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Search Results: 1 - 10 of 208582 matches for " Alexander G. Fletcher "
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Multiscale modelling of intestinal crypt organization and carcinogenesis
Alexander G. Fletcher,Philip J. Murray,Philip K. Maini
Quantitative Biology , 2015,
Abstract: Colorectal cancers are the third most common type of cancer. They originate from intestinal crypts, glands that descend from the intestinal lumen into the underlying connective tissue. Normal crypts are thought to exist in a dynamic equilibrium where the rate of cell production at the base of a crypt is matched by that of loss at the top. Understanding how genetic alterations accumulate and proceed to disrupt this dynamic equilibrium is fundamental to understanding the origins of colorectal cancer. Colorectal cancer emerges from the interaction of biological processes that span several spatial scales, from mutations that cause inappropriate intracellular responses to changes at the cell/tissue level, such as uncontrolled proliferation and altered motility and adhesion. Multiscale mathematical modelling can provide insight into the spatiotemporal organisation of such a complex, highly regulated and dynamic system. Moreover, the aforementioned challenges are inherent to the multiscale modelling of biological tissue more generally. In this review we describe the mathematical approaches that have been applied to investigate multiscale aspects of crypt behaviour, highlighting a number of model predictions that have since been validated experimentally. We also discuss some of the key mathematical and computational challenges associated with the multiscale modelling approach. We conclude by discussing recent efforts to derive coarse-grained descriptions of such models, which may offer one way of reducing the computational cost of simulation by leveraging well-established tools of mathematical analysis to address key problems in multiscale modelling.
Mathematical modeling of the metastatic process
Jacob G. Scott,Philip Gerlee,David Basanta,Alexander G. Fletcher,Philip K. Maini,Alexander RA Anderson
Quantitative Biology , 2013,
Abstract: Mathematical modeling in cancer has been growing in popularity and impact since its inception in 1932. The first theoretical mathematical modeling in cancer research was focused on understanding tumor growth laws and has grown to include the competition between healthy and normal tissue, carcinogenesis, therapy and metastasis. It is the latter topic, metastasis, on which we will focus this short review, specifically discussing various computational and mathematical models of different portions of the metastatic process, including: the emergence of the metastatic phenotype, the timing and size distribution of metastases, the factors that influence the dormancy of micrometastases and patterns of spread from a given primary tumor.
A filter-flow perspective of hematogenous metastasis offers a non-genetic paradigm for personalized cancer therapy
Jacob G. Scott,Alexander G. Fletcher,Philip K. Maini,Alexander R. A. Anderson,Philip Gerlee
Quantitative Biology , 2013,
Abstract: Research into mechanisms of hematogenous metastasis has largely become genetic in focus, attempting to understand the molecular basis of `seed-soil' relationships. Preceeding this biological mechanism is the physical process of dissemination of circulating tumour cells (CTCs). We utilize a `filter-flow' paradigm to show that assumptions about CTC dynamics strongly affect metastatic efficiency: without data on CTC dynamics, any attempt to predict metastatic spread in individual patients is impossible.
Spatial Metrics of Tumour Vascular Organisation Predict Radiation Efficacy in a Computational Model
Jacob G. Scott?,Alexander G. Fletcher,Alexander R. A. Anderson?,Philip K. Maini
PLOS Computational Biology , 2016, DOI: 10.1371/journal.pcbi.1004712
Abstract: Intratumoural heterogeneity is known to contribute to poor therapeutic response. Variations in oxygen tension in particular have been correlated with changes in radiation response in vitro and at the clinical scale with overall survival. Heterogeneity at the microscopic scale in tumour blood vessel architecture has been described, and is one source of the underlying variations in oxygen tension. We seek to determine whether histologic scale measures of the erratic distribution of blood vessels within a tumour can be used to predict differing radiation response. Using a two-dimensional hybrid cellular automaton model of tumour growth, we evaluate the effect of vessel distribution on cell survival outcomes of simulated radiation therapy. Using the standard equations for the oxygen enhancement ratio for cell survival probability under differing oxygen tensions, we calculate average radiation effect over a range of different vessel densities and organisations. We go on to quantify the vessel distribution heterogeneity and measure spatial organization using Ripley’s L function, a measure designed to detect deviations from complete spatial randomness. We find that under differing regimes of vessel density the correlation coefficient between the measure of spatial organization and radiation effect changes sign. This provides not only a useful way to understand the differences seen in radiation effect for tissues based on vessel architecture, but also an alternate explanation for the vessel normalization hypothesis.
Capabilities and Limitations of Tissue Size Control through Passive Mechanical Forces
Jochen Kursawe?,Pavel A. Brodskiy?,Jeremiah J. Zartman?,Ruth E. Baker?,Alexander G. Fletcher
PLOS Computational Biology , 2015, DOI: 10.1371/journal.pcbi.1004679
Abstract: Embryogenesis is an extraordinarily robust process, exhibiting the ability to control tissue size and repair patterning defects in the face of environmental and genetic perturbations. The size and shape of a developing tissue is a function of the number and size of its constituent cells as well as their geometric packing. How these cellular properties are coordinated at the tissue level to ensure developmental robustness remains a mystery; understanding this process requires studying multiple concurrent processes that make up morphogenesis, including the spatial patterning of cell fates and apoptosis, as well as cell intercalations. In this work, we develop a computational model that aims to understand aspects of the robust pattern repair mechanisms of the Drosophila embryonic epidermal tissues. Size control in this system has previously been shown to rely on the regulation of apoptosis rather than proliferation; however, to date little work has been done to understand the role of cellular mechanics in this process. We employ a vertex model of an embryonic segment to test hypotheses about the emergence of this size control. Comparing the model to previously published data across wild type and genetic perturbations, we show that passive mechanical forces suffice to explain the observed size control in the posterior (P) compartment of a segment. However, observed asymmetries in cell death frequencies across the segment are demonstrated to require patterning of cellular properties in the model. Finally, we show that distinct forms of mechanical regulation in the model may be distinguished by differences in cell shapes in the P compartment, as quantified through experimentally accessible summary statistics, as well as by the tissue recoil after laser ablation experiments.
Steering Evolution with Sequential Therapy to Prevent the Emergence of Bacterial Antibiotic Resistance
Daniel Nichol?,Peter Jeavons?,Alexander G. Fletcher,Robert A. Bonomo?,Philip K. Maini?,Jerome L. Paul?,Robert A. Gatenby?,Alexander R.A. Anderson?,Jacob G. Scott
PLOS Computational Biology , 2015, DOI: 10.1371/journal.pcbi.1004493
Abstract: The increasing rate of antibiotic resistance and slowing discovery of novel antibiotic treatments presents a growing threat to public health. Here, we consider a simple model of evolution in asexually reproducing populations which considers adaptation as a biased random walk on a fitness landscape. This model associates the global properties of the fitness landscape with the algebraic properties of a Markov chain transition matrix and allows us to derive general results on the non-commutativity and irreversibility of natural selection as well as antibiotic cycling strategies. Using this formalism, we analyze 15 empirical fitness landscapes of E. coli under selection by different β-lactam antibiotics and demonstrate that the emergence of resistance to a given antibiotic can be either hindered or promoted by different sequences of drug application. Specifically, we demonstrate that the majority, approximately 70%, of sequential drug treatments with 2–4 drugs promote resistance to the final antibiotic. Further, we derive optimal drug application sequences with which we can probabilistically ‘steer’ the population through genotype space to avoid the emergence of resistance. This suggests a new strategy in the war against antibiotic–resistant organisms: drug sequencing to shepherd evolution through genotype space to states from which resistance cannot emerge and by which to maximize the chance of successful therapy.
Novel Methods for Analysing Bacterial Tracks Reveal Persistence in Rhodobacter sphaeroides
Gabriel Rosser,Alexander G. Fletcher ,David A. Wilkinson,Jennifer A. de Beyer,Christian A. Yates,Judith P. Armitage,Philip K. Maini,Ruth E. Baker
PLOS Computational Biology , 2013, DOI: 10.1371/journal.pcbi.1003276
Abstract: Tracking bacteria using video microscopy is a powerful experimental approach to probe their motile behaviour. The trajectories obtained contain much information relating to the complex patterns of bacterial motility. However, methods for the quantitative analysis of such data are limited. Most swimming bacteria move in approximately straight lines, interspersed with random reorientation phases. It is therefore necessary to segment observed tracks into swimming and reorientation phases to extract useful statistics. We present novel robust analysis tools to discern these two phases in tracks. Our methods comprise a simple and effective protocol for removing spurious tracks from tracking datasets, followed by analysis based on a two-state hidden Markov model, taking advantage of the availability of mutant strains that exhibit swimming-only or reorientating-only motion to generate an empirical prior distribution. Using simulated tracks with varying levels of added noise, we validate our methods and compare them with an existing heuristic method. To our knowledge this is the first example of a systematic assessment of analysis methods in this field. The new methods are substantially more robust to noise and introduce less systematic bias than the heuristic method. We apply our methods to tracks obtained from the bacterial species Rhodobacter sphaeroides and Escherichia coli. Our results demonstrate that R. sphaeroides exhibits persistence over the course of a tumbling event, which is a novel result with important implications in the study of this and similar species.
Heat Shock Protein 27 Is Spatially Distributed in the Human Placenta and Decreased during Labor
Akrem Abdulsid, Alexander Fletcher, Fiona Lyall
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0071127
Abstract: Placental oxidative stress is a feature of human labor. Heat shock proteins (HSPs) play a key role in cellular stress. We hypothesized that placental expression of the small HSP 27 would be altered during labor and expression would vary in different regions of the placenta. Six women in labor who delivered vaginally and 6 women not in labor, who were delivered by Cesarean section, were recruited. Four equally spaced pieces were sampled from the inner, middle and outer regions of each placenta (total 12 samples per placenta). HSP 27 expression was investigated by Western blot analysis and RT-PCR. For non-labor, there was less HSP 27 protein in the inner placenta region compared with both the middle region (p<0.05) and outer region (p<0.05). For labor, there was also less HSP 27 protein in the inner region compared with both the middle (p<0.02) and outer region (p<0.01). When the 3 regions of the placenta were compared for non-labor versus labor there was less HSP 27 in the labor group at both the inner (p<0.05) and middle regions (p<0.005) compared to non-labor. Similar to HSP 27 protein, there was less HSP 27 mRNA in the labor group in both the inner region (p<0.05) and middle region (p<0.02) compared to non-labor. This study suggests that placental HSP 27 may play a role in labor and is spatially controlled. The results have important implications for how data obtained from studies in the placenta can be influenced by sampling methods.
Propagation of Alfvénic Waves From Corona to Chromosphere and Consequences for Solar Flares
Alexander J. B. Russell,Lyndsay Fletcher
Physics , 2013, DOI: 10.1088/0004-637X/765/2/81
Abstract: How do magnetohydrodynamic waves travel from the fully ionized corona, into and through the underlying partially ionized chromosphere, and what are the consequences for solar flares? To address these questions, we have developed a 2-fluid model (of plasma and neutrals) and used it to perform 1D simulations of Alfv\'en waves in a solar atmosphere with realistic density and temperature structure. Studies of a range of solar features (faculae, plage, penumbra and umbra) show that energy transmission from corona to chromosphere can exceed 20% of incident energy for wave periods of one second or less. Damping of waves in the chromosphere depends strongly on wave frequency: waves with periods 10 seconds or longer pass through the chromosphere with relatively little damping, however, for periods of 1 second or less, a substantial fraction (37%-100%) of wave energy entering the chromosphere is damped by ion-neutral friction in the mid and upper chromosphere, with electron resistivity playing some role in the lower chromosphere and in umbras. We therefore conclude that Alfv\'enic waves with periods of a few seconds or less are capable of heating the chromosphere during solar flares, and speculate that they could also contribute to electron acceleration or exciting sunquakes.
Challenge and Opportunity: the ALI/III Global Principles Project
IF Fletcher
Potchefstroom Electronic Law Journal/Potchefstroomse Elektroniese Regsblad , 2008,
Abstract: This article deals with an international project to establish the extent to which it is feasible to achieve a worldwide acceptance of the Principles of Cooperation among the NAFTA Countries together with the Guidelines Applicable to Court-to-Court Communications in Cross-Border Cases. This contribution explains the process whereby the American Law Institute and the International Insolvency Institute (1) developed principles of cooperation with regard to cross-border insolvency; (2) established acceptance of these principles in jurisdictions across the world, subject to any necessary local modifications; and (3) obtained the endorsement of leading domestic associations, courts, and other groups in those jurisdictions. This article may contribute to the development the South African cross-border insolvency law. The inclusion of the challenges of harmonisation of private international law is also contributing to current debate. PER/PELJ Vol. 1 2008: pp. 1-28
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