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81.
82.
Apolipoprotein-mediated pathways of lipid antigen presentation 总被引:1,自引:0,他引:1
van den Elzen P Garg S León L Brigl M Leadbetter EA Gumperz JE Dascher CC Cheng TY Sacks FM Illarionov PA Besra GS Kent SC Moody DB Brenner MB 《Nature》2005,437(7060):906-910
Peptide antigens are presented to T cells by major histocompatibility complex (MHC) molecules, with endogenous peptides presented by MHC class I and exogenous peptides presented by MHC class II. In contrast to the MHC system, CD1 molecules bind lipid antigens that are presented at the antigen-presenting cell (APC) surface to lipid antigen-reactive T cells. Because CD1 molecules survey endocytic compartments, it is self-evident that they encounter antigens from extracellular sources. However, the mechanisms of exogenous lipid antigen delivery to CD1-antigen-loading compartments are not known. Serum apolipoproteins are mediators of extracellular lipid transport for metabolic needs. Here we define the pathways mediating markedly efficient exogenous lipid antigen delivery by apolipoproteins to achieve T-cell activation. Apolipoprotein E binds lipid antigens and delivers them by receptor-mediated uptake into endosomal compartments containing CD1 in APCs. Apolipoprotein E mediates the presentation of serum-borne lipid antigens and can be secreted by APCs as a mechanism to survey the local environment to capture antigens or to transfer microbial lipids from infected cells to bystander APCs. Thus, the immune system has co-opted a component of lipid metabolism to develop immunological responses to lipid antigens. 相似文献
83.
Remission in models of type 1 diabetes by gene therapy using a single-chain insulin analogue 总被引:11,自引:0,他引:11
A cure for diabetes has long been sought using several different approaches, including islet transplantation, regeneration of beta cells and insulin gene therapy. However, permanent remission of type 1 diabetes has not yet been satisfactorily achieved. The development of type 1 diabetes results from the almost total destruction of insulin-producing pancreatic beta cells by autoimmune responses specific to beta cells. Standard insulin therapy may not maintain blood glucose concentrations within the relatively narrow range that occurs in the presence of normal pancreatic beta cells. We used a recombinant adeno-associated virus (rAAV) that expresses a single-chain insulin analogue (SIA), which possesses biologically active insulin activity without enzymatic conversion, under the control of hepatocyte-specific L-type pyruvate kinase (LPK) promoter, which regulates SIA expression in response to blood glucose levels. Here we show that SIA produced from the gene construct rAAV-LPK-SIA caused remission of diabetes in streptozotocin-induced diabetic rats and autoimmune diabetic mice for a prolonged time without any apparent side effects. This new SIA gene therapy may have potential therapeutic value for the cure of autoimmune diabetes in humans. 相似文献
84.
85.
Shaw C 《Population trends》2002,(107):5-13
The 2000-based national population projections, carried out by the Government Actuary at the request of the Registrars General, show the population of the United Kingdom rising from 59.8 million in 2000 to nearly 65 million by 2025. Longer-term projections suggest the population will peak at nearly 66 million around 2040 and then gradually start to fall. The population will become gradually older with the median age expected to rise from 37.4 years in 2000 to 42.4 years by 2025. In 2000, there were 1.3 million (12 per cent) more children aged under 16, than people of state pensionable age. However, by 2007, the population of state pensionable age is projected to exceed the number of children. 相似文献
86.
Shaw C 《Population trends》2002,(109):15-26
Interest has been growing steadily in understanding the impact of the inherent uncertainty in the national population projections. As a result, the Government Acturay's Department has recently produced the most extensive set of official variant projections ever published in the United Kingdom. These include 'standard' variants based on alternative high and low assumptions for future fertility, life expectancy and net migration and also a number of 'special case scenarios.' All of these variants have been produced at both UK and individual country level. This article describes the full range of variant projections available from the 2000-based national projections and summaries some of the key results for both the UK and the individual countries. 相似文献
87.
Carlton JM Angiuoli SV Suh BB Kooij TW Pertea M Silva JC Ermolaeva MD Allen JE Selengut JD Koo HL Peterson JD Pop M Kosack DS Shumway MF Bidwell SL Shallom SJ van Aken SE Riedmuller SB Feldblyum TV Cho JK Quackenbush J Sedegah M Shoaibi A Cummings LM Florens L Yates JR Raine JD Sinden RE Harris MA Cunningham DA Preiser PR Bergman LW Vaidya AB van Lin LH Janse CJ Waters AP Smith HO White OR Salzberg SL Venter JC Fraser CM Hoffman SL Gardner MJ Carucci DJ 《Nature》2002,419(6906):512-519
Species of malaria parasite that infect rodents have long been used as models for malaria disease research. Here we report the whole-genome shotgun sequence of one species, Plasmodium yoelii yoelii, and comparative studies with the genome of the human malaria parasite Plasmodium falciparum clone 3D7. A synteny map of 2,212 P. y. yoelii contiguous DNA sequences (contigs) aligned to 14 P. falciparum chromosomes reveals marked conservation of gene synteny within the body of each chromosome. Of about 5,300 P. falciparum genes, more than 3,300 P. y. yoelii orthologues of predominantly metabolic function were identified. Over 800 copies of a variant antigen gene located in subtelomeric regions were found. This is the first genome sequence of a model eukaryotic parasite, and it provides insight into the use of such systems in the modelling of Plasmodium biology and disease. 相似文献
88.
A physical map of the mouse genome 总被引:1,自引:0,他引:1
Gregory SG Sekhon M Schein J Zhao S Osoegawa K Scott CE Evans RS Burridge PW Cox TV Fox CA Hutton RD Mullenger IR Phillips KJ Smith J Stalker J Threadgold GJ Birney E Wylie K Chinwalla A Wallis J Hillier L Carter J Gaige T Jaeger S Kremitzki C Layman D Maas J McGrane R Mead K Walker R Jones S Smith M Asano J Bosdet I Chan S Chittaranjan S Chiu R Fjell C Fuhrmann D Girn N Gray C Guin R Hsiao L Krzywinski M Kutsche R Lee SS Mathewson C McLeavy C Messervier S Ness S Pandoh P Prabhu AL Saeedi P 《Nature》2002,418(6899):743-750
A physical map of a genome is an essential guide for navigation, allowing the location of any gene or other landmark in the chromosomal DNA. We have constructed a physical map of the mouse genome that contains 296 contigs of overlapping bacterial clones and 16,992 unique markers. The mouse contigs were aligned to the human genome sequence on the basis of 51,486 homology matches, thus enabling use of the conserved synteny (correspondence between chromosome blocks) of the two genomes to accelerate construction of the mouse map. The map provides a framework for assembly of whole-genome shotgun sequence data, and a tile path of clones for generation of the reference sequence. Definition of the human-mouse alignment at this level of resolution enables identification of a mouse clone that corresponds to almost any position in the human genome. The human sequence may be used to facilitate construction of other mammalian genome maps using the same strategy. 相似文献
89.
Glutamic acid decarboxylase (GAD) is considered to be one of the strongest candidate autoantigens involved in triggering
β-cell-specific autoimmunity. The majority of recent onset type 1 diabetes patients and prediabetic subjects have anti-GAD
antibodies in their sera, as do nonobese diabetic (NOD) mice, one of the best animal models for human type 1 diabetes. Immunization
of young NOD mice with GAD results in the prevention or delay of the disease as a result of tolerizing autoreactive T cells.
Autoimmune diabetes can also be prevented by the suppression of GAD expression in antisense GAD trans genic mice backcrossed
with NOD mice for seven generations. These results support the hypothesis that GAD plays an important role in the development
of T-cell-mediated autoimmune diabetes. However, there is some controversy regarding the role of GAD in the pathogenesis of
diabetes. Whether GAD truly plays a key role in the initiation of this disease remains to be determined. The examination of
the development of insulitis and diabetes in β-cell-specific GAD knockout NOD mice will answer this remaining question.
Received 12 April 2002; received after revision 24 May 2002; accepted 27 May 2002
RID="*"
ID="*"Corresponding author. 相似文献
90.
Hoogenraad CC Koekkoek B Akhmanova A Krugers H Dortland B Miedema M van Alphen A Kistler WM Jaegle M Koutsourakis M Van Camp N Verhoye M van der Linden A Kaverina I Grosveld F De Zeeuw CI Galjart N 《Nature genetics》2002,32(1):116-127
Williams syndrome is a neurodevelopmental disorder caused by the hemizygous deletion of 1.6 Mb on human chromosome 7q11.23. This region comprises the gene CYLN2, encoding CLIP-115, a microtubule-binding protein of 115 kD. Using a gene-targeting approach, we provide evidence that mice with haploinsufficiency for Cyln2 have features reminiscent of Williams syndrome, including mild growth deficiency, brain abnormalities, hippocampal dysfunction and particular deficits in motor coordination. Absence of CLIP-115 also leads to increased levels of CLIP-170 (a closely related cytoplasmic linker protein) and dynactin at the tips of growing microtubules. This protein redistribution may affect dynein motor regulation and, together with the loss of CLIP-115-specific functions, underlie neurological alterations in Williams syndrome. 相似文献