Persistence of RNAi-Mediated Knockdown in Drosophila Complicates Mosaic Analysis Yet Enables Highly Sensitive Lineage Tracing.

RNA interference (RNAi) has emerged as a powerful way of reducing gene function in Drosophila melanogaster tissues. By expressing synthetic short hairpin RNAs (shRNAs) using the Gal4/UAS system, knockdown is efficiently achieved in specific tissues or in clones of marked cells. Here we show that knockdown by shRNAs is so potent and persistent that even transient exposure of cells to shRNAs can reduce gene function in their descendants. When using the FLP-out Gal4 method, in some instances we observed unmarked "shadow RNAi" clones adjacent to Gal4-expressing clones, which may have resulted from brief Gal4 expression following recombination but prior to cell division. Similarly, Gal4 driver lines with dynamic expression patterns can generate shadow RNAi cells after their activity has ceased in those cells. Importantly, these effects can lead to erroneous conclusions regarding the cell autonomy of knockdown phenotypes. We have investigated the basis of this phenomenon and suggested experimental designs for eliminating ambiguities in interpretation. We have also exploited the persistence of shRNA-mediated knockdown to design a sensitive lineage-tracing method, i-TRACE, which is capable of detecting even low levels of past reporter expression. Using i-TRACE, we demonstrate transient infidelities in the expression of some cell-identity markers near compartment boundaries in the wing imaginal disc

The Drosophila F-box protein Fbxl7 binds to the protocadherin fat and regulates Dachs localization and Hippo signaling.

The Drosophila protocadherin Fat (Ft) regulates growth, planar cell polarity (PCP) and proximodistal patterning. A key downstream component of Ft signaling is the atypical myosin Dachs (D). Multiple regions of the intracellular domain of Ft have been implicated in regulating growth and PCP but how Ft regulates D is not known. Mutations in Fbxl7, which encodes an F-box protein, result in tissue overgrowth and abnormalities in proximodistal patterning that phenocopy deleting a specific portion of the intracellular domain (ICD) of Ft that regulates both growth and PCP. Fbxl7 binds to this same portion of the Ft ICD, co-localizes with Ft to the proximal edge of cells and regulates the levels and asymmetry of D at the apical membrane. Fbxl7 can also regulate the trafficking of proteins between the apical membrane and intracellular vesicles. Thus Fbxl7 functions in a subset of pathways downstream of Ft and links Ft to D localization

Pragmatic randomised clinical trial of proton versus photon therapy for patients with non-metastatic breast cancer: The Radiotherapy Comparative Effectiveness (RadComp) Consortium trial protocol

INTRODUCTION: A broad range of stakeholders have called for randomised evidence on the potential clinical benefits and harms of proton therapy, a type of radiation therapy, for patients with breast cancer. Radiation therapy is an important component of curative treatment, reducing cancer recurrence and extending survival. Compared with photon therapy, the international treatment standard, proton therapy reduces incidental radiation to the heart. Our overall objective is to evaluate whether the differences between proton and photon therapy cardiac radiation dose distributions lead to meaningful reductions in cardiac morbidity and mortality after treatment for breast cancer. METHODS: We are conducting a large scale, multicentre pragmatic randomised clinical trial for patients with breast cancer who will be followed longitudinally for cardiovascular morbidity and mortality, health-related quality of life and cancer control outcomes. A total of 1278 patients with non-metastatic breast cancer will be randomly allocated to receive either photon or proton therapy. The primary outcomes are major cardiovascular events, defined as myocardial infarction, coronary revascularisation, cardiovascular death or hospitalisation for unstable angina, heart failure, valvular disease, arrhythmia or pericardial disease. Secondary endpoints are urgent or unanticipated outpatient or emergency room visits for heart failure, arrhythmia, valvular disease or pericardial disease. The Radiotherapy Comparative Effectiveness (RadComp) Clinical Events Centre will conduct centralised, blinded adjudication of primary outcome events. ETHICS AND DISSEMINATION: The RadComp trial has been approved by the institutional review boards of all participating sites. Recruitment began in February 2016. Current version of the protocol is A3, dated 08 November 2018. Dissemination plans include presentations at scientific conferences, scientific publications, stakeholder engagement efforts and presentation to the public via lay media outlets. TRIAL REGISTRATION NUMBER: NCT02603341

Exploratory Innovation, Exploitative Innovation, and Performance: Effects of Organizational Antecedents and Environmental Moderators

Research on exploration and exploitation is burgeoning, yet our understanding of the antecedents and consequences of both activities remains rather unclear. We advance the growing body of literature by focusing on the apparent differences of exploration and exploitation and examining implications for using formal (i.e. centralization and formalization) and informal (i.e. connectedness) coordination mechanisms. This study further examines how environmental aspects (i.e. dynamism and competitiveness) moderate the effectiveness of exploratory and exploitative innovation. Results indicate that centralization negatively affects exploratory innovation while formalization positively influences exploitative innovation. Interestingly, connectedness within units appears to be an important antecedent of both exploratory and exploitative innovation. Furthermore, our findings reveal that pursuing exploratory innovation is more effective in dynamic environments whereas pursuing exploitative innovation is more beneficial to a unit’s financial performance in more competitive environments. Through this richer explanation and empirical assessment, we contribute to a greater clarity and better understanding of how ambidextrous organizations coordinate the development of exploratory and exploitative innovation in organizational units and successfully respond to multiple environmental conditions

Exploratory innovation, exploitative innovation and ambidexterity

Organizational ambidexterity (i.e., the ability to pursue exploratory and exploitative innovation simultaneously) is crucial to firm survival. In this study we explore how multiunit firms might develop ambidextrous organizational units in response to environmental demands. We examine how environmental and organizational antecedents affect a unit’s level of organizational ambidexterity. Our study reveals that multiunit firms develop ambidextrous organizational units to compete in dynamically competitive environments. Moreover, we show that organizational units with decentralized and densely connected social relations are able to act ambidextrously and pursue exploratory and exploitative innovations simultaneously. Our study provides new insights how multiunit firms can cope with contradictorily pressures for exploratory and exploitative innovations

Managing Potential and Realized Absorptive Capacity: How do Organizational Antecedents matter?

This study explores how organizational antecedents affect potential and realized absorptive capacity. Our study identifies differential effects for both components of absorptive capacity. Results indicate that organizational mechanisms associated with coordination capabilities (i.e. cross-functional interfaces, participation in decision-making, and job rotation) primarily enhance a unit’s potential absorptive capacity. Organizational mechanisms associated with socialization capabilities (i.e. connectedness and socialization tactics) primarily increase a unit’s realized absorptive capacity. Our findings reveal why units may have difficulties in managing levels of potential and realized absorptive capacity and vary in their ability to create value from their absorptive capacity

Structural differentiation and ambidexterity: The mediating role of integration mechanisms

Prior studies have emphasized that structural attributes are crucial to simultaneously pursuing exploration and exploitation, yet our understanding of antecedents of ambidexterity is still limited. Structural differentiation can help ambidextrous organizations to maintain multiple inconsistent and conflicting demands; however, differentiated exploratory and exploitative activities need to be mobilized, coordinated, integrated, and applied. Based on this idea, we delineate formal and informal senior team integration mechanisms (e.g., contingency rewards and social integration) and formal and informal organizational integration mechanisms (e.g., cross-functional interfaces and connectedness) and examine how they mediate the relationship between structural differentiation and ambidexterity. Overall, our findings suggest that the previously asserted direct effect of structural differentiation on ambidexterity operates through informal senior team (i.e., senior team social integration) and formal organizational (i.e., cross-functional interfaces) integration mechanisms. Through this richer explanation and empirical assessment, we contribute to a greater clarity and better understanding of how organizations may effectively pursue exploration and exploitation simultaneously to achieve ambidexterity

A new population of recently quenched elliptical galaxies in the SDSS

We use the Sloan Digital Sky Survey to investigate the properties of massive elliptical galaxies in the local Universe (z\leq0.08) that have unusually blue optical colors. Through careful inspection, we distinguish elliptical from non-elliptical morphologies among a large sample of similarly blue galaxies with high central light concentrations (c_r\geq2.6). These blue ellipticals comprise 3.7 per cent of all c_r\geq2.6 galaxies with stellar masses between 10^10 and 10^11 h^{-2} {\rm M}_{\sun}. Using published fiber spectra diagnostics, we identify a unique subset of 172 non-star-forming ellipticals with distinctly blue urz colors and young (< 3 Gyr) light-weighted stellar ages. These recently quenched ellipticals (RQEs) have a number density of 2.7-4.7\times 10^{-5}\,h^3\,{\rm Mpc}^{-3} and sufficient numbers above 2.5\times10^{10} h^{-2} {\rm M}_{\sun} to account for more than half of the expected quiescent growth at late cosmic time assuming this phase lasts 0.5 Gyr. RQEs have properties that are consistent with a recent merger origin (i.e., they are strong `first-generation' elliptical candidates), yet few involved a starburst strong enough to produce an E+A signature. The preferred environment of RQEs (90 per cent reside at the centers of < 3\times 10^{12}\,h^{-1}{\rm M}_{\sun} groups) agrees well with the `small group scale' predicted for maximally efficient spiral merging onto their halo center and rules out satellite-specific quenching processes. The high incidence of Seyfert and LINER activity in RQEs and their plausible descendents may heat the atmospheres of small host halos sufficiently to maintain quenching.Comment: 26 pages, 9 figures. Revised version; accepted for publication in MNRA