Contact with farming environment as a major risk factor for Shiga toxin (Vero cytotoxin)-producing Escherichia coli O157 infection in humans.

In a prospective, unmatched case-control study of sporadic Shiga toxin (Vero cytotoxin)-producing Escherichia coli O157 (STEC O157) infection in England, exposure to the farming environment emerged strongly as a risk factor (adjusted odds ratio = 2.45; 95% confidence intervals = 1.49-4.02; p=0.0004) posing further challenges and opportunities for prevention

INFERNO: a fire and emissions scheme for the UK Met Office's Unified Model

Warm and dry climatological conditions favour the occurrence of forest fires. These fires then become a significant emission source to the atmosphere. Despite this global importance, fires are a local phenomenon and are difficult to represent in a large-scale Earth System Model (ESM). To address this, the INteractive Fire and Emission algoRithm for Natural envirOnments (INFERNO) was developed. INFERNO follows a reduced complexity approach and is intended for decadal to centennial scale climate simulations and assessment models for policy making. Fuel flammability is simulated using temperature, relative humidity, fuel density as well as precipitation and soil moisture. Combining flammability with ignitions and vegetation, burnt area is diagnosed. Emissions of carbon and key species are estimated using the carbon scheme in the JULES land surface model. JULES also possesses fire index diagnostics which we document and compare with our fire scheme. Two meteorology datasets and three ignition modes are used to validate the model. INFERNO is shown to effectively diagnose global fire occurrence (R = 0.66) and emissions (R = 0.59) through an approach appropriate to the complexity of an ESM, although regional biases remain

Two-dimensional models of hydrodynamical accretion flows into black holes

We present a systematic numerical study of two-dimensional axisymmetric accretion flows around black holes. The flows have no radiative cooling and are treated in the framework of the hydrodynamical approximation. The models calculated in this study cover the large range of the relevant parameter space. There are four types of flows, determined by the values of the viscosity parameter $\alpha$ and the adiabatic index $\gamma$: convective flows, large-scale circulations, pure inflows and bipolar outflows. Thermal conduction introduces significant changes to the solutions, but does not create a new flow type. Convective accretion flows and flows with large-scale circulations have significant outward-directed energy fluxes, which have important implications for the spectra and luminosities of accreting black holes.Comment: 43 pages, 23 figures, submitted to Ap

On the Radial Structure of Radiatively Inefficient Accretion Flows with Convection

We consider the radial structure of radiatively inefficient hydrodynamic accretion flows around black holes. We show that low-viscosity flows consist of two zones: an outer convection-dominated zone and an inner advection-dominated zone. The transition between these two zones occurs at ~50 Schwarzschild radii.Comment: 11 pages, 3 figures, accepted for publication in Ap

Three-dimensional MHD Simulations of Radiatively Inefficient Accretion Flows

We present three-dimensional MHD simulations of rotating radiatively inefficient accretion flows onto black holes. In the simulations, we continuously inject magnetized matter into the computational domain near the outer boundary, and we run the calculations long enough for the resulting accretion flow to reach a quasi-steady state. We have studied two limiting cases for the geometry of the injected magnetic field: pure toroidal field and pure poloidal field. In the case of toroidal field injection, the accreting matter forms a nearly axisymmetric, geometrically-thick, turbulent accretion disk. The disk resembles in many respects the convection-dominated accretion flows found in previous numerical and analytical investigations of viscous hydrodynamic flows. Models with poloidal field injection evolve through two distinct phases. In an initial transient phase, the flow forms a relatively flattened, quasi-Keplerian disk with a hot corona and a bipolar outflow. However, when the flow later achieves steady state, it changes in character completely. The magnetized accreting gas becomes two-phase, with most of the volume being dominated by a strong dipolar magnetic field from which a thermal low-density wind flows out. Accretion occurs mainly via narrow slowly-rotating radial streams which `diffuse' through the magnetic field with the help of magnetic reconnection events.Comment: 35 pages including 3 built-in plots and 14 separate jpg-plots; version accepted by Ap

Heterogeneity in Surface Sensing Suggests a Division of Labor in Pseudomonas aeruginosa Populations

The second messenger signaling molecule cyclic diguanylate monophosphate (c-di-GMP) drives the transition between planktonic and biofilm growth in many bacterial species. Pseudomonas aeruginosa has two surface sensing systems that produce c-di-GMP in response to surface adherence. Current thinking in the field is that once cells attach to a surface, they uniformly respond by producing c-di-GMP. Here, we describe how the Wsp system generates heterogeneity in surface sensing, resulting in two physiologically distinct subpopulations of cells. One subpopulation has elevated c-di-GMP and produces biofilm matrix, serving as the founders of initial microcolonies. The other subpopulation has low c-di-GMP and engages in surface motility, allowing for exploration of the surface. We also show that this heterogeneity strongly correlates to surface behavior for descendent cells. Together, our results suggest that after surface attachment, P. aeruginosa engages in a division of labor that persists across generations, accelerating early biofilm formation and surface exploration

Assessing methods for representing soil heterogeneity through a flexible approach within the Joint UK Land Environment Simulator (JULES) at version 3.4.1

The interactions between the land surface and the atmosphere can impact weather and climate through the exchanges of water, energy, carbon and momentum. The properties of the land surface are important when modelling these exchanges correctly especially with models being used at increasingly higher resolution. The Joint UK Land Environment Simulator (JULES) currently uses a tiled representation of land cover but can only model a single dominant soil type within a grid box. Hence, there is no representation of sub-grid-scale soil heterogeneity. This paper introduces and evaluates a new flexible surface–soil tiling scheme in JULES. Several different soil tiling approaches are presented for a synthetic case study. The changes to model performance have been compared to the current single-soil scheme and a high-resolution “Truth” scenario. Results have shown that the different soil tiling strategies do have an impact on the water and energy exchanges due to the way vegetation accesses the soil moisture. Tiling the soil according to the surface type, with the soil properties set to the dominant soil type under each surface is the best performing configuration. The results from this setup simulate water and energy fluxes that are the closest to the high-resolution Truth scenario but require much less information on the soil type than the high-resolution soil configuration.</p

The clinical efficacy of first-generation carcinoembryonic antigen (CEACAM5)-specific CAR T cells is limited by poor persistence and transient pre-conditioning-dependent respiratory toxicity

The primary aim of this clinical trial was to determine the feasibility of delivering first-generation CAR T cell therapy to patients with advanced, CEACAM5(+) malignancy. Secondary aims were to assess clinical efficacy, immune effector function and optimal dose of CAR T cells. Three cohorts of patients received increasing doses of CEACAM5(+)-specific CAR T cells after fludarabine pre-conditioning plus systemic IL2 support post T cell infusion. Patients in cohort 4 received increased intensity pre-conditioning (cyclophosphamide and fludarabine), systemic IL2 support and CAR T cells. No objective clinical responses were observed. CAR T cell engraftment in patients within cohort 4 was significantly higher. However, engraftment was short-lived with a rapid decline of systemic CAR T cells within 14 days. Patients in cohort 4 had transient, acute respiratory toxicity which, in combination with lack of prolonged CAR T cell persistence, resulted in the premature closure of the trial. Elevated levels of systemic IFNγ and IL-6 implied that the CEACAM5-specific T cells had undergone immune activation in vivo but only in patients receiving high-intensity pre-conditioning. Expression of CEACAM5 on lung epithelium may have resulted in this transient toxicity. Raised levels of serum cytokines including IL-6 in these patients implicate cytokine release as one of several potential factors exacerbating the observed respiratory toxicity. Whilst improved CAR designs and T cell production methods could improve the systemic persistence and activity, methods to control CAR T 'on-target, off-tissue' toxicity are required to enable a clinical impact of this approach in solid malignancies

CD3ζ-based chimeric antigen receptors mediate T cell activation viacis- andtrans-signalling mechanisms: implications for optimization of receptor structure for adoptive cell therapy

Chimeric antigen receptors (CARs) can mediate redirected lysis of tumour cells in a major histocompatibility complex (MHC)-independent manner, thereby enabling autologous adoptive T cell therapy for a variety of malignant neoplasms. Currently, most CARs incorporate the T cell receptor (TCR) CD3ζ signalling chain; however, the precise mechanisms responsible for CAR-mediated T cell activation are unclear. In this study, we used a series of immunoreceptor tyrosine-based activation motif (ITAM)-mutant and transmembrane-modified receptors to demonstrate that CARs activate T cells both directly via the antigen-ligated signalling chain and indirectly via associated chains within the TCR complex. These observations allowed us to generate new receptors capable of eliciting polyfunctional responses in primary human T cells. This work increases our understanding of CAR function and identifies new avenues for the optimization of CAR-based therapeutic interventions