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1.
Glycine binding primes NMDA receptor internalization   总被引:18,自引:0,他引:18  
Nong Y  Huang YQ  Ju W  Kalia LV  Ahmadian G  Wang YT  Salter MW 《Nature》2003,422(6929):302-307
NMDA (N-methyl-d-aspartate) receptors (NMDARs) are a principal subtype of excitatory ligand-gated ion channel with prominent roles in physiological and disease processes in the central nervous system. Recognition that glycine potentiates NMDAR-mediated currents as well as being a requisite co-agonist of the NMDAR subtype of 'glutamate' receptor profoundly changed our understanding of chemical synaptic communication in the central nervous system. The binding of both glycine and glutamate is necessary to cause opening of the NMDAR conductance pore. Although binding of either agonist alone is insufficient to cause current flow through the channel, we report here that stimulation of the glycine site initiates signalling through the NMDAR complex, priming the receptors for clathrin-dependent endocytosis. Glycine binding alone does not cause the receptor to be endocytosed; this requires both glycine and glutamate site activation of NMDARs. The priming effect of glycine is mimicked by the NMDAR glycine site agonist d-serine, and is blocked by competitive glycine site antagonists. Synaptic as well as extrasynaptic NMDARs are primed for internalization by glycine site stimulation. Our results demonstrate transmembrane signal transduction through activating the glycine site of NMDARs, and elucidate a model for modulating cell-cell communication in the central nervous system.  相似文献   
2.
U Nachbur  JE Vince  LA O'Reilly  A Strasser  J Silke 《Nature》2012,488(7412):E4-6; discussion E6-8
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3.
Summary Prenatal stress significantly reduced the number of progeny born to 47% of the female offspring and significantly increased the incidence of low birthweight young. None of these litters survived by the tenth postpartum day when serum prolactin levels were significantly reduced. Upon autopsy, these females had twice as many uterine implantation sites than the number of fetuses they bore, suggesting that a) the reduced postpartum serum prolactin most likely was the cause rather than the effect of the neonatal mortality and b) major hormonal deficiencies (possibly gonadotropic-related) were present even before giving birth.  相似文献   
4.
The immune system consists of two evolutionarily different but closely related responses, innate immunity and adaptive immunity. Each of these responses has characteristic receptors-Toll-like receptors (TLRs) for innate immunity and antigen-specific receptors for adaptive immunity. Here we show that the caspase recruitment domain (CARD)-containing serine/threonine kinase Rip2 (also known as RICK, CARDIAK, CCK and Ripk2) transduces signals from receptors of both immune responses. Rip2 was recruited to TLR2 signalling complexes after ligand stimulation. Moreover, cytokine production in Rip2-deficient cells was reduced on stimulation of TLRs with lipopolysaccharide, peptidoglycan and double-stranded RNA, but not with bacterial DNA, indicating that Rip2 is downstream of TLR2/3/4 but not TLR9. Rip2-deficient cells were also hyporesponsive to signalling through interleukin (IL)-1 and IL-18 receptors, and deficient for signalling through Nod proteins-molecules also implicated in the innate immune response. Furthermore, Rip2-deficient T cells showed severely reduced NF-kappaB activation, IL-2 production and proliferation on T-cell-receptor (TCR) engagement, and impaired differentiation to T-helper subtype 1 (TH1) cells, indicating that Rip2 is required for optimal TCR signalling and T-cell differentiation. Rip2 is therefore a signal transducer and integrator of signals for both the innate and adaptive immune systems.  相似文献   
5.
Lisiecki LE  Raymo ME  Curry WB 《Nature》2008,456(7218):85-88
The factors driving glacial changes in ocean overturning circulation are not well understood. On the basis of a comparison of 20 climate variables over the past four glacial cycles, the SPECMAP project proposed that summer insolation at high northern latitudes (that is, Milankovitch forcing) drives the same sequence of ocean circulation and other climate responses over 100-kyr eccentricity cycles, 41-kyr obliquity cycles and 23-kyr precession cycles. SPECMAP analysed the circulation response at only a few sites in the Atlantic Ocean, however, and the phase of circulation response has been shown to vary by site and orbital band. Here we test the SPECMAP hypothesis by measuring the phase of orbital responses in benthic delta(13)C (a proxy indicator of ocean nutrient content) at 24 sites throughout the Atlantic over the past 425 kyr. On the basis of delta(13)C responses at 3,000-4,010 m water depth, we find that maxima in Milankovitch forcing are associated with greater mid-depth overturning in the obliquity band but less overturning in the precession band. This suggests that Atlantic overturning is strongly sensitive to factors beyond ice volume and summer insolation at high northern latitudes. A better understanding of these processes could lead to improvements in model estimates of overturning rates, which range from a 40 per cent increase to a 40 per cent decrease at the Last Glacial Maximum and a 10-50 per cent decrease over the next 140 yr in response to projected increases in atmospheric CO(2) (ref. 4).  相似文献   
6.
The Milankovitch theory of climate change proposes that glacial-interglacial cycles are driven by changes in summer insolation at high northern latitudes. The timing of climate change in the Southern Hemisphere at glacial-interglacial transitions (which are known as terminations) relative to variations in summer insolation in the Northern Hemisphere is an important test of this hypothesis. So far, it has only been possible to apply this test to the most recent termination, because the dating uncertainty associated with older terminations is too large to allow phase relationships to be determined. Here we present a new chronology of Antarctic climate change over the past 360,000 years that is based on the ratio of oxygen to nitrogen molecules in air trapped in the Dome Fuji and Vostok ice cores. This ratio is a proxy for local summer insolation, and thus allows the chronology to be constructed by orbital tuning without the need to assume a lag between a climate record and an orbital parameter. The accuracy of the chronology allows us to examine the phase relationships between climate records from the ice cores and changes in insolation. Our results indicate that orbital-scale Antarctic climate change lags Northern Hemisphere insolation by a few millennia, and that the increases in Antarctic temperature and atmospheric carbon dioxide concentration during the last four terminations occurred within the rising phase of Northern Hemisphere summer insolation. These results support the Milankovitch theory that Northern Hemisphere summer insolation triggered the last four deglaciations.  相似文献   
7.
Smith CE  Llorente B  Symington LS 《Nature》2007,447(7140):102-105
DNA double-strand breaks (DSBs) are potentially lethal lesions that arise spontaneously during normal cellular metabolism, as a consequence of environmental genotoxins or radiation, or during programmed recombination processes. Repair of DSBs by homologous recombination generally occurs by gene conversion resulting from transfer of information from an intact donor duplex to both ends of the break site of the broken chromosome. In mitotic cells, gene conversion is rarely associated with reciprocal exchange and thus limits loss of heterozygosity for markers downstream of the site of repair and restricts potentially deleterious chromosome rearrangements. DSBs that arise by replication fork collapse or by erosion of uncapped telomeres have only one free end and are thought to repair by strand invasion into a homologous duplex DNA followed by replication to the chromosome end (break-induced replication, BIR). BIR from one of the two ends of a DSB would result in loss of heterozygosity, suggesting that BIR is suppressed when DSBs have two ends so that repair occurs by the more conservative gene conversion mechanism. Here we show that BIR can occur by several rounds of strand invasion, DNA synthesis and dissociation. We further show that chromosome rearrangements can occur during BIR if dissociation and reinvasion occur within dispersed repeated sequences. This dynamic process could function to promote gene conversion by capture of the displaced invading strand at two-ended DSBs to prevent BIR.  相似文献   
8.
Gut microbiota composition correlates with diet and health in the elderly   总被引:6,自引:0,他引:6  
Alterations in intestinal microbiota composition are associated with several chronic conditions, including obesity and inflammatory diseases. The microbiota of older people displays greater inter-individual variation than that of younger adults. Here we show that the faecal microbiota composition from 178 elderly subjects formed groups, correlating with residence location in the community, day-hospital, rehabilitation or in long-term residential care. However, clustering of subjects by diet separated them by the same residence location and microbiota groupings. The separation of microbiota composition significantly correlated with measures of frailty, co-morbidity, nutritional status, markers of inflammation and with metabolites in faecal water. The individual microbiota of people in long-stay care was significantly less diverse than that of community dwellers. Loss of community-associated microbiota correlated with increased frailty. Collectively, the data support a relationship between diet, microbiota and health status, and indicate a role for diet-driven microbiota alterations in varying rates of health decline upon ageing.  相似文献   
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10.
<正>以目前的态势看,虽然现在中国企业在劳工方面的问题会对中国制造的低成本优势形成挑战,但是来自中国的电视生产企业将可能会占据新型超大屏幕超薄电视市场的最大份额。就在平板液晶电视的全球需求飙升之际,索尼公司  相似文献   
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