Model studies on the role of moist convection as a mechanism for interaction between the mesoscales

A three year research effort is described which had as its goal the development of techniques to improve the numerical prediction of cumulus convection on the meso-beta and meso-gamma scales. Two MESO models are used, the MASS (mesoscale) and TASS (cloud scale) models. The primary meteorological situation studied is the 28-29 Jun. 1986 Cooperative Huntsville Meteorological Experiment (COHMEX) study area on a day with relatively weak large scale forcing. The problem of determining where and when convection should be initiated is considered to be a major problem of current approaches. Assimilation of moisture data from satellite, radar, and surface data is shown to significantly improve mesoscale simulations. The TASS model is shown to reproduce some observed mesoscale features when initialized with 3-D observational data. Convection evolution studies center on comparison of the Kuo and Fritsch-Chappell cumulus parameterization schemes to each other, and to cloud model results. The Fritsch-Chappell scheme is found to be superior at about 30 km resolution, while the Kuo scheme does surprisingly well in simulating convection down to 10 km in cases where convergence features are well-resolved by the model grid. Results from MASS-TASS interaction experiments are presented and discussed. A discussion of the future of convective simulation is given, with the conclusion that significant progress is possible on several fronts in the next few years

The structure of human 5-lipoxygenase

The synthesis of both proinflammatory leukotrienes and anti-inflammatory lipoxins requires the enzyme 5-lipoxygenase (5-LOX). 5-LOX activity is short-lived, apparently in part because of an intrinsic instability of the enzyme. We identified a 5-LOX-specific destabilizing sequence that is involved in orienting the carboxyl terminus, which binds the catalytic iron. Here, we report the crystal structure at 2.4 angstrom resolution of human 5-LOX stabilized by replacement of this sequence

Conversion of human 5-lipoxygenase to a 15-lipoxygenase by a point mutation to mimic phosphorylation at Serine-663

The enzyme 5-lipoxygenase (5-LOX) initiates biosynthesis of the proinflammatory leukotriene lipid mediators and, together with 15-LOX, is also required for synthesis of the anti-inflammatory lipoxins. The catalytic activity of 5-LOX is regulated through multiple mechanisms, including Ca 2+-targeted membrane binding and phosphorylation at specific serine residues. To investigate the consequences of phosphorylation at S663, we mutated the residue to the phosphorylation mimic Asp, providing a homogenous preparation suitable for catalytic and structural studies. The S663D enzyme exhibits robust 15-LOX activity, as determined by spectrophotometric and HPLC analyses, with only traces of 5-LOX activity remaining; synthesis of the anti-inflammatory lipoxin A4 from arachidonic acid is also detected. The crystal structure of the S663D mutant in the absence and presence of arachidonic acid (in the context of the previously reported Stable-5-LOX) reveals substantial remodeling of helices that define the active site so that the once fully encapsulated catalytic machinery is solvent accessible. Our results suggest that phosphorylation of 5-LOX at S663 could not only down-regulate leukotriene synthesis but also stimulate lipoxin production in inflammatory cells that do not express 15-LOX, thus redirecting lipid mediator biosynthesis to the production of proresolving mediators of inflammation. © FASEB

TIGIT can inhibit T cell activation via ligation-induced nanoclusters, independent of CD226 co-stimulation

TIGIT is an inhibitory receptor expressed on lymphocytes and can inhibit T cells by preventing CD226 co-stimulation through interactions in cis or through competition of shared ligands. Whether TIGIT directly delivers cell-intrinsic inhibitory signals in T cells remains unclear. Here we show, by analysing lymphocytes from matched human tumour and peripheral blood samples, that TIGIT and CD226 co-expression is rare on tumour-infiltrating lymphocytes. Using super-resolution microscopy and other techniques, we demonstrate that ligation with CD155 causes TIGIT to reorganise into dense nanoclusters, which coalesce with T cell receptor (TCR)-rich clusters at immune synapses. Functionally, this reduces cytokine secretion in a manner dependent on TIGIT’s intracellular ITT-like signalling motif. Thus, we provide evidence that TIGIT directly inhibits lymphocyte activation, acting independently of CD226, requiring intracellular signalling that is proximal to the TCR. Within the subset of tumours where TIGIT-expressing cells do not commonly co-express CD226, this will likely be the dominant mechanism of action

Safety and immunogenicity of AS03B adjuvanted split virion versus non-adjuvanted whole virion H1N1 influenza vaccine in UK children aged 6 months-12 years: open label, randomised, parallel group, multicentre study

Objectives To compare the safety, reactogenicity, and immunogenicity of an adjuvanted split virion H1N1 vaccine and a non-adjuvanted whole virion vaccine used in the pandemic immunisation programme in the United Kingdom

Community-acquired pneumonia in the United Kingdom:a call to action

Abstract Pneumococcal disease has a high burden in adults in the United Kingdom (UK); however, the total burden is underestimated, principally because most cases of community-acquired pneumonia (CAP) are non-invasive. Research into pneumonia receives poor funding relative to its disease burden (global mortality, disability-adjusted life years, and years lived with disability), ranking just 20 out of 25 for investment in infectious diseases in the UK. The current accuracy of data for establishing incidence rates is questionable, and it is a reflection of the paucity of research that much of the background information available derives from nearly 30 years ago. Given the relationship between CAP and mortality (pneumonia accounts for 29,000 deaths per annum in the UK, and 5–15% of patients hospitalised with CAP die within 30 days of admission), and the increasing threat of antimicrobial resistance associated with inappropriate antibiotic prescribing, such neglect of a highly prevalent problem is concerning. In this Call to Action, we explore the poorly understood burden of CAP in the UK, discuss the importance of an accurate diagnosis and appropriate treatment, and suggest how national collaboration could improve the management of an often life-threatening, yet potentially preventable disease

The convective storm initiation project

Copyright @ 2007 AMSThe Convective Storm Initiation Project (CSIP) is an international project to understand precisely where, when, and how convective clouds form and develop into showers in the mainly maritime environment of southern England. A major aim of CSIP is to compare the results of the very high resolution Met Office weather forecasting model with detailed observations of the early stages of convective clouds and to use the newly gained understanding to improve the predictions of the model. A large array of ground-based instruments plus two instrumented aircraft, from the U.K. National Centre for Atmospheric Science (NCAS) and the German Institute for Meteorology and Climate Research (IMK), Karlsruhe, were deployed in southern England, over an area centered on the meteorological radars at Chilbolton, during the summers of 2004 and 2005. In addition to a variety of ground-based remote-sensing instruments, numerous rawin-sondes were released at one- to two-hourly intervals from six closely spaced sites. The Met Office weather radar network and Meteosat satellite imagery were used to provide context for the observations made by the instruments deployed during CSIP. This article presents an overview of the CSIP field campaign and examples from CSIP of the types of convective initiation phenomena that are typical in the United Kingdom. It shows the way in which certain kinds of observational data are able to reveal these phenomena and gives an explanation of how the analyses of data from the field campaign will be used in the development of an improved very high resolution NWP model for operational use.This work is funded by the National Environment Research Council following an initial award from the HEFCE Joint Infrastructure Fund

Neutrophils in cancer: neutral no more

Neutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view. The traditionally held belief that neutrophils are inert bystanders is being challenged by the recent literature. Emerging evidence indicates that tumours manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumour behaviour. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets

Effect of Pneumococcal Conjugate Vaccination on Serotype-Specific Carriage and Invasive Disease in England: A Cross-Sectional Study

A cross sectional study by Stefan Flasche and coworkers document the serotype replacement of Streptococcus pneumoniae that has occurred in England since the introduction of PCV7 vaccination

Problems in obtaining precise and accurate Sr isotope analysis from geological materials using laser ablation MC-ICPMS

This paper reviews the problems encountered in eleven studies of Sr isotope analysis using laser ablation multicollector inductively coupled plasma mass spectrometry (LA-MC-ICPMS) in the period 1995–2006. This technique has been shown to have great potential, but the accuracy and precision are limited by: (1) large instrumental mass discrimination, (2) laser-induced isotopic and elemental fractionations and (3) molecular interferences. The most important isobaric interferences are Kr and Rb, whereas Ca dimer/argides and doubly charged rare earth elements (REE) are limited to sample materials which contain substantial amounts of these elements. With modern laser (193 nm) and MC-ICPMS equipment, minerals with >500 ppm Sr content can be analysed with a precision of better than 100 ppm and a spatial resolution (spot size) of approximately 100 μm. The LA MC-ICPMS analysis of 87Sr/86Sr of both carbonate material and plagioclase is successful in all reported studies, although the higher 84Sr/86Sr ratios do suggest in some cases an influence of Ca dimer and/or argides. High Rb/Sr (>0.01) materials have been successfully analysed by carefully measuring the 85Rb/87Rb in standard material and by applying the standard-sample bracketing method for accurate Rb corrections. However, published LA-MC-ICPMS data on clinopyroxene, apatite and sphene records differences when compared with 87Sr/86Sr measured by thermal ionisation mass spectrometry (TIMS) and solution MC-ICPMS. This suggests that further studies are required to ensure that the most optimal correction methods are applied for all isobaric interferences