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The mechanisms that determine the lifespan of an organism are still largely a mystery. One goal of ageing research is to find drugs that would increase lifespan and vitality when given to an adult animal. To this end, we tested 88,000 chemicals for the ability to extend the lifespan of adult Caenorhabditis elegans nematodes. Here we report that a drug used as an antidepressant in humans increases C. elegans lifespan. In humans, this drug blocks neural signalling by the neurotransmitter serotonin. In C. elegans, the effect of the drug on lifespan is reduced or eradicated by mutations that affect serotonin synthesis, serotonin re-uptake at synapses, or either of two G-protein-coupled receptors: one that recognizes serotonin and the other that detects another neurotransmitter, octopamine. In vitro studies show that the drug acts as an antagonist at both receptors. Testing of the drug on dietary-restricted animals or animals with mutations that affect lifespan indicates that its effect on lifespan involves mechanisms associated with lifespan extension by dietary restriction. These studies indicate that lifespan can be extended by blocking certain types of neurotransmission implicated in food sensing in the adult animal, possibly leading to a state of perceived, although not real, starvation. 相似文献
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Receptive fields of sensory cortical neurons are plastic, changing in response to alterations of neural activity or sensory experience. In this way, cortical representations of the sensory environment can incorporate new information about the world, depending on the relevance or value of particular stimuli. Neuromodulation is required for cortical plasticity, but it is uncertain how subcortical neuromodulatory systems, such as the cholinergic nucleus basalis, interact with and refine cortical circuits. Here we determine the dynamics of synaptic receptive field plasticity in the adult primary auditory cortex (also known as AI) using in vivo whole-cell recording. Pairing sensory stimulation with nucleus basalis activation shifted the preferred stimuli of cortical neurons by inducing a rapid reduction of synaptic inhibition within seconds, which was followed by a large increase in excitation, both specific to the paired stimulus. Although nucleus basalis was stimulated only for a few minutes, reorganization of synaptic tuning curves progressed for hours thereafter: inhibition slowly increased in an activity-dependent manner to rebalance the persistent enhancement of excitation, leading to a retuned receptive field with new preference for the paired stimulus. This restricted period of disinhibition may be a fundamental mechanism for receptive field plasticity, and could serve as a memory trace for stimuli or episodes that have acquired new behavioural significance. 相似文献
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Zhou T Xu L Dey B Hessell AJ Van Ryk D Xiang SH Yang X Zhang MY Zwick MB Arthos J Burton DR Dimitrov DS Sodroski J Wyatt R Nabel GJ Kwong PD 《Nature》2007,445(7129):732-737
The remarkable diversity, glycosylation and conformational flexibility of the human immunodeficiency virus type 1 (HIV-1) envelope (Env), including substantial rearrangement of the gp120 glycoprotein upon binding the CD4 receptor, allow it to evade antibody-mediated neutralization. Despite this complexity, the HIV-1 Env must retain conserved determinants that mediate CD4 binding. To evaluate how these determinants might provide opportunities for antibody recognition, we created variants of gp120 stabilized in the CD4-bound state, assessed binding of CD4 and of receptor-binding-site antibodies, and determined the structure at 2.3 A resolution of the broadly neutralizing antibody b12 in complex with gp120. b12 binds to a conformationally invariant surface that overlaps a distinct subset of the CD4-binding site. This surface is involved in the metastable attachment of CD4, before the gp120 rearrangement required for stable engagement. A site of vulnerability, related to a functional requirement for efficient association with CD4, can therefore be targeted by antibody to neutralize HIV-1. 相似文献
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Wilker EW van Vugt MA Artim SA Huang PH Petersen CP Reinhardt HC Feng Y Sharp PA Sonenberg N White FM Yaffe MB 《Nature》2007,446(7133):329-332
14-3-3 proteins are crucial in a wide variety of cellular responses including cell cycle progression, DNA damage checkpoints and apoptosis. One particular 14-3-3 isoform, sigma, is a p53-responsive gene, the function of which is frequently lost in human tumours, including breast and prostate cancers as a result of either hypermethylation of the 14-3-3sigma promoter or induction of an oestrogen-responsive ubiquitin ligase that specifically targets 14-3-3sigma for proteasomal degradation. Loss of 14-3-3sigma protein occurs not only within the tumours themselves but also in the surrounding pre-dysplastic tissue (so-called field cancerization), indicating that 14-3-3sigma might have an important tumour suppressor function that becomes lost early in the process of tumour evolution. The molecular basis for the tumour suppressor function of 14-3-3sigma is unknown. Here we report a previously unknown function for 14-3-3sigma as a regulator of mitotic translation through its direct mitosis-specific binding to a variety of translation/initiation factors, including eukaryotic initiation factor 4B in a stoichiometric manner. Cells lacking 14-3-3sigma, in marked contrast to normal cells, cannot suppress cap-dependent translation and do not stimulate cap-independent translation during and immediately after mitosis. This defective switch in the mechanism of translation results in reduced mitotic-specific expression of the endogenous internal ribosomal entry site (IRES)-dependent form of the cyclin-dependent kinase Cdk11 (p58 PITSLRE), leading to impaired cytokinesis, loss of Polo-like kinase-1 at the midbody, and the accumulation of binucleate cells. The aberrant mitotic phenotype of 14-3-3sigma-depleted cells can be rescued by forced expression of p58 PITSLRE or by extinguishing cap-dependent translation and increasing cap-independent translation during mitosis by using rapamycin. Our findings show how aberrant mitotic translation in the absence of 14-3-3sigma impairs mitotic exit to generate binucleate cells and provides a potential explanation of how 14-3-3sigma-deficient cells may progress on the path to aneuploidy and tumorigenesis. 相似文献
70.
Aeschlimann M Bauer M Bayer D Brixner T García de Abajo FJ Pfeiffer W Rohmer M Spindler C Steeb F 《Nature》2007,446(7133):301-304
Adaptive shaping of the phase and amplitude of femtosecond laser pulses has been developed into an efficient tool for the directed manipulation of interference phenomena, thus providing coherent control over various quantum-mechanical systems. Temporal resolution in the femtosecond or even attosecond range has been demonstrated, but spatial resolution is limited by diffraction to approximately half the wavelength of the light field (that is, several hundred nanometres). Theory has indicated that the spatial limitation to coherent control can be overcome with the illumination of nanostructures: the spatial near-field distribution was shown to depend on the linear chirp of an irradiating laser pulse. An extension of this idea to adaptive control, combining multiparameter pulse shaping with a learning algorithm, demonstrated the generation of user-specified optical near-field distributions in an optimal and flexible fashion. Shaping of the polarization of the laser pulse provides a particularly efficient and versatile nano-optical manipulation method. Here we demonstrate the feasibility of this concept experimentally, by tailoring the optical near field in the vicinity of silver nanostructures through adaptive polarization shaping of femtosecond laser pulses and then probing the lateral field distribution by two-photon photoemission electron microscopy. In this combination of adaptive control and nano-optics, we achieve subwavelength dynamic localization of electromagnetic intensity on the nanometre scale and thus overcome the spatial restrictions of conventional optics. This experimental realization of theoretical suggestions opens a number of perspectives in coherent control, nano-optics, nonlinear spectroscopy, and other research fields in which optical investigations are carried out with spatial or temporal resolution. 相似文献