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101.
102.
Arron JR Winslow MM Polleri A Chang CP Wu H Gao X Neilson JR Chen L Heit JJ Kim SK Yamasaki N Miyakawa T Francke U Graef IA Crabtree GR 《Nature》2006,441(7093):595-600
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104.
Henao-Mejia J Elinav E Jin C Hao L Mehal WZ Strowig T Thaiss CA Kau AL Eisenbarth SC Jurczak MJ Camporez JP Shulman GI Gordon JI Hoffman HM Flavell RA 《Nature》2012,482(7384):179-185
Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and the leading cause of chronic liver disease in the Western world. Twenty per cent of NAFLD individuals develop chronic hepatic inflammation (non-alcoholic steatohepatitis, NASH) associated with cirrhosis, portal hypertension and hepatocellular carcinoma, yet the causes of progression from NAFLD to NASH remain obscure. Here, we show that the NLRP6 and NLRP3 inflammasomes and the effector protein IL-18 negatively regulate NAFLD/NASH progression, as well as multiple aspects of metabolic syndrome via modulation of the gut microbiota. Different mouse models reveal that inflammasome-deficiency-associated changes in the configuration of the gut microbiota are associated with exacerbated hepatic steatosis and inflammation through influx of TLR4 and TLR9 agonists into the portal circulation, leading to enhanced hepatic tumour-necrosis factor (TNF)-α expression that drives NASH progression. Furthermore, co-housing of inflammasome-deficient mice with wild-type mice results in exacerbation of hepatic steatosis and obesity. Thus, altered interactions between the gut microbiota and the host, produced by defective NLRP3 and NLRP6 inflammasome sensing, may govern the rate of progression of multiple metabolic syndrome-associated abnormalities, highlighting the central role of the microbiota in the pathogenesis of heretofore seemingly unrelated systemic auto-inflammatory and metabolic disorders. 相似文献
105.
Polar ocean stratification in a cold climate 总被引:1,自引:0,他引:1
The low-latitude ocean is strongly stratified by the warmth of its surface water. As a result, the great volume of the deep ocean has easiest access to the atmosphere through the polar surface ocean. In the modern polar ocean during the winter, the vertical distribution of temperature promotes overturning, with colder water over warmer, while the salinity distribution typically promotes stratification, with fresher water over saltier. However, the sensitivity of seawater density to temperature is reduced as temperature approaches the freezing point, with potential consequences for global ocean circulation under cold climates. Here we present deep-sea records of biogenic opal accumulation and sedimentary nitrogen isotopic composition from the Subarctic North Pacific Ocean and the Southern Ocean. These records indicate that vertical stratification increased in both northern and southern high latitudes 2.7 million years ago, when Northern Hemisphere glaciation intensified in association with global cooling during the late Pliocene epoch. We propose that the cooling caused this increased stratification by weakening the role of temperature in polar ocean density structure so as to reduce its opposition to the stratifying effect of the vertical salinity distribution. The shift towards stratification in the polar ocean 2.7 million years ago may have increased the quantity of carbon dioxide trapped in the abyss, amplifying the global cooling. 相似文献
106.
A ribozyme composed of only two different nucleotides 总被引:4,自引:0,他引:4
RNA molecules are thought to have been prominent in the early history of life on Earth because of their ability both to encode genetic information and to exhibit catalytic function. The modern genetic alphabet relies on two sets of complementary base pairs to store genetic information. However, owing to the chemical instability of cytosine, which readily deaminates to uracil, a primitive genetic system composed of the bases A, U, G and C may have been difficult to establish. It has been suggested that the first genetic material instead contained only a single base-pairing unit. Here we show that binary informational macromolecules, containing only two different nucleotide subunits, can act as catalysts. In vitro evolution was used to obtain ligase ribozymes composed of only 2,6-diaminopurine and uracil nucleotides, which catalyse the template-directed joining of two RNA molecules, one bearing a 5'-triphosphate and the other a 3'-hydroxyl. The active conformation of the fastest isolated ribozyme had a catalytic rate that was about 36,000-fold faster than the uncatalysed rate of reaction. This ribozyme is specific for the formation of biologically relevant 3',5'-phosphodiester linkages. 相似文献
107.
Identification of the gene (BBS1) most commonly involved in Bardet-Biedl syndrome,a complex human obesity syndrome 总被引:11,自引:0,他引:11
Mykytyn K Nishimura DY Searby CC Shastri M Yen HJ Beck JS Braun T Streb LM Cornier AS Cox GF Fulton AB Carmi R Lüleci G Chandrasekharappa SC Collins FS Jacobson SG Heckenlively JR Weleber RG Stone EM Sheffield VC 《Nature genetics》2002,31(4):435-438
Bardet-Biedl syndrome (BBS, OMIM 209900) is a genetic disorder with the primary features of obesity, pigmentary retinopathy, polydactyly, renal malformations, mental retardation and hypogenitalism. Individuals with BBS are also at increased risk for diabetes mellitus, hypertension and congenital heart disease. What was once thought to be a homogeneous autosomal recessive disorder is now known to map to at least six loci: 11q13 (BBS1), 16q21 (BBS2), 3p13 p12 (BBS3), 15q22.3 q23 (BBS4), 2q31 (BBS5) and 20p12 (BBS6). There has been considerable interest in identifying the genes that underlie BBS, because some components of the phenotype are common. Cases of BBS mapping ro BBS6 are caused by mutations in MKKS; mutations in this gene also cause McKusick-Kaufman syndrome (hydrometrocolpos, post-axial polydactyly and congenital heart defects). In addition, we recently used positional cloning to identify the genes underlying BBS2 (ref. 16) and BBS4 (ref. 17). The BBS6 protein has similarity to a Thermoplasma acidophilum chaperonin, whereas BBS2 and BBS4 have no significant similarity to chaperonins. It has recently been suggested that three mutated alleles (two at one locus, and a third at a second locus) may be required for manifestation of BBS (triallelic inheritance). Here we report the identification of the gene BBS1 and show that a missense mutation of this gene is a frequent cause of BBS. In addition, we provide data showing that this common mutation is not involved in triallelic inheritance. 相似文献
108.
Gerald Midgley 《Systemic Practice and Action Research》1992,5(1):85-87
This paper looks at what we mean by being critical about systems. In particular, it seeks to expand our understanding of the process of making boundary judgments so as to explore the relationship these judgments have with values and ethics. 相似文献
109.
Gerald Midgley 《Systemic Practice and Action Research》1992,5(1):5-16
This paper looks at what we mean by being critical about systems. In particular, it seeks to expand our understanding of the process of making boundary judgments so as to explore the relationship these judgments have with values and ethics. 相似文献
110.