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741.
Barber DL Wherry EJ Masopust D Zhu B Allison JP Sharpe AH Freeman GJ Ahmed R 《Nature》2006,439(7077):682-687
Functional impairment of antigen-specific T cells is a defining characteristic of many chronic infections, but the underlying mechanisms of T-cell dysfunction are not well understood. To address this question, we analysed genes expressed in functionally impaired virus-specific CD8 T cells present in mice chronically infected with lymphocytic choriomeningitis virus (LCMV), and compared these with the gene profile of functional memory CD8 T cells. Here we report that PD-1 (programmed death 1; also known as Pdcd1) was selectively upregulated by the exhausted T cells, and that in vivo administration of antibodies that blocked the interaction of this inhibitory receptor with its ligand, PD-L1 (also known as B7-H1), enhanced T-cell responses. Notably, we found that even in persistently infected mice that were lacking CD4 T-cell help, blockade of the PD-1/PD-L1 inhibitory pathway had a beneficial effect on the 'helpless' CD8 T cells, restoring their ability to undergo proliferation, secrete cytokines, kill infected cells and decrease viral load. Blockade of the CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) inhibitory pathway had no effect on either T-cell function or viral control. These studies identify a specific mechanism of T-cell exhaustion and define a potentially effective immunological strategy for the treatment of chronic viral infections. 相似文献
742.
743.
In mammals, sperm cells become motile during ejaculation and swim up the female reproductive tract. Before fertilization and to overcome various barriers, their motility must be hyperactivated, a motion that is characterized by vigorous asymmetric tail beating. Hyperactivation requires an increase in calcium in the flagella, a process that probably involves plasmalemmal ion channels. Numerous attempts in the past two decades to understand sperm cell channels have been frustrated by the difficulty of measuring spermatozoan transmembrane ion currents. Here, by using a simple approach to patch-clamp spermatozoa and to characterize whole-spermatozoan currents, we describe a constitutively active flagellar calcium channel that is strongly potentiated by intracellular alkalinization. This current is not present in spermatozoa lacking the sperm-specific putative ion channel protein, CatSper1. This plasma membrane protein of the six transmembrane-spanning ion channel superfamily is specifically localized to the principal piece of the sperm tail and is required for sperm cell hyperactivation and male fertility. Our results identify CatSper1 as a component of the key flagellar calcium channel, and suggest that intracellular alkalinization potentiates CatSper current to increase intraflagellar calcium and induce sperm hyperactivation. 相似文献
744.
Erbse A Schmidt R Bornemann T Schneider-Mergener J Mogk A Zahn R Dougan DA Bukau B 《Nature》2006,439(7077):753-756
The N-end rule states that the half-life of a protein is determined by the nature of its amino-terminal residue. Eukaryotes and prokaryotes use N-terminal destabilizing residues as a signal to target proteins for degradation by the N-end rule pathway. In eukaryotes an E3 ligase, N-recognin, recognizes N-end rule substrates and mediates their ubiquitination and degradation by the proteasome. In Escherichia coli, N-end rule substrates are degraded by the AAA + chaperone ClpA in complex with the ClpP peptidase (ClpAP). Little is known of the molecular mechanism by which N-end rule substrates are initially selected for proteolysis. Here we report that the ClpAP-specific adaptor, ClpS, is essential for degradation of N-end rule substrates by ClpAP in bacteria. ClpS binds directly to N-terminal destabilizing residues through its substrate-binding site distal to the ClpS-ClpA interface, and targets these substrates to ClpAP for degradation. Degradation by the N-end rule pathway is more complex than anticipated and several other features are involved, including a net positive charge near the N terminus and an unstructured region between the N-terminal signal and the folded protein substrate. Through interaction with this signal, ClpS converts the ClpAP machine into a protease with exquisitely defined specificity, ideally suited to regulatory proteolysis. 相似文献
745.
Omega-3 and omega-6 fatty acids stimulate cell membrane expansion by acting on syntaxin 3 总被引:1,自引:0,他引:1
Growth of neurite processes from the cell body is the critical step in neuronal development and involves a large increase in cell membrane surface area. Arachidonic-acid-releasing phospholipases are highly enriched in nerve growth cones and have previously been implicated in neurite outgrowth. Cell membrane expansion is achieved through the fusion of transport organelles with the plasma membrane; however, the identity of the molecular target of arachidonic acid has remained elusive. Here we show that syntaxin 3 (STX3), a plasma membrane protein, has an important role in the growth of neurites, and also serves as a direct target for omega-6 arachidonic acid. By using syntaxin 3 in a screening assay, we determined that the dietary omega-3 linolenic and docosahexaenoic acids can efficiently substitute for arachidonic acid in activating syntaxin 3. Our findings provide a molecular basis for the previously established action of omega-3 and omega-6 polyunsaturated fatty acids in membrane expansion at the growth cones, and represent the first identification of a single effector molecule for these essential nutrients. 相似文献
746.
White TD WoldeGabriel G Asfaw B Ambrose S Beyene Y Bernor RL Boisserie JR Currie B Gilbert H Haile-Selassie Y Hart WK Hlusko LJ Howell FC Kono RT Lehmann T Louchart A Lovejoy CO Renne PR Saegusa H Vrba ES Wesselman H Suwa G 《Nature》2006,440(7086):883-889
The origin of Australopithecus, the genus widely interpreted as ancestral to Homo, is a central problem in human evolutionary studies. Australopithecus species differ markedly from extant African apes and candidate ancestral hominids such as Ardipithecus, Orrorin and Sahelanthropus. The earliest described Australopithecus species is Au. anamensis, the probable chronospecies ancestor of Au. afarensis. Here we describe newly discovered fossils from the Middle Awash study area that extend the known Au. anamensis range into northeastern Ethiopia. The new fossils are from chronometrically controlled stratigraphic sequences and date to about 4.1-4.2 million years ago. They include diagnostic craniodental remains, the largest hominid canine yet recovered, and the earliest Australopithecus femur. These new fossils are sampled from a woodland context. Temporal and anatomical intermediacy between Ar. ramidus and Au. afarensis suggest a relatively rapid shift from Ardipithecus to Australopithecus in this region of Africa, involving either replacement or accelerated phyletic evolution. 相似文献
747.
Wooding S Bufe B Grassi C Howard MT Stone AC Vazquez M Dunn DM Meyerhof W Weiss RB Bamshad MJ 《Nature》2006,440(7086):930-934
It was reported over 65 years ago that chimpanzees, like humans, vary in taste sensitivity to the bitter compound phenylthiocarbamide (PTC). This was suggested to be the result of a shared balanced polymorphism, defining the first, and now classic, example of the effects of balancing selection in great apes. In humans, variable PTC sensitivity is largely controlled by the segregation of two common alleles at the TAS2R38 locus, which encode receptor variants with different ligand affinities. Here we show that PTC taste sensitivity in chimpanzees is also controlled by two common alleles of TAS2R38; however, neither of these alleles is shared with humans. Instead, a mutation of the initiation codon results in the use of an alternative downstream start codon and production of a truncated receptor variant that fails to respond to PTC in vitro. Association testing of PTC sensitivity in a cohort of captive chimpanzees confirmed that chimpanzee TAS2R38 genotype accurately predicts taster status in vivo. Therefore, although Fisher et al.'s observations were accurate, their explanation was wrong. Humans and chimpanzees share variable taste sensitivity to bitter compounds mediated by PTC receptor variants, but the molecular basis of this variation has arisen twice, independently, in the two species. 相似文献
748.
Aharonian F Akhperjanian AG Bazer-Bachi AR Beilicke M Benbow W Berge D Bernlöhr K Boisson C Bolz O Borrel V Braun I Breitling F Brown AM Chadwick PM Chounet LM Cornils R Costamante L Degrange B Dickinson HJ Djannati-Ataï A Drury LO Dubus G Emmanoulopoulos D Espigat P Feinstein F Fontaine G Fuchs Y Funk S Gallant YA Giebels B Gillessen S Glicenstein JF Goret P Hadjichristidis C Hauser D Hauser M Heinzelmann G Henri G Hermann G Hinton JA Hofmann W Holleran M Horns D Jacholkowska A de Jager OC 《Nature》2006,439(7077):695-698
The source of Galactic cosmic rays (with energies up to 10(15) eV) remains unclear, although it is widely believed that they originate in the shock waves of expanding supernova remnants. At present the best way to investigate their acceleration and propagation is by observing the gamma-rays produced when cosmic rays interact with interstellar gas. Here we report observations of an extended region of very-high-energy (> 10(11) eV) gamma-ray emission correlated spatially with a complex of giant molecular clouds in the central 200 parsecs of the Milky Way. The hardness of the gamma-ray spectrum and the conditions in those molecular clouds indicate that the cosmic rays giving rise to the gamma-rays are likely to be protons and nuclei rather than electrons. The energy associated with the cosmic rays could have come from a single supernova explosion around 10(4) years ago. 相似文献
749.
750.
本书重现和扩充了结式和判别式经典理论,在研究超几何函数与代数、组合数学的联系过程中引进超行列式即多维行列式这样重要的概念。本书的另一特色是作者将经典数学与代数几何、同调代数和组合论中最新发展成果相结合,形成了许多原创性结果。 相似文献