Strain-dependent host transcriptional responses to toxoplasma infection are largely conserved in mammalian and avian hosts

Toxoplasma gondii has a remarkable ability to infect an enormous variety of mammalian and avian species. Given this, it is surprising that three strains (Types I/II/III) account for the majority of isolates from Europe/North America. The selective pressures that have driven the emergence of these particular strains, however, remain enigmatic. We hypothesized that strain selection might be partially driven by adaptation of strains for mammalian versus avian hosts. To test this, we examine in vitro, strain-dependent host responses in fibroblasts of a representative avian host, the chicken (Gallus gallus). Using gene expression profiling of infected chicken embryonic fibroblasts and pathway analysis to assess host response, we show here that chicken cells respond with distinct transcriptional profiles upon infection with Type II versus III strains that are reminiscent of profiles observed in mammalian cells. To identify the parasite drivers of these differences, chicken fibroblasts were infected with individual F1 progeny of a Type II x III cross and host gene expression was assessed for each by microarray. QTL mapping of transcriptional differences suggested, and deletion strains confirmed, that, as in mammalian cells, the polymorphic rhoptry kinase ROP16 is the major driver of strain-specific responses. We originally hypothesized that comparing avian versus mammalian host response might reveal an inversion in parasite strain-dependent phenotypes; specifically, for polymorphic effectors like ROP16, we hypothesized that the allele with most activity in mammalian cells might be less active in avian cells. Instead, we found that activity of ROP16 alleles appears to be conserved across host species; moreover, additional parasite loci that were previously mapped for strain-specific effects on mammalian response showed similar strain-specific effects in chicken cells. These results indicate that if different hosts select for different parasite genotypes, the selection operates downstream of the signaling occurring during the beginning of the host's immune response. © 2011 Ong et al

Predictive use of the Maximum Entropy Production principle for Past and Present Climates

In this paper, we show how the MEP hypothesis may be used to build simple climate models without representing explicitly the energy transport by the atmosphere. The purpose is twofold. First, we assess the performance of the MEP hypothesis by comparing a simple model with minimal input data to a complex, state-of-the-art General Circulation Model. Next, we show how to improve the realism of MEP climate models by including climate feedbacks, focusing on the case of the water-vapour feedback. We also discuss the dependence of the entropy production rate and predicted surface temperature on the resolution of the model

Intercomparison of the northern hemisphere winter mid-latitude atmospheric variability of the IPCC models

We compare, for the overlapping time frame 1962-2000, the estimate of the northern hemisphere (NH) mid-latitude winter atmospheric variability within the XX century simulations of 17 global climate models (GCMs) included in the IPCC-4AR with the NCEP and ECMWF reanalyses. We compute the Hayashi spectra of the 500hPa geopotential height fields and introduce an integral measure of the variability observed in the NH on different spectral sub-domains. Only two high-resolution GCMs have a good agreement with reanalyses. Large biases, in most cases larger than 20%, are found between the wave climatologies of most GCMs and the reanalyses, with a relative span of around 50%. The travelling baroclinic waves are usually overestimated, while the planetary waves are usually underestimated, in agreement with previous studies performed on global weather forecasting models. When comparing the results of various versions of similar GCMs, it is clear that in some cases the vertical resolution of the atmosphere and, somewhat unexpectedly, of the adopted ocean model seem to be critical in determining the agreement with the reanalyses. The GCMs ensemble is biased with respect to the reanalyses but is comparable to the best 5 GCMs. This study suggests serious caveats with respect to the ability of most of the presently available GCMs in representing the statistics of the global scale atmospheric dynamics of the present climate and, a fortiori, in the perspective of modelling climate change.Comment: 39 pages, 8 figures, 2 table

Entropy production and coarse graining of the climate fields in a general circulation model

We extend the analysis of the thermodynamics of the climate system by investigating the role played by processes taking place at various spatial and temporal scales through a procedure of coarse graining. We show that the coarser is the graining of the climatic fields, the lower is the resulting estimate of the material entropy production. In other terms, all the spatial and temporal scales of variability of the thermodynamic fields provide a positive contribution to the material entropy production. This may be interpreted also as that, at all scales, the temperature fields and the heating fields resulting from the convergence of turbulent fluxes have a negative correlation, while the opposite holds between the temperature fields and the radiative heating fields. Moreover, we obtain that the latter correlations are stronger, which confirms that radiation acts as primary driver for the climatic processes, while the material fluxes dampen the resulting fluctuations through dissipative processes. We also show, using specific coarse-graining procedures, how one can separate the various contributions to the material entropy production coming from the dissipation of kinetic energy, the vertical sensible and latent heat fluxes, and the large scale horizontal fluxes, without resorting to the full three-dimensional time dependent fields. We find that most of the entropy production is associated to irreversible exchanges occurring along the vertical direction, and that neglecting the horizontal and time variability of the fields has a relatively small impact on the estimate of the material entropy production. The approach presented here seems promising for testing climate models, for assessing the impact of changing their parametrizations and their resolution, as well as for investigating the atmosphere of exoplanets, because it allows for evaluating the error in the estimate of their thermodynamical properties due to the lack of high-resolution data. The findings on the impact of coarse graining on the thermodynamic fields on the estimate of the material entropy production deserve to be explored in a more general context, because they provide a way for understanding the relationship between forced fluctuations and dissipative processes in continuum systems

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Mast Cells Express 11 beta-hydroxysteroid Dehydrogenase Type 1: A Role in Restraining Mast Cell Degranulation:a role in restraining mast cell degranulation

Mast cells are key initiators of allergic, anaphylactic and inflammatory reactions, producing mediators that affect vascular permeability, angiogenesis and fibrosis. Glucocorticoid pharmacotherapy reduces mast cell number, maturation and activation but effects at physiological levels are unknown. Within cells, glucocorticoid concentration is modulated by the 11β-hydroxysteroid dehydrogenases (11β-HSDs). Here we show expression and activity of 11β-HSD1, but not 11β-HSD2, in mouse mast cells with 11β-HSD activity only in the keto-reductase direction, regenerating active glucocorticoids (cortisol, corticosterone) from inert substrates (cortisone, 11-dehydrocorticosterone). Mast cells from 11β-HSD1-deficient mice show ultrastructural evidence of increased activation, including piecemeal degranulation and have a reduced threshold for IgG immune complex-induced mast cell degranulation. Consistent with reduced intracellular glucocorticoid action in mast cells, levels of carboxypeptidase A3 mRNA, a glucocorticoid-inducible mast cell-specific transcript, are lower in peritoneal cells from 11β-HSD1-deficient than control mice. These findings suggest that 11β-HSD1-generated glucocorticoids may tonically restrain mast cell degranulation, potentially influencing allergic, anaphylactic and inflammatory responses

Transcriptional Analysis of Murine Macrophages Infected with Different Toxoplasma Strains Identifies Novel Regulation of Host Signaling Pathways

Most isolates of Toxoplasma from Europe and North America fall into one of three genetically distinct clonal lineages, the type I, II and III lineages. However, in South America these strains are rarely isolated and instead a great variety of other strains are found. T. gondii strains differ widely in a number of phenotypes in mice, such as virulence, persistence, oral infectivity, migratory capacity, induction of cytokine expression and modulation of host gene expression. The outcome of toxoplasmosis in patients is also variable and we hypothesize that, besides host and environmental factors, the genotype of the parasite strain plays a major role. The molecular basis for these differences in pathogenesis, especially in strains other than the clonal lineages, remains largely unexplored. Macrophages play an essential role in the early immune response against T. gondii and are also the cell type preferentially infected in vivo. To determine if non-canonical Toxoplasma strains have unique interactions with the host cell, we infected murine macrophages with 29 different Toxoplasma strains, representing global diversity, and used RNA-sequencing to determine host and parasite transcriptomes. We identified large differences between strains in the expression level of known parasite effectors and large chromosomal structural variation in some strains. We also identified novel strain-specifically regulated host pathways, including the regulation of the type I interferon response by some atypical strains. IFNβ production by infected cells was associated with parasite killing, independent of interferon gamma activation, and dependent on endosomal Toll-like receptors in macrophages and the cytoplasmic receptor retinoic acid-inducible gene 1 (RIG-I) in fibroblasts.National Institutes of Health (U.S.) (R01-AI080621)New England Regional Center of Excellence for Biodefense and Emerging Infectious Diseases (Developmental Grant AIO57159)Pew Charitable Trusts (Biomedical Scholars Program)Robert A. Swanson Career Development awardThe Knights Templar Eye Foundation, Inc.Pre-Doctoral Grant in the Biological Sciences (5-T32-GM007287-33)Cleo and Paul Schimmel Foundatio

New challenges for BRCA testing:a view from the diagnostic laboratory

Increased demand for BRCA testing is placing pressures on diagnostic laboratories to raise their mutation screening capacity and handle the challenges associated with classifying BRCA sequence variants for clinical significance, for example interpretation of pathogenic mutations or variants of unknown significance, accurate determination of large genomic rearrangements and detection of somatic mutations in DNA extracted from formalin-fixed, paraffin-embedded tumour samples. Many diagnostic laboratories are adopting next-generation sequencing (NGS) technology to increase their screening capacity and reduce processing time and unit costs. However, migration to NGS introduces complexities arising from choice of components of the BRCA testing workflow, such as NGS platform, enrichment method and bioinformatics analysis process. An efficient, cost-effective accurate mutation detection strategy and a standardised, systematic approach to the reporting of BRCA test results is imperative for diagnostic laboratories. This review covers the challenges of BRCA testing from the perspective of a diagnostics laboratory

Predicting climate change using response theory: global averages and spatial patterns

The provision of accurate methods for predicting the climate response to anthropogenic and natural forcings is a key contemporary scientific challenge. Using a simplified and efficient open-source general circulation model of the atmosphere featuring O(105105) degrees of freedom, we show how it is possible to approach such a problem using nonequilibrium statistical mechanics. Response theory allows one to practically compute the time-dependent measure supported on the pullback attractor of the climate system, whose dynamics is non-autonomous as a result of time-dependent forcings. We propose a simple yet efficient method for predicting—at any lead time and in an ensemble sense—the change in climate properties resulting from increase in the concentration of CO22 using test perturbation model runs. We assess strengths and limitations of the response theory in predicting the changes in the globally averaged values of surface temperature and of the yearly total precipitation, as well as in their spatial patterns. The quality of the predictions obtained for the surface temperature fields is rather good, while in the case of precipitation a good skill is observed only for the global average. We also show how it is possible to define accurately concepts like the inertia of the climate system or to predict when climate change is detectable given a scenario of forcing. Our analysis can be extended for dealing with more complex portfolios of forcings and can be adapted to treat, in principle, any climate observable. Our conclusion is that climate change is indeed a problem that can be effectively seen through a statistical mechanical lens, and that there is great potential for optimizing the current coordinated modelling exercises run for the preparation of the subsequent reports of the Intergovernmental Panel for Climate Change

Broadening Risk Factor or Disease Definition as a Driver for Overdiagnosis: A Narrative Review

Medical overuse-defined as the provision of health services for which potential harms exceed potential benefits-constitutes a paradigm of low-value care and is seen as a threat to the quality of care. Value in healthcare implies a precise definition of disease. However, defining a disease may not be straightforward since clinical data do not show discrete boundaries, calling for some clinical judgment. And, if in time a redefinition of disease is needed, it is important to recognize that it can induce overdiagnosis, the identification of medical conditions that would, otherwise, never cause any significant symptoms or lead to clinical harm. A classic example is the impact of recommendations from professional societies in the late 1990s, lowering the threshold for abnormal total cholesterol from 240 mg/dl to 200 mg/dl. Due to these changes in risk factor definition, literally overnight there were 42 million new cases eligible for treatment in the United States. The same happened with hypertension-using either the 2019 NICE guidelines or the 2018 ESC/ECC guidelines criteria for arterial hypertension, the proportion of people overdiagnosed with hypertension was calculated to be between 14% and 33%. In this review, we will start by discussing resource overuse. We then present the basis for disease definition and its conceptual problems. Finally, we will discuss the impact of changing risk factor/disease definitions in the prevalence of disease and its consequences in overdiagnosis and overtreatment (a problem particularly relevant when definitions are widened to include earlier or milder disease).info:eu-repo/semantics/publishedVersio