Proceedings of the workshop "Standard Model at the LHC" University College London 30 March - 1 April 2009

Proceedings from a 3-day discussion on Standard Model discoveries with the first LHC dataComment: 9 contributions to the proceedings of the LHC Standard Model worksho

Axl-EGFR receptor tyrosine kinase hetero-interaction provides EGFR with access to pro-invasive signalling in cancer cells

© The Author(s) 2016. Acquired resistance to conventional and targeted therapies is becoming a major hindrance in cancer management. It is increasingly clear that cancer cells are able to evolve and rewire canonical signalling pathways to their advantage, thus evading cell death and promoting cell invasion. The Axl receptor tyrosine kinase (RTK) has been shown to modulate acquired resistance to EGFR-targeted therapies in both breast and lung cancers. Glioblastoma multiforme (GBM) is a highly infiltrative and invasive form of brain tumour with little response to therapy. Both Axl and EGFR have been identified as major players in gliomagenesis and invasiveness. However, the mechanisms underlying a potential signalling crosstalk between EGFR and Axl RTKs are unknown. The purpose of this study was to investigate this novel and unconventional interaction among RTKs of different families in human GBM cells. With the use of western blotting, in vitro kinase activity, co-immunoprecipitation and bimolecular fluorescence complementation assays, we show that EGF stimulates activation of Axl kinase and that there is a hetero-interaction between the two RTKs. Through small interfering RNA knockdown and quantitative PCR screening, we identified distinct gene expression patterns in GBM cells that were specifically regulated by signalling from EGFR-EGFR, Axl-Axl and EGFR-Axl RTK parings. These included genes that promote invasion, which were activated only via the EGFR-Axl axis (MMP9), while EGFR-EGFR distinctly regulated the cell cycle and Axl-Axl regulated invasion. Our findings provide critical insights into the role of EGFR-Axl hetero-dimerisation in cancer cells and reveal regulation of cell invasion via Axl as a novel function of EGFR signalling

Discovery of an X-ray Jet and Extended Jet Structure in the Quasar PKS 1055+201

This letter reports rich X-ray jet structures found in the Chandra observation of PKS 1055+201. In addition to an X-ray jet coincident with the radio jet we detect a region of extended X-ray emission surrounding the jet as far from the core as the radio hotspot to the North, and a similar extended X-ray region along the presumed path of the unseen counterjet to the Southern radio lobe. Both X-ray regions show a similar curvature to the west, relative to the quasar. We interpret this as the first example where we separately detect the X-ray emission from a narrow jet and extended, residual jet plasma over the entire length of a powerful FRII jet.Comment: Accepted for publication in Ap. J. Letters. 4 pages, 3 figure

The stellar metallicity distribution of disc galaxies and bulges in cosmological simulations

By means of high-resolution cosmological hydrodynamical simulations of Milky Way-like disc galaxies, we conduct an analysis of the associated stellar metallicity distribution functions (MDFs). After undertaking a kinematic decomposition of each simulation into spheroid and disc sub-components, we compare the predicted MDFs to those observed in the solar neighbourhood and the Galactic bulge. The effects of the star formation density threshold are visible in the star formation histories, which show a modulation in their behaviour driven by the threshold. The derived MDFs show median metallicities lower by 0.2-0.3 dex than the MDF observed locally in the disc and in the Galactic bulge. Possible reasons for this apparent discrepancy include the use of low stellar yields and/or centrally-concentrated star formation. The dispersions are larger than the one of the observed MDF; this could be due to simulated discs being kinematically hotter relative to the Milky Way. The fraction of low metallicity stars is largely overestimated, visible from the more negatively skewed MDF with respect to the observational sample. For our fiducial Milky Way analog, we study the metallicity distribution of the stars born "in situ" relative to those formed via accretion (from disrupted satellites), and demonstrate that this low-metallicity tail to the MDF is populated primarily by accreted stars. Enhanced supernova and stellar radiation energy feedback to the surrounding interstellar media of these pre-disrupted satellites is suggested as an important regulator of the MDF skewness.Comment: 20 pages, 14 figures, MNRAS, accepte

Co-complex protein membership evaluation using Maximum Entropy on GO ontology and InterPro annotation.

MOTIVATION: Protein-protein interactions (PPI) play a crucial role in our understanding of protein function and biological processes. The standardization and recording of experimental findings is increasingly stored in ontologies, with the Gene Ontology (GO) being one of the most successful projects. Several PPI evaluation algorithms have been based on the application of probabilistic frameworks or machine learning algorithms to GO properties. Here, we introduce a new training set design and machine learning based approach that combines dependent heterogeneous protein annotations from the entire ontology to evaluate putative co-complex protein interactions determined by empirical studies. RESULTS: PPI annotations are built combinatorically using corresponding GO terms and InterPro annotation. We use a S.cerevisiae high-confidence complex dataset as a positive training set. A series of classifiers based on Maximum Entropy and support vector machines (SVMs), each with a composite counterpart algorithm, are trained on a series of training sets. These achieve a high performance area under the ROC curve of ≤0.97, outperforming go2ppi-a previously established prediction tool for protein-protein interactions (PPI) based on Gene Ontology (GO) annotations. AVAILABILITY AND IMPLEMENTATION: https://github.com/ima23/maxent-ppi. CONTACT: [email protected]. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online

The politics of in/visibility: carving out queer space in Ul'yanovsk

<p>In spite of a growing interest within sexualities studies in the concept of queer space (Oswin 2008), existing literature focuses almost exclusively on its most visible and territorialised forms, such as the gay scene, thus privileging Western metropolitan areas as hubs of queer consumer culture (Binnie 2004). While the literature has emphasised the political significance of queer space as a site of resistance to hegemonic gender and sexual norms, it has again predominantly focused on overt claims to public space embodied in Pride events, neglecting other less open forms of resistance.</p><p> This article contributes new insights to current debates about the construction and meaning of queer space by considering how city space is appropriated by an informal queer network in Ul’ianovsk. The group routinely occupied very public locations meeting and socialising on the street or in mainstream cafés in central Ul’ianovsk, although claims to these spaces as queer were mostly contingent, precarious or invisible to outsiders. The article considers how provincial location affects tactics used to carve out communal space, foregrounding the importance of local context and collective agency in shaping specific forms of resistance, and questioning ethnocentric assumptions about the empowering potential of visibility.</p&gt

Whose voices should shape global health education? Curriculum codesign and codelivery by people with direct expertise and lived experience

There are contrasting opinions of what Global Health (GH) curricula should contain and limited discussion on whose voices should shape it. In GH education, those with first-hand expertise of living and working in the contexts discussed in GH classrooms are often absent when designing curricula. To address this, we developed a new model of curriculum co-design called Virtual Roundtable for Collaborative Education Design (ViRCoED). This paper describes the rationale and outputs of the ViRCoED approach in designing a new section of the Global Health BSc curriculum at Imperial College London, with a focus on healthcare in the Syrian conflict. The team, importantly, involved partners with lived and/or professional experience of the conflict as well as alumni of the course, and educators in all stages of design and delivery through to marking and project evaluation. The project experimented with disrupting power dynamics and extending ownership of the curriculum beyond traditional faculty by co-designing and co-delivering module contents together with colleagues with direct expertise and experience of the Syrian context. An authentic approach was applied to assessment design using real-time syndromic healthcare data from the Aleppo and Idlib Governorates. We discuss the challenges involved in our collaborative partnership and describe how it may have enhanced the validity of our curriculum with students engaging in a richer representation of key health issues in the conflict. We observed an enhanced self-reflexivity in the students’ approach to quantitative data and its complex interpretation. The dialogic nature of this collaborative design was also a formative process for partners and an opportunity for GH educators to reflect on their own positionality. The project aims to challenge current standards and structures in GH curriculum development and gesture towards a GH education sector eventually led by those with lived experience and expertise to significantly enhance the validity of GH education

Stringent neutron-star limits on large extra dimensions

Supernovae (SNe) are copious sources for Kaluza-Klein gravitons which are generic for theories with large extra dimensions. These massive particles are produced with average velocities ~0.5 c so that many of them are gravitationally retained by the SN core. Every neutron star thus has a halo of KK gravitons which decay into nu bar-nu, e^+e^- and gamma gamma on time scales \~10^9 years. The EGRET gamma-flux limits (E_gamma ~ 100 MeV) for nearby neutron stars constrain the fundamental scale for n=2 extra dimensions to M >500 TeV, and M>30 TeV for n=3. The upcoming GLAST satellite is a factor ~30 more sensitive and thus may detect KK decays, for example at the nearby neutron star RX J185635--3754. The requirement that neutron stars are not excessively heated by KK decays implies M>1700 TeV for n=2, and M>60 TeV for n=3.Comment: Minor changes, matches version to appear in PR

Juvenile Dermatomyositis: what comes next? Long-term outcomes in childhood myositis from a patient perspective

BACKGROUND: To describe long-term outcomes in JDM using patient questionnaires and link to longitudinal, prospectively collected data for each patient within the Juvenile Dermatomyositis Cohort and Biomarker Study, UK and Ireland (JDCBS) to determine outcome predictors.  METHODS: JDCBS participants aged ≥ 16y completed the SF36, HAQ and a questionnaire regarding current disease features, medications, education and employment. Data collected from the JDCBS included disease subtype, demographics, clinical and laboratory features. Intensity indices were calculated for physician VAS, modified skin DAS, CMAS and MMT8 by dividing area under the curve (AUC) from longitudinal score trajectories by duration of study follow-up (y). Relationships between questionnaire and JDCBS clinical / laboratory data were investigated fitting statistical models appropriate for cross sectional and longitudinal data. RESULTS: Of 190 questionnaires sent, 84 (44%) were returned. Average age of respondents was 20.6 years (SD 3.9), time since diagnosis was 12.4 years (SD 5.0), age at onset was 9.2 years (SD 4.3), female to male ratio 4.25:1. Forty-nine (59%) self-reported persistently active disease, 54 (65%) were still taking immunosuppressive medication. 14/32 at school/higher education reported myositis adversely affecting academic results. 18–24 year-olds were twice as likely to be unemployed compared the UK population (OR = 0.456, 95% CI 0.24, 0.84, p = 0.001). Participants ≥ 18 years were three times as likely to be living with a parent/guardian (OR = 3.39, p < 0.001). SF36 MCS and MMT8 intensity index scores were significantly correlated (ρ = 0.328, p = 0.007). CONCLUSIONS: After 12.4 years, questionnaire responders reported self-perceived high rates of persistently active disease and medication use, reduced rates of employment and were more likely to live with a parent/guardian. Perceived persistently active muscle disease appeared to affect quality of life in these patients and was the most significant contributor to long-term outcomes. Our findings highlight the importance of including the patient perspective in the assessment of long term outcomes, so that that we can start to target initial management strategies more effectively based on a combination of clinical and patient-reported data