Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer.

Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of preexisting subclones, remains unclear. In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires Aurora kinase A (AURKA) activity. Nongenetic resistance through the activation of AURKA by its coactivator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in preclinical models. Treatment-induced activation of AURKA is associated with resistance to EGFR inhibitors in vitro, in vivo and in most individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a molecular path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA-driven residual disease and acquired resistance

Seeking legitimacy through CSR: Institutional Pressures and Corporate Responses of Multinationals in Sri Lanka

Arguably, the corporate social responsibility (CSR) practices of multinational enterprises (MNEs) are influenced by a wide range of both internal and external factors. Perhaps most critical among the exogenous forces operating on MNEs are those exerted by state and other key institutional actors in host countries. Crucially, academic research conducted to date offers little data about how MNEs use their CSR activities to strategically manage their relationship with those actors in order to gain legitimisation advantages in host countries. This paper addresses that gap by exploring interactions between external institutional pressures and firm-level CSR activities, which take the form of community initiatives, to examine how MNEs develop their legitimacy-seeking policies and practices. In focusing on a developing country, Sri Lanka, this paper provides valuable insights into how MNEs instrumentally utilise community initiatives in a country where relationship-building with governmental and other powerful non-governmental actors can be vitally important for the long-term viability of the business. Drawing on neo-institutional theory and CSR literature, this paper examines and contributes to the embryonic but emerging debate about the instrumental and political implications of CSR. The evidence presented and discussed here reveals the extent to which, and the reasons why, MNEs engage in complex legitimacy-seeking relationships with Sri Lankan institutions

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

Ultrafast entangling gates between nuclear spins using photo-excited triplet states

The representation of information within the spins of electrons and nuclei has been powerful in the ongoing development of quantum computers. Although nuclear spins are advantageous as quantum bits (qubits) due to their long coherence lifetimes (exceeding seconds), they exhibit very slow spin interactions and have weak polarisation. A coupled electron spin can be used to polarise the nuclear spin and create fast single-qubit gates, however, the permanent presence of electron spins is a source of nuclear decoherence. Here we show how a transient electron spin, arising from the optically excited triplet state of C60, can be used to hyperpolarise, manipulate and measure two nearby nuclear spins. Implementing a scheme which uses the spinor nature of the electron, we performed an entangling gate in hundreds of nanoseconds: five orders of magnitude faster than the liquid-state J coupling. This approach can be widely applied to systems comprising an electron spin coupled to multiple nuclear spins, such as NV centres, while the successful use of a transient electron spin motivates the design of new molecules able to exploit photo-excited triplet states.Comment: 5 pages, 3 figure

Conformal symmetry of the critical 3D Ising model inside a sphere

We perform Monte-Carlo simulations of the three-dimensional Ising model at the critical temperature and zero magnetic field. We simulate the system in a ball with free boundary conditions on the two dimensional spherical boundary. Our results for one and two point functions in this geometry are consistent with the predictions from the conjectured conformal symmetry of the critical Ising model.We are grateful to Slava Rychkov for useful discussions and for suggesting this work. The research leading to these results has received funding from the [European Union] Seventh Framework Programme [FP7-People-2010-IRSES] and [FP7/2007-2013] under grant agreements No 269217, 317089 and No 247252, and from the grant CERN/FP/123599/2011. Centro de Física do Porto is partially funded by the Foundation for Science and Technology of Portugal (FCT). J.V.P.L. acknowledges funding from projecto Operacional Regional do Norte, within Quadro de Referência Estratégico Nacional (QREN) and through Fundo Europeu de Desenvolvimento Regional (FEDER), Ref. NORTE-07-0124-FEDER- 00003

Exploring How We Teach: Lived Experiences, Lessons, and Research about Graduate Instructors by Graduate Instructors

This book combines the knowledge of 30 graduate student instructors sharing about how they teach and how they’ve learned how to teach

Perception of Shadows in Children with Autism Spectrum Disorders

Background: Cast shadows in visual scenes can have profound effects on visual perception. Much as they are informative, they also constitute noise as they are salient features of the visual scene potentially interfering with the processing of other features. Here we asked i) whether individuals with autism can exploit the information conveyed by cast shadows; ii) whether they are especially sensitive to noise aspects of shadows. Methodology/Principal Findings: Twenty high-functioning children with autism and twenty typically developing children were asked to recognize familiar objects while the presence, position, and shape of the cast shadow were systematically manipulated. Analysis of vocal reaction time revealed that whereas typically developing children used information from cast shadows to improve object recognition, in autistic children the presence of cast shadows—either congruent or incongruent—interfered with object recognition. Critically, vocal reaction times were faster when the object was presented without a cast shadow. Conclusions/Significance: We conclude that shadow-processing mechanisms are abnormal in autism. As a result, processing shadows becomes costly and cast shadows interfere rather than help object recognition

Extremality and dynamically defined measures, part I: Diophantine properties of quasi-decaying measures

We present a new method of proving the Diophantine extremality of various dynamically defined measures, vastly expanding the class of measures known to be extremal. This generalizes and improves the celebrated theorem of Kleinbock and Margulis (’98) resolving Sprindžuk’s conjecture, as well as its extension by Kleinbock, Lindenstrauss, and Weiss (’04), hereafter abbreviated KLW. As applications we prove the extremality of all hyperbolic measures of smooth dynamical systems with sufficiently large Hausdorff dimension, of the Patterson–Sullivan measures of all nonplanar geometrically finite groups, and of the Gibbs measures (including conformal measures) of infinite iterated function systems. The key technical idea, which has led to a plethora of new applications, is a significant weakening of KLW’s sufficient conditions for extremality. In Part I, we introduce and develop a systematic account of two classes of measures, which we call quasi-decaying and weakly quasi-decaying. We prove that weak quasi-decay implies strong extremality in the matrix approximation framework, thus proving a conjecture of KLW. We also prove the “inherited exponent of irrationality” version of this theorem, describing the relationship between the Diophantine properties of certain subspaces of the space of matrices and measures supported on these subspaces. In subsequent papers, we exhibit numerous examples of quasi-decaying measures, in support of the thesis that “almost any measure from dynamics and/or fractal geometry is quasi-decaying”. We also discuss examples of non-extremal measures coming from dynamics, illustrating where the theory must halt

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal