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91.
Broadhead R Dawe HR Farr H Griffiths S Hart SR Portman N Shaw MK Ginger ML Gaskell SJ McKean PG Gull K 《Nature》2006,440(7081):224-227
The 9 + 2 microtubule axoneme of flagella and cilia represents one of the most iconic structures built by eukaryotic cells and organisms. Both unity and diversity are present among cilia and flagella on the evolutionary as well as the developmental scale. Some cilia are motile, whereas others function as sensory organelles and can variously possess 9 + 2 and 9 + 0 axonemes and other associated structures. How such unity and diversity are reflected in molecular repertoires is unclear. The flagellated protozoan parasite Trypanosoma brucei is endemic in sub-Saharan Africa, causing devastating disease in humans and other animals. There is little hope of a vaccine for African sleeping sickness and a desperate need for modern drug therapies. Here we present a detailed proteomic analysis of the trypanosome flagellum. RNA interference (RNAi)-based interrogation of this proteome provides functional insights into human ciliary diseases and establishes that flagellar function is essential to the bloodstream-form trypanosome. We show that RNAi-mediated ablation of various proteins identified in the trypanosome flagellar proteome leads to a rapid and marked failure of cytokinesis in bloodstream-form (but not procyclic insect-form) trypanosomes, suggesting that impairment of flagellar function may provide a method of disease control. A postgenomic meta-analysis, comparing the evolutionarily ancient trypanosome with other eukaryotes including humans, identifies numerous trypanosome-specific flagellar proteins, suggesting new avenues for selective intervention. 相似文献
92.
Shaw C 《Population trends》2001,(105):45-47
This article summarises the long-term assumptions of fertility, mortality and net migration which will underlie the forthcoming 2000-based national population projections. Compared with the current (1998-based) projections, the new projections will assume lower levels of fertility, but higher levels of inward net migration. There will be relatively little change to mortality assumptions. Results of the new projections will be available on 15 November 2001. 相似文献
93.
Shaw PJ 《Nature genetics》2001,29(2):103-104
Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disease causing cell death of motor neurons and progressive muscle weakness. The disease is familial in ten percent of cases, of which one-fifth are due to mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Two papers in this issue of Nature Genetics describe homozygous mutations in a new gene on chromosome 2q33 in 4 families of Arabian origin with a rare form of juvenile onset ALS (ALS2). The predicted protein structure has domains homologous to GTPase regulatory proteins, and both the types of mutation and the pattern of inheritance suggest that motor neuron degeneration is the result of a loss of function. Further work will determine the relevance of this breakthrough to other, more common forms of ALS. 相似文献
94.
Characterization of single-nucleotide polymorphisms in coding regions of human genes. 总被引:46,自引:0,他引:46
M Cargill D Altshuler J Ireland P Sklar K Ardlie N Patil N Shaw C R Lane E P Lim N Kalyanaraman J Nemesh L Ziaugra L Friedland A Rolfe J Warrington R Lipshutz G Q Daley E S Lander 《Nature genetics》1999,22(3):231-238
A major goal in human genetics is to understand the role of common genetic variants in susceptibility to common diseases. This will require characterizing the nature of gene variation in human populations, assembling an extensive catalogue of single-nucleotide polymorphisms (SNPs) in candidate genes and performing association studies for particular diseases. At present, our knowledge of human gene variation remains rudimentary. Here we describe a systematic survey of SNPs in the coding regions of human genes. We identified SNPs in 106 genes relevant to cardiovascular disease, endocrinology and neuropsychiatry by screening an average of 114 independent alleles using 2 independent screening methods. To ensure high accuracy, all reported SNPs were confirmed by DNA sequencing. We identified 560 SNPs, including 392 coding-region SNPs (cSNPs) divided roughly equally between those causing synonymous and non-synonymous changes. We observed different rates of polymorphism among classes of sites within genes (non-coding, degenerate and non-degenerate) as well as between genes. The cSNPs most likely to influence disease, those that alter the amino acid sequence of the encoded protein, are found at a lower rate and with lower allele frequencies than silent substitutions. This likely reflects selection acting against deleterious alleles during human evolution. The lower allele frequency of missense cSNPs has implications for the compilation of a comprehensive catalogue, as well as for the subsequent application to disease association. 相似文献
95.
Shaw C 《Population trends》2003,(111):7-17
This article describes new 2001-based national population projections which were carried out following the publication in September 2002 of the first results of the 2001 Census. These "interim" projections, carried out by the Government Actuary in consultation with the Registrars General, take preliminary account of the results of the Census which showed that the base population used in previous projections was overestimated. The interim projections also incorporate a reduced assumption of net international migration to the United Kingdom, informed by the first results of the 2001 Census and taking account of more recent migration information. The population of the United Kingdom is now projected to increase from an estimated 58.8 million in 2001 to reach 63.2 million by 2026. The projected population at 2026 is about 1.8 million (2.8 per cent) lower than in the previous (2000-based) projections. 相似文献
96.
McGregor L Makela V Darling SM Vrontou S Chalepakis G Roberts C Smart N Rutland P Prescott N Hopkins J Bentley E Shaw A Roberts E Mueller R Jadeja S Philip N Nelson J Francannet C Perez-Aytes A Megarbane A Kerr B Wainwright B Woolf AS Winter RM Scambler PJ 《Nature genetics》2003,34(2):203-208
Fraser syndrome (OMIM 219000) is a multisystem malformation usually comprising cryptophthalmos, syndactyly and renal defects. Here we report autozygosity mapping and show that the locus FS1 at chromosome 4q21 is associated with Fraser syndrome, although the condition is genetically heterogeneous. Mutation analysis identified five frameshift mutations in FRAS1, which encodes one member of a family of novel proteins related to an extracellular matrix (ECM) blastocoelar protein found in sea urchin. The FRAS1 protein contains a series of N-terminal cysteine-rich repeat motifs previously implicated in BMP metabolism, suggesting that it has a role in both structure and signal propagation in the ECM. It has been speculated that Fraser syndrome is a human equivalent of the blebbed phenotype in the mouse, which has been associated with mutations in at least five loci including bl. As mapping data were consistent with homology of FRAS1 and bl, we screened DNA from bl/bl mice and identified a premature termination of mouse Fras1. Thus, the bl mouse is a model for Fraser syndrome in humans, a disorder caused by disrupted epithelial integrity in utero. 相似文献
97.
Stress response genes protect against lethal effects of sleep deprivation in Drosophila 总被引:11,自引:0,他引:11
Sleep is controlled by two processes: a homeostatic drive that increases during waking and dissipates during sleep, and a circadian pacemaker that controls its timing. Although these two systems can operate independently, recent studies indicate a more intimate relationship. To study the interaction between homeostatic and circadian processes in Drosophila, we examined homeostasis in the canonical loss-of-function clock mutants period (per(01)), timeless (tim(01)), clock (Clk(jrk)) and cycle (cyc(01)). cyc(01) mutants showed a disproportionately large sleep rebound and died after 10 hours of sleep deprivation, although they were more resistant than other clock mutants to various stressors. Unlike other clock mutants, cyc(01) flies showed a reduced expression of heat-shock genes after sleep loss. However, activating heat-shock genes before sleep deprivation rescued cyc(01) flies from its lethal effects. Consistent with the protective effect of heat-shock genes, was the observation that flies carrying a mutation for the heat-shock protein Hsp83 (Hsp83(08445)) showed exaggerated homeostatic response and died after sleep deprivation. These data represent the first step in identifying the molecular mechanisms that constitute the sleep homeostat. 相似文献
98.
The T lymphocyte glycoprotein CD2 binds the cell surface ligand LFA-3 总被引:15,自引:0,他引:15
CD2 (known also as T11 (ref. 1), LFA-2 (ref. 2) and the erythrocyte rosette receptor (ref. 3] is a functionally important T lymphocyte surface glycoprotein of relative molecular mass 50,000 to 58,000 (Mr 50-58 K) which appears early in thymocyte ontogeny and is present on all mature T cells. Monoclonal antibodies to CD2 inhibit cytotoxic T-lymphocyte (CTL)-mediated killing by binding to the T lymphocyte and blocking adhesion to the target cell. Such antibodies also inhibit T helper cell responses including antigen-stimulated proliferation, interleukin-2 (IL-2) secretion, and IL-2 receptor expression. Certain combinations of monoclonal antibodies to CD2 epitopes trigger proliferation of peripheral blood T lymphocytes, cytotoxic effector function and expression of IL-2 receptors by thymocytes, resulting in thymocyte proliferation in the presence of exogenous IL-2 (ref. 11). These findings suggest that CD2 can function in signalling as well as being an adhesion molecule. To understand the role of CD2 in T-cell adhesion and activation, it is essential to define its natural ligand. Our previous observation that purified CD2 inhibits rosetting of T lymphocytes with sheep erythrocytes and can be absorbed by sheep erythrocytes suggested it also might bind with detectable affinity to human cells. We now report that CD2 binds to a cell-surface antigen known as lymphocyte function-associated antigen-3 (LFA-3) with high affinity, and can mediate adhesion of lymphoid cells via interaction with LFA-3. 相似文献
99.
在探讨密码学中布尔函数性质的基础上,提出了一个具有高代数免疫阶布尔函数的构造方法,利用这种方法可以构造出一类具有高代数免疫阶的布尔函数,并给出了一个实例。 相似文献
100.
A. E. Beezer R. J. Miles E. J. Shaw P. Willis 《Cellular and molecular life sciences : CMLS》1979,35(6):795-796
Summary The proposed flow microcalorimetric method for the diagnosis of bacteriuria has been extended to include antibiotic sensitivity testing. Sensitive organisms rapidly (4–8 min) show thermal responses to the added antibiotics over the normal range of concentrations (1×, 2×, MIC value). 相似文献