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

Generalized Wilson Chain for solving multichannel quantum impurity problems

The Numerical Renormalization Group is used to solve quantum impurity problems, which describe magnetic impurities in metals, nanodevices, and correlated materials within DMFT. Here we present a simple generalization of the Wilson Chain, which improves the scaling of computational cost with the number of channels/bands, bringing new problems within reach. The method is applied to calculate the t-matrix of the three-channel Kondo model at T=0, which shows universal crossovers near non-Fermi liquid critical points. A non-integrable three-impurity problem with three bands is also studied, revealing a rich phase diagram and novel screening/overscreening mechanisms.Comment: 5 pages + 5 pages supplementary materia

Toward New Therapeutic Mechanisms in Bipolar Disorder: Analog Investigation of Self-Compassion and Nonattachment to Self

There is growing interest in psychological processes that might be targeted in treatments for bipolar disorder (BD). One such process is a vulnerability at the level of self-concept, characterized by presence of, and fluctuations between positive and negative self-concept. The aim of the present study was to advance this literature by investigating the role of two emerging meta-cognitive processes – self-compassion and nonattachment to self – which have potential to therapeutically modulate this unstable self-concept in BD. Using an analog design, it was hypothesized that both variables would mediate the relationship between bipolar tendencies and psychological distress in a general population sample. Participants (N = 372 Australian university students) completed self-report measures of manic and depressive tendencies, selfcompassion, nonattachment to self and psychological distress. To investigate the specificity of the two hypothesized mediators, a better-researched psychological variable – rumination – was also included in mediation analyses. Bivariate analyses found tendencies toward mania and depression to be associated with diminished self-compassion and nonattachment to self, while both psychological processes were negatively associated with psychological distress. Mediation analyses showed, as expected, self-compassion and nonattachment to self mediated the relationship between bipolar tendencies and psychological distress after controlling for the effects of rumination. The present findings add incrementally to this literature by demonstrating that two meta-cognitive processes – self-compassion and nonattachment to self – act as mediators, and may be modifiable mechanisms linking bipolar vulnerability to negative mood outcomes. Future research should tackle longstanding conceptual issues in this domain, including the relationship between contents of self-concept (an established focus of BD research) and the person’s meta-cognitive approach to their self-concept (the focus here)

The relationship between Indian monsoon rainfall and low-pressure systems

Indian summer monsoon precipitation is significantly modulated by synoptic-scale tropical low pressure areas (LPAs), the strongest of which are known as monsoon depressions (MDs). Despite their apparent importance, previous studies attempting to constrain the fraction of monsoon precipitation for which such systems are responsible have yielded an unsatisfyingly wide range of estimates. Here, a variant of the DBSCAN algorithm is implemented to identify nontrivial, coherent rainfall structures in TRMM-3B42 precipitation data. Using theoretical considerations and an idealised model, an effective capture radius is computed to be 200 km, providing upper-bound attribution fractions of 57% (17%) for LPAs (MDs) over the monsoon core zone and 44% (12%) over all India. These results are also placed in the context of simpler attribution techniques. A climatology of these clusters suggests that the central Bay of Bengal (BoB) is the region of strongest synoptic organisation. A k-means clustering technique is used to identify four distinct partitions of LPA (and two of MD) track, and their regional contributions to monsoon precipitation are assessed. Most synoptic rainfall over India is attributable to short-lived LPAs originating at the head of the BoB, though longer-lived systems are required to bring rain to west India and east Pakistan. Secondary contributions from systems originating in the Arabian Sea and south BoB are shown to be important for west Pakistan and Sri Lanka respectively. Finally, a database of precipitating-event types is used to show that small-scale deep convection happens independently of MDs, whereas the density of larger-scale convective and stratiform events are sensitive to their presence - justifying the use of a noise-rejecting algorithm

Nestling diet, secondary sexual traits and fitness in the zebra finch

We examined the effect of nestling diet quality on a suite of physiological, morphological and life-history traits in adult male zebra finches,Taeniopygia guttata. Compared with birds reared on a supplemented diet, nestlings reared on a seed-only diet showed a reduced rate of growth and reduced cell-mediated immune function as measured by an in vivo response to aT lymphocyte-dependent mitogen. There were no differences between birds reared on the two diets in any of the following adult traits: body size, primary sexual traits (testes mass, numbers of stored sperm, sperm function, velocity and morphology), secondary sexual traits (beak colour and song rate), serological traits or immunological traits. The only differences we detected were a lower body mass and a greater proportion of individuals with plumage abnormalities among those reared on a seed-only diet (this latter effect was transient). The fact that male zebra finches reared on a seed-only diet were, as adults, virtually indistinguishable from those reared on a supple- mented diet, despite having reduced growth and immune function as nestlings, demonstrates that they subsequently compensated through the di¡erential allocation of resources. Our results indicate that differ- ential allocation is costly in terms of fitness since birds reared on a seed-only diet experienced a significantly greater mortality rate than those reared on a supplemented diet. This in turn suggests the existence of a trade-of between the development of traits important for reproduction, such as primary and secondary sexual traits and longevity

A genome-wide investigation of the worldwide invader Sargassum muticum shows high success albeit (almost) no genetic diversity

Twenty years of genetic studies of marine invaders have shown that successful invaders are often characterized by native and introduced populations displaying similar levels of genetic diversity. This pattern is presumably due to high propagule pressure and repeated introductions. The opposite pattern is reported in this study of the brown seaweed, Sargassum muticum, an emblematic species for circumglobal invasions. Albeit demonstrating polymorphism in the native range, microsatellites failed to detect any genetic variation over 1,269 individuals sampled from 46 locations over the Pacific-Atlantic introduction range. Single-nucleotide polymorphisms (SNPs) obtained from ddRAD sequencing revealed some genetic variation, but confirmed severe founder events in both the Pacific and Atlantic introduction ranges. Our study thus exemplifies the need for extreme caution in interpreting neutral genetic diversity as a proxy for invasive potential. Our results confirm a previously hypothesized transoceanic secondary introduction from NE Pacific to Europe. However, the SNP panel unexpectedly revealed two additional distinct genetic origins of introductions. Also, conversely to scenarios based on historical records, southern rather than northern NE Pacific populations could have seeded most of the European populations. Finally, the most recently introduced populations showed the lowest selfing rates, suggesting higher levels of recombination might be beneficial at the early stage of the introduction process (i.e., facilitating evolutionary novelties), whereas uniparental reproduction might be favored later in sustainably established populations (i.e., sustaining local adaptation).Agence Nationale de la Recherche - ANR-10-BTBR-04; European Regional Development Fund; Fundacao para a Ciencia e a Tecnologia - SFRH/BPD/107878/2015, UID/Multi/04326/2016, UID/Multi/04326/2019; Brittany Region;info:eu-repo/semantics/publishedVersio

A polynomial training algorithm for calculating perceptrons of optimal stability

Recomi (REpeated COrrelation Matrix Inversion) is a polynomially fast algorithm for searching optimally stable solutions of the perceptron learning problem. For random unbiased and biased patterns it is shown that the algorithm is able to find optimal solutions, if any exist, in at worst O(N^4) floating point operations. Even beyond the critical storage capacity alpha_c the algorithm is able to find locally stable solutions (with negative stability) at the same speed. There are no divergent time scales in the learning process. A full proof of convergence cannot yet be given, only major constituents of a proof are shown.Comment: 11 pages, Latex, 4 EPS figure