A non-myeloablative chimeric mouse model accurately defines microglia and macrophage contribution in glioma.

Resident and peripherally-derived glioma associated microglia/macrophages (GAMM) play a key role in driving tumour progression, angiogenesis, invasion, and attenuating host immune responses. Differentiating these cells' origins is challenging and current pre-clinical models such as irradiation-based adoptive transfer, parabiosis and transgenic mice have limitations. We aimed to develop a novel non-myeloablative transplantation (NMT) mouse model that permits high levels of peripheral chimerism without blood-brain barrier (BBB) damage or brain infiltration prior to tumour implantation.NMT dosing was determined in C57BL/6J or Pep3/CD45.1 mice conditioned with concentrations of busulfan ranging from 25mg/kg to 125mg/kg. Donor haematopoietic cells labelled with eGFP or CD45.2 were injected via tail vein. Donor chimerism was measured in peripheral blood, bone marrow and spleen using flow cytometry. BBB integrity was assessed with anti-IgG and anti-fibrinogen antibodies. Immunocompetent chimerised animals were orthotopically implanted with murine glioma GL-261 cells. Central and peripheral cell contributions were assessed using immunohistochemistry and flow cytometry. GAMM subpopulation analysis of peripheral cells was performed using Ly6C/MHCII/MerTK/CD64.NMT achieves >80% haematopoietic chimerism by 12 weeks without BBB damage and normal life span. Bone marrow derived cells (BMDC) and peripheral macrophages accounted for approximately 45% of the GAMM population in GL-261 implanted tumours. Existing markers such as CD45 high/low proved inaccurate to determine central and peripheral populations while Ly6C/MHCII/MerTK/CD64 reliably differentiated GAMM subpopulations in chimerised and unchimerised mice.NMT is a powerful method for dissecting tumour microglia and macrophage subpopulations and can guide further investigation of BMDC subsets in glioma and neuro-inflammatory diseases. This article is protected by copyright. All rights reserved

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

Privatisation

The increased intelligence support required for the global war on terrorism has led to exponential growth in the private intelligence industry. The privatisation of intelligence has been particularly apparent in the USA, where public-private collaboration now permeates practically all parts of the national intelligence effort. This chapter seeks to understand what is the privatisation of intelligence, and why the USA has increasingly relied on the private sector to carry out core intelligence functions. An examination of the US case reveals the risks posed by the privatisation of intelligence and the need for governments to plan and control their reliance on the private sector

Total Neutron Cross-Section Measurement on CH with a Novel 3D-Projection Scintillator Detector

Long-baseline neutrino oscillation experiments rely on detailed models of neutrino interactions on nuclei. These models constitute an important source of systematic uncertainty, partially because detectors to date have been unable to detect final state neutrons. A novel three-dimensional projection scintillator tracker will be a component of the upgraded off-axis near detector of the T2K experiment. Due to the good timing resolution and fine granularity, this technology is capable of measuring neutron kinematics in neutrino interactions on an event-by-event basis and will provide valuable data for refining neutrino interaction models. A prototype is exposed to the neutron beamline at Los Alamos National Laboratory with neutron energies between 0 and 800 MeV. In order to demonstrate the capability to measure neutron kinematics, the total neutron–scintillator cross section as a function of the neutron kinetic energy is measured