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

Disruptive Innovations and Disruptive Assurance: Assuring Machine Learning and Autonomy

Autonomous and machine learning-based systems are disruptive innovations and thus require a corresponding disruptive assurance strategy. We offer an overview of a framework based on claims, arguments, and evidence aimed at addressing these systems and use it to identify specific gaps, challenges, and potential solutions

Implementing vertex dynamics models of cell populations in biology within a consistent computational framework

The dynamic behaviour of epithelial cell sheets plays a central role during development, growth, disease and wound healing. These processes occur as a result of cell adhesion, migration, division, differentiation and death, and involve multiple processes acting at the cellular and molecular level. Computational models offer a useful means by which to investigate and test hypotheses about these processes, and have played a key role in the study of cell–cell interactions. However, the necessarily complex nature of such models means that it is difficult to make accurate comparison between different models, since it is often impossible to distinguish between differences in behaviour that are due to the underlying model assumptions, and those due to differences in the in silico implementation of the model. In this work, an approach is described for the implementation of vertex dynamics models, a discrete approach that represents each cell by a polygon (or polyhedron) whose vertices may move in response to forces. The implementation is undertaken in a consistent manner within a single open source computational framework, Chaste, which comprises fully tested, industrial-grade software that has been developed using an agile approach. This framework allows one to easily change assumptions regarding force generation and cell rearrangement processes within these models. The versatility and generality of this framework is illustrated using a number of biological examples. In each case we provide full details of all technical aspects of our model implementations, and in some cases provide extensions to make the models more generally applicable

The optical transmission spectrum of the hot Jupiter HAT-P-32b: clouds explain the absence of broad spectral features?

We report Gemini-North GMOS observations of the inflated hot Jupiter HAT-P-32b during two primary transits. We simultaneously observed two comparison stars and used differential spectro-photometry to produce multi-wavelength light curves. 'White' light curves and 29 'spectral' light curves were extracted for each transit and analysed to refine the system parameters and produce transmission spectra from 520-930nm in ~14nm bins. The light curves contain time-varying white noise as well as time-correlated noise, and we used a Gaussian process model to fit this complex noise model. Common mode corrections derived from the white light curve fits were applied to the spectral light curves which significantly improved our precision, reaching typical uncertainties in the transit depth of ~2x10^-4, corresponding to about half a pressure scale height. The low resolution transmission spectra are consistent with a featureless model, and we can confidently rule out broad features larger than about one scale height. The absence of Na/K wings or prominent TiO/VO features is most easily explained by grey absorption from clouds in the upper atmosphere, masking the spectral features. However, we cannot confidently rule out clear atmosphere models with low abundances (~10^-3 solar) of TiO, VO or even metal hydrides masking the Na and K wings. A smaller scale height or ionisation could also contribute to muted spectral features, but alone are unable to to account for the absence of features reported here.Comment: 17 pages, 11 figures, 2 tables, accepted for publication in MNRA

A Gemini ground-based transmission spectrum of WASP-29b: a featureless spectrum from 515 to 720nm

We report Gemini-South GMOS observations of the exoplanet system WASP-29 during primary transit as a test case for differential spectrophotometry. We use the multi-object spectrograph to observe the target star and a comparison star simultaneously to produce multiple light curves at varying wavelengths. The 'white' light curve and fifteen 'spectral' light curves are analysed to refine the system parameters and produce a transmission spectrum from 515 to 720nm. All light curves exhibit time-correlated noise, which we model using a variety of techniques. These include a simple noise rescaling, a Gaussian process model, and a wavelet based method. These methods all produce consistent results, although with different uncertainties. The precision of the transmission spectrum is improved by subtracting a common signal from all the spectral light curves, reaching a typical precision of ~1x10^-4 in transit depth. The transmission spectrum is free of spectral features, and given the non-detection of a pressure broadened Na feature, we can rule out the presence of a Na rich atmosphere free of clouds or hazes, although we cannot rule out a narrow Na core. This indicates that Na is not present in the atmosphere, and/or that clouds/hazes play a significant role in the atmosphere and mask the broad wings of the Na feature, although the former is a more likely explanation given WASP-29b's equilibrium temperature of ~970 K, at which Na can form various compounds. We also briefly discuss the use of Gaussian process and wavelet methods to account for time correlated noise in transit light curves.Comment: 15 pages, 9 figures, 3 tables. Published in MNRAS. Figure 2 corrected in version

Trajectories in the Context of the Quantum Newton's Law

In this paper, we apply the one dimensional quantum law of motion, that we recently formulated in the context of the trajectory representation of quantum mechanics, to the constant potential, the linear potential and the harmonic oscillator. In the classically allowed regions, we show that to each classical trajectory there is a family of quantum trajectories which all pass through some points constituting nodes and belonging to the classical trajectory. We also discuss the generalization to any potential and give a new definition for de Broglie's wavelength in such a way as to link it with the length separating adjacent nodes. In particular, we show how quantum trajectories have as a limit when $\hbar \to 0$ the classical ones. In the classically forbidden regions, the nodal structure of the trajectories is lost and the particle velocity rapidly diverges.Comment: 17 pages, LateX, 6 eps figures, minor modifications, Title changed, to appear in Physica Script

Observations of Reconnection Flows in a Flare on the Solar Disk

Magnetic reconnection is a well-accepted part of the theory of solar eruptive events, though the evidence is still circumstantial. Intrinsic to the reconnection picture of a solar eruptive event, particularly in the standard model for two-ribbon flares ("CSHKP" model), are an advective flow of magnetized plasma into the reconnection region, expansion of field above the reconnection region as a flux rope erupts, retraction of heated post-reconnection loops, and downflows of cooling plasma along those loops. We report on a unique set of SDO/AIA imaging and Hinode/EIS spectroscopic observations of the disk flare SOL2016-03-23T03:54 in which all four flows are present simultaneously. This includes spectroscopic evidence for a plasma upflow in association with large-scale expanding closed inflow field. The reconnection inflows are symmetric, and consistent with fast reconnection, and the post-reconnection loops show a clear cooling and deceleration as they retract. Observations of coronal reconnection flows are still rare, and most events are observed at the solar limb, obscured by complex foregrounds, making their relationship to the flare ribbons, cusp field and arcades formed in the lower atmosphere difficult to interpret. The disk location and favorable perspective of this event have removed these ambiguities giving a clear picture of the reconnection dynamics.Comment: 9 pages, 5 figures, and 1 table. Accepted for publication in ApJ

Geometric approach to Fletcher's ideal penalty function

Original article can be found at: www.springerlink.com Copyright Springer. [Originally produced as UH Technical Report 280, 1993]In this note, we derive a geometric formulation of an ideal penalty function for equality constrained problems. This differentiable penalty function requires no parameter estimation or adjustment, has numerical conditioning similar to that of the target function from which it is constructed, and also has the desirable property that the strict second-order constrained minima of the target function are precisely those strict second-order unconstrained minima of the penalty function which satisfy the constraints. Such a penalty function can be used to establish termination properties for algorithms which avoid ill-conditioned steps. Numerical values for the penalty function and its derivatives can be calculated efficiently using automatic differentiation techniques.Peer reviewe