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991.
992.
Croucher NJ Harris SR Fraser C Quail MA Burton J van der Linden M McGee L von Gottberg A Song JH Ko KS Pichon B Baker S Parry CM Lambertsen LM Shahinas D Pillai DR Mitchell TJ Dougan G Tomasz A Klugman KP Parkhill J Hanage WP Bentley SD 《Science (New York, N.Y.)》2011,331(6016):430-434
Epidemiological studies of the naturally transformable bacterial pathogen Streptococcus pneumoniae have previously been confounded by high rates of recombination. Sequencing 240 isolates of the PMEN1 (Spain(23F)-1) multidrug-resistant lineage enabled base substitutions to be distinguished from polymorphisms arising through horizontal sequence transfer. More than 700 recombinations were detected, with genes encoding major antigens frequently affected. Among these were 10 capsule-switching events, one of which accompanied a population shift as vaccine-escape serotype 19A isolates emerged in the USA after the introduction of the conjugate polysaccharide vaccine. The evolution of resistance to fluoroquinolones, rifampicin, and macrolides was observed to occur on multiple occasions. This study details how genomic plasticity within lineages of recombinogenic bacteria can permit adaptation to clinical interventions over remarkably short time scales. 相似文献
993.
Yin H Slusky JS Berger BW Walters RS Vilaire G Litvinov RI Lear JD Caputo GA Bennett JS DeGrado WF 《Science (New York, N.Y.)》2007,315(5820):1817-1822
A variety of methods exist for the design or selection of antibodies and other proteins that recognize the water-soluble regions of proteins; however, companion methods for targeting transmembrane (TM) regions are not available. Here, we describe a method for the computational design of peptides that target TM helices in a sequence-specific manner. To illustrate the method, peptides were designed that specifically recognize the TM helices of two closely related integrins (alphaIIbbeta3 and alphavbeta3) in micelles, bacterial membranes, and mammalian cells. These data show that sequence-specific recognition of helices in TM proteins can be achieved through optimization of the geometric complementarity of the target-host complex. 相似文献
994.
Gallarda BW Bonanomi D Müller D Brown A Alaynick WA Andrews SE Lemke G Pfaff SL Marquardt T 《Science (New York, N.Y.)》2008,320(5873):233-236
Execution of motor behaviors relies on circuitries effectively integrating immediate sensory feedback to efferent pathways controlling muscle activity. It remains unclear how, during neuromuscular circuit assembly, sensory and motor projections become incorporated into tightly coordinated, yet functionally separate pathways. We report that, within axial nerves, establishment of discrete afferent and efferent pathways depends on coordinate signaling between coextending sensory and motor projections. These heterotypic axon-axon interactions require motor axonal EphA3/EphA4 receptor tyrosine kinases activated by cognate sensory axonal ephrin-A ligands. Genetic elimination of trans-axonal ephrin-A --> EphA signaling in mice triggers drastic motor-sensory miswiring, culminating in functional efferents within proximal afferent pathways. Effective assembly of a key circuit underlying motor behaviors thus critically depends on trans-axonal signaling interactions resolving motor and sensory projections into discrete pathways. 相似文献
995.
The protein components of eukaryotic cells face acute and chronic challenges to their integrity. Eukaryotic protein homeostasis, or proteostasis, enables healthy cell and organismal development and aging and protects against disease. Here, we describe the proteostasis network, a set of interacting activities that maintain the health of proteome and the organism. Deficiencies in proteostasis lead to many metabolic, oncological, neurodegenerative, and cardiovascular disorders. Small-molecule or biological proteostasis regulators that manipulate the concentration, conformation, quaternary structure, and/or the location of protein(s) have the potential to ameliorate some of the most challenging diseases of our era. 相似文献
996.
Valente EM Abou-Sleiman PM Caputo V Muqit MM Harvey K Gispert S Ali Z Del Turco D Bentivoglio AR Healy DG Albanese A Nussbaum R González-Maldonado R Deller T Salvi S Cortelli P Gilks WP Latchman DS Harvey RJ Dallapiccola B Auburger G Wood NW 《Science (New York, N.Y.)》2004,304(5674):1158-1160
Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons in the substantia nigra. We previously mapped a locus for a rare familial form of PD to chromosome 1p36 (PARK6). Here we show that mutations in PINK1 (PTEN-induced kinase 1) are associated with PARK6. We have identified two homozygous mutations affecting the PINK1 kinase domain in three consanguineous PARK6 families: a truncating nonsense mutation and a missense mutation at a highly conserved amino acid. Cell culture studies suggest that PINK1 is mitochondrially located and may exert a protective effect on the cell that is abrogated by the mutations, resulting in increased susceptibility to cellular stress. These data provide a direct molecular link between mitochondria and the pathogenesis of PD. 相似文献
997.
Antioxidants in photosynthesis and human nutrition 总被引:3,自引:0,他引:3
The harnessing of solar energy by photosynthesis depends on a safety valve that effectively eliminates hazardous excess energy and prevents oxidative damage to the plant cells. Many of the compounds that protect plant cells also protect human cells. Improving plant resistance to stress may thus have the beneficial side effect of also improving the nutritional quality of plants in the human diet. The pathways that synthesize these compounds are becoming amenable to genetic manipulation, which may yield benefits as widespread as improved plant stress tolerance and improved human physical and mental health. 相似文献
998.
Life originated, according to the RNA World hypothesis, from self-replicating ribozymes that catalyzed ligation of RNA fragments. We have solved the 2.6 angstrom crystal structure of a ligase ribozyme that catalyzes regiospecific formation of a 5' to 3' phosphodiester bond between the 5'-triphosphate and the 3'-hydroxyl termini of two RNA fragments. Invariant residues form tertiary contacts that stabilize a flexible stem of the ribozyme at the ligation site, where an essential magnesium ion coordinates three phosphates. The structure of the active site permits us to suggest how transition-state stabilization and a general base may catalyze the ligation reaction required for prebiotic RNA assembly. 相似文献
999.
Genome-wide insertional mutagenesis of Arabidopsis thaliana 总被引:2,自引:0,他引:2
Alonso JM Stepanova AN Leisse TJ Kim CJ Chen H Shinn P Stevenson DK Zimmerman J Barajas P Cheuk R Gadrinab C Heller C Jeske A Koesema E Meyers CC Parker H Prednis L Ansari Y Choy N Deen H Geralt M Hazari N Hom E Karnes M Mulholland C Ndubaku R Schmidt I Guzman P Aguilar-Henonin L Schmid M Weigel D Carter DE Marchand T Risseeuw E Brogden D Zeko A Crosby WL Berry CC Ecker JR 《Science (New York, N.Y.)》2003,301(5633):653-657
Over 225,000 independent Agrobacterium transferred DNA (T-DNA) insertion events in the genome of the reference plant Arabidopsis thaliana have been created that represent near saturation of the gene space. The precise locations were determined for more than 88,000 T-DNA insertions, which resulted in the identification of mutations in more than 21,700 of the approximately 29,454 predicted Arabidopsis genes. Genome-wide analysis of the distribution of integration events revealed the existence of a large integration site bias at both the chromosome and gene levels. Insertion mutations were identified in genes that are regulated in response to the plant hormone ethylene. 相似文献
1000.
The squeezing of polymers in narrow gaps is important for the dynamics of nanostructure fabrication by nanoimprint embossing and the operation of polymer boundary lubricants. We measured stress versus strain behavior while squeezing entangled polystyrene films to large strains. In confined conditions where films were prepared to a thickness less than the size of the bulk macromolecule, resistance to deformation was markedly reduced for both solid-glass forging and liquid-melt molding. For melt flow, we further observed a complete inversion of conventional polymer viscosity scaling with molecular weight. Our results show that squeeze flow is accelerated at small scales by an unexpected influence of film thickness in polymer materials. 相似文献