A theoretical investigation of the effect of proliferation & adhesion on monoclonal conversion in the colonic crypt

The surface epithelium lining the intestinal tract renews itself rapidly by a coordinated programme of cell proliferation, migration and differentiation events that is initiated in the crypts of Lieberkühn. It is generally believed that colorectal cancer arises due to mutations that disrupt the normal cellular dynamics of the crypts. Using a spatially structured cell-based model of a colonic crypt, we investigate the likelihood that the progeny of a mutated cell will dominate, or be sloughed out of, a crypt. Our approach is to perform multiple simulations, varying the spatial location of the initial mutation, and the proliferative and adhesive properties of the mutant cells, to obtain statistical distributions for the probability of their domination. Our simulations lead us to make a number of predictions. The process of monoclonal conversion always occurs, and does not require that the cell which initially gave rise to the population remains in the crypt. Mutations occurring more than one to two cells from the base of the crypt are unlikely to become the dominant clone. The probability of a mutant clone persisting in the crypt is sensitive to dysregulation of adhesion. By comparing simulation results with those from a simple one-dimensional stochastic model of population dynamics at the base of the crypt, we infer that this sensitivity is due to direct competition between wild-type and mutant cells at the base of the crypt. We also predict that increases in the extent of the spatial domain in which the mutant cells proliferate can give rise to counter-intuitive, non-linear changes to the probability of their fixation, due to effects that cannot be captured in simpler models

A theoretical investigation of the effect of proliferation and\ud adhesion on monoclonal conversion in the colonic crypt

Colorectal cancers are initiated by the accumulation of mutations in the colonic epithelium. Using a spatially structured cell-based model of a colonic crypt, we investigate the likelihood that the progeny of a mutated cell will dominate, or be sloughed out of, a crypt. Our approach is to perform multiple simulations, varying the spatial location of the initial mutation, and its proliferative and adhesive properties, to obtain statistical distributions for the probability of domination. Our simulations lead us to make a number of predictions. The process of monoclonal conversion always occurs, and does not require that the cell which initially gave rise to the population remains in the crypt. Mutations occurring more than one to two cells from the base of the crypt are unlikely to become the dominant clone. The probability of a mutant clone persisting in the crypt is sensitive to dysregulation of adhesion, and comparison with a one-dimensional model suggests that this is caused by competition directly at the base of the crypt.\ud We also predict that increases in the extent of the spatial domain in which the mutant cells proliferate cause counter-intuitive non-linear changes to the probability of its fixation, due to effects that cannot be captured in simpler models

A note on heat and mass transfer from a sphere in Stokes\ud flow at low Péclet number

We consider the low Péclet number, Pe ≪ 1, asymptotic solution for steady-state heat and mass transfer from a sphere immersed in Stokes flow with a Robin boundary condition on its surface, representing Newton cooling or a first-order chemical reaction. The application of van Dyke’s rule up to terms of O(Pe3) shows that the O(Pe3 log Pe) terms in the expression for the average Nusselt/Sherwood number are double those previously derived in the literature. Inclusion of the O(Pe3) terms is shown to increase significantly the range of validity of the expansion

Medical Malpractice Law

Health care reform took center stage on a national level overthe past year. Despite suggestions that medical liability reform might be incorporated into the federal legislation, in the end, it was not. Similarly, this year saw few legislative developments at the state level in medical malpractice law, as the Virginia General Assembly focused its energy primarily on the budget shortfall and other issues. There were, however, several health care legislative and case developments of note which will impact the medical liability landscape in the coming years. Board of Medicine activity and medical malpractice trial results of interest are also highlighted as we look back at the year\u27s noteworthy legal developments in Virginia medical malpractice law

The perception and management of risk in UK office property development

Risk is an ever-present aspect of business, and risk taking is necessary for profit and economic progress. Speculative property development is popularly perceived as a 'risky business' yet, like other entrepreneurs, developers have opportunities to manage the risks they face; techniques include phasing and joint ventures. The associated areas of investment portfolio risk, development risk analysis and construction risk management have all been addressed by research. This article presents new knowledge about how developers perceive risks and the means they subsequently adopt to manage them. The developers of office projects across the UK were sent questionnaires by post. Respondents were asked about their perceptions of risks at the first appraisal stage and currently and about the risk management techniques that they had adopted. In-depth interviews with a selection of respondents were then used to discuss and augment the findings. Developers were most concerned about market-based risks at both stages. Concern about production-orientated risks was lower and fell significantly between the two stages. A fixed price contract was the most common risk management technique. Risk management techniques were used more often outside London and the South East. Developer type affects both the perception and management of risk. While developers do manage risk, decisions are made on the basis of professional and business experience. These findings should help development companies manage risk in a more objective and analytical way

Modelling spatially regulated B-catenin dynamics & invasion in intestinal crypts

Experimental data (e.g., genetic lineage and cell population studies) on intestinal crypts reveal that regulatory features of crypt behavior, such as control via morphogen gradients, are remarkably well conserved among numerous organisms (e.g., from mouse and rat to human) and throughout the different regions of the small and large intestines. In this article, we construct a partial differential equation model of a single colonic crypt that describes the spatial distribution of Wnt pathway proteins along the crypt axis. The novelty of our continuum model is that it is based upon assumptions that can be directly related to processes at the cellular and subcellular scales. We use the model to predict how the distributions of Wnt pathway proteins are affected by mutations. The model is then extended to investigate how mutant cell populations can invade neighboring crypts. The model simulations suggest that cell crowding caused by increased proliferation and decreased cell loss may be sufficient for a mutant cell population to colonize a neighboring healthy crypt

Evidence for Accretion in the High-resolution X-ray Spectrum of the T Tauri Star System Hen 3-600

We present high-resolution X-ray spectra of the multiple T Tauri star system Hen 3-600, obtained with the High Energy Transmission Grating Spectrograph on the Chandra X-ray Observatory. Two binary components were detected in the zeroth-order image. Hen 3-600-A, which has a large mid-infrared excess, is a 2-3 times fainter in X-rays than Hen 3-600-B, due to a large flare on B. The dispersed X-ray spectra of the two primary components overlap spatially; spectral analysis was performed on the combined system. Analysis of the individual spectra was limited to regions where the contributions of A and B can be disentangled. This analysis results in two lines of evidence indicating that the X-ray emission from Hen 3-600 is derived from accretion processes: line ratios of O VII indicate that the characteristic density of its X-ray-emitting plasma is large; a significant component of low-temperature plasma is present and is stronger in component A. These results are consistent with results obtained from X-ray gratings spectroscopy of more rapidly accreting systems. All of the signatures of Hen 3-600 that are potential diagnostics of accretion activity -- X-ray emission, UV excess, H-alpha emission, and weak infrared excess -- suggest that its components represent a transition phase between rapidly accreting, classical T Tauri stars and non-accreting, weak-lined T Tauri stars.Comment: latex, 27 pages, 12 figures, 6 tables; accepted by Ap

Prevalence of sulfonamide resistance genes in bacterial isolates from manured agricultural soils and pig slurry in the United Kingdom

Prevalence of three sulfonamide resistance genes, sul1, sul2 and sul3 and sulfachloropyridazine (SCP) resistance was determined in bacteria isolated from UK manured agricultural clay soils and slurry samples, over a two year period. Slurry from tylosin-fed pigs amended with SCP and oxytetracycline (OTC) was used for manuring. Sul gene positive isolates were further screened for the presence of class 1 and 2 integrons. Phenotypic resistance to SCP was significantly higher in pig slurry and post application soil than in pre-application soil. Of 5isolates, 23 % carried sul1, 18 % sul2 and 9 % sul3 only. Two percent of isolates contained all three sul genes. Class 1 and class 2 integrons were identified in 5 % and 11.7 % of sul positive isolates. In previous reports, sul1 was linked to class 1 integrons, but in this study only 8 % of sul1 positive isolates carried the intI1 gene. Sulfonamide resistant pathogens were identified in slurry amended soil and soil leachate, including Shigella flexneri, Aerococcus spp. and Acinetobacter baumanni, suggesting a potential environmental reservoir. Sulfonamide resistance in Psychrobacter, Enterococcus and Bacillus spp. is reported for the first time, and this study also provides the first description of the genotype sul1, sul2 and sul3 outside the Enterobacteriacae, and in the soil environment

Integron prevalence and diversity in manured soil

Integron abundance and diversity were studied in soil amended with pig slurry. Real-time PCR illustrated a significant increase in class 1 integron prevalence post slurry-application with increased prevalence still evident at 10 months post-application. Culture dependent data revealed 10 genera, including putative human pathogens, carrying class 1 and 2 integrons