A combined model reduction algorithm for controlled biochemical systems

Background: Systems Biology continues to produce increasingly large models of complex biochemical reaction networks. In applications requiring, for example, parameter estimation, the use of agent-based modelling approaches, or real-time simulation, this growing model complexity can present a significant hurdle. Often, however, not all portions of a model are of equal interest in a given setting. In such situations methods of model reduction offer one possible approach for addressing the issue of complexity by seeking to eliminate those portions of a pathway that can be shown to have the least effect upon the properties of interest. Methods: In this paper a model reduction algorithm bringing together the complementary aspects of proper lumping and empirical balanced truncation is presented. Additional contributions include the development of a criterion for the selection of state-variable elimination via conservation analysis and use of an ‘averaged’ lumping inverse. This combined algorithm is highly automatable and of particular applicability in the context of ‘controlled’ biochemical networks. Results: The algorithm is demonstrated here via application to two examples; an 11 dimensional model of bacterial chemotaxis in Escherichia coli and a 99 dimensional model of extracellular regulatory kinase activation (ERK) mediated via the epidermal growth factor (EGF) and nerve growth factor (NGF) receptor pathways. In the case of the chemotaxis model the algorithm was able to reduce the model to 2 state-variables producing a maximal relative error between the dynamics of the original and reduced models of only 2.8% whilst yielding a 26 fold speed up in simulation time. For the ERK activation model the algorithm was able to reduce the system to 7 state-variables, incurring a maximal relative error of 4.8%, and producing an approximately 10 fold speed up in the rate of simulation. Indices of controllability and observability are additionally developed and demonstrated throughout the paper. These provide insight into the relative importance of individual reactants in mediating a biochemical system’s input-output response even for highly complex networks. Conclusions: Through application, this paper demonstrates that combined model reduction methods can produce a significant simplification of complex Systems Biology models whilst retaining a high degree of predictive accuracy. In particular, it is shown that by combining the methods of proper lumping and empirical balanced truncation it is often possible to produce more accurate reductions than can be obtained by the use of either method in isolation

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention

Errors in Judicial Decisions

In criminal cases the task of the judge is to transform the uncertainty about the facts into the certainty of the verdict. In this experiment we examine the relationship between evidence of which the strength is known, subjective probability of guilt and verdict for abstract cases. We look at two situations: (1) all evidence is given and (2) evidence can be acquired. Roughly half of the participants do not base their decision on a subjective belief of the probability of guilt. The others underestimate in general the probability of guilt, but this is more than compensated by a tendency to convict at too low probability of guilt. In the situation where evidence can be acquired, participants do not acquire enough evidence

O cuidado de enfermagem como prática empreendedora: oportunidades e possibilidades

OBJETIVOS: Compreender o significado do cuidado de enfermagem como prática social empreendedora. MÉTODOS: Foi baseada na Grounded Theory que, de forma sistemática, criativa e interativa possibilitou o desenvolvimento da teoria: "Vislumbrando o cuidado de enfermagem como prática social empreendedora". Amostra teórica constituiu-se de 35 sujeitos entrevistados, distribuídos em diferentes grupos amostrais. RESULTADOS: O cuidado de enfermagem como prática social empreendedora está associado ao sistema de relações e interações, à capacidade de interagir com os diferentes atores sociais, na capacidade de criar novos canais de comunicação e ações pró-ativas. CONCLUSÃO: A partir do cuidado como prática social empreendedora é possível atuar de forma pró-ativa, inovadora e participativa, sem desconsiderar as contradições sociais emergentes.OBJETIVO: Comprender el significado y desarrollar una teoría sustantiva sobre el cuidado de enfermería como una práctica social emprendedora. METODOS: Se basó en la Grounded Theory que, como un proceso sistemático, creativo e interactivo permitió el desarrollo de la teoría sustantiva: "Vislumbrando el cuidado de enfermería como una práctica social emprendedora". La muestra teórica estuvo constituida por treinta y cinco entrevistados distribuidos en diferentes grupos de muestras. RESULTADOS: El cuidado de enfermería como una práctica social emprendedora se asocia con el sistema de relaciones e interacciones, con la capacidad de interactuar con diferentes actores sociales y, con la capacidad de crear nuevos canales de comunicación y de acciones proactivas. CONCLUSIÓN: A partir del cuidado como una práctica emprendedora es posible actuar de manera proactiva, innovadora y participativa, sin dejar de lado las contradicciones sociales emergentes.OBJECTIVE: To understand the meaning and to develop a substantive theory about nursing care as an enterprising social practice. The METHODS: Was based on the Grounded Theory which, in a systematic, creative and interactive manner allowed the development of the substantive theory: "Realizing the nursing care as an enterprising social practice." The theoretical sample consisted of thirty-five subjects distributed among different groups of samples. RESULTS: The nursing care as an enterprising social practice is associated with the system of relationships and interactions, the ability to interact with different social actors and, the ability to create new channels of communication and proactive actions. CONCLUSION: Considering the care as an enterprising practice is possible to act in a proactive, innovative and participatory way, without neglecting the emerging aspects of social contradictions

Global reward state affects learning and activity in raphe nucleus and anterior insula in monkeys

202009 bcrcVersion of RecordPublishe