Integrative analyses identify modulators of response to neoadjuvant aromatase inhibitors in patients with early breast cancer

Introduction Aromatase inhibitors (AIs) are a vital component of estrogen receptor positive (ER+) breast cancer treatment. De novo and acquired resistance, however, is common. The aims of this study were to relate patterns of copy number aberrations to molecular and proliferative response to AIs, to study differences in the patterns of copy number aberrations between breast cancer samples pre- and post-AI neoadjuvant therapy, and to identify putative biomarkers for resistance to neoadjuvant AI therapy using an integrative analysis approach. Methods Samples from 84 patients derived from two neoadjuvant AI therapy trials were subjected to copy number profiling by microarray-based comparative genomic hybridisation (aCGH, n = 84), gene expression profiling (n = 47), matched pre- and post-AI aCGH (n = 19 pairs) and Ki67-based AI-response analysis (n = 39). Results Integrative analysis of these datasets identified a set of nine genes that, when amplified, were associated with a poor response to AIs, and were significantly overexpressed when amplified, including CHKA, LRP5 and SAPS3. Functional validation in vitro, using cell lines with and without amplification of these genes (SUM44, MDA-MB134-VI, T47D and MCF7) and a model of acquired AI-resistance (MCF7-LTED) identified CHKA as a gene that when amplified modulates estrogen receptor (ER)-driven proliferation, ER/estrogen response element (ERE) transactivation, expression of ER-regulated genes and phosphorylation of V-AKT murine thymoma viral oncogene homolog 1 (AKT1). Conclusions These data provide a rationale for investigation of the role of CHKA in further models of de novo and acquired resistance to AIs, and provide proof of concept that integrative genomic analyses can identify biologically relevant modulators of AI response

Mitigating agency risk between investors and ventures’ managers

The general management literature has long focused on the agency risks involved in the relationship between general managers and shareholders. Shareholders can deploy contractual and non-contractual mechanisms to reduce these inefficiencies. This study examines - based on a broad international sample of investment contracts - how the use of contractual and non-contractual mechanisms is related to the degree of risks associated with the venture’s development stage as well as how these practices differ across countries. Hypotheses are tested using a proprietary dataset of 265 hand-collected investment contracts associated with ventures in the U.S., Israel and nine European countries. Findings suggest that the use of mitigating contractual and non-contractual mechanisms is related to the degree of agency risks, and that these practices vary across countries. This study draws implications for how investors can best deploy their capital in different institutional settings whilst nurturing their relationships with managers and entrepreneurs

Roy-Steiner equations for pion-nucleon scattering

Starting from hyperbolic dispersion relations, we derive a closed system of Roy-Steiner equations for pion-nucleon scattering that respects analyticity, unitarity, and crossing symmetry. We work out analytically all kernel functions and unitarity relations required for the lowest partial waves. In order to suppress the dependence on the high-energy regime we also consider once- and twice-subtracted versions of the equations, where we identify the subtraction constants with subthreshold parameters. Assuming Mandelstam analyticity we determine the maximal range of validity of these equations. As a first step towards the solution of the full system we cast the equations for the $\pi\pi\to\bar NN$ partial waves into the form of a Muskhelishvili-Omn\`es problem with finite matching point, which we solve numerically in the single-channel approximation. We investigate in detail the role of individual contributions to our solutions and discuss some consequences for the spectral functions of the nucleon electromagnetic form factors.Comment: 106 pages, 18 figures; version published in JHE

On the Stability and Structural Dynamics of Metal Nanowires

This article presents a brief review of the nanoscale free-electron model, which provides a continuum description of metal nanostructures. It is argued that surface and quantum-size effects are the two dominant factors in the energetics of metal nanowires, and that much of the phenomenology of nanowire stability and structural dynamics can be understood based on the interplay of these two competing factors. A linear stability analysis reveals that metal nanocylinders with certain magic conductance values G=1, 3, 6, 12, 17, 23, 34, 42, 51, 67, 78, 96, ... times the conductance quantum are exceptionally stable. A nonlinear dynamical simulation of nanowire structural evolution reveals a universal equilibrium shape consisting of a magic cylinder suspended between unduloidal contacts. The lifetimes of these metastable structures are also computed.Comment: 8 pages, 6 figure

Phylogeography of Japanese encephalitis virus:genotype is associated with climate

The circulation of vector-borne zoonotic viruses is largely determined by the overlap in the geographical distributions of virus-competent vectors and reservoir hosts. What is less clear are the factors influencing the distribution of virus-specific lineages. Japanese encephalitis virus (JEV) is the most important etiologic agent of epidemic encephalitis worldwide, and is primarily maintained between vertebrate reservoir hosts (avian and swine) and culicine mosquitoes. There are five genotypes of JEV: GI-V. In recent years, GI has displaced GIII as the dominant JEV genotype and GV has re-emerged after almost 60 years of undetected virus circulation. JEV is found throughout most of Asia, extending from maritime Siberia in the north to Australia in the south, and as far as Pakistan to the west and Saipan to the east. Transmission of JEV in temperate zones is epidemic with the majority of cases occurring in summer months, while transmission in tropical zones is endemic and occurs year-round at lower rates. To test the hypothesis that viruses circulating in these two geographical zones are genetically distinct, we applied Bayesian phylogeographic, categorical data analysis and phylogeny-trait association test techniques to the largest JEV dataset compiled to date, representing the envelope (E) gene of 487 isolates collected from 12 countries over 75 years. We demonstrated that GIII and the recently emerged GI-b are temperate genotypes likely maintained year-round in northern latitudes, while GI-a and GII are tropical genotypes likely maintained primarily through mosquito-avian and mosquito-swine transmission cycles. This study represents a new paradigm directly linking viral molecular evolution and climate

Imbibition in Disordered Media

The physics of liquids in porous media gives rise to many interesting phenomena, including imbibition where a viscous fluid displaces a less viscous one. Here we discuss the theoretical and experimental progress made in recent years in this field. The emphasis is on an interfacial description, akin to the focus of a statistical physics approach. Coarse-grained equations of motion have been recently presented in the literature. These contain terms that take into account the pertinent features of imbibition: non-locality and the quenched noise that arises from the random environment, fluctuations of the fluid flow and capillary forces. The theoretical progress has highlighted the presence of intrinsic length-scales that invalidate scale invariance often assumed to be present in kinetic roughening processes such as that of a two-phase boundary in liquid penetration. Another important fact is that the macroscopic fluid flow, the kinetic roughening properties, and the effective noise in the problem are all coupled. Many possible deviations from simple scaling behaviour exist, and we outline the experimental evidence. Finally, prospects for further work, both theoretical and experimental, are discussed.Comment: Review article, to appear in Advances in Physics, 53 pages LaTe

Evolutionary Novelty in a Butterfly Wing Pattern through Enhancer Shuffling.

An important goal in evolutionary biology is to understand the genetic changes underlying novel morphological structures. We investigated the origins of a complex wing pattern found among Amazonian Heliconius butterflies. Genome sequence data from 142 individuals across 17 species identified narrow regions associated with two distinct red colour pattern elements, dennis and ray. We hypothesise that these modules in non-coding sequence represent distinct cis-regulatory loci that control expression of the transcription factor optix, which in turn controls red pattern variation across Heliconius. Phylogenetic analysis of the two elements demonstrated that they have distinct evolutionary histories and that novel adaptive morphological variation was created by shuffling these cis-regulatory modules through recombination between divergent lineages. In addition, recombination of modules into different combinations within species further contributes to diversity. Analysis of the timing of diversification in these two regions supports the hypothesis of introgression moving regulatory modules between species, rather than shared ancestral variation. The dennis phenotype introgressed into Heliconius melpomene at about the same time that ray originated in this group, while ray introgressed back into H. elevatus much more recently. We show that shuffling of existing enhancer elements both within and between species provides a mechanism for rapid diversification and generation of novel morphological combinations during adaptive radiation.This work was funded by BBSRC grant H01439X/1, ERC grant MimEvol and ANR grant HybEvol to MJ.This is the final version of the article. It was first available from PLOS via http://dx.doi.org/10.1371/journal.pbio.100235

On staying grounded and avoiding Quixotic dead ends

The 15 articles in this special issue on The Representation of Concepts illustrate the rich variety of theoretical positions and supporting research that characterize the area. Although much agreement exists among contributors, much disagreement exists as well, especially about the roles of grounding and abstraction in conceptual processing. I first review theoretical approaches raised in these articles that I believe are Quixotic dead ends, namely, approaches that are principled and inspired but likely to fail. In the process, I review various theories of amodal symbols, their distortions of grounded theories, and fallacies in the evidence used to support them. Incorporating further contributions across articles, I then sketch a theoretical approach that I believe is likely to be successful, which includes grounding, abstraction, flexibility, explaining classic conceptual phenomena, and making contact with real-world situations. This account further proposes that (1) a key element of grounding is neural reuse, (2) abstraction takes the forms of multimodal compression, distilled abstraction, and distributed linguistic representation (but not amodal symbols), and (3) flexible context-dependent representations are a hallmark of conceptual processing

Postcopulatory sexual selection

The female reproductive tract is where competition between the sperm of different males takes place, aided and abetted by the female herself. Intense postcopulatory sexual selection fosters inter-sexual conflict and drives rapid evolutionary change to generate a startling diversity of morphological, behavioural and physiological adaptations. We identify three main issues that should be resolved to advance our understanding of postcopulatory sexual selection. We need to determine the genetic basis of different male fertility traits and female traits that mediate sperm selection; identify the genes or genomic regions that control these traits; and establish the coevolutionary trajectory of sexes

Human behaviour and economic growth: a psychocultural perspective on local and regional development

A renewed emphasis on behavioural traits has emerged as a means of explaining regional and local differences in economic performance and development. Given this, the aim of this study is to identify distinct local psychocultural behavioural profiles and to examine the extent to which these are associated with economic growth. Combining theories of community culture and personality psychology into a holistic spatially-oriented perspective, the paper argues that the types of human behaviour found across local places emerges from the co-evolution of cultural and personality factors. An empirical analysis of localities in Great Britain identifies and explores three underlying psychocultural profiles: Diverse Extraversion; Inclusive Amenability and Individual Commitment. It is found that inclusive amenable and individually committed psychocultural behaviour generally appear to hold back local economic growth, with the exception of recessionary periods. The reverse relationship is somewhat the case for diverse extravert behaviour. It is concluded that a better understanding of the holistic relationship and co-evolution of the cultural and psychological behavioural make-up of localities and regions has the potential to provide new insights into expected development outcomes as well as the forms of policy intervention that are required within regions and localities, each of which has its own individual psychocultural character