90 research outputs found

    Consultancy-Based Projects

    Get PDF
    This chapter will:; ; ; Show how consultancy work can inform business discourse teaching;; ; ; Discuss how needs analysis and communication audits can be used to generate recommendations for teaching and training;; ; ; Profile a number of consultancy-based business discourse projects and show how they have informed training and course development;; ; ; Provide a case study, together with a set of tasks appropriate for the business discourse classroom, and a set of further readings

    A siRNA-Based Screen for Genes Involved in Chromosome End Protection

    Get PDF
    Telomeres are nucleoprotein complexes which protect the ends of linear chromosomes from detection as DNA damage and provide a sequence buffer against replication-associated shortening. In mammals, telomeres consist of repetitive DNA sequence (TTAGGG) and associated proteins. The telomeric core complex is called shelterin and is comprised of the proteins TRF1, TRF2, POT1, TIN2, TPP1 and RAP1. Excessive telomere shortening or de-protection of telomeres through the loss of shelterin subunits allows the detection of telomeres as DNA damage, which can be visualized as DNA damage protein foci at chromosome ends called TIF (Telomere Dysfunction-Induced Foci). We sought to exploit the TIF phenotype as marker for telomere dysfunction to identify novel genes involved in telomere protection by siRNA-mediated knock-down of a set of 386 candidates. Here we report the establishment, specificity and feasibility of such a screen and the results of the genes tested. Only one of the candidate genes showed a unique TIF phenotype comparable to the suppression of the main shelterin components TRF2 or TRF1 and that gene was identified as a TRF1-like pseudogene. We also identified a weak TIF phenotype for SKIIP (SNW1), a splicing factor and transcriptional co-activator. However, the knock-down of SKIIP also induced a general, not telomere-specific DNA damage response, which complicates conclusions about a telomeric role. In summary, this report is a technical demonstration of the feasibility of a cell-based screen for telomere deprotection with the potential of scaling it to a high-throughput approach

    Expression of the Serpin Serine Protease Inhibitor 6 Protects Dendritic Cells from Cytotoxic T Lymphocyte–Induced Apoptosis: Differential Modulation by T Helper Type 1 and Type 2 Cells

    Get PDF
    Dendritic cells (DCs) play a central role in the immune system as they drive activation of T lymphocytes by cognate interactions. However, as DCs express high levels of major histocompatibility complex class I, this intimate contact may also result in elimination of DCs by activated cytotoxic T lymphocytes (CTLs) and thereby limit induction of immunity. We show here that immature DCs are indeed susceptible to CTL-induced killing, but become resistant upon maturation with anti-CD40 or lipopolysaccharide. Protection is achieved by expression of serine protease inhibitor (SPI)-6, a member of the serpin family that specifically inactivates granzyme B and thereby blocks CTL-induced apoptosis. Anti-CD40 and LPS-induced SPI-6 expression is sustained for long periods of time, suggesting a role for SPI-6 in the longevity of DCs. Importantly, T helper 1 cells, which mature DCs and boost CTL immunity, induce SPI-6 expression and subsequent DC resistance. In contrast, T helper 2 cells neither induce SPI-6 nor convey protection, despite the fact that they trigger DC maturation with comparable efficiency. Our data identify SPI-6 as a novel marker for DC function, which protects DCs against CTL-induced apoptosis

    A wide field-of-view low-resolution spectrometer at APEX: Instrument design and scientific forecast

    Get PDF
    Context. Characterising the large-scale structure in the Universe from present times to the high redshift epoch of reionisation is essential to constraining the cosmology, the history of star formation, and reionisation, to measuring the gas content of the Universe, and to obtaining a better understanding of the physical processes that drive galaxy formation and evolution. Using the integrated emission from unresolved galaxies or gas clouds, line intensity mapping (LIM) provides a new observational window to measure the larger properties of structures. This very promising technique motivates the community to plan for LIM experiments. Aims. We describe the development of a large field-of-view instrument, named CONCERTO (for CarbON CII line in post-rEionisation and ReionisaTiOn epoch), operating in the range 130-310 GHz from the APEX 12-m telescope (5100 m above sea level). CONCERTO is a low-resolution spectrometer based on the lumped element kinetic inductance detectors (LEKID) technology. Spectra are obtained using a fast Fourier transform spectrometer (FTS), coupled to a dilution cryostat with a base temperature of 0.1 K. Two two kilo-pixel arrays of LEKID are mounted inside the cryostat that also contains the cold optics and the front-end electronics. Methods. We present, in detail, the technological choices leading to the instrumental concept, together with the design and fabrication of the instrument and preliminary laboratory tests on the detectors. We also give our best estimates for CONCERTO sensitivity and give predictions for two of the main scientific goals of CONCERTO, that is, a [CII]-intensity mapping survey and observations of galaxy clusters. Results. We provide a detailed description of the instrument design. Based on realistic comparisons with existing instruments developed by our group (NIKA, NIKA2, and KISS), and on the laboratory characterisation of our detectors, we provide an estimate for CONCERTO sensitivity on the sky. Finally, we describe, in detail, two of the main scientific goals offered by CONCERTO at APEX

    First demonstration of 30 eVee ionization energy resolution with Ricochet germanium cryogenic bolometers

    Full text link
    The future Ricochet experiment aims to search for new physics in the electroweak sector by measuring the Coherent Elastic Neutrino-Nucleus Scattering process from reactor antineutrinos with high precision down to the sub-100 eV nuclear recoil energy range. While the Ricochet collaboration is currently building the experimental setup at the reactor site, it is also finalizing the cryogenic detector arrays that will be integrated into the cryostat at the Institut Laue Langevin in early 2024. In this paper, we report on recent progress from the Ge cryogenic detector technology, called the CryoCube. More specifically, we present the first demonstration of a 30~eVee (electron equivalent) baseline ionization resolution (RMS) achieved with an early design of the detector assembly and its dedicated High Electron Mobility Transistor (HEMT) based front-end electronics. This represents an order of magnitude improvement over the best ionization resolutions obtained on similar heat-and-ionization germanium cryogenic detectors from the EDELWEISS and SuperCDMS dark matter experiments, and a factor of three improvement compared to the first fully-cryogenic HEMT-based preamplifier coupled to a CDMS-II germanium detector. Additionally, we discuss the implications of these results in the context of the future Ricochet experiment and its expected background mitigation performance.Comment: 10 pages, 5 figures, 1 tabl

    An Investigation of a Role for U2 snRNP Spliceosomal Components in Regulating Transcription

    Get PDF
    There is mounting evidence to suggest that the synthesis of pre-mRNA transcripts and their subsequent splicing are coordinated events. Previous studies have implicated the mammalian spliceosomal U2 snRNP as having a novel role in stimulating transcriptional elongation in vitro through interactions with the elongation factors P-TEFb and Tat-SF1; however, the mechanism remains unknown [1]. These factors are conserved in Saccharomyces cerevisiae, a fact that suggests that a similar interaction may occur in yeast to stimulate transcriptional elongation in vivo. To address this possibility we have looked for evidence of a role for the yeast Tat-SF1 homolog, Cus2, and the U2 snRNA in regulating transcription. Specifically, we have performed a genetic analysis to look for functional interactions between Cus2 or U2 snRNA and the P-TEFb yeast homologs, the Bur1/2 and Ctk1/2/3 complexes. In addition, we have analyzed Cus2-deleted or -overexpressing cells and U2 snRNA mutant cells to determine if they show transcription-related phenotypes similar to those displayed by the P-TEFb homolog mutants. In no case have we been able to observe phenotypes consistent with a role for either spliceosomal factor in transcription elongation. Furthermore, we did not find evidence for physical interactions between the yeast U2 snRNP factors and the P-TEFb homologs. These results suggest that in vivo, S. cerevisiae do not exhibit functional or physical interactions similar to those exhibited by their mammalian counterparts in vitro. The significance of the difference between our in vivo findings and the previously published in vitro results remains unclear; however, we discuss the potential importance of other factors, including viral proteins, in mediating the mammalian interactions

    Fast neutron background characterization of the future Ricochet experiment at the ILL research nuclear reactor

    Full text link
    The future Ricochet experiment aims at searching for new physics in the electroweak sector by providing a high precision measurement of the Coherent Elastic Neutrino-Nucleus Scattering (CENNS) process down to the sub-100 eV nuclear recoil energy range. The experiment will deploy a kg-scale low-energy-threshold detector array combining Ge and Zn target crystals 8.8 meters away from the 58 MW research nuclear reactor core of the Institut Laue Langevin (ILL) in Grenoble, France. Currently, the Ricochet collaboration is characterizing the backgrounds at its future experimental site in order to optimize the experiment's shielding design. The most threatening background component, which cannot be actively rejected by particle identification, consists of keV-scale neutron-induced nuclear recoils. These initial fast neutrons are generated by the reactor core and surrounding experiments (reactogenics), and by the cosmic rays producing primary neutrons and muon-induced neutrons in the surrounding materials. In this paper, we present the Ricochet neutron background characterization using 3^3He proportional counters which exhibit a high sensitivity to thermal, epithermal and fast neutrons. We compare these measurements to the Ricochet Geant4 simulations to validate our reactogenic and cosmogenic neutron background estimations. Eventually, we present our estimated neutron background for the future Ricochet experiment and the resulting CENNS detection significance.Comment: 14 pages, 14 figures, 1 tabl

    Quantitative Phosphoproteomics of CXCL12 (SDF-1) Signaling

    Get PDF
    CXCL12 (SDF-1) is a chemokine that binds to and signals through the seven transmembrane receptor CXCR4. The CXCL12/CXCR4 signaling axis has been implicated in both cancer metastases and human immunodeficiency virus type 1 (HIV-1) infection and a more complete understanding of CXCL12/CXCR4 signaling pathways may support efforts to develop therapeutics for these diseases. Mass spectrometry-based phosphoproteomics has emerged as an important tool in studying signaling networks in an unbiased fashion. We employed stable isotope labeling with amino acids in cell culture (SILAC) quantitative phosphoproteomics to examine the CXCL12/CXCR4 signaling axis in the human lymphoblastic CEM cell line. We quantified 4,074 unique SILAC pairs from 1,673 proteins and 89 phosphopeptides were deemed CXCL12-responsive in biological replicates. Several well established CXCL12-responsive phosphosites such as AKT (pS473) and ERK2 (pY204) were confirmed in our study. We also validated two novel CXCL12-responsive phosphosites, stathmin (pS16) and AKT1S1 (pT246) by Western blot. Pathway analysis and comparisons with other phosphoproteomic datasets revealed that genes from CXCL12-responsive phosphosites are enriched for cellular pathways such as T cell activation, epidermal growth factor and mammalian target of rapamycin (mTOR) signaling, pathways which have previously been linked to CXCL12/CXCR4 signaling. Several of the novel CXCL12-responsive phosphoproteins from our study have also been implicated with cellular migration and HIV-1 infection, thus providing an attractive list of potential targets for the development of cancer metastasis and HIV-1 therapeutics and for furthering our understanding of chemokine signaling regulation by reversible phosphorylation
    • …
    corecore