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991.
Approaches to the Internalism–Externalism controversy in the philosophy of mind often involve both (broadly) metaphysical and explanatory considerations. Whereas originally most emphasis seems to have been placed on metaphysical concerns, recently the explanation angle is getting more attention. Explanatory considerations promise to offer more neutral grounds for cognitive systems demarcation than (broadly) metaphysical ones. However, it has been argued that explanation-based approaches are incapable of determining the plausibility of internalist-based conceptions of cognition vis-à-vis externalist ones. On this perspective, improved metaphysics is the route along which to solve the Internalist–Externalist stalemate. In this paper we challenge this claim. Although we agree that explanation-orientated approaches have indeed so far failed to deliver solid means for cognitive system demarcation, we elaborate a more promising explanation-oriented framework to address this issue. We argue that the mutual manipulability account of constitutive relevance in mechanisms, extended with the criterion of ‘fat-handedness’, is capable of plausibly addressing the cognitive systems demarcation problem, and thus able to decide on the explanatory traction of Internalist vs. Externalist conceptions, on a case-by-case basis. Our analysis also highlights why some other recent mechanistic takes on the problem of cognitive systems demarcation have been unsuccessful. We illustrate our claims with a case on gestures and learning. 相似文献
992.
Borgonie G García-Moyano A Litthauer D Bert W Bester A van Heerden E Möller C Erasmus M Onstott TC 《Nature》2011,474(7349):79-82
Since its discovery over two decades ago, the deep subsurface biosphere has been considered to be the realm of single-cell organisms, extending over three kilometres into the Earth's crust and comprising a significant fraction of the global biosphere. The constraints of temperature, energy, dioxygen and space seemed to preclude the possibility of more-complex, multicellular organisms from surviving at these depths. Here we report species of the phylum Nematoda that have been detected in or recovered from 0.9-3.6-kilometre-deep fracture water in the deep mines of South Africa but have not been detected in the mining water. These subsurface nematodes, including a new species, Halicephalobus mephisto, tolerate high temperature, reproduce asexually and preferentially feed upon subsurface bacteria. Carbon-14 data indicate that the fracture water in which the nematodes reside is 3,000-12,000-year-old palaeometeoric water. Our data suggest that nematodes should be found in other deep hypoxic settings where temperature permits, and that they may control the microbial population density by grazing on fracture surface biofilm patches. Our results expand the known metazoan biosphere and demonstrate that deep ecosystems are more complex than previously accepted. The discovery of multicellular life in the deep subsurface of the Earth also has important implications for the search for subsurface life on other planets in our Solar System. 相似文献
993.
Anderson K Lutz C van Delft FW Bateman CM Guo Y Colman SM Kempski H Moorman AV Titley I Swansbury J Kearney L Enver T Greaves M 《Nature》2011,469(7330):356-361
Little is known of the genetic architecture of cancer at the subclonal and single-cell level or in the cells responsible for cancer clone maintenance and propagation. Here we have examined this issue in childhood acute lymphoblastic leukaemia in which the ETV6-RUNX1 gene fusion is an early or initiating genetic lesion followed by a modest number of recurrent or 'driver' copy number alterations. By multiplexing fluorescence in situ hybridization probes for these mutations, up to eight genetic abnormalities can be detected in single cells, a genetic signature of subclones identified and a composite picture of subclonal architecture and putative ancestral trees assembled. Subclones in acute lymphoblastic leukaemia have variegated genetics and complex, nonlinear or branching evolutionary histories. Copy number alterations are independently and reiteratively acquired in subclones of individual patients, and in no preferential order. Clonal architecture is dynamic and is subject to change in the lead-up to a diagnosis and in relapse. Leukaemia propagating cells, assayed by serial transplantation in NOD/SCID IL2Rγ(null) mice, are also genetically variegated, mirroring subclonal patterns, and vary in competitive regenerative capacity in vivo. These data have implications for cancer genomics and for the targeted therapy of cancer. 相似文献
994.
de Lau W Barker N Low TY Koo BK Li VS Teunissen H Kujala P Haegebarth A Peters PJ van de Wetering M Stange DE van Es JE Guardavaccaro D Schasfoort RB Mohri Y Nishimori K Mohammed S Heck AJ Clevers H 《Nature》2011,476(7360):293-297
The adult stem cell marker Lgr5 and its relative Lgr4 are often co-expressed in Wnt-driven proliferative compartments. We find that conditional deletion of both genes in the mouse gut impairs Wnt target gene expression and results in the rapid demise of intestinal crypts, thus phenocopying Wnt pathway inhibition. Mass spectrometry demonstrates that Lgr4 and Lgr5 associate with the Frizzled/Lrp Wnt receptor complex. Each of the four R-spondins, secreted Wnt pathway agonists, can bind to Lgr4, -5 and -6. In HEK293 cells, RSPO1 enhances canonical WNT signals initiated by WNT3A. Removal of LGR4 does not affect WNT3A signalling, but abrogates the RSPO1-mediated signal enhancement, a phenomenon rescued by re-expression of LGR4, -5 or -6. Genetic deletion of Lgr4/5 in mouse intestinal crypt cultures phenocopies withdrawal of Rspo1 and can be rescued by Wnt pathway activation. Lgr5 homologues are facultative Wnt receptor components that mediate Wnt signal enhancement by soluble R-spondin proteins. These results will guide future studies towards the application of R-spondins for regenerative purposes of tissues expressing Lgr5 homologues. 相似文献
995.
Too much of a good thing 总被引:3,自引:0,他引:3
996.
Sato T van Es JH Snippert HJ Stange DE Vries RG van den Born M Barker N Shroyer NF van de Wetering M Clevers H 《Nature》2011,469(7330):415-418
Homeostasis of self-renewing small intestinal crypts results from neutral competition between Lgr5 stem cells, which are small cycling cells located at crypt bottoms. Lgr5 stem cells are interspersed between terminally differentiated Paneth cells that are known to produce bactericidal products such as lysozyme and cryptdins/defensins. Single Lgr5-expressing stem cells can be cultured to form long-lived, self-organizing crypt-villus organoids in the absence of non-epithelial niche cells. Here we find a close physical association of Lgr5 stem cells with Paneth cells in mice, both in vivo and in vitro. CD24(+) Paneth cells express EGF, TGF-α, Wnt3 and the Notch ligand Dll4, all essential signals for stem-cell maintenance in culture. Co-culturing of sorted stem cells with Paneth cells markedly improves organoid formation. This Paneth cell requirement can be substituted by a pulse of exogenous Wnt. Genetic removal of Paneth cells in vivo results in the concomitant loss of Lgr5 stem cells. In colon crypts, CD24(+) cells residing between Lgr5 stem cells may represent the Paneth cell equivalents. We conclude that Lgr5 stem cells compete for essential niche signals provided by a specialized daughter cell, the Paneth cell. 相似文献
997.
Gieger C Radhakrishnan A Cvejic A Tang W Porcu E Pistis G Serbanovic-Canic J Elling U Goodall AH Labrune Y Lopez LM Mägi R Meacham S Okada Y Pirastu N Sorice R Teumer A Voss K Zhang W Ramirez-Solis R Bis JC Ellinghaus D Gögele M Hottenga JJ Langenberg C Kovacs P O'Reilly PF Shin SY Esko T Hartiala J Kanoni S Murgia F Parsa A Stephens J van der Harst P Ellen van der Schoot C Allayee H Attwood A Balkau B Bastardot F Basu S Baumeister SE Biino G Bomba L Bonnefond A Cambien F Chambers JC Cucca F 《Nature》2011,480(7376):201-208
Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function. 相似文献
998.
Keane TM Goodstadt L Danecek P White MA Wong K Yalcin B Heger A Agam A Slater G Goodson M Furlotte NA Eskin E Nellåker C Whitley H Cleak J Janowitz D Hernandez-Pliego P Edwards A Belgard TG Oliver PL McIntyre RE Bhomra A Nicod J Gan X Yuan W van der Weyden L Steward CA Bala S Stalker J Mott R Durbin R Jackson IJ Czechanski A Guerra-Assunção JA Donahue LR Reinholdt LG Payseur BA Ponting CP Birney E Flint J Adams DJ 《Nature》2011,477(7364):289-294
999.
Baker DJ Wijshake T Tchkonia T LeBrasseur NK Childs BG van de Sluis B Kirkland JL van Deursen JM 《Nature》2011,479(7372):232-236
Advanced age is the main risk factor for most chronic diseases and functional deficits in humans, but the fundamental mechanisms that drive ageing remain largely unknown, impeding the development of interventions that might delay or prevent age-related disorders and maximize healthy lifespan. Cellular senescence, which halts the proliferation of damaged or dysfunctional cells, is an important mechanism to constrain the malignant progression of tumour cells. Senescent cells accumulate in various tissues and organs with ageing and have been hypothesized to disrupt tissue structure and function because of the components they secrete. However, whether senescent cells are causally implicated in age-related dysfunction and whether their removal is beneficial has remained unknown. To address these fundamental questions, we made use of a biomarker for senescence, p16(Ink4a), to design a novel transgene, INK-ATTAC, for inducible elimination of p16(Ink4a)-positive senescent cells upon administration of a drug. Here we show that in the BubR1 progeroid mouse background, INK-ATTAC removes p16(Ink4a)-positive senescent cells upon drug treatment. In tissues--such as adipose tissue, skeletal muscle and eye--in which p16(Ink4a) contributes to the acquisition of age-related pathologies, life-long removal of p16(Ink4a)-expressing cells delayed onset of these phenotypes. Furthermore, late-life clearance attenuated progression of already established age-related disorders. These data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan. 相似文献
1000.
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