Phosphorylation of mineralocorticoid receptor ligand binding domain impairs receptor activation and has a dominant negative effect over non-phosphorylated receptors

Post-translational modification of steroid receptors allows fine-tuning different properties of this family of proteins, including stability, activation, or interaction with co-regulators. Recently, a novel effect of phosphorylation on steroid receptor biology was described. Phosphorylation of human mineralocor ticoid receptor (MR) on Ser-843, a residue placed on the ligand binding domain, lowers affinity for agonists, producing inhibi tion of gene transactivation. We now show that MR inhibition by phosphorylation occurs even at high agonist concentration, suggesting that phosphorylation may also impair coupling between ligand binding and receptor activation. Our results demonstrate that agonists are able to induce partial nuclear translocation of MR but fail to produce transactivation due at least in part to impaired co-activator recruitment. The inhibi tory effect of phosphorylation on MR acts in a dominant-nega tive manner, effectively amplifying its functional effect on gene transactivation.info:eu-repo/semantics/publishedVersio

Transport of desert dust mixed with North African industrial pollutants in the subtropical Saharan Air Layer

An analysis of chemical composition data of particulate matter samples (TSP, PM<sub>10</sub> and PM<sub>2.5</sub>) collected from 2002 to 2008 in the North Atlantic free troposphere at the Izaña Global Atmospheric Watch (GAW) observatory (Tenerife, Canary Islands) shows that desert dust is very frequently mixed with particulate pollutants in the Saharan Air Layer (SAL). The study of this data set with Median Concentrations At Receptor (MCAR) plots allowed the identification of the potential source regions of the dust and particulate pollutants. Areas located at the south of the southern slope of the Atlas mountains emerge as the most frequent source of the soil desert dust advected to the northern edge of the SAL in summer. Industrial emissions occurring in Northern Algeria, Eastern Algeria, Tunisia and the Atlantic coast of Morocco appear as the most important source of the nitrate, ammonium and a fraction of sulphate (at least 60 % of the sulphate <10 μm transported from some regions) observed in the SAL. These emissions are mostly linked to crude oil refineries, phosphate-based fertilizer industry and power plants. Although desert dust emissions appear as the most frequent source of the phosphorous observed in the SAL, high P concentrations are observed when the SAL is affected by emissions from open mines of phosphate and phosphate based fertilizer industry. The results also show that a significant fraction of the sulphate (up to 90 % of sulphate <10 μm transported from some regions) observed in the SAL may be influenced by soil emissions of evaporite minerals in well defined regions where dry saline lakes (chotts) are present. These interpretations of the MCAR plots are consistent with the results obtained with the Positive Matrix Factorization (PMF2) receptor modelling. The results of this study show that North African industrial pollutants may be mixed with desert dust and exported to the North Atlantic in the Saharan Air Layer

Size distribution and chemical composition of metalliferous stack emissions in the San Roque petroleum refinery complex, southern Spain

We demonstrate that there is great variation in the size range and chemical composition of metalliferous particulate matter (PM) present within petrochemical complex chimney stacks. Cascade impactor PM samples from seven size ranges (17, 14, 5, 2.5, 1.3, 0.67, and 0.33 mu m) were collected from inside stacks within the San Roque complex which includes the largest oil refinery in Spain. SEM analysis demonstrates the PM to be mostly carbonaceous and aluminous fly ash and abundant fine metalliferous particles. The metals with the most extreme concentrations averaged over all size ranges were Ni (up to 3295 mu g m(-3)), Cr (962 mu g m(-3)), V (638 mu g m(-3)), Zn (225 mu g m(-3)), Mo (91 mu g m(-3)), La (865 mu g m(-3)), and Co (94 mu g m(-3)). Most metal PM are strongly concentrated into the finest fraction (200 mu g m(-3) in PM(0.67-1.3)). Cr and Ni in a relatively coarse PM size range (0.7-14 mu m). Our unique database, directly sampled from chimney stacks, confirms that oil refinery complexes such as San Roque are a potent source of a variety of fine, deeply inhalable metalliferous atmospheric PM emissionsThis study was supported by the Department of the Environment and the Department of Innovation, Science and Enterprise (project RNM2007-02729) of the Autonomous Government of Andalusia, and Projects GRACCIE-CSD2007 of the Spanish Ministry of Science and Innovation. The authors are indebted to Juan Contreras, Francisca Godoy and Antonio Lozano of the Department of Air Quality in the Environmental Office of Andalusia Government for their collaboration with this study. Thanks are due to Wes Gibbons for his revision of the manuscript

Understanding the local and remote source contributions to ambient O3 during a pollution episode using a combination of experimental approaches in the Guadalquivir valley, southern Spain

The Guadalquivir Valley is one of three major O3 hotspots in Spain. An airborne and surface measurement campaign was carried out from July 9th to 11th, 2019 to quantify the local/regional O3 contributions using experimental approaches. Air quality and meteorology data from surface measurements, a microlight aircraft, a helium balloon, and remote sensing data (TROPOMI-NO2-ESA) were used to obtain the 3D distribution of O3 and various tracer pollutants. O3 accumulation over 2.5 days started with inputs from oceanic air masses transported inland by sea breezes, which drew O3 and its precursors from a local/regional origin to the northeastern end of the basin. The orographic–meteorological setting of the valley caused vertical recirculation of the air masses inside the valley that caused the accumulation by increasing regional background O3 concentration by 25–30 ppb. Furthermore, possible Mediterranean O3 contributions and additional vertical recirculation through the entrainment zone of the convective boundary layer also contributed. Using particulate matter finer than 2.5 μm (PM2.5), ultrafine particles (UFP), and black carbon (BC) as tracers of local sources, we calculated that local contributions increased regional O3 levels by 20 ppb inside specific pollution plumes transported by the breeze into the valley, and by 10 ppb during midday when flying over an area with abundant agricultural burning during the morning. Air masses that crossed the southern boundaries of the Betic system at mid-altitude (400–1850 m a.s.l.) on July 10th and 11th may have provided additional O3. Meanwhile, a decreasing trend at high altitudes (3000–5000 m a.s.l.) was observed, signifying that the impact of stratospheric O3 intrusion decreased during the campaign

Precise CRISPR/Cas-mediated gene repair with minimal off-target and unintended on-target mutations in human hematopoietic stem cells

While CRISPR-Cas9 is key for the development of gene therapy, its potential off-target mutations are still a major concern. Here, we establish a "spacer-nick" gene correction approach that combines the Cas9(D10A) nickase with a pair of PAM-out sgRNAs at a distance of 200 to 350 bp. In combination with adeno-associated virus (AAV) serotype 6 template delivery, our approach led to efficient HDR in human hematopoietic stem and progenitor cells (HSPCs including long-term HSCs) and T cells, with minimal NHEJ-mediated on-target mutations. Using spacer-nick, we developed an approach to repair disease-causing mutations occurring in the HBB, ELANE, IL7R, and PRF1 genes. We achieved gene correction efficiencies of 20 to 50% with minimal NHEJ-mediated on-target mutations. On the basis of in-depth off-target assessment, frequent unintended genetic alterations induced by classical CRISPR-Cas9 were significantly reduced or absent in the HSPCs treated with spacer-nick. Thus, the spacer-nick gene correction approach provides improved safety and suitability for gene therapy

Parâmetros elétricos para a insensibilização de frangos: qual a corrente elétrica que atinge o cérebro?

RESUMO: Exportar frango aos membros da União Europeia implica em atender o Regulamento CE 1099/2009 que versa sobre os parâmetros elétricos a serem aplicados na insensibiliza- ção quando do abate das aves. Considerando os relatos de que o uso destes parâmetros implica em impacto negativo na qualidade da carcaça dos frangos, parâmetros alternativos, notadamente baixa amperagem com maiores frequências estão sendo avaliados. Para melhor avaliar a eficiência dos métodos alternativos quanto ao bem estar, ou seja, se de fato insensibilizam as aves, este ensaio é o primeiro relato mensurando a corrente elétrica que atinge o cérebro da ave no momento da insensibilização. O resultado indicou que a insensibilização elétrica de frangos com corrente aproximada de 100 mA e frequência de 600 Hz possibilita passagem de corrente no cérebro da ave em magnitude que não permite a manutenção da capacidade de transmissão da dor, mostrando-se eficiente, portanto. Sugere-se que esta metodologia seja considerada para a avaliação de propostas alternativas a serem submetidas ao grupo de inteligência científica do Mercado Comum Europeu

Caracterização do estado de inconsciência dos frangos após eletronarcose com baixa corrente e alta frequência

A insensibilização elétrica de frangos baseada em baixa corrente e alta frequência é de uso comum nos abatedouros comerciais por propiciar menor impacto na qualidade da carcaça. Devido a questionamentos, principalmente da União Europeia, é necessário demonstrar que o método assegure o bem-estar às aves durante o processo de abate (1). Nesse sentido, é importante que seja mantido o estado de inconsciência das aves desde a saída da cuba até a morte após a sangria. O objetivo do presente trabalho é avaliar a eficiência da eletronarcose realizada com baixa corrente e alta frequência em provocar estado de inconsciência duradouro, visando o bem estar no abate

Vertical variability of trophic positions of zooplankton in the deep Ocean

Zooplankton plays a key role in oceanic ecosystems. However, the trophic ecology of organisms in deep layers of the ocean is poorly known. In this study we analyze the variability of trophic positions of zooplankton collected across three ocean basins in the epi-, meso and bathypelagic domains. Stable carbon and nitrogen isotopes were used as indicators of the sources of nutrients and positions within the food web. The enrichment in heavy nitrogen isotopes with depth and the correlation between surface and deep samples revealed that deep zooplankton was supported by local epipelagic production, subsequently processed through the water column. In addition the nitrogen isotope enrichment of carnivores vs. omnivores was consistent across ocean biomes and water layers, suggesting a similar trophic structure of the pelagic food web in the deep ocean despite variations in the nitrogen sources. Siphonofora, Chaetognata and Myctophida were the top predators while Calanoid Copepoda and Mysidacea displayed the lowest trophic positions. In contrast, carbon isotopes did not show significant variations with depth or trophic groups implying low influence of coastal production in deep ocean food webs

Modeling relationships between calving traits: a comparison between standard and recursive mixed models

<p>Abstract</p> <p>Background</p> <p>The use of structural equation models for the analysis of recursive and simultaneous relationships between phenotypes has become more popular recently. The aim of this paper is to illustrate how these models can be applied in animal breeding to achieve parameterizations of different levels of complexity and, more specifically, to model phenotypic recursion between three calving traits: gestation length (GL), calving difficulty (CD) and stillbirth (SB). All recursive models considered here postulate heterogeneous recursive relationships between GL and liabilities to CD and SB, and between liability to CD and liability to SB, depending on categories of GL phenotype.</p> <p>Methods</p> <p>Four models were compared in terms of goodness of fit and predictive ability: 1) standard mixed model (SMM), a model with unstructured (co)variance matrices; 2) recursive mixed model 1 (RMM1), assuming that residual correlations are due to the recursive relationships between phenotypes; 3) RMM2, assuming that correlations between residuals and contemporary groups are due to recursive relationships between phenotypes; and 4) RMM3, postulating that the correlations between genetic effects, contemporary groups and residuals are due to recursive relationships between phenotypes.</p> <p>Results</p> <p>For all the RMM considered, the estimates of the structural coefficients were similar. Results revealed a nonlinear relationship between GL and the liabilities both to CD and to SB, and a linear relationship between the liabilities to CD and SB.</p> <p>Differences in terms of goodness of fit and predictive ability of the models considered were negligible, suggesting that RMM3 is plausible.</p> <p>Conclusions</p> <p>The applications examined in this study suggest the plausibility of a nonlinear recursive effect from GL onto CD and SB. Also, the fact that the most restrictive model RMM3, which assumes that the only cause of correlation is phenotypic recursion, performs as well as the others indicates that the phenotypic recursion may be an important cause of the observed patterns of genetic and environmental correlations.</p

Aplicação dos parâmetros elétricos do regulamento CE 1099/2009 na eletronarcose de frangos: Impactos na carcaça.

A eletronarcose por imersão é o método de insensibilização para frangos mais usado no mundo e o único em uso nos abatedouros do Brasil. Na Comunidade Europeia está em vigor o Regulamento CE1099/2009 (1) o qual contempla os parâmetros elétricos para este tipo de atordoamento, os quais devem ser utilizados pelos países membros e por parceiros exportadores. O Brasil, como exportador, deve se ajustar às exigências ou defender metodologia equivalente, considerando o bem-estar animal. Os parâmetros elétricos comumente utilizados na insensibilização no Brasil, assim como nos Estados Unidos, diferem da CE1099/2009, supostamente privilegiando a qualidade da carcaça que seria afetada pelo uso de corrente elétrica elevada (2). O objetivo do presente trabalho foi verificar o impacto dos parâmetros europeus na qualidade da carcaça de frangos de corte com vistas a possível busca por alternativas que atendam as exigências europeias e que sejam ética e economicamente aceitáveis