In this article, the 2009 European League Against Rheumatism (EULAR) recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have been updated. ...The 2009 recommendations were on the management of primary small and medium vessel vasculitis. The 2015 update has been developed by an international task force representing EULAR, the European Renal Association and the European Vasculitis Society (EUVAS). The recommendations are based upon evidence from systematic literature reviews, as well as expert opinion where appropriate. The evidence presented was discussed and summarised by the experts in the course of a consensus-finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) determined. In addition to the voting by the task force members, the relevance of the recommendations was assessed by an online voting survey among members of EUVAS. Fifteen recommendations were developed, covering general aspects, such as attaining remission and the need for shared decision making between clinicians and patients. More specific items relate to starting immunosuppressive therapy in combination with glucocorticoids to induce remission, followed by a period of remission maintenance; for remission induction in life-threatening or organ-threatening AAV, cyclophosphamide and rituximab are considered to have similar efficacy; plasma exchange which is recommended, where licensed, in the setting of rapidly progressive renal failure or severe diffuse pulmonary haemorrhage. These recommendations are intended for use by healthcare professionals, doctors in specialist training, medical students, pharmaceutical industries and drug regulatory organisations.
We study relations between stellar mass, star formation and gas-phase metallicity in a sample of 177 071 unique emission line galaxies from the Sloan Digital Sky Survey Data Release 7, as well as in ...a sample of 43 767 star-forming galaxies at z= 0 from the cosmological semi-analytic model l-galaxies. We demonstrate that metallicity is dependent on star formation rate at fixed mass, but that the trend is opposite for low and for high stellar mass galaxies. Low-mass galaxies that are actively forming stars are more metal poor than quiescent low-mass galaxies. High-mass galaxies, on the other hand, have lower gas-phase metallicities if their star formation rates are small. Remarkably, the same trends are found for our sample of model galaxies. By examining the evolution of the stellar component, gas and metals as a function of time in these galaxies, we gain some insight into the physical processes that may be responsible for these trends. We find that massive galaxies with low gas-phase metallicities have undergone a gas-rich merger in the past, inducing a starburst which exhausted their cold gas reservoirs and shutdown star formation. Thereafter, these galaxies were able to accrete metal-poor gas, but this gas remained at too low a density to form stars efficiently. This led to a gradual dilution in the gas-phase metallicities of these systems over time. These model galaxies are predicted to have lower-than-average gas-to-stellar mass ratios and higher-than-average central black hole masses. We use our observational sample to confirm that real massive galaxies with low gas-phase metallicities also have very massive black holes. We propose that accretion may therefore play a significant role in regulating the gas-phase metallicities of present-day massive galaxies.
Phyre2 is a suite of tools available on the web to predict and analyze protein structure, function and mutations. The focus of Phyre2 is to provide biologists with a simple and intuitive interface to ...state-of-the-art protein bioinformatics tools. Phyre2 replaces Phyre, the original version of the server for which we previously published a paper in Nature Protocols. In this updated protocol, we describe Phyre2, which uses advanced remote homology detection methods to build 3D models, predict ligand binding sites and analyze the effect of amino acid variants (e.g., nonsynonymous SNPs (nsSNPs)) for a user's protein sequence. Users are guided through results by a simple interface at a level of detail they determine. This protocol will guide users from submitting a protein sequence to interpreting the secondary and tertiary structure of their models, their domain composition and model quality. A range of additional available tools is described to find a protein structure in a genome, to submit large number of sequences at once and to automatically run weekly searches for proteins that are difficult to model. The server is available at http://www.sbg.bio.ic.ac.uk/phyre2. A typical structure prediction will be returned between 30 min and 2 h after submission.
Omega-3 (n-3) polyunsaturated fatty acids (n-3 PUFAs) have well documented anti-inflammatory properties, and consequently therapeutic potential in chronic inflammatory diseases. Here we discuss the ...effects of n-3 PUFAs on various inflammatory pathways and how this leads to alterations in the function of inflammatory cells, most importantly endothelial cells and leukocytes. Strong evidence indicates n-3 PUFAs are beneficial as a dietary supplement in certain diseases such as rheumatoid arthritis; however for other conditions such as asthma, the data are less robust. A clearer understanding of the pharmacology of n-3 PUFAs will help to establish targets to modulate chronic inflammatory diseases.
Des travaux antérieurs dans le modèle murin ont révélé que la ménine contrôlait la croissance de la glande thyroïde. Dans le but de rechercher si la ménine exerce un contrôle sur la prolifération ...cellulaire, nous avons examiné le niveau d’expression de trois lignées de thyrocytes de rat (FRT, FRTL5 et PCCL 3) puis nous avons réduit le niveau d’expression du gène Men1 grâce à une approche d’ARN interférents et analysé les conséquences de la réduction de l’expression de Men1 sur la prolifération cellulaire. L’expression de la ménine a été analysée par Western-blot en utilisant un Ac anti-ménine (dilution : 1/10 000). Nous avons mis en évidence un doublet de 68–70 kDa correspondant aux formes phosphorylées et non-phosphorylées. L’homogénat cellulaire a été centrifugé à 100 000 g/30 min, une bande de 68 kDa a été détectée dans la fraction particulaire mais pas dans la fraction soluble suggérant une localisation nucléaire. L’intensité du signal dans la lignée dédifférenciée FRT est deux fois plus élevée que dans les lignées différenciées PCCL3 et FRTL5 suggérant une éventuelle corrélation entre le contenu en ménine et l’état de différenciation. À partir de conditions optimales de transfection de siRNA, (4 μL Dharmafect/10 000 cellules) pendant une durée de 48 à 72 h, nous avons observé une perte d’expression du gène Men1 de 80 % dans les lignées FRTL5 et PCCL3. Cette réduction conduit à une augmentation de la prolifération de 40 à 60 % déterminée par le test MTT et le comptage des cellules. En conclusion, la ménine agit comme un régulateur négatif de la prolifération cellulaire thyroïdienne.
Following phagocytosis, the nascent phagosome undergoes maturation to become a phagolysosome with an acidic, hydrolytic, and often oxidative lumen that can efficiently kill and digest engulfed ...microbes, cells, and debris. The fusion of phagosomes with lysosomes is a principal driver of phagosomal maturation and is targeted by several adapted intracellular pathogens. Impairment of this process has significant consequences for microbial infection, tissue inflammation, the onset of adaptive immunity, and disease. Given the importance of phagosome-lysosome fusion to phagocyte function and the many virulence factors that target it, it is unsurprising that multiple molecular pathways have evolved to mediate this essential process. While the full range of these pathways has yet to be fully characterized, several pathways involving proteins such as members of the Rab GTPases, tethering factors and SNAREs have been identified. Here, we summarize the current state of knowledge to clarify the ambiguities in the field and construct a more comprehensive phagolysosome formation model. Lastly, we discuss how other cellular pathways help support phagolysosome biogenesis and, consequently, phagocyte function.
ABSTRACT
We contrast the latest observations of the cosmic metal density in neutral gas ($\rho _{ {met,neu}}$) with three cosmological galaxy evolution simulations: L-Galaxies 2020, TNG100, and ...EAGLE. We find that the fraction of total metals that are in neutral gas is <40 per cent at 3 ≲ $z$ ≲ 5 in these simulations, whereas observations of damped Lyman-α (DLA) systems suggest ≳ 85 per cent. In all three simulations, hot, low-density gas is also a major contributor to the cosmic metal budget, even at high redshift. By considering the evolution in cosmic SFR density ($\rho _{ {\rm {\small {sfr}}}$), neutral gas density ($\rho _{ {HI}}$), and mean gas-phase metallicity ($\langle {} {M/H}\rangle _{ {neu}}$), we determine two possible ways in which the absolute $\rho _{ {met,neu}}$ observed in DLAs at high redshift can be matched by simulations: (i) the $\rho _{ {\rm {\small {sfr}}}$ at $z$ ≳ 3 is greater than inferred from current FUV observations, or (ii) current high-redshift DLA metallicity samples have a higher mean host mass than the overall galaxy population. If the first is correct, TNG100 would match the ensemble data best, however there would be an outstanding tension between the currently observed $\rho _{ {\rm {\small {sfr}}}$ and $\rho _{ {met,neu}}$. If the second is correct, L-Galaxies 2020 would match the ensemble data best, but would require an increase in neutral gas mass inside subhaloes above $z$ ∼ 2.5. If neither is correct, EAGLE would match the ensemble data best, although at the expense of overestimating $\langle {} {M/H}\rangle _{ {neu}}$. Modulo details related to numerical resolution and H i mass modelling in simulations, these incompatibilities highlight current tensions between key observed cosmic properties at high redshift.
Non-synonymous single nucleotide polymorphisms (nsSNPs) are single base changes leading to a change to the amino acid sequence of the encoded protein. Many of these variants are associated with ...disease, so nsSNPs have been well studied, with studies looking at the effects of nsSNPs on individual proteins, for example, on stability and enzyme active sites. In recent years, the impact of nsSNPs upon protein–protein interactions has also been investigated, giving a greater insight into the mechanisms by which nsSNPs can lead to disease.
In this review, we summarize these studies, looking at the various mechanisms by which nsSNPs can affect protein–protein interactions. We focus on structural changes that can impair interaction, changes to disorder, gain of interaction, and post-translational modifications before looking at some examples of nsSNPs at human–pathogen protein–protein interfaces and the analysis of nsSNPs from a network perspective.
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•Mutations affecting amino acids at protein–protein interfaces can lead to disease.•There are numerous mechanisms by which these variants can have their effects.•Variants can impair individual or multiple interactions, cause novel interactions, or change post-translational modification.
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