Monorail/Foxa2 regulates floorplate differentiation and specification of oligodendrocytes, serotonergic raphe neurones and cranial motoneurones

In this study, we elucidate the roles of the winged-helix transcription factor Foxa2 in ventral CNS development in zebrafish. Through cloning of monorail (mol), which we find encodes the transcription factor Foxa2, and phenotypic analysis of mol(-/-) embryos, we show that floorplate is induced in the absence of Foxa2 function but fails to further differentiate. In mol(-/-) mutants, expression of Foxa and Hh family genes is not maintained in floorplate cells and lateral expansion of the floorplate fails to occur. Our results suggest that this is due to defects both in the regulation of Hh activity in medial floorplate cells as well as cell-autonomous requirements for Foxa2 in the prospective laterally positioned floorplate cells themselves. Foxa2 is also required for induction and/or patterning of several distinct cell types in the ventral CNS. Serotonergic neurones of the raphe nucleus and the trochlear motor nucleus are absent in mol(-/-) embryos, and oculomotor and facial motoneurones ectopically occupy ventral CNS midline positions in the midbrain and hindbrain. There is also a severe reduction of prospective oligodendrocytes in the midbrain and hindbrain. Finally, in the absence of Foxa2, at least two likely Hh pathway target genes are ectopically expressed in more dorsal regions of the midbrain and hindbrain ventricular neuroepithelium, raising the possibility that Foxa2 activity may normally be required to limit the range of action of secreted Hh proteins

Fast Protection-Domain Crossing in the CHERI Capability-System Architecture

Capability Hardware Enhanced RISC Instructions (CHERI) supplement the conventional memory management unit (MMU) with instruction-set architecture (ISA) extensions that implement a capability system model in the address space. CHERI can also underpin a hardware-software object-capability model for scalable application compartmentalization that can mitigate broader classes of attack. This article describes ISA additions to CHERI that support fast protection-domain switching, not only in terms of low cycle count, but also efficient memory sharing with mutual distrust. The authors propose ISA support for sealed capabilities, hardware-assisted checking during protection-domain switching, a lightweight capability flow-control model, and fast register clearing, while retaining the flexibility of a software-defined protection-domain transition model. They validate this approach through a full-system experimental design, including ISA extensions, a field-programmable gate array prototype (implemented in Bluespec SystemVerilog), and a software stack including an OS (based on FreeBSD), compiler (based on LLVM), software compartmentalization model, and open-source applications.This work is part of the CTSRD and MRC2 projects sponsored by the Defense Advanced Research Projects Agency (DARPA) and the Air Force Research Laboratory (AFRL), under contracts FA8750-10-C-0237 and FA8750-11-C-0249. We also acknowledge the Engineering and Physical Sciences Research Council (EPSRC) REMS Programme Grant [EP/K008528/1], the EPSRC Impact Acceleration Account [EP/K503757/1], EPSRC/ARM iCASE studentship [13220009], Microsoft studentship [MRS2011-031], the Isaac Newton Trust, the UK Higher Education Innovation Fund (HEIF), Thales E-Security, and Google, Inc.This is the author accepted manuscript. The final version of the article can be found at: http://ieeexplore.ieee.org/document/7723791

CHERI: A hybrid capability-system architecture for scalable software compartmentalization

CHERI extends a conventional RISC Instruction- Set Architecture, compiler, and operating system to support fine-grained, capability-based memory protection to mitigate memory-related vulnerabilities in C-language TCBs. We describe how CHERI capabilities can also underpin a hardware-software object-capability model for application compartmentalization that can mitigate broader classes of attack. Prototyped as an extension to the open-source 64-bit BERI RISC FPGA softcore processor, FreeBSD operating system, and LLVM compiler, we demonstrate multiple orders-of-magnitude improvement in scalability, simplified programmability, and resulting tangible security benefits as compared to compartmentalization based on pure Memory-Management Unit (MMU) designs. We evaluate incrementally deployable CHERI-based compartmentalization using several real-world UNIX libraries and applications.We thank our colleagues Ross Anderson, Ruslan Bukin, Gregory Chadwick, Steve Hand, Alexandre Joannou, Chris Kitching, Wojciech Koszek, Bob Laddaga, Patrick Lincoln, Ilias Marinos, A Theodore Markettos, Ed Maste, Andrew W. Moore, Alan Mujumdar, Prashanth Mundkur, Colin Rothwell, Philip Paeps, Jeunese Payne, Hassen Saidi, Howie Shrobe, and Bjoern Zeeb, our anonymous reviewers, and shepherd Frank Piessens, for their feedback and assistance. This work is part of the CTSRD and MRC2 projects sponsored by the Defense Advanced Research Projects Agency (DARPA) and the Air Force Research Laboratory (AFRL), under contracts FA8750-10-C- 0237 and FA8750-11-C-0249. The views, opinions, and/or findings contained in this paper are those of the authors and should not be interpreted as representing the official views or policies, either expressed or implied, of the Department of Defense or the U.S. Government. We acknowledge the EPSRC REMS Programme Grant [EP/K008528/1], Isaac Newton Trust, UK Higher Education Innovation Fund (HEIF), Thales E-Security, and Google, Inc.This is the author accepted manuscript. The final version is available at http://dx.doi.org/10.1109/SP.2015.

Mathematical modeling of the metastatic process

Mathematical modeling in cancer has been growing in popularity and impact since its inception in 1932. The first theoretical mathematical modeling in cancer research was focused on understanding tumor growth laws and has grown to include the competition between healthy and normal tissue, carcinogenesis, therapy and metastasis. It is the latter topic, metastasis, on which we will focus this short review, specifically discussing various computational and mathematical models of different portions of the metastatic process, including: the emergence of the metastatic phenotype, the timing and size distribution of metastases, the factors that influence the dormancy of micrometastases and patterns of spread from a given primary tumor.Comment: 24 pages, 6 figures, Revie

Search for direct production of charginos and neutralinos in events with three leptons and missing transverse momentum in √s = 7 TeV pp collisions with the ATLAS detector

A search for the direct production of charginos and neutralinos in final states with three electrons or muons and missing transverse momentum is presented. The analysis is based on 4.7 fb−1 of proton–proton collision data delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in three signal regions that are either depleted or enriched in Z-boson decays. Upper limits at 95% confidence level are set in R-parity conserving phenomenological minimal supersymmetric models and in simplified models, significantly extending previous results

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

Single hadron response measurement and calorimeter jet energy scale uncertainty with the ATLAS detector at the LHC

The uncertainty on the calorimeter energy response to jets of particles is derived for the ATLAS experiment at the Large Hadron Collider (LHC). First, the calorimeter response to single isolated charged hadrons is measured and compared to the Monte Carlo simulation using proton-proton collisions at centre-of-mass energies of sqrt(s) = 900 GeV and 7 TeV collected during 2009 and 2010. Then, using the decay of K_s and Lambda particles, the calorimeter response to specific types of particles (positively and negatively charged pions, protons, and anti-protons) is measured and compared to the Monte Carlo predictions. Finally, the jet energy scale uncertainty is determined by propagating the response uncertainty for single charged and neutral particles to jets. The response uncertainty is 2-5% for central isolated hadrons and 1-3% for the final calorimeter jet energy scale.Comment: 24 pages plus author list (36 pages total), 23 figures, 1 table, submitted to European Physical Journal

Exploring factors that influence the spread and sustainability of a dysphagia innovation: an instrumental case study

Background: Swallowing difficulties challenge patient safety due to the increased risk of malnutrition, dehydration and aspiration pneumonia. A theoretically driven study was undertaken to examine the spread and sustainability of a locally developed innovation that involved using the Inter-Professional Dysphagia Framework to structure education for the workforce. A conceptual framework with 3 spread strategies (hierarchical control, participatory adaptation and facilitated evolution) was blended with a processual approach to sustaining organisational change. The aim was to understand the processes, mechanism and outcomes associated with the spread and sustainability of this safety initiative. Methods: An instrumental case study, prospectively tracked a dysphagia innovation for 34 months (April 2011 to January 2014) in a large health care organisation in England. A train-the-trainer intervention (as participatory adaptation) was deployed on care pathways for stroke and fractured neck of femur. Data were collected at the organisational and clinical level through interviews (n = 30) and document review. The coding frame combined the processual approach with the spread mechanisms. Pre-determined outcomes included the number of staff trained about dysphagia and impact related to changes in practice. Results: The features and processes associated with hierarchical control and participatory adaptation were identified. Leadership, critical junctures, temporality and making the innovation routine were aspects of hierarchical control. Participatory adaptation was evident on the care pathways through stakeholder responses, workload and resource pressures. Six of the 25 ward based trainers cascaded the dysphagia training. The expected outcomes were achieved when the top-down mandate (hierarchical control) was supplemented by local engagement and support (participatory adaptation). Conclusions: Frameworks for spread and sustainability were combined to create a ‘small theory’ that described the interventions, the processes and desired outcomes a priori. This novel methodological approach confirmed what is known about spread and sustainability, highlighted the particularity of change and offered new insights into the factors associated with hierarchical control and participatory adaptation. The findings illustrate the dualities of organisational change as universal and context specific; as particular and amendable to theoretical generalisation. Appreciating these dualities may contribute to understanding why many innovations fail to become routine

Search for R-parity-violating supersymmetry in events with four or more leptons in sqrt(s) =7 TeV pp collisions with the ATLAS detector

A search for new phenomena in final states with four or more leptons (electrons or muons) is presented. The analysis is based on 4.7 fb−1 of $\sqrt{s}=7\;\mathrm{TeV}$ proton-proton collisions delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in two signal regions: one that requires moderate values of missing transverse momentum and another that requires large effective mass. The results are interpreted in a simplified model of R-parity-violating supersymmetry in which a 95% CL exclusion region is set for charged wino masses up to 540 GeV. In an R-parity-violating MSUGRA/CMSSM model, values of m 1/2 up to 820 GeV are excluded for 10 < tan β < 40