Development of reliability methodology for systems engineering. Volume II - Application - Design reliability analysis of a 250 volt-ampere static inverter Final report

Design stage reliability analysis application to static inverte

Quantitative constraint-based computational model of tumor-to-stroma coupling via lactate shuttle

Cancer cells utilize large amounts of ATP to sustain growth, relying primarily on non-oxidative, fermentative pathways for its production. In many types of cancers this leads, even in the presence of oxygen, to the secretion of carbon equivalents (usually in the form of lactate) in the cell’s surroundings, a feature known as the Warburg effect. While the molecular basis of this phenomenon are still to be elucidated, it is clear that the spilling of energy resources contributes to creating a peculiar microenvironment for tumors, possibly characterized by a degree of toxicity. This suggests that mechanisms for recycling the fermentation products (e.g. a lactate shuttle) may be active, effectively inducing a mutually beneficial metabolic coupling between aberrant and non-aberrant cells. Here we analyze this scenario through a large-scale in silico metabolic model of interacting human cells. By going beyond the cell-autonomous description, we show that elementary physico- chemical constraints indeed favor the establishment of such a coupling under very broad conditions. The characterization we obtained by tuning the aberrant cell’s demand for ATP, amino-acids and fatty acids and/or the imbalance in nutrient partitioning provides quantitative support to the idea that synergistic multi-cell effects play a central role in cancer sustainmen

Evolution of adaptation mechanisms: adaptation energy, stress, and oscillating death

In 1938, H. Selye proposed the notion of adaptation energy and published "Experimental evidence supporting the conception of adaptation energy". Adaptation of an animal to different factors appears as the spending of one resource. Adaptation energy is a hypothetical extensive quantity spent for adaptation. This term causes much debate when one takes it literally, as a physical quantity, i.e. a sort of energy. The controversial points of view impede the systematic use of the notion of adaptation energy despite experimental evidence. Nevertheless, the response to many harmful factors often has general non-specific form and we suggest that the mechanisms of physiological adaptation admit a very general and nonspecific description. We aim to demonstrate that Selye's adaptation energy is the cornerstone of the top-down approach to modelling of non-specific adaptation processes. We analyse Selye's axioms of adaptation energy together with Goldstone's modifications and propose a series of models for interpretation of these axioms. {\em Adaptation energy is considered as an internal coordinate on the `dominant path' in the model of adaptation}. The phenomena of `oscillating death' and `oscillating remission' are predicted on the base of the dynamical models of adaptation. Natural selection plays a key role in the evolution of mechanisms of physiological adaptation. We use the fitness optimization approach to study of the distribution of resources for neutralization of harmful factors, during adaptation to a multifactor environment, and analyse the optimal strategies for different systems of factors

How enzyme economy shapes metabolic fluxes

Metabolic fluxes are governed by physical and economic principles. Stationarity constrains them to a subspace in flux space and thermodynamics makes them lead from higher to lower chemical potentials. At the same time, fluxes in cells represent a compromise between metabolic performance and enzyme cost. To capture this, some flux prediction methods penalise larger fluxes by heuristic cost terms. Economic flux analysis, in contrast, postulates a balance between enzyme costs and metabolic benefits as a necessary condition for fluxes to be realised by kinetic models with optimal enzyme levels. The constraints are formulated using economic potentials, state variables that capture the enzyme labour embodied in metabolites. Generally, fluxes must lead from lower to higher economic potentials. This principle, which resembles thermodynamic constraints, can complement stationarity and thermodynamic constraints in flux analysis. Futile modes, which would be incompatible with economic potentials, are defined algebraically and can be systematically removed from flux distributions. Enzymes that participate in potential futile modes are likely targets of regulation. Economic flux analysis can predict high-yield and low-yield strategies, and captures preemptive expression, multi-objective optimisation, and flux distributions across several cells living in symbiosis. Inspired by labour value theories in economics, it justifies and extends the principle of minimal fluxes and provides an intuitive framework to model the complex interplay of fluxes, metabolic control, and enzyme costs in cells