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...of variants that affect risk for disease could potentially be used in individualized preventive medicine — including diet, exercise, lifestyle and pharmaceutical intervention — to maximize the likelihood of staying well. For example, the discovery of variants that correlate with successful outcomes of drug therapy, or with unfortunate side effects, could potentially be rapidly translated into clinical practice. Turning this vision into reality will require the following: (1) unbiased determination of the risk associated with a particular gene variant, often overestimated in initial studies31; (2) technological advances to reduce the cost of genotyping (Box 2; see ‘Quantum leaps’, below); (3) research on whether this kind of personalized genomic information will actually alter health behaviours (see Grand Challenge II-5); (4) oversight of the implementation of genetic tests to ensure that only those with demonstrated clinical validity are applied outside of the research setting (Box 5); and (5) education of healthcare professionals and the public to be well-informed participants in this new form of preventive medicine (Box 6). The time is right for a focused effort to understand, and p...

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...lecules in a biochemical pathway. This view became progressively more explicit and mechanistic in later decades. Definition 1950s: Gene as a physical molecule The fact that heredity has a physical, molecular basis was demonstrated by the observation that X rays could cause mutations (Muller 1927). Griffith’s (1928) demonstration that something in virulent but dead Pneumococcus strains could be taken up by live nonvirulent Pneumococcus and transform them into virulent bacteria was further evidence in this direction. It was later shown that this substance could be destroyed by the enzyme DNase (Avery et al. 1944). In 1955, Hershey and Chase established that the substance actually transmitted by bacteriophage to their progeny is DNA and not protein (Hershey and Chase 1955). Moreover, the idea that a gene’s product is a diffusible substance underlies the complementation test that was used to define genes in the early years of bacteriology. A practical view of the gene was that of the cistron, a region of DNA defined by mutations that in trans could not genetically complement each other (Benzer 1955). Definition 1960s: Gene as transcribed code It was the solution of the three-dimensional structure of DNA...

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...(21), was obtained from Dr. R. Lancefield, The Rockefeller University. S. typhimurium, SR-11 (22), was obtained from Dr. L. J. Berry, The University of Texas at Austin. Streptococcus pneumoniae, R36A =-=(23)-=-, was obtained from Dr. A. Tomasz, The Rockefeller University. Listeria monocytogenes, LM-22, was obtained from Dr. D. M¢/Gregor, Cornell University. All cultures were stored at -70°C in media (see be...

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...structed by deleting the first nine genes of the D39 capsule locus (Table 3). This is the same deletion contained in R36A, which is the spontaneous, highly passaged, nonencapsulated derivative of D39 =-=(4, 31)-=-. For all of the mutant and parent strains, no differences were detected in the teichoic acid levels, and all appeared opaque. Nasopharyngeal colonization. The abilities of strains producing reduced l...

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... acid sequence variation between PsaAs from different strains of S. pneumoniae. MATERIALS AND METHODS Bacterial strains and plasmids. The S. pneumoniae strains used were a virulent type 2 strain, D39 =-=(4)-=- (obtained from the National Collection of Type Cultures, London, United Kingdom; strain number NCTC7466), and its nonencapsulated, highly transformable derivative Rx1 (32). Pneumococci were routinely...

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...elonging to the other major phylogenetic groups of the genus Streptococcus. Natural transformation has long been described as a characteristic of species within the mitis group, such as S. pneumoniae =-=(1)-=-, S. gordonii, and S. sanguis (5, 16). The high incidence of comCDE1 strains in this group was therefore expected. The status of the anginosus group with regard to competence, however, has been more u...

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...in Table 1. Those strains marked with a G are 33 recent clinical isolates that were randomly chosen from an Italian collection (15). Others were the classic Avery strain D39S (the Rx1 parental strain =-=[2]-=-), SV1 (1), four American Type Culture Collection strains, and two strains from the collection of Glaxo Wellcome Verona (AII and 3496). The capsules were typed with the Pneumotest kit (Statens Serumin...

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...ired for genetic transformation. MATERIALS AND METHODS Bacterial strains and plasmids. S. pneumoniae CP strains used in this study are descended from strain Rx, which was originally derived from R36A =-=(3)-=-. Strain CP1500 (hex nov-r1 bry-r str-r1 ery-r2 ery-r6) was used as a source of the Nov r marker in transformation assays. CP1250 (hex malM511 str-1 bgl-1) is a CP1200 derivative with low �-galactosid...

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...f antigens. Pneumococcal antigens were purified from recombinant Escherichia coli expressing the respective cloned gene. The original source of the gene in each case was a capsular type 2 strain, D39 =-=(2)-=-. For pneumolysin, a mutated gene encoding a derivative with a Trp-4333Phe substitution was used. This genetic toxoid, designated PdB, has only 0.1% residual cytotoxic activity relative to the native ...

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...encapsulated pneumococci with the same capsular type as the heatkilled strain (158). Years later, the nature of this ‘‘transforming principle,’’ or carrier of genetic information, was shown to be DNA =-=(14)-=-. Other important discoveries resulting from investigations on pneumococci were the therapeutic efficacy of penicillin, the role of the bacterial capsule in resistance to phagocytosis, the ability of ...