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排序方式: 共有189条查询结果,搜索用时 15 毫秒
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Significant decadal-scale impact of volcanic eruptions on sea level and ocean heat content 总被引:2,自引:0,他引:2
Ocean thermal expansion contributes significantly to sea-level variability and rise. However, observed decadal variability in ocean heat content and sea level has not been reproduced well in climate models. Aerosols injected into the stratosphere during volcanic eruptions scatter incoming solar radiation, and cause a rapid cooling of the atmosphere and a reduction in rainfall, as well as other changes in the climate system. Here we use observations of ocean heat content and a set of climate simulations to show that large volcanic eruptions result in rapid reductions in ocean heat content and global mean sea level. For the Mt Pinatubo eruption, we estimate a reduction in ocean heat content of about 3 x 10(22) J and a global sea-level fall of about 5 mm. Over the three years following such an eruption, we estimate a decrease in evaporation of up to 0.1 mm d(-1), comparable to observed changes in mean land precipitation. The recovery of sea level following the Mt Pinatubo eruption in 1991 explains about half of the difference between the long-term rate of sea-level rise of 1.8 mm yr(-1) (for 1950-2000), and the higher rate estimated for the more recent period where satellite altimeter data are available (1993-2000). 相似文献
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Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss 总被引:1,自引:0,他引:1
Klein CJ Botuyan MV Wu Y Ward CJ Nicholson GA Hammans S Hojo K Yamanishi H Karpf AR Wallace DC Simon M Lander C Boardman LA Cunningham JM Smith GE Litchy WJ Boes B Atkinson EJ Middha S B Dyck PJ Parisi JE Mer G Smith DI Dyck PJ 《Nature genetics》2011,43(6):595-600
DNA methyltransferase 1 (DNMT1) is crucial for maintenance of methylation, gene regulation and chromatin stability. DNA mismatch repair, cell cycle regulation in post-mitotic neurons and neurogenesis are influenced by DNA methylation. Here we show that mutations in DNMT1 cause both central and peripheral neurodegeneration in one form of hereditary sensory and autonomic neuropathy with dementia and hearing loss. Exome sequencing led to the identification of DNMT1 mutation c.1484A>G (p.Tyr495Cys) in two American kindreds and one Japanese kindred and a triple nucleotide change, c.1470-1472TCC>ATA (p.Asp490Glu-Pro491Tyr), in one European kindred. All mutations are within the targeting-sequence domain of DNMT1. These mutations cause premature degradation of mutant proteins, reduced methyltransferase activity and impaired heterochromatin binding during the G2 cell cycle phase leading to global hypomethylation and site-specific hypermethylation. Our study shows that DNMT1 mutations cause the aberrant methylation implicated in complex pathogenesis. The discovered DNMT1 mutations provide a new framework for the study of neurodegenerative diseases. 相似文献
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In humans, up to 75% of newly generated B cells and about 30% of mature B cells show some degree of autoreactivity. Yet, how B cells establish and maintain tolerance in the face of autoantigen exposure during and after development is not certain. Studies of model B-cell antigen receptor (BCR) transgenic systems have highlighted the critical role of functional unresponsiveness or ‘anergy’. Unlike T cells, evidence suggests that receptor editing and anergy, rather than deletion, account for much of B-cell tolerance. However, it remains unclear whether the mature diverse B-cell repertoire of mice contains anergic autoreactive B cells, and if so, whether antigen was encountered during or after their development. By taking advantage of a reporter mouse in which BCR signalling rapidly and robustly induces green fluorescent protein expression under the control of the Nur77 regulatory region, antigen-dependent and antigen-independent BCR signalling events in vivo during B-cell maturation were visualized. Here we show that B cells encounter antigen during development in the spleen, and that this antigen exposure, in turn, tunes the responsiveness of BCR signalling in B cells at least partly by downmodulating expression of surface IgM but not IgD BCRs, and by modifying basal calcium levels. By contrast, no analogous process occurs in naive mature T cells. Our data demonstrate not only that autoreactive B cells persist in the mature repertoire, but that functional unresponsiveness or anergy exists in the mature B-cell repertoire along a continuum, a fact that has long been suspected, but never yet shown. These results have important implications for understanding how tolerance in T and B cells is differently imposed, and how these processes might go awry in disease. 相似文献
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Ellis MJ Ding L Shen D Luo J Suman VJ Wallis JW Van Tine BA Hoog J Goiffon RJ Goldstein TC Ng S Lin L Crowder R Snider J Ballman K Weber J Chen K Koboldt DC Kandoth C Schierding WS McMichael JF Miller CA Lu C Harris CC McLellan MD Wendl MC DeSchryver K Allred DC Esserman L Unzeitig G Margenthaler J Babiera GV Marcom PK Guenther JM Leitch M Hunt K Olson J Tao Y Maher CA Fulton LL Fulton RS Harrison M Oberkfell B Du F Demeter R Vickery TL Elhammali A Piwnica-Worms H McDonald S Watson M Dooling DJ 《Nature》2012,486(7403):353-360
To correlate the variable clinical features of oestrogen-receptor-positive breast cancer with somatic alterations, we studied pretreatment tumour biopsies accrued from patients in two studies of neoadjuvant aromatase inhibitor therapy by massively parallel sequencing and analysis. Eighteen significantly mutated genes were identified, including five genes (RUNX1, CBFB, MYH9, MLL3 and SF3B1) previously linked to haematopoietic disorders. Mutant MAP3K1 was associated with luminal A status, low-grade histology and low proliferation rates, whereas mutant TP53 was associated with the opposite pattern. Moreover, mutant GATA3 correlated with suppression of proliferation upon aromatase inhibitor treatment. Pathway analysis demonstrated that mutations in MAP2K4, a MAP3K1 substrate, produced similar perturbations as MAP3K1 loss. Distinct phenotypes in oestrogen-receptor-positive breast cancer are associated with specific patterns of somatic mutations that map into cellular pathways linked to tumour biology, but most recurrent mutations are relatively infrequent. Prospective clinical trials based on these findings will require comprehensive genome sequencing. 相似文献
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Moreno JA Radford H Peretti D Steinert JR Verity N Martin MG Halliday M Morgan J Dinsdale D Ortori CA Barrett DA Tsaytler P Bertolotti A Willis AE Bushell M Mallucci GR 《Nature》2012,485(7399):507-511
The mechanisms leading to neuronal death in neurodegenerative disease are poorly understood. Many of these disorders, including Alzheimer's, Parkinson's and prion diseases, are associated with the accumulation of misfolded disease-specific proteins. The unfolded protein response is a protective cellular mechanism triggered by rising levels of misfolded proteins. One arm of this pathway results in the transient shutdown of protein translation, through phosphorylation of the α-subunit of eukaryotic translation initiation factor, eIF2. Activation of the unfolded protein response and/or increased eIF2α-P levels are seen in patients with Alzheimer's, Parkinson's and prion diseases, but how this links to neurodegeneration is unknown. Here we show that accumulation of prion protein during prion replication causes persistent translational repression of global protein synthesis by eIF2α-P, associated with synaptic failure and neuronal loss in prion-diseased mice. Further, we show that promoting translational recovery in hippocampi of prion-infected mice is neuroprotective. Overexpression of GADD34, a specific eIF2α-P phosphatase, as well as reduction of levels of prion protein by lentivirally mediated RNA interference, reduced eIF2α-P levels. As a result, both approaches restored vital translation rates during prion disease, rescuing synaptic deficits and neuronal loss, thereby significantly increasing survival. In contrast, salubrinal, an inhibitor of eIF2α-P dephosphorylation, increased eIF2α-P levels, exacerbating neurotoxicity and significantly reducing survival in prion-diseased mice. Given the prevalence of protein misfolding and activation of the unfolded protein response in several neurodegenerative diseases, our results suggest that manipulation of common pathways such as translational control, rather than disease-specific approaches, may lead to new therapies preventing synaptic failure and neuronal loss across the spectrum of these disorders. 相似文献
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Lebreton-Anberrée Julie Li Shihu Li Shu-Feng Spicer Robert A. Zhang Shi-Tao Su Tao Deng Chenglong Zhou Zhe-Kun 《科学通报(英文版)》2016,61(11):897-910
Science Bulletin - The Mid-Miocene Climatic Optimum (MMCO; ~15–17 Ma) was one of the short-term climatic warm events that punctuated the Cenozoic long-term cooling trend. Because... 相似文献
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