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301.
Ann-Karin Haas Gunnar Kleinau Inna Hoyer Susanne Neumann Jens Furkert Claudia Rutz Ralf Schülein Marvin C. Gershengorn Gerd Krause 《Cellular and molecular life sciences : CMLS》2011,68(1):159-167
The thyrotropin receptor (TSHR) exhibits elevated cAMP signaling in the basal state and becomes fully activated by thyrotropin.
Previously we presented evidence that small-molecule ligands act allosterically within the transmembrane region in contrast
to the orthosteric extracellular hormone-binding sites. Our goal in this study was to identify positions that surround the
allosteric pocket and that are sensitive for inactivation of TSHR. Homology modeling combined with site-directed mutagenesis
and functional characterization revealed seven mutants located in the allosteric binding site that led to a decrease of basal
cAMP signaling activity. The majority of these silencing mutations, which constrain the TSHR in an inactive conformation,
are found in two clusters when mapped onto the 3D structural model. We suggest that the amino acid positions identified herein
are indicating locations where small-molecule antagonists, both neutral antagonists and inverse agonists, might interfere
with active TSHR conformations. 相似文献
302.
303.
Dunham A Matthews LH Burton J Ashurst JL Howe KL Ashcroft KJ Beare DM Burford DC Hunt SE Griffiths-Jones S Jones MC Keenan SJ Oliver K Scott CE Ainscough R Almeida JP Ambrose KD Andrews DT Ashwell RI Babbage AK Bagguley CL Bailey J Bannerjee R Barlow KF Bates K Beasley H Bird CP Bray-Allen S Brown AJ Brown JY Burrill W Carder C Carter NP Chapman JC Clamp ME Clark SY Clarke G Clee CM Clegg SC Cobley V Collins JE Corby N Coville GJ Deloukas P Dhami P Dunham I Dunn M Earthrowl ME Ellington AG 《Nature》2004,428(6982):522-528
Chromosome 13 is the largest acrocentric human chromosome. It carries genes involved in cancer including the breast cancer type 2 (BRCA2) and retinoblastoma (RB1) genes, is frequently rearranged in B-cell chronic lymphocytic leukaemia, and contains the DAOA locus associated with bipolar disorder and schizophrenia. We describe completion and analysis of 95.5 megabases (Mb) of sequence from chromosome 13, which contains 633 genes and 296 pseudogenes. We estimate that more than 95.4% of the protein-coding genes of this chromosome have been identified, on the basis of comparison with other vertebrate genome sequences. Additionally, 105 putative non-coding RNA genes were found. Chromosome 13 has one of the lowest gene densities (6.5 genes per Mb) among human chromosomes, and contains a central region of 38 Mb where the gene density drops to only 3.1 genes per Mb. 相似文献
304.
305.
Continental runoff has increased through the twentieth century despite more intensive human water consumption. Possible reasons for the increase include: climate change and variability, deforestation, solar dimming, and direct atmospheric carbon dioxide (CO2) effects on plant transpiration. All of these mechanisms have the potential to affect precipitation and/or evaporation and thereby modify runoff. Here we use a mechanistic land-surface model and optimal fingerprinting statistical techniques to attribute observational runoff changes into contributions due to these factors. The model successfully captures the climate-driven inter-annual runoff variability, but twentieth-century climate alone is insufficient to explain the runoff trends. Instead we find that the trends are consistent with a suppression of plant transpiration due to CO2-induced stomatal closure. This result will affect projections of freshwater availability, and also represents the detection of a direct CO2 effect on the functioning of the terrestrial biosphere. 相似文献
306.
307.
E A Donley N R Claussen S L Cornish J L Roberts E A Cornell C E Wieman 《Nature》2001,412(6844):295-299
When atoms in a gas are cooled to extremely low temperatures, they will-under the appropriate conditions-condense into a single quantum-mechanical state known as a Bose-Einstein condensate. In such systems, quantum-mechanical behaviour is evident on a macroscopic scale. Here we explore the dynamics of how a Bose-Einstein condensate collapses and subsequently explodes when the balance of forces governing its size and shape is suddenly altered. A condensate's equilibrium size and shape is strongly affected by the interatomic interactions. Our ability to induce a collapse by switching the interactions from repulsive to attractive by tuning an externally applied magnetic field yields detailed information on the violent collapse process. We observe anisotropic atom bursts that explode from the condensate, atoms leaving the condensate in undetected forms, spikes appearing in the condensate wavefunction and oscillating remnant condensates that survive the collapse. All these processes have curious dependences on time, on the strength of the interaction and on the number of condensate atoms. Although the system would seem to be simple and well characterized, our measurements reveal many phenomena that challenge theoretical models. 相似文献
308.
Reef corals bleach to survive change. 总被引:33,自引:0,他引:33
309.
Equilibrating metal-oxide cluster ensembles for oxidation reactions using oxygen in water. 总被引:2,自引:0,他引:2
I A Weinstock E M Barbuzzi M W Wemple J J Cowan R S Reiner D M Sonnen R A Heintz J S Bond C L Hill 《Nature》2001,414(6860):191-195
Although many enzymes can readily and selectively use oxygen in water-the most familiar and attractive of all oxidants and solvents, respectively-the design of synthetic catalysts for selective water-based oxidation processes utilizing molecular oxygen remains a daunting task. Particularly problematic is the fact that oxidation of substrates by O2 involves radical chemistry, which is intrinsically non-selective and difficult to control. In addition, metallo-organic catalysts are inherently susceptible to degradation by oxygen-based radicals, while their transition-metal-ion active sites often react with water to give insoluble, and thus inactive, oxides or hydroxides. Furthermore, pH control is often required to avoid acid or base degradation of organic substrates or products. Unlike metallo-organic catalysts, polyoxometalate anions are oxidatively stable and are reversible oxidants for use with O2 (refs 8,9,10). Here we show how thermodynamically controlled self-assembly of an equilibrated ensemble of polyoxometalates, with the heteropolytungstate anion [AIVVW11O40]6- as its main component, imparts both stability in water and internal pH-management. Designed to operate at near-neutral pH, this system facilitates a two-step O2-based process for the selective delignification of wood (lignocellulose) fibres. By directly monitoring the central Al atom, we show that equilibration reactions typical of polyoxometalate anions keep the pH of the system near 7 during both process steps. 相似文献
310.
Individual recognition in mice mediated by major urinary proteins. 总被引:25,自引:0,他引:25
J L Hurst C E Payne C M Nevison A D Marie R E Humphries D H Robertson A Cavaggioni R J Beynon 《Nature》2001,414(6864):631-634
The ability to recognize individuals is essential to many aspects of social behaviour, such as the maintenance of stable social groups, parent-offspring or mate recognition, inbreeding avoidance and the modulation of competitive relationships. Odours are a primary mediator of individuality signals among many mammals. One source of odour complexity in rodents, and possibly in humans, resides in the highly polymorphic major histocompatibility complex (MHC). The olfactory acuity of mice and rats allows them to distinguish between the urinary odours of congenic strains differing only in single genes within the MHC, although the chemical mediators or odorants are unknown. However, rodent urine also contains a class of proteins, termed major urinary proteins (MUPs), that bind and release small volatile pheromones. We have shown that the combinatorial diversity of expression of MUPs among wild mice might be as great as for MHC, and at protein concentrations a million times higher. Here we show in wild house mice (Mus domesticus) that urinary MUPs play an important role in the individual recognition mechanism. 相似文献