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排序方式: 共有626条查询结果,搜索用时 62 毫秒
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Weiss J Pyrski M Jacobi E Bufe B Willnecker V Schick B Zizzari P Gossage SJ Greer CA Leinders-Zufall T Woods CG Wood JN Zufall F 《Nature》2011,472(7342):186-190
Loss of function of the gene SCN9A, encoding the voltage-gated sodium channel Na(v)1.7, causes a congenital inability to experience pain in humans. Here we show that Na(v)1.7 is not only necessary for pain sensation but is also an essential requirement for odour perception in both mice and humans. We examined human patients with loss-of-function mutations in SCN9A and show that they are unable to sense odours. To establish the essential role of Na(v)1.7 in odour perception, we generated conditional null mice in which Na(v)1.7 was removed from all olfactory sensory neurons. In the absence of Na(v)1.7, these neurons still produce odour-evoked action potentials but fail to initiate synaptic signalling from their axon terminals at the first synapse in the olfactory system. The mutant mice no longer display vital, odour-guided behaviours such as innate odour recognition and avoidance, short-term odour learning, and maternal pup retrieval. Our study creates a mouse model of congenital general anosmia and provides new strategies to explore the genetic basis of the human sense of smell. 相似文献
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Suppression of lung adenocarcinoma progression by Nkx2-1 总被引:1,自引:0,他引:1
595.
Lee JM Lee YK Mamrosh JL Busby SA Griffin PR Pathak MC Ortlund EA Moore DD 《Nature》2011,474(7352):506-510
Nuclear hormone receptors regulate diverse metabolic pathways and the orphan nuclear receptor LRH-1 (also known as NR5A2) regulates bile acid biosynthesis. Structural studies have identified phospholipids as potential LRH-1 ligands, but their functional relevance is unclear. Here we show that an unusual phosphatidylcholine species with two saturated 12 carbon fatty acid acyl side chains (dilauroyl phosphatidylcholine (DLPC)) is an LRH-1 agonist ligand in vitro. DLPC treatment induces bile acid biosynthetic enzymes in mouse liver, increases bile acid levels, and lowers hepatic triglycerides and serum glucose. DLPC treatment also decreases hepatic steatosis and improves glucose homeostasis in two mouse models of insulin resistance. Both the antidiabetic and lipotropic effects are lost in liver-specific Lrh-1 knockouts. These findings identify an LRH-1 dependent phosphatidylcholine signalling pathway that regulates bile acid metabolism and glucose homeostasis. 相似文献
596.
Fast inhibitory neurotransmission is essential for nervous system function and is mediated by binding of inhibitory neurotransmitters to receptors of the Cys-loop family embedded in the membranes of neurons. Neurotransmitter binding triggers a conformational change in the receptor, opening an intrinsic chloride channel and thereby dampening neuronal excitability. Here we present the first three-dimensional structure, to our knowledge, of an inhibitory anion-selective Cys-loop receptor, the homopentameric Caenorhabditis elegans glutamate-gated chloride channel α (GluCl), at 3.3?? resolution. The X-ray structure of the GluCl-Fab complex was determined with the allosteric agonist ivermectin and in additional structures with the endogenous neurotransmitter L-glutamate and the open-channel blocker picrotoxin. Ivermectin, used to treat river blindness, binds in the transmembrane domain of the receptor and stabilizes an open-pore conformation. Glutamate binds in the classical agonist site at subunit interfaces, and picrotoxin directly occludes the pore near its cytosolic base. GluCl provides a framework for understanding mechanisms of fast inhibitory neurotransmission and allosteric modulation of Cys-loop receptors. 相似文献
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Abbot P Abe J Alcock J Alizon S Alpedrinha JA Andersson M Andre JB van Baalen M Balloux F Balshine S Barton N Beukeboom LW Biernaskie JM Bilde T Borgia G Breed M Brown S Bshary R Buckling A Burley NT Burton-Chellew MN Cant MA Chapuisat M Charnov EL Clutton-Brock T Cockburn A Cole BJ Colegrave N Cosmides L Couzin ID Coyne JA Creel S Crespi B Curry RL Dall SR Day T Dickinson JL Dugatkin LA El Mouden C Emlen ST Evans J Ferriere R Field J Foitzik S Foster K Foster WA Fox CW Gadau J Gandon S 《Nature》2011,471(7339):E1-4; author reply E9-10
Arising from M. A. Nowak, C. E. Tarnita & E. O. Wilson 466, 1057-1062 (2010); Nowak et al. reply. Nowak et al. argue that inclusive fitness theory has been of little value in explaining the natural world, and that it has led to negligible progress in explaining the evolution of eusociality. However, we believe that their arguments are based upon a misunderstanding of evolutionary theory and a misrepresentation of the empirical literature. We will focus our comments on three general issues. 相似文献
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Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity 总被引:1,自引:0,他引:1
Inflammasomes are a family of cytosolic multiprotein complexes that initiate innate immune responses to pathogenic microbes by activating the caspase 1 protease. Although genetic data support a critical role for inflammasomes in immune defence and inflammatory diseases, the molecular basis by which individual inflammasomes respond to specific stimuli remains poorly understood. The inflammasome that contains the NLRC4 (NLR family, CARD domain containing 4) protein was previously shown to be activated in response to two distinct bacterial proteins, flagellin and PrgJ, a conserved component of pathogen-associated type III secretion systems. However, direct binding between NLRC4 and flagellin or PrgJ has never been demonstrated. A homologue of NLRC4, NAIP5 (NLR family, apoptosis inhibitory protein 5), has been implicated in activation of NLRC4 (refs 7-11), but is widely assumed to have only an auxiliary role, as NAIP5 is often dispensable for NLRC4 activation. However, Naip5 is a member of a small multigene family, raising the possibility of redundancy and functional specialization among Naip genes. Here we show in mice that different NAIP paralogues determine the specificity of the NLRC4 inflammasome for distinct bacterial ligands. In particular, we found that activation of endogenous NLRC4 by bacterial PrgJ requires NAIP2, a previously uncharacterized member of the NAIP gene family, whereas NAIP5 and NAIP6 activate NLRC4 specifically in response to bacterial flagellin. We dissected the biochemical mechanism underlying the requirement for NAIP proteins by use of a reconstituted NLRC4 inflammasome system. We found that NAIP proteins control ligand-dependent oligomerization of NLRC4 and that the NAIP2-NLRC4 complex physically associates with PrgJ but not flagellin, whereas NAIP5-NLRC4 associates with flagellin but not PrgJ. Our results identify NAIPs as immune sensor proteins and provide biochemical evidence for a simple receptor-ligand model for activation of the NAIP-NLRC4 inflammasomes. 相似文献
600.
Interaction blockade occurs when strong interactions in a confined, few-body system prevent a particle from occupying an otherwise accessible quantum state. Blockade phenomena reveal the underlying granular nature of quantum systems and allow for the detection and manipulation of the constituent particles, be they electrons, spins, atoms or photons. Applications include single-electron transistors based on electronic Coulomb blockade and quantum logic gates in Rydberg atoms. Here we report a form of interaction blockade that occurs when transferring ultracold atoms between orbitals in an optical lattice. We call this orbital excitation blockade (OEB). In this system, atoms at the same lattice site undergo coherent collisions described by a contact interaction whose strength depends strongly on the orbital wavefunctions of the atoms. We induce coherent orbital excitations by modulating the lattice depth, and observe staircase-like excitation behaviour as we cross the interaction-split resonances by tuning the modulation frequency. As an application of OEB, we demonstrate algorithmic cooling of quantum gases: a sequence of reversible OEB-based quantum operations isolates the entropy in one part of the system and then an irreversible step removes the entropy from the gas. This technique may make it possible to cool quantum gases to have the ultralow entropies required for quantum simulation of strongly correlated electron systems. In addition, the close analogy between OEB and dipole blockade in Rydberg atoms provides a plan for the implementation of two-quantum-bit gates in a quantum computing architecture with natural scalability. 相似文献