Dynamic Interpretation of Hedgehog Signaling in the Drosophila Wing Disc

Morphogens are classically defined as molecules that control patterning by acting at a distance to regulate gene expression in a concentration-dependent manner. In the Drosophila wing imaginal disc, secreted Hedgehog (Hh) forms an extracellular gradient that organizes patterning along the anterior–posterior axis and specifies at least three different domains of gene expression. Although the prevailing view is that Hh functions in the Drosophila wing disc as a classical morphogen, a direct correspondence between the borders of these patterns and Hh concentration thresholds has not been demonstrated. Here, we provide evidence that the interpretation of Hh signaling depends on the history of exposure to Hh and propose that a single concentration threshold is sufficient to support multiple outputs. Using mathematical modeling, we predict that at steady state, only two domains can be defined in response to Hh, suggesting that the boundaries of two or more gene expression patterns cannot be specified by a static Hh gradient. Computer simulations suggest that a spatial “overshoot” of the Hh gradient occurs, i.e., a transient state in which the Hh profile is expanded compared to the Hh steady-state gradient. Through a temporal examination of Hh target gene expression, we observe that the patterns initially expand anteriorly and then refine, providing in vivo evidence for the overshoot. The Hh gene network architecture suggests this overshoot results from the Hh-dependent up-regulation of the receptor, Patched (Ptc). In fact, when the network structure was altered such that the ptc gene is no longer up-regulated in response to Hh-signaling activation, we found that the patterns of gene expression, which have distinct borders in wild-type discs, now overlap. Our results support a model in which Hh gradient dynamics, resulting from Ptc up-regulation, play an instructional role in the establishment of patterns of gene expression

The role of mechanical forces in the planar-to-bulk transition in growing Escherichia coli microcolonies

Mechanical forces are obviously important in the assembly of three-dimensional multicellular structures, but their detailed role is often unclear. We have used growing microcolonies of the bacterium \emph{Escherichia coli} to investigate the role of mechanical forces in the transition from two-dimensional growth (on the interface between a hard surface and a soft agarose pad) to three-dimensional growth (invasion of the agarose). We measure the position within the colony where the invasion transition happens, the cell density within the colony, and the colony size at the transition as functions of the concentration of the agarose. We use a phenomenological theory, combined with individual-based computer simulations, to show how mechanical forces acting between the bacterial cells, and between the bacteria and the surrounding matrix, lead to the complex phenomena observed in our experiments - in particular a non-trivial dependence of the colony size at the transition on the agarose concentration. Matching these approaches leads to a prediction for how the friction coefficient between the bacteria and the agarose should vary with agarose concentration. Our experimental conditions mimic numerous clinical and environmental scenarios in which bacteria invade soft matrices, as well as shedding more general light on the transition between two- and three-dimensional growth in multicellular assemblies

Dpp Signaling Activity Requires Pentagone to Scale with Tissue Size in the Growing Drosophila Wing Imaginal Disc

The activity of the Dpp morphogen adapts to tissue size in the growing Drosophila wing imaginal disc, and Pentagone, an important secreted feedback regulator of the Dpp pathway, is required for this adaptation

Community-level impacts of the third sector: Does the local distribution of voluntary organizations influence the likelihood of volunteering?

Scholars have attributed various beneficial outcomes to the presence and density of the voluntary, third or non-profit sector in communities. One way in which the distribution of such organizations may benefit communities is through providing opportunities for volunteering. We hypothesize that the distribution of third-sector organizations has an influence, after controlling for relevant individual and area characteristics, on the likelihood of engaging in formal volunteering (defined as unpaid help given through, and to, third-sector organizations, rather than directly to individuals). Using administrative data from the Charity Commission, we classify organizations in terms of their geographical scale of operation. We then construct indicators of the distribution of charities, and their expenditures, for local authorities in England. We obtain data on volunteering by individuals from the Citizenship Survey and link this to administrative data contained in the Charity Commission register on the distribution of charities. We find that there is a positive relationship between the numbers of charities operating locally and the likelihood of volunteering. Other measures, however, including the distribution of charities operating either regionally or nationally, have no statistically significant effects. We find no relationship between a measure of the size of charities (the median expenditures of charities within local authorities) and the likelihood of volunteering. These findings are relevant beyond the UK to debates about the understanding of variations in voluntary action, and to discussions about the impact of the third sector upon communities

Evolving Sensitivity Balances Boolean Networks

We investigate the sensitivity of Boolean Networks (BNs) to mutations. We are interested in Boolean Networks as a model of Gene Regulatory Networks (GRNs). We adopt Ribeiro and Kauffman’s Ergodic Set and use it to study the long term dynamics of a BN. We define the sensitivity of a BN to be the mean change in its Ergodic Set structure under all possible loss of interaction mutations. Insilico experiments were used to selectively evolve BNs for sensitivity to losing interactions. We find that maximum sensitivity was often achievable and resulted in the BNs becoming topologically balanced, i.e. they evolve towards network structures in which they have a similar number of inhibitory and excitatory interactions. In terms of the dynamics, the dominant sensitivity strategy that evolved was to build BNs with Ergodic Sets dominated by a single long limit cycle which is easily destabilised by mutations. We discuss the relevance of our findings in the context of Stem Cell Differentiation and propose a relationship between pluripotent stem cells and our evolved sensitive networks

Outcomes following small bowel obstruction due to malignancy in the national audit of small bowel obstruction

Introduction Patients with cancer who develop small bowel obstruction are at high risk of malnutrition and morbidity following compromise of gastrointestinal tract continuity. This study aimed to characterise current management and outcomes following malignant small bowel obstruction. Methods A prospective, multicentre cohort study of patients with small bowel obstruction who presented to UK hospitals between 16th January and 13th March 2017. Patients who presented with small bowel obstruction due to primary tumours of the intestine (excluding left-sided colonic tumours) or disseminated intra-abdominal malignancy were included. Outcomes included 30-day mortality and in-hospital complications. Cox-proportional hazards models were used to generate adjusted effects estimates, which are presented as hazard ratios (HR) alongside the corresponding 95% confidence interval (95% CI). The threshold for statistical significance was set at the level of P ≤ 0.05 a-priori. Results 205 patients with malignant small bowel obstruction presented to emergency surgery services during the study period. Of these patients, 50 had obstruction due to right sided colon cancer, 143 due to disseminated intraabdominal malignancy, 10 had primary tumours of the small bowel and 2 patients had gastrointestinal stromal tumours. In total 100 out of 205 patients underwent a surgical intervention for obstruction. 30-day in-hospital mortality rate was 11.3% for those with primary tumours and 19.6% for those with disseminated malignancy. Severe risk of malnutrition was an independent predictor for poor mortality in this cohort (adjusted HR 16.18, 95% CI 1.86 to 140.84, p = 0.012). Patients with right-sided colon cancer had high rates of morbidity. Conclusions Mortality rates were high in patients with disseminated malignancy and in those with right sided colon cancer. Further research should identify optimal management strategy to reduce morbidity for these patient groups

Effect of Rootstock on Vineyard Establishment Using Green-Growing Benchgrafts

Demand for vine plant material has increased drastically due to the ongoing expansion of viticulture, and recent widespread replanting efforts. Nurseries and growers are turning to green-grafted vines to meet demand. Unfortunately, most vineyard establishment studies have centered around dormant benchgrafted vines. Thus, little is known regarding the specific establishment trends of green-growing benchgrafts. This study aimed to explore the role rootstock selection has in green-growing benchgraft establishment and development over the first four years post-planting. Vitis vinifera L. cv. Sauvignon blanc was grafted onto multiple rootstocks of varying parentage, including ‘101-14MGT’ (V. riparia × V. rupestris), ‘1103P’ (V. berlandieri × V. rupestris), ‘110R’ (V. berlandieri × V. rupestris), ‘420A MGT’ (V. berlandieri × V. riparia), and ‘Teleki 5C’ (V. berlandieri × V. riparia). The experimental site was organized using a completely randomized design (n = 12) with all vines managed to industry-standard cultural practices. Vines grafted onto 1103P had the largest average trunk diameter (p = 0.0012) and circumference (p p p = 0.0008). The larger trunk size and more extensive carbohydrate reserves suggest that green-growing benchgrafts using 110R or 1103P have a higher capacity and likelihood of establishment success

Modeling proliferative tissue growth: A general approach and an avian case study

During development, tissues often undergo rapid physical expansion due to cell proliferation. Continuous and discrete models of one- and two-dimensional tissue growth are developed and applied to observational data of the developing avian gut, where the gut tissue cells undergo dramatic proliferation. The discrete cellular automata model provides results at the level of individual cells that reflect a realistic stochasticity and nonuniformity expected in cellular systems. Averaging the discrete results predicts population-level properties of the system, which match those of the continuous model. This dual approach provides an understanding of the interaction between the individual-level and population-level aspects of a developmental growth process. Both models are applied to a case study involving the developing intestinal tract of a quail embryo. A nonuniform growth model accurately predicts the positions of measurable biological landmarks within the growing tissue. Furthermore, the discrete model provides a framework for modeling the interactions between growing tissues and other biological mechanisms, such as cell motility and proliferation on an expanding tissue.Benjamin J. Binder, Kerry A. Landman, Matthew J. Simpson, Michael Mariani and Donald F. Newgree