone at Rainier Mesa have encountered perched water and, after the perched water was drained, flow in fractures and faults. Although flow observations have been primarily qualitative, Rainier Mesa hydrology is a potential analog for Yucca Mountain hydrology in a wetter climate. In this paper, a groundwater flow model that has been used in the performance assessment of Yucca Mountain--the weeps model--is applied to Rainier Mesa. The intent is to gain insight in both Rainier Mesa and the weeps flow model.

Modeling human-technology interaction as a sociotechnical system of systems

As system of systems (SoS) models become increasingly complex and interconnected a new approach is needed to capture the effects of humans within the SoS. Many real-life events have shown the detrimental outcomes of failing to account for humans in the loop. This research introduces a novel and cross-disciplinary methodology for modeling humans interacting with technologies to perform tasks within an SoS specifically within a layered physical security system use case. Metrics and formulations developed for this new way of looking at SoS termed sociotechnical SoS allow for the quantification of the interplay of effectiveness and efficiency seen in detection theory to measure the ability of a physical security system to detect and respond to threats. This methodology has been applied to a notional representation of a small military Forward Operating Base (FOB) as a proof-of-concept.

Operational Excellence through Schedule Optimization and Production Simulation of Application Specific Integrated Circuits.

Upcoming weapon programs require an aggressive increase in Application Specific Integrated Circuit (ASIC) production at Sandia National Laboratories (SNL). SNL has developed unique modeling and optimization tools that have been instrumental in improving ASIC production productivity and efficiency, identifying optimal operational and tactical execution plans under resource constraints, and providing confidence in successful mission execution. With ten products and unprecedented levels of demand, a single set of shared resources, highly variable processes, and the need for external supplier task synchronization, scheduling is an integral part of successful manufacturing. The scheduler uses an iterative multi-objective genetic algorithm and a multi-dimensional performance evaluator. Schedule feasibility is assessed using a discrete event simulation (DES) that incorporates operational uncertainty, variability, and resource availability. The tools provide rapid scenario assessments and responses to variances in the operational environment, and have been used to inform major equipment investments and workforce planning decisions in multiple SNL facilities.

Quantitative adaptation analytics for assessing dynamic systems of systems: LDRD Final Report

Our society is increasingly reliant on systems and interoperating collections of systems, known as systems of systems (SoS). These SoS are often subject to changing missions (e.g., nation- building, arms-control treaties), threats (e.g., asymmetric warfare, terrorism), natural environments (e.g., climate, weather, natural disasters) and budgets. How well can SoS adapt to these types of dynamic conditions? This report details the results of a three year Laboratory Directed Research and Development (LDRD) project aimed at developing metrics and methodologies for quantifying the adaptability of systems and SoS. Work products include: derivation of a set of adaptability metrics, a method for combining the metrics into a system of systems adaptability index (SoSAI) used to compare adaptability of SoS designs, development of a prototype dynamic SoS (proto-dSoS) simulation environment which provides the ability to investigate the validity of the adaptability metric set, and two test cases that evaluate the usefulness of a subset of the adaptability metrics and SoSAI for distinguishing good from poor adaptability in a SoS. Intellectual property results include three patents pending: A Method For Quantifying Relative System Adaptability, Method for Evaluating System Performance, and A Method for Determining Systems Re-Tasking.

Supply Chain Lifecycle Decision Analytics.

The globalization of todays supply chains (e.g., information and communication technologies, military systems, etc.) has created an emerging security threat that could degrade the integrity and availability of sensitive and critical government data, control systems, and infrastructures. Commercial-off-the-shelf (COTS) and even government-off-the-self (GOTS) products often are designed, developed, and manufactured overseas. Counterfeit items, from individual chips to entire systems, have been found in commercial and government sectors. Supply chain attacks can be initiated at any point during the product or system lifecycle, and can have detrimental effects to mission success. To date, there is a lack of analytics and decision support tools used to analyze supply chain security holistically, and to perform tradeoff analyses to determine how to invest in or deploy possible mitigation options for supply chain security such that the return on investment is optimal with respect to cost, efficiency, and security. This paper discusses the development of a supply chain decision analytics framework that will assist decision makers and stakeholders in performing risk-based cost-benefit prioritization of security investments to manage supply chain risk. Key aspects of our framework include the hierarchical supply chain representation, vulnerability and mitigation modeling, risk assessment and optimization. This work is a part of a long term research effort on supply chain decision analytics for trusted systems and communications research challenge.