Immunoregulation by Mycobacterium vaccae: effects on CD11c+ antigen-presenting cells in a mouse model of pulmonary inflammation.

Throughout evolution, mammals have co-existed with many harmless organisms such as saprophytic mycobacteria. These "Old Friends" have helped the hosts' immune system to evolve immunoregulatory mechanisms that prevent inappropriate immune responses. Exposure, once a common occurrence has now become increasingly rare. A revised version of the hygiene hypothesis proposes that this reduced exposure may be a contributing factor to the recent increase in allergic diseases in developed countries. In models of allergic pulmonary inflammation, treatment with M. vaccae inhibits airway hyperreactivity and induces allergen specific regulatory T cells (Tregs), which secrete IL-10 and depend upon production of IL-10 and TGF-p in vivo. Since Treg-induction is dependent on antigen presenting cells (APCs) such as CD11c+ cells, this thesis addresses the effects that M. vaccae has on CD11c+ APCs, in a mouse model of allergic pulmonary inflammation. M. vaccae treatment reduces pulmonary allergic inflammation by decreasing type-2 responses such as eosinophilia and IL-4 expression. Rather than an increase in type-1 cytokines, IL-10 is elevated in the lungs, both at the protein and message level. Characterization of pulmonary CD11c+ APCs by ELISA, FACS and real time RT-PCR, shows an immunoregulatory cytokine profile with increased expression of IL-10, TGF-fJ and IFN-oc. In passive transfer experiments, CD11c+ cells appear not play a role as regulatory cells themselves, but may be involved in the induction of Treg through their cytokine release. In vitro studies show these CD11c+ APCs are capable of inducing naive T cells to become Tregs, as measured by increased production of IL-10 and Foxp3 expression. M. vaccae has been used in clinical trials of asthma and eczema, with encouraging results. This thesis goes some way to understanding one mechanism behind a potentially valuable form of immunotherapy

Far-infrared vibrational properties of high-pressure-high-temperature C60 polymers and the C60 dimer

We report high-resolution far-infrared transmission measurements of the 2 + 2 cycloaddition C-60 dimer and two-dimensional rhombohedral and one-dimensional orthorhombic high-pressure high-temperature C60 polymers. In the spectral region investigated(20-650 cm(-1)), we see no low-energy interball modes, but symmetry breaking of the linked C-60 balls is evident in the complex spectrum of intramolecular modes. Experimental features suggest large splittings or frequency shifts of some IhC60-derived modes that are activated by symmetry reduction, implying that the balls are strongly distorted in these structures. We have calculated the vibrations of all three systems by first-principles quantum molecular dynamics and use them to assign the predominant IhC60 symmetries of observed modes. Pur calculations show unprecedentedly large downshifts of T-1u(2)-derived modes and extremely large splittings of other modes, both of which are consistent with the experimental spectra. For the rhombohedral and orthorhombic polymers, the T-1u(2)-derived mode that is polarized along the bonding direction is calculated to downshift below any T-1u(1)-derived modes. We also identify a previously unassigned feature near 610 cm(-1) in all three systems as a widely split or shifted mode derived from various silent IhC60 vibrations, confirming a strong perturbation model for these linked fullerene structures

MerTK expressing hepatic macrophages promote the resolution of inflammation in acute liver failure

Objective: Acute liver failure (ALF) is characterised by overwhelming hepatocyte death and liver inflammation with massive infiltration of myeloid cells in necrotic areas. The mechanisms underlying resolution of acute hepatic inflammation are largely unknown. Here, we aimed to investigate the impact of Mer tyrosine kinase (MerTK) during ALF and also examine how the microenvironmental mediator, secretory leucocyte protease inhibitor (SLPI), governs this response. Design: Flow cytometry, immunohistochemistry, confocal imaging and gene expression analyses determined the phenotype, functional/transcriptomic profile and tissue topography of MerTK+ monocytes/macrophages in ALF, healthy and disease controls. The temporal evolution of macrophage MerTK expression and its impact on resolution was examined in APAP-induced acute liver injury using wild-type (WT) and Mer-deficient (Mer−/−) mice. SLPI effects on hepatic myeloid cells were determined in vitro and in vivo using APAP-treated WT mice. Results: We demonstrate a significant expansion of resolution-like MerTK+HLA-DRhigh cells in circulatory and tissue compartments of patients with ALF. Compared with WT mice which show an increase of MerTK+MHCIIhigh macrophages during the resolution phase in ALF, APAP-treated Mer−/− mice exhibit persistent liver injury and inflammation, characterised by a decreased proportion of resident Kupffer cells and increased number of neutrophils. Both in vitro and in APAP-treated mice, SLPI reprogrammes myeloid cells towards resolution responses through induction of a MerTK+HLA-DRhigh phenotype which promotes neutrophil apoptosis and their subsequent clearance. Conclusions: We identify a hepatoprotective, MerTK+, macrophage phenotype that evolves during the resolution phase following ALF and represents a novel immunotherapeutic target to promote resolution responses following acute liver injury

Hypogene Calcitization: Evaporite Diagenesis in the Western Delaware Basin

Evaporite calcitization within the Castile Formation of the Delaware Basin is more widespread and diverse than originally recognized. Coupled field and GIS studies have identified more than 1000 individual occurrences of calcitization within the Castile Formation outcrop area, which includes both calcitized masses (limestone buttes) and laterally extensive calcitized horizons (limestone sheets). Both limestone buttes and sheets commonly contain a central brecciated zone that we attribute to hypogene dissolution. Lithologic fabric of calcitized zones ranges from little alteration of original varved laminae to fabrics showing extensive laminae distortion as well as extensive vuggy and open cavernous porosity. Calcitization is most abundant in the western portion of the Castile outcrop region where surface denudation has been greatest. Calcitization often forms linear trends, indicating fluid migration along fractures, but also occurs as dense clusters indicating focused, ascending, hydrocarbon-rich fluids. Native sulfur, secondary tabular gypsum (i.e. selenite) and hypogene caves are commonly associated with clusters of calcitization. This assemblage suggests that calcium sulfate diagenesis within the Castile Formation is dominated by hypogene speleogemesis

The performance of the jet trigger for the ATLAS detector during 2011 data taking

The performance of the jet trigger for the ATLAS detector at the LHC during the 2011 data taking period is described. During 2011 the LHC provided proton–proton collisions with a centre-of-mass energy of 7 TeV and heavy ion collisions with a 2.76 TeV per nucleon–nucleon collision energy. The ATLAS trigger is a three level system designed to reduce the rate of events from the 40 MHz nominal maximum bunch crossing rate to the approximate 400 Hz which can be written to offline storage. The ATLAS jet trigger is the primary means for the online selection of events containing jets. Events are accepted by the trigger if they contain one or more jets above some transverse energy threshold. During 2011 data taking the jet trigger was fully efficient for jets with transverse energy above 25 GeV for triggers seeded randomly at Level 1. For triggers which require a jet to be identified at each of the three trigger levels, full efficiency is reached for offline jets with transverse energy above 60 GeV. Jets reconstructed in the final trigger level and corresponding to offline jets with transverse energy greater than 60 GeV, are reconstructed with a resolution in transverse energy with respect to offline jets, of better than 4 % in the central region and better than 2.5 % in the forward direction

Search for jet extinction in the inclusive jet-pT spectrum from proton-proton collisions at s=8 TeV

Published by the American Physical Society under the terms of the Creative Commons Attribution 3.0 License. Further distribution of this work must maintain attribution to the author(s) and the published articles title, journal citation, and DOI.The first search at the LHC for the extinction of QCD jet production is presented, using data collected with the CMS detector corresponding to an integrated luminosity of 10.7  fb−1 of proton-proton collisions at a center-of-mass energy of 8 TeV. The extinction model studied in this analysis is motivated by the search for signatures of strong gravity at the TeV scale (terascale gravity) and assumes the existence of string couplings in the strong-coupling limit. In this limit, the string model predicts the suppression of all high-transverse-momentum standard model processes, including jet production, beyond a certain energy scale. To test this prediction, the measured transverse-momentum spectrum is compared to the theoretical prediction of the standard model. No significant deficit of events is found at high transverse momentum. A 95% confidence level lower limit of 3.3 TeV is set on the extinction mass scale