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31.
De novo engineering of gene circuits inside cells is extremely difficult, and efforts to realize predictable and robust performance must deal with noise in gene expression and variation in phenotypes between cells. Here we demonstrate that by coupling gene expression to cell survival and death using cell-cell communication, we can programme the dynamics of a population despite variability in the behaviour of individual cells. Specifically, we have built and characterized a 'population control' circuit that autonomously regulates the density of an Escherichia coli population. The cell density is broadcasted and detected by elements from a bacterial quorum-sensing system, which in turn regulate the death rate. As predicted by a simple mathematical model, the circuit can set a stable steady state in terms of cell density and gene expression that is easily tunable by varying the stability of the cell-cell communication signal. This circuit incorporates a mechanism for programmed death in response to changes in the environment, and allows us to probe the design principles of its more complex natural counterparts. 相似文献
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Yu X Tsibane T McGraw PA House FS Keefer CJ Hicar MD Tumpey TM Pappas C Perrone LA Martinez O Stevens J Wilson IA Aguilar PV Altschuler EL Basler CF Crowe JE 《Nature》2008,455(7212):532-536
Investigation of the human antibody response to influenza virus infection has been largely limited to serology, with relatively little analysis at the molecular level. The 1918 H1N1 influenza virus pandemic was the most severe of the modern era. Recent work has recovered the gene sequences of this unusual strain, so that the 1918 pandemic virus could be reconstituted to display its unique virulence phenotypes. However, little is known about adaptive immunity to this virus. We took advantage of the 1918 virus sequencing and the resultant production of recombinant 1918 haemagglutinin (HA) protein antigen to characterize at the clonal level neutralizing antibodies induced by natural exposure of survivors to the 1918 pandemic virus. Here we show that of the 32 individuals tested that were born in or before 1915, each showed seroreactivity with the 1918 virus, nearly 90 years after the pandemic. Seven of the eight donor samples tested had circulating B cells that secreted antibodies that bound the 1918 HA. We isolated B cells from subjects and generated five monoclonal antibodies that showed potent neutralizing activity against 1918 virus from three separate donors. These antibodies also cross-reacted with the genetically similar HA of a 1930 swine H1N1 influenza strain, but did not cross-react with HAs of more contemporary human influenza viruses. The antibody genes had an unusually high degree of somatic mutation. The antibodies bound to the 1918 HA protein with high affinity, had exceptional virus-neutralizing potency and protected mice from lethal infection. Isolation of viruses that escaped inhibition suggested that the antibodies recognize classical antigenic sites on the HA surface. Thus, these studies demonstrate that survivors of the 1918 influenza pandemic possess highly functional, virus-neutralizing antibodies to this uniquely virulent virus, and that humans can sustain circulating B memory cells to viruses for many decades after exposure-well into the tenth decade of life. 相似文献
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Mutations in the chromatin modifier gene KANSL1 cause the 17q21.31 microdeletion syndrome 总被引:1,自引:0,他引:1
Koolen DA Kramer JM Neveling K Nillesen WM Moore-Barton HL Elmslie FV Toutain A Amiel J Malan V Tsai AC Cheung SW Gilissen C Verwiel ET Martens S Feuth T Bongers EM de Vries P Scheffer H Vissers LE de Brouwer AP Brunner HG Veltman JA Schenck A Yntema HG de Vries BB 《Nature genetics》2012,44(6):639-641
We show that haploinsufficiency of KANSL1 is sufficient to cause the 17q21.31 microdeletion syndrome, a multisystem disorder characterized by intellectual disability, hypotonia and distinctive facial features. The KANSL1 protein is an evolutionarily conserved regulator of the chromatin modifier KAT8, which influences gene expression through histone H4 lysine 16 (H4K16) acetylation. RNA sequencing studies in cell lines derived from affected individuals and the presence of learning deficits in Drosophila melanogaster mutants suggest a role for KANSL1 in neuronal processes. 相似文献
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Church C Moir L McMurray F Girard C Banks GT Teboul L Wells S Brüning JC Nolan PM Ashcroft FM Cox RD 《Nature genetics》2010,42(12):1086-1092
Genome-wide association studies have identified SNPs within FTO, the human fat mass and obesity-associated gene, that are strongly associated with obesity. Individuals homozygous for the at-risk rs9939609 A allele weigh, on average, ~3 kg more than individuals with the low-risk T allele. Mice that lack FTO function and/or Fto expression display increased energy expenditure and a lean phenotype. We show here that ubiquitous overexpression of Fto leads to a dose-dependent increase in body and fat mass, irrespective of whether mice are fed a standard or a high-fat diet. Our results suggest that increased body mass results primarily from increased food intake. Mice with increased Fto expression on a high-fat diet develop glucose intolerance. This study provides the first direct evidence that increased Fto expression causes obesity in mice. 相似文献
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Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris 总被引:21,自引:0,他引:21
Smith FJ Irvine AD Terron-Kwiatkowski A Sandilands A Campbell LE Zhao Y Liao H Evans AT Goudie DR Lewis-Jones S Arseculeratne G Munro CS Sergeant A O'Regan G Bale SJ Compton JG DiGiovanna JJ Presland RB Fleckman P McLean WH 《Nature genetics》2006,38(3):337-342
Ichthyosis vulgaris (OMIM 146700) is the most common inherited disorder of keratinization and one of the most frequent single-gene disorders in humans. The most widely cited incidence figure is 1 in 250 based on a survey of 6,051 healthy English schoolchildren. We have identified homozygous or compound heterozygous mutations R501X and 2282del4 in the gene encoding filaggrin (FLG) as the cause of moderate or severe ichthyosis vulgaris in 15 kindreds. In addition, these mutations are semidominant; heterozygotes show a very mild phenotype with incomplete penetrance. The mutations show a combined allele frequency of approximately 4% in populations of European ancestry, explaining the high incidence of ichthyosis vulgaris. Profilaggrin is the major protein of keratohyalin granules in the epidermis. During terminal differentiation, it is cleaved into multiple filaggrin peptides that aggregate keratin filaments. The resultant matrix is cross-linked to form a major component of the cornified cell envelope. We find that loss or reduction of this major structural protein leads to varying degrees of impaired keratinization. 相似文献
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Sandilands A Terron-Kwiatkowski A Hull PR O'Regan GM Clayton TH Watson RM Carrick T Evans AT Liao H Zhao Y Campbell LE Schmuth M Gruber R Janecke AR Elias PM van Steensel MA Nagtzaam I van Geel M Steijlen PM Munro CS Bradley DG Palmer CN Smith FJ McLean WH Irvine AD 《Nature genetics》2007,39(5):650-654
We recently reported two common filaggrin (FLG) null mutations that cause ichthyosis vulgaris and predispose to eczema and secondary allergic diseases. We show here that these common European mutations are ancestral variants carried on conserved haplotypes. To facilitate comprehensive analysis of other populations, we report a strategy for full sequencing of this large, highly repetitive gene, and we describe 15 variants, including seven that are prevalent. All the variants are either nonsense or frameshift mutations that, in representative cases, resulted in loss of filaggrin production in the epidermis. In an Irish case-control study, the five most common European mutations showed a strong association with moderate-to-severe childhood eczema (chi2 test: P = 2.12 x 10(-51); Fisher's exact test: heterozygote odds ratio (OR) = 7.44 (95% confidence interval (c.i.) = 4.9-11.3), and homozygote OR = 151 (95% c.i. = 20-1,136)). We found three additional rare null mutations in this case series, suggesting that the genetic architecture of filaggrin-related atopic dermatitis consists of both prevalent and rare risk alleles. 相似文献
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Garnett MJ Edelman EJ Heidorn SJ Greenman CD Dastur A Lau KW Greninger P Thompson IR Luo X Soares J Liu Q Iorio F Surdez D Chen L Milano RJ Bignell GR Tam AT Davies H Stevenson JA Barthorpe S Lutz SR Kogera F Lawrence K McLaren-Douglas A Mitropoulos X Mironenko T Thi H Richardson L Zhou W Jewitt F Zhang T O'Brien P Boisvert JL Price S Hur W Yang W Deng X Butler A Choi HG Chang JW Baselga J Stamenkovic I Engelman JA Sharma SV Delattre O Saez-Rodriguez J Gray NS Settleman J Futreal PA Haber DA 《Nature》2012,483(7391):570-575
Clinical responses to anticancer therapies are often restricted to a subset of patients. In some cases, mutated cancer genes are potent biomarkers for responses to targeted agents. Here, to uncover new biomarkers of sensitivity and resistance to cancer therapeutics, we screened a panel of several hundred cancer cell lines--which represent much of the tissue-type and genetic diversity of human cancers--with 130 drugs under clinical and preclinical investigation. In aggregate, we found that mutated cancer genes were associated with cellular response to most currently available cancer drugs. Classic oncogene addiction paradigms were modified by additional tissue-specific or expression biomarkers, and some frequently mutated genes were associated with sensitivity to a broad range of therapeutic agents. Unexpected relationships were revealed, including the marked sensitivity of Ewing's sarcoma cells harbouring the EWS (also known as EWSR1)-FLI1 gene translocation to poly(ADP-ribose) polymerase (PARP) inhibitors. By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies. 相似文献
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Jason A. Crisp James R. Tweedley Frances M. L. D’Souza Gavin J. Partridge Navid R. Moheimani 《Journal of Natural History》2016,50(27-28):1699-1724
The six Naupliar, three Protozoea, three Mysis and first post-larval forms of the western school prawn Metapenaeus dalli Racek, 1957 were cultured in the laboratory. These stages were described in detail and compared to those of other metapenaeids. The ontogenetic development occurred in 12 days at 26°C, with both the growth rate and morphological patterns of development in M. dalli broadly following those recorded for other metapenaeids. Differences were found between M. dalli and other metapenaeids at corresponding stages of larval development, with these being the number, location and composition of individual setae and other minor spinal development. 相似文献