A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases

The NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its aberrant activation is pathogenic in inherited disorders such as cryopyrin-associated periodic syndrome (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease and atherosclerosis. We describe the development of MCC950, a potent, selective, small-molecule inhibitor of NLRP3. MCC950 blocked canonical and noncanonical NLRP3 activation at nanomolar concentrations. MCC950 specifically inhibited activation of NLRP3 but not the AIM2, NLRC4 or NLRP1 inflammasomes. MCC950 reduced interleukin-1 beta (IL-1 beta) production in vivo and attenuated the severity of experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis. Furthermore, MCC950 treatment rescued neonatal lethality in a mouse model of CAPS and was active in ex vivo samples from individuals with Muckle-Wells syndrome. MCC950 is thus a potential therapeutic for NLRP3-associated syndromes, including autoinflammatory and autoimmune diseases, and a tool for further study of the NLRP3 inflammasome in human health and disease

MCC950 is a potent and specific inhibitor of the NLRP3 inflammasome and a novel potential therapeutic for NLRP3 driven diseases

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Vertical structure of small eukaryotes in three lakes that differ by their trophic status : a quantitative approach

In lakes, the diversity of eukaryotic picoplankton has been recently studied by the analysis of 18S ribosomal RNA gene sequences; however, quantitative data are rare. In this study, the vertical structure and abundance of the small eukaryotic size fraction (0.2-5 mu m) were investigated in three lakes by tyramide signal amplification-fluorescent in situ hybridization targeting six phylogenetic groups: Chlorophyta, Haptophyta, Cercozoa, LKM11, Perkinsozoa and fungi. The groups targeted in this study are found in all lakes; however, both the abundance and structure of small eukaryotes are dependent on the system's productivity and depth. These data highlighted the presence of Chlorophyta contributing on an average to 19.3%, 14.7% and 41.2% of total small eukaryotes in lakes Bourget, Aydat and Pavin, respectively. This study also revealed the unexpected importance of Haptophyta, reaching 62.8% of eukaryotes in the euphotic zone of Lake Bourget. The high proportions of these pigmented cells highlight the underestimation of these groups by PCR-based methods. The presence of pigmented Chlorophyta in the deepest zones of the lakes suggests a mixotrophic behaviour of these taxa. We also confirmed the presence of putative parasites such as Perkinsozoa (5.1% of small eukaryotes in Lake Pavin and Bourget) and, with lower abundances, fungi (targeted by the MY1574 probe). Cells targeted by LKM11 probes represented the second group of abundance within heterotrophs. Open questions regarding the functional roles of the targeted groups arise from this study, especially regarding parasitism and mixotrophy, which are interactions poorly taken into account in planktonic food web models. The ISME Journal (2010) 4, 1509-1519; doi:10.1038/ismej.2010.83; published online 24 June 201