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481.
Sebaihia M Wren BW Mullany P Fairweather NF Minton N Stabler R Thomson NR Roberts AP Cerdeño-Tárraga AM Wang H Holden MT Wright A Churcher C Quail MA Baker S Bason N Brooks K Chillingworth T Cronin A Davis P Dowd L Fraser A Feltwell T Hance Z Holroyd S Jagels K Moule S Mungall K Price C Rabbinowitsch E Sharp S Simmonds M Stevens K Unwin L Whithead S Dupuy B Dougan G Barrell B Parkhill J 《Nature genetics》2006,38(7):779-786
We determined the complete genome sequence of Clostridium difficile strain 630, a virulent and multidrug-resistant strain. Our analysis indicates that a large proportion (11%) of the genome consists of mobile genetic elements, mainly in the form of conjugative transposons. These mobile elements are putatively responsible for the acquisition by C. difficile of an extensive array of genes involved in antimicrobial resistance, virulence, host interaction and the production of surface structures. The metabolic capabilities encoded in the genome show multiple adaptations for survival and growth within the gut environment. The extreme genome variability was confirmed by whole-genome microarray analysis; it may reflect the organism's niche in the gut and should provide information on the evolution of virulence in this organism. 相似文献
482.
Ramirez A Heimbach A Gründemann J Stiller B Hampshire D Cid LP Goebel I Mubaidin AF Wriekat AL Roeper J Al-Din A Hillmer AM Karsak M Liss B Woods CG Behrens MI Kubisch C 《Nature genetics》2006,38(10):1184-1191
Neurodegenerative disorders such as Parkinson and Alzheimer disease cause motor and cognitive dysfunction and belong to a heterogeneous group of common and disabling disorders. Although the complex molecular pathophysiology of neurodegeneration is largely unknown, major advances have been achieved by elucidating the genetic defects underlying mendelian forms of these diseases. This has led to the discovery of common pathophysiological pathways such as enhanced oxidative stress, protein misfolding and aggregation and dysfunction of the ubiquitin-proteasome system. Here, we describe loss-of-function mutations in a previously uncharacterized, predominantly neuronal P-type ATPase gene, ATP13A2, underlying an autosomal recessive form of early-onset parkinsonism with pyramidal degeneration and dementia (PARK9, Kufor-Rakeb syndrome). Whereas the wild-type protein was located in the lysosome of transiently transfected cells, the unstable truncated mutants were retained in the endoplasmic reticulum and degraded by the proteasome. Our findings link a class of proteins with unknown function and substrate specificity to the protein networks implicated in neurodegeneration and parkinsonism. 相似文献
483.
Genetic analysis of the nematode Caenorhabditis elegans reveals that all dpy-5 alleles are dominant suppressors of bli-4 blistering. Molecular cloning of dpy-5 establishes that it encodes a cuticle procollagen, defects in which are responsible for the short-body, dumpy phenotype.
The null mutation, e907 removes the entire coding region, whereas the dpy-5 reference allele, e61, contains a nonsense substitution. RT-PCR analysis and a dpy-5::gfp fusion show that dpy-5 is expressed only in hypodermal cells at all post-embryonic life-cycle stages. Variable expression of dpy-5 in V lineage-derived seam cells suggests an alternative regulatory mechanism in these cells. The dpy-5 gene product contains an Arg-X-X-Arg cleavage motif that could be recognized by a proprotein convertase, such as BLI-4. Mutation
of this site cause a dominant dumpy phenotype suggesting Dpy-5 procollagen requires processing for normal cuticle production.
Received 13 January 2006; accepted 23 March 2006 相似文献
484.
Rees MI Harvey K Pearce BR Chung SK Duguid IC Thomas P Beatty S Graham GE Armstrong L Shiang R Abbott KJ Zuberi SM Stephenson JB Owen MJ Tijssen MA van den Maagdenberg AM Smart TG Supplisson S Harvey RJ 《Nature genetics》2006,38(7):801-806
Hyperekplexia is a human neurological disorder characterized by an excessive startle response and is typically caused by missense and nonsense mutations in the gene encoding the inhibitory glycine receptor (GlyR) alpha1 subunit (GLRA1). Genetic heterogeneity has been confirmed in rare sporadic cases, with mutations affecting other postsynaptic glycinergic proteins including the GlyR beta subunit (GLRB), gephyrin (GPHN) and RhoGEF collybistin (ARHGEF9). However, many individuals diagnosed with sporadic hyperekplexia do not carry mutations in these genes. Here we show that missense, nonsense and frameshift mutations in SLC6A5 (ref. 8), encoding the presynaptic glycine transporter 2 (GlyT2), also cause hyperekplexia. Individuals with mutations in SLC6A5 present with hypertonia, an exaggerated startle response to tactile or acoustic stimuli, and life-threatening neonatal apnea episodes. SLC6A5 mutations result in defective subcellular GlyT2 localization, decreased glycine uptake or both, with selected mutations affecting predicted glycine and Na+ binding sites. 相似文献
485.
Young ND Debellé F Oldroyd GE Geurts R Cannon SB Udvardi MK Benedito VA Mayer KF Gouzy J Schoof H Van de Peer Y Proost S Cook DR Meyers BC Spannagl M Cheung F De Mita S Krishnakumar V Gundlach H Zhou S Mudge J Bharti AK Murray JD Naoumkina MA Rosen B Silverstein KA Tang H Rombauts S Zhao PX Zhou P Barbe V Bardou P Bechner M Bellec A Berger A Bergès H Bidwell S Bisseling T Choisne N Couloux A Denny R Deshpande S Dai X Doyle JJ Dudez AM Farmer AD Fouteau S Franken C Gibelin C Gish J Goldstein S 《Nature》2011,480(7378):520-524
Legumes (Fabaceae or Leguminosae) are unique among cultivated plants for their ability to carry out endosymbiotic nitrogen fixation with rhizobial bacteria, a process that takes place in a specialized structure known as the nodule. Legumes belong to one of the two main groups of eurosids, the Fabidae, which includes most species capable of endosymbiotic nitrogen fixation. Legumes comprise several evolutionary lineages derived from a common ancestor 60 million years ago (Myr ago). Papilionoids are the largest clade, dating nearly to the origin of legumes and containing most cultivated species. Medicago truncatula is a long-established model for the study of legume biology. Here we describe the draft sequence of the M. truncatula euchromatin based on a recently completed BAC assembly supplemented with Illumina shotgun sequence, together capturing ~94% of all M. truncatula genes. A whole-genome duplication (WGD) approximately 58 Myr ago had a major role in shaping the M. truncatula genome and thereby contributed to the evolution of endosymbiotic nitrogen fixation. Subsequent to the WGD, the M. truncatula genome experienced higher levels of rearrangement than two other sequenced legumes, Glycine max and Lotus japonicus. M. truncatula is a close relative of alfalfa (Medicago sativa), a widely cultivated crop with limited genomics tools and complex autotetraploid genetics. As such, the M. truncatula genome sequence provides significant opportunities to expand alfalfa's genomic toolbox. 相似文献
486.
Yazawa M Hsueh B Jia X Pasca AM Bernstein JA Hallmayer J Dolmetsch RE 《Nature》2011,471(7337):230-234
Individuals with congenital or acquired prolongation of the QT interval, or long QT syndrome (LQTS), are at risk of life-threatening ventricular arrhythmia. LQTS is commonly genetic in origin but can also be caused or exacerbated by environmental factors. A missense mutation in the L-type calcium channel Ca(V)1.2 leads to LQTS in patients with Timothy syndrome. To explore the effect of the Timothy syndrome mutation on the electrical activity and contraction of human cardiomyocytes, we reprogrammed human skin cells from Timothy syndrome patients to generate induced pluripotent stem cells, and differentiated these cells into cardiomyocytes. Electrophysiological recording and calcium (Ca(2+)) imaging studies of these cells revealed irregular contraction, excess Ca(2+) influx, prolonged action potentials, irregular electrical activity and abnormal calcium transients in ventricular-like cells. We found that roscovitine, a compound that increases the voltage-dependent inactivation of Ca(V)1.2 (refs 6-8), restored the electrical and Ca(2+) signalling properties of cardiomyocytes from Timothy syndrome patients. This study provides new opportunities for studying the molecular and cellular mechanisms of cardiac arrhythmias in humans, and provides a robust assay for developing new drugs to treat these diseases. 相似文献
487.
Bock DD Lee WC Kerlin AM Andermann ML Hood G Wetzel AW Yurgenson S Soucy ER Kim HS Reid RC 《Nature》2011,471(7337):177-182
In the cerebral cortex, local circuits consist of tens of thousands of neurons, each of which makes thousands of synaptic connections. Perhaps the biggest impediment to understanding these networks is that we have no wiring diagrams of their interconnections. Even if we had a partial or complete wiring diagram, however, understanding the network would also require information about each neuron's function. Here we show that the relationship between structure and function can be studied in the cortex with a combination of in vivo physiology and network anatomy. We used two-photon calcium imaging to characterize a functional property--the preferred stimulus orientation--of a group of neurons in the mouse primary visual cortex. Large-scale electron microscopy of serial thin sections was then used to trace a portion of these neurons' local network. Consistent with a prediction from recent physiological experiments, inhibitory interneurons received convergent anatomical input from nearby excitatory neurons with a broad range of preferred orientations, although weak biases could not be rejected. 相似文献
488.
Flying birds often form flocks, with social, navigational and anti-predator implications. Further, flying in a flock can result in aerodynamic benefits, thus reducing power requirements, as demonstrated by a reduction in heart rate and wingbeat frequency in pelicans flying in a V-formation. But how general is an aerodynamic power reduction due to group-flight? V-formation flocks are limited to moderately steady flight in relatively large birds, and may represent a special case. What are the aerodynamic consequences of flying in the more usual 'cluster' flock? Here we use data from innovative back-mounted Global Positioning System (GPS) and 6-degrees-of-freedom inertial sensors to show that pigeons (1) maintain powered, banked turns like aircraft, imposing dorsal accelerations of up to 2g, effectively doubling body weight and quadrupling induced power requirements; (2) increase flap frequency with increases in all conventional aerodynamic power requirements; and (3) increase flap frequency when flying near, particularly behind, other birds. Therefore, unlike V-formation pelicans, pigeons do not gain an aerodynamic advantage from flying in a flock. Indeed, the increased flap frequency, whether due to direct aerodynamic interactions or requirements for increased stability or control, suggests a considerable energetic cost to flight in a tight cluster flock. 相似文献
489.
490.
Allergic disorders, such as anaphylaxis, hay fever, eczema and asthma, now afflict roughly 25% of people in the developed world. In allergic subjects, persistent or repetitive exposure to allergens, which typically are intrinsically innocuous substances common in the environment, results in chronic allergic inflammation. This in turn produces long-term changes in the structure of the affected organs and substantial abnormalities in their function. It is therefore important to understand the characteristics and consequences of acute and chronic allergic inflammation, and in particular to explore how mast cells can contribute to several features of this maladaptive pattern of immunological reactivity. 相似文献