An alternative conformation of ERβ bound to estradiol reveals H12 in a stable antagonist position

FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOThe natural ligand 17β-estradiol (E2) is so far believed to induce a unique agonist-bound active conformation in the ligand binding domain (LBD) of the estrogen receptors (ERs). Both subtypes, ERα and ERβ, are transcriptionally activated in the presence o7FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO2014/22007-02013/08293-72012/24750-6301981/2011-6This work was supported by the São Paulo Research Foundation FAPESP (grants 2014/22007-0, 2013/08293-7, 2012/24750-6) and by CNPq (grant 301981/2011-6

Modeling of biomass smoke injection into the lower stratosphere by a large forest fire (Part I): reference simulation

Wildland fires in boreal regions have the potential to initiate deep convection, so-called pyro-convection, due to their release of sensible heat. Under favorable atmospheric conditions, large fires can result in pyro-convection that transports the emissions into the upper troposphere and the lower stratosphere. Here, we present three-dimensional model simulations of the injection of fire emissions into the lower stratosphere by pyro-convection. These model simulations are constrained and evaluated with observations obtained from the Chisholm fire in Alberta, Canada, in 2001. The active tracer high resolution atmospheric model (ATHAM) is initialized with observations obtained by radiosonde. Information on the fire forcing is obtained from ground-based observations of the mass and moisture of the burned fuel. Based on radar observations, the pyro-convection reached an altitude of about 13 km, well above the tropopause, which was located at about 11.2 km. The model simulation yields a similarly strong convection with an overshoot of the convection above the tropopause. The main outflow from the pyro-convection occurs at about 10.6 km, but a significant fraction (about 8%) of the emitted mass of the smoke aerosol is transported above the tropopause. In contrast to regular convection, the region with maximum updraft velocity in the pyro-convection is located close to the surface above the fire. This results in high updraft velocities >10 m s^−1 at cloud base. The temperature anomaly in the plume decreases rapidly with height from values above 50 K at the fire to about 5 K at about 3000 m above the fire. While the sensible heat released from the fire is responsible for the initiation of convection in the model, the release of latent heat from condensation and freezing dominates the overall energy budget. Emissions of water vapor from the fire do not significantly contribute to the energy budget of the convection

Context Dependence, MOPs,WHIMs and procedures Recanati and Kaplan on Cognitive Aspects in Semantics

After presenting Kripke’s criticism to Frege’s ideas on context dependence of thoughts, I present two recent attempts of considering cognitive aspects of context dependent expressions inside a truth conditional pragmatics or semantics: Recanati’s non-descriptive modes of presentation (MOPs) and Kaplan’s ways of having in mind (WHIMs). After analysing the two attempts and verifying which answers they should give to the problem discussed by Kripke, I suggest a possible interpretation of these attempts: to insert a procedural or algorithmic level in semantic representations of indexicals. That a function may be computed by different procedures might suggest new possibilities of integrating contextual cognitive aspects in model theoretic semanti

The effect of harmonized emissions on aerosol properties in global models – an AeroCom experiment

The effects of unified aerosol sources on global aerosol fields simulated by different models are examined in this paper. We compare results from two AeroCom experiments, one with different (ExpA) and one with unified emissions, injection heights, and particle sizes at the source (ExpB). Surprisingly, harmonization of aerosol sources has only a small impact on the simulated diversity for aerosol burden, and consequently optical properties, as the results are largely controlled by model-specific transport, removal, chemistry (leading to the formation of secondary aerosols) and parameterizations of aerosol microphysics (e.g. the split between deposition pathways) and to a lesser extent on the spatial and temporal distributions of the (precursor) emissions. The burdens of black carbon and especially sea salt become more coherent in ExpB only, because the large ExpA diversity for these two species was caused by few outliers. The experiment also indicated that despite prescribing emission fluxes and size distributions, ambiguities in the implementation in individual models can lead to substantial differences. These results indicate the need for a better understanding of aerosol life cycles at process level (including spatial dispersal and interaction with meteorological parameters) in order to obtain more reliable results from global aerosol simulations. This is particularly important as such model results are used to assess the consequences of specific air pollution abatement strategies

Harnessing RNA sequencing for global, unbiased evaluation of two new adjuvants for dendritic-cell immunotherapy

Effective stimulation of immune cells is crucial for the success of cancer immunotherapies. Current approaches to evaluate the efficiency of stimuli are mainly defined by known flow cytometry-based cell activation or cell maturation markers. This method however does not give a complete overview of the achieved activation state and may leave important side effects unnoticed. Here, we used an unbiased RNA sequencing (RNA-seq)-based approach to compare the capacity of four clinical-grade dendritic cell (DC) activation stimuli used to prepare DC-vaccines composed of various types of DC subsets; the already clinically applied GM-CSF and Frühsommer meningoencephalitis (FSME) prophylactic vaccine and the novel clinical grade adjuvants protamine-RNA complexes (pRNA) and CpG-P. We found that GM-CSF and pRNA had similar effects on their target cells, whereas pRNA and CpG-P induced stronger type I interferon (IFN) expression than FSME. In general, the pathways most affected by all stimuli were related to immune activity and cell migration. GM-CSF stimulation, however, also induced a significant increase of genes related to nonsense-mediated decay, indicating a possible deleterious effect of this stimulus. Taken together, the two novel stimuli appear to be promising alternatives. Our study demonstrates how RNA-seq based investigation of changes in a large number of genes and gene groups can be exploited for fast and unbiased, global evaluation of clinical-grade stimuli, as opposed to the general limited evaluation of a pre-specified set of genes, by which one might miss important biological effects that are detrimental for vaccine efficacy

Numerical simulation of explosive volcanic eruptions from the conduit flow to global atmospheric scales

Volcanic eruptions are unsteady multiphase phenomena, which encompass many inter-related processes across the whole range of scales from molecular and microscopic to macroscopic, synoptic and global. We provide an overview of recent advances in numerical modelling of volcanic effects, from conduit and eruption column processes to those on the Earth s climate. Conduit flow models examine ascent dynamics and multiphase processes like fragmentation, chemical reactions and mass transfer below the Earth surface. Other models simulate atmospheric dispersal of the erupted gas-particle mixture, focusing on rapid processes occurring in the jet, the lower convective regions, and pyroclastic density currents. The ascending eruption column and intrusive gravity current generated by it, as well as sedimentation and ash dispersal from those flows in the immediate environment of the volcano are examined with modular and generic models. These apply simplifications to the equations describing the system depending on the specific focus of scrutiny. The atmospheric dispersion of volcanic clouds is simulated by ash tracking models. These are inadequate for the first hours of spreading in many cases but focus on long-range prediction of ash location to prevent hazardous aircraft - ash encounters. The climate impact is investigated with global models. All processes and effects of explosive eruptions cannot be simulated by a single model, due to the complexity and hugely contrasting spatial and temporal scales involved. There is now the opportunity to establish a closer integration between different models and to develop the first comprehensive description of explosive eruptions and of their effects on the ground, in the atmosphere, and on the global climate

An AeroCom initial assessment – optical properties in aerosol component modules of global models

The AeroCom exercise diagnoses multi-component aerosol modules in global modeling. In an initial assessment simulated global distributions for mass and mid-visible aerosol optical thickness (aot) were compared among 20 different modules. Model diversity was also explored in the context of previous comparisons. For the component combined aot general agreement has improved for the annual global mean. At 0.11 to 0.14, simulated aot values are at the lower end of global averages suggested by remote sensing from ground (AERONET ca. 0.135) and space (satellite composite ca. 0.15). More detailed comparisons, however, reveal that larger differences in regional distribution and significant differences in compositional mixture remain. Of particular concern are large model diversities for contributions by dust and carbonaceous aerosol, because they lead to significant uncertainty in aerosol absorption (aab). Since aot and aab, both, influence the aerosol impact on the radiative energy-balance, the aerosol (direct) forcing uncertainty in modeling is larger than differences in aot might suggest. New diagnostic approaches are proposed to trace model differences in terms of aerosol processing and transport: These include the prescription of common input (e.g. amount, size and injection of aerosol component emissions) and the use of observational capabilities from ground (e.g. measurements networks) or space (e.g. correlations between aerosol and clouds)

Johannesburg's 'poor housing, good health' paradox: the role of health status assessment, statistical modelling, residential context and migrant status

The 'poor housing, good health' paradox observed by De Wet et al. (2011) across eight of Johannesburg's poorest Wards (neighbourhoods), was re-examined using: a more generic measure of self-reported health; better-specified adjustment for measured confounders; household data from a range of Wards and income strata across Johannesburg and Gauteng; and adjustment for migrant status. The present study examined the relationship between (formal vs. informal) housing and self-reported health (-limited work and/or social activities) across four subsamples of respondents to the 2013 Quality of Life survey undertaken by the Gauteng City Regional Observatory: n = 1494 from households in the eight Wards examined by De Wet et al. (2011); n = 3059 from households with the lowest income tertile in Johannesburg; n = 8263 from households throughout Johannesburg; and n = 24,727 from households throughout Gauteng Province, irrespective of Ward or income. The relationship between housing and self-reported health in each of these subsamples was examined before and after adjustment for measured confounders identified using a temporally determined causal path diagram in the form of a directed acyclic graph. Following adjustment for measured confounders, 'informal housing' was only associated with 'good' self-reported health in Johannesburg's poorest Wards (odds ratio [OR]: 1.39; 95% confidence interval [CI]: 1.07, 1.79) and Johannesburg as a whole (OR: 1.15; 95%CI: 1.00, 1.31). These associations were substantially attenuated following adjustment for migrant status (OR: 1.26; 95%CI: 0.97, 1.65; OR: 1.07; 95%CI: 0.93, 1.22, respectively). While the present study found that Johannesburg's 'poor housing, good health' paradox was still evident when using a more generic/subjective (self-reported) measure of health, the apparent paradox appears to reflect, at least in part: the differential aggregation of migrant-headed households in Johannesburg neighbourhoods exhibiting a high concentration of informal housing; and the likely impact of the health-related selection on the health of migrant-headed households. [Abstract copyright: Copyright © 2020 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.