An intrinsic timer specifies distal structures of the vertebrate limb

How the positional values along the proximo-distal axis (stylopod-zeugopod-autopod) of the limb are specified is intensely debated. Early work suggested that cells intrinsically change their proximo-distal positional values by measuring time. Recently, however, it is suggested that instructive extrinsic signals from the trunk and apical ectodermal ridge specify the stylopod and zeugopod/autopod, respectively. Here, we show that the zeugopod and autopod are specified by an intrinsic timing mechanism. By grafting green fluorescent protein-expressing cells from early to late chick wing buds, we demonstrate that distal mesenchyme cells intrinsically time Hoxa13 expression, cell cycle parameters and the duration of the overlying apical ectodermal ridge. In addition, we reveal that cell affinities intrinsically change in the distal mesenchyme, which we suggest results in a gradient of positional values along the proximo-distal axis. We propose a complete model in which a switch from extrinsic signalling to intrinsic timing patterns the vertebrate limb

Solitons in Triangular and Honeycomb Dynamical Lattices with the Cubic Nonlinearity

We study the existence and stability of localized states in the discrete nonlinear Schr{\"o}dinger equation (DNLS) on two-dimensional non-square lattices. The model includes both the nearest-neighbor and long-range interactions. For the fundamental strongly localized soliton, the results depend on the coordination number, i.e., on the particular type of the lattice. The long-range interactions additionally destabilize the discrete soliton, or make it more stable, if the sign of the interaction is, respectively, the same as or opposite to the sign of the short-range interaction. We also explore more complicated solutions, such as twisted localized modes (TLM's) and solutions carrying multiple topological charge (vortices) that are specific to the triangular and honeycomb lattices. In the cases when such vortices are unstable, direct simulations demonstrate that they turn into zero-vorticity fundamental solitons.Comment: 17 pages, 13 figures, Phys. Rev.

Body mass index and breast cancer survival: a Mendelian randomization analysis

There is increasing evidence that elevated body mass index (BMI) is associated with reduced survival for women with breast cancer. However, the underlying reasons remain unclear. We conducted a Mendelian randomization analysis to investigate a possible causal role of BMI in survival from breast cancer. We used individual-level data from six large breast cancer case-cohorts including a total of 36 210 individuals (2475 events) of European ancestry. We created a BMI genetic risk score (GRS) based on genotypes at 94 known BMI-associated genetic variants. Association between the BMI genetic score and breast cancer survival was analysed by Cox regression for each study separately. Study-specific hazard ratios were pooled using fixed-effect meta-analysis. BMI genetic score was found to be associated with reduced breast cancer-specific survival for estrogen receptor (ER)-positive cases [hazard ratio (HR) = 1.11, per one-unit increment of GRS, 95% confidence interval (CI) 1.01-1.22, P = 0.03). We observed no association for ER-negative cases (HR = 1.00, per one-unit increment of GRS, 95% CI 0.89-1.13,P = 0.95). Our findings suggest a causal effect of increased BMI on reduced breast cancer survival for ER-positive breast cancer. There is no evidence of a causal effect of higher BMI on survival for ER-negative breast cancer cases.Peer reviewe

Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes

Surgical oncolog