13,244 research outputs found
Preface
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Preface
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On the foundations of cancer modelling: selected topics, speculations, & perspectives
This paper presents a critical review of selected topics related to the modelling of cancer onset, evolution and growth, with the aim of illustrating, to a wide applied mathematical readership, some of the novel mathematical problems in the field. This review attempts to capture, from the appropriate literature, the main issues involved in the modelling of phenomena related to cancer dynamics at all scales which characterise this highly complex system: from the molecular scale up to that of tissue. The last part of the paper discusses the challenge of developing a mathematical biological theory of tumour onset and evolution
Agent-based modeling: a systematic assessment of use cases and requirements for enhancing pharmaceutical research and development productivity.
A crisis continues to brew within the pharmaceutical research and development (R&D) enterprise: productivity continues declining as costs rise, despite ongoing, often dramatic scientific and technical advances. To reverse this trend, we offer various suggestions for both the expansion and broader adoption of modeling and simulation (M&S) methods. We suggest strategies and scenarios intended to enable new M&S use cases that directly engage R&D knowledge generation and build actionable mechanistic insight, thereby opening the door to enhanced productivity. What M&S requirements must be satisfied to access and open the door, and begin reversing the productivity decline? Can current methods and tools fulfill the requirements, or are new methods necessary? We draw on the relevant, recent literature to provide and explore answers. In so doing, we identify essential, key roles for agent-based and other methods. We assemble a list of requirements necessary for M&S to meet the diverse needs distilled from a collection of research, review, and opinion articles. We argue that to realize its full potential, M&S should be actualized within a larger information technology framework--a dynamic knowledge repository--wherein models of various types execute, evolve, and increase in accuracy over time. We offer some details of the issues that must be addressed for such a repository to accrue the capabilities needed to reverse the productivity decline
Multiscale metabolic modeling of C4 plants: connecting nonlinear genome-scale models to leaf-scale metabolism in developing maize leaves
C4 plants, such as maize, concentrate carbon dioxide in a specialized
compartment surrounding the veins of their leaves to improve the efficiency of
carbon dioxide assimilation. Nonlinear relationships between carbon dioxide and
oxygen levels and reaction rates are key to their physiology but cannot be
handled with standard techniques of constraint-based metabolic modeling. We
demonstrate that incorporating these relationships as constraints on reaction
rates and solving the resulting nonlinear optimization problem yields realistic
predictions of the response of C4 systems to environmental and biochemical
perturbations. Using a new genome-scale reconstruction of maize metabolism, we
build an 18000-reaction, nonlinearly constrained model describing mesophyll and
bundle sheath cells in 15 segments of the developing maize leaf, interacting
via metabolite exchange, and use RNA-seq and enzyme activity measurements to
predict spatial variation in metabolic state by a novel method that optimizes
correlation between fluxes and expression data. Though such correlations are
known to be weak in general, here the predicted fluxes achieve high correlation
with the data, successfully capture the experimentally observed base-to-tip
transition between carbon-importing tissue and carbon-exporting tissue, and
include a nonzero growth rate, in contrast to prior results from similar
methods in other systems. We suggest that developmental gradients may be
particularly suited to the inference of metabolic fluxes from expression data.Comment: 57 pages, 14 figures; submitted to PLoS Computational Biology; source
code available at http://github.com/ebogart/fluxtools and
http://github.com/ebogart/multiscale_c4_sourc
Characterizing neuromorphologic alterations with additive shape functionals
The complexity of a neuronal cell shape is known to be related to its
function. Specifically, among other indicators, a decreased complexity in the
dendritic trees of cortical pyramidal neurons has been associated with mental
retardation. In this paper we develop a procedure to address the
characterization of morphological changes induced in cultured neurons by
over-expressing a gene involved in mental retardation. Measures associated with
the multiscale connectivity, an additive image functional, are found to give a
reasonable separation criterion between two categories of cells. One category
consists of a control group and two transfected groups of neurons, and the
other, a class of cat ganglionary cells. The reported framework also identified
a trend towards lower complexity in one of the transfected groups. Such results
establish the suggested measures as an effective descriptors of cell shape
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