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951.
The harlequin mouse mutation downregulates apoptosis-inducing factor 总被引:35,自引:0,他引:35
Klein JA Longo-Guess CM Rossmann MP Seburn KL Hurd RE Frankel WN Bronson RT Ackerman SL 《Nature》2002,419(6905):367-374
Harlequin (Hq) mutant mice have progressive degeneration of terminally differentiated cerebellar and retinal neurons. We have identified the Hq mutation as a proviral insertion in the apoptosis-inducing factor (Aif) gene, causing about an 80% reduction in AIF expression. Mutant cerebellar granule cells are susceptible to exogenous and endogenous peroxide-mediated apoptosis, but can be rescued by AIF expression. Overexpression of AIF in wild-type granule cells further decreases peroxide-mediated cell death, suggesting that AIF serves as a free radical scavenger. In agreement, dying neurons in aged Hq mutant mice show oxidative stress. In addition, neurons damaged by oxidative stress in both the cerebellum and retina of Hq mutant mice re-enter the cell cycle before undergoing apoptosis. Our results provide a genetic model of oxidative stress-mediated neurodegeneration and demonstrate a direct connection between cell cycle re-entry and oxidative stress in the ageing central nervous system. 相似文献
952.
Active genes are tri-methylated at K4 of histone H3 总被引:92,自引:0,他引:92
Santos-Rosa H Schneider R Bannister AJ Sherriff J Bernstein BE Emre NC Schreiber SL Mellor J Kouzarides T 《Nature》2002,419(6905):407-411
Lysine methylation of histones in vivo occurs in three states: mono-, di- and tri-methyl. Histone H3 has been found to be di-methylated at lysine 4 (K4) in active euchromatic regions but not in silent heterochromatic sites. Here we show that the Saccharomyces cerevisiae Set1 protein can catalyse di- and tri-methylation of K4 and stimulate the activity of many genes. Using antibodies that discriminate between the di- and tri-methylated state of K4 we show that di-methylation occurs at both inactive and active euchromatic genes, whereas tri-methylation is present exclusively at active genes. It is therefore the presence of a tri-methylated K4 that defines an active state of gene expression. These findings establish the concept of methyl status as a determinant for gene activity and thus extend considerably the complexity of histone modifications. 相似文献
953.
954.
Coulomb blockade and the Kondo effect in single-atom transistors 总被引:7,自引:0,他引:7
Park J Pasupathy AN Goldsmith JI Chang C Yaish Y Petta JR Rinkoski M Sethna JP Abruña HD McEuen PL Ralph DC 《Nature》2002,417(6890):722-725
Using molecules as electronic components is a powerful new direction in the science and technology of nanometre-scale systems. Experiments to date have examined a multitude of molecules conducting in parallel, or, in some cases, transport through single molecules. The latter includes molecules probed in a two-terminal geometry using mechanically controlled break junctions or scanning probes as well as three-terminal single-molecule transistors made from carbon nanotubes, C(60) molecules, and conjugated molecules diluted in a less-conducting molecular layer. The ultimate limit would be a device where electrons hop on to, and off from, a single atom between two contacts. Here we describe transistors incorporating a transition-metal complex designed so that electron transport occurs through well-defined charge states of a single atom. We examine two related molecules containing a Co ion bonded to polypyridyl ligands, attached to insulating tethers of different lengths. Changing the length of the insulating tether alters the coupling of the ion to the electrodes, enabling the fabrication of devices that exhibit either single-electron phenomena, such as Coulomb blockade, or the Kondo effect. 相似文献
955.
NMR analysis of a 900K GroEL GroES complex 总被引:16,自引:0,他引:16
Biomacromolecular structures with a relative molecular mass (M(r)) of 50,000 to 100,000 (50K 100K) have been generally considered to be inaccessible to analysis by solution NMR spectroscopy. Here we report spectra recorded from bacterial chaperonin complexes ten times this size limit (up to M(r) 900K) using the techniques of transverse relaxation-optimized spectroscopy and cross-correlated relaxation-enhanced polarization transfer. These techniques prevent deterioration of the NMR spectra by the rapid transverse relaxation of the magnetization to which large, slowly tumbling molecules are otherwise subject. We tested the resolving power of these techniques by examining the isotope-labelled homoheptameric co-chaperonin GroES (M(r) 72K), either free in solution or in complex with the homotetradecameric chaperonin GroEL (M(r) 800K) or with the single-ring GroEL variant SR1 (M(r) 400K). Most amino acids of GroES show the same resonances whether free in solution or in complex with chaperonin; however, residues 17 32 show large chemical shift changes on binding. These amino acids belong to a mobile loop region of GroES that forms contacts with GroEL. This establishes the utility of these techniques for solution NMR studies that should permit the exploration of structure, dynamics and interactions in large macromolecular complexes. 相似文献
956.
Transmitter-evoked local calcium release stabilizes developing dendrites 总被引:10,自引:0,他引:10
In the central nervous system, dendritic arborizations of neurons undergo dynamic structural remodelling during development. Processes are elaborated, maintained or eliminated to attain the adult pattern of synaptic connections. Although neuronal activity influences this remodelling, it is not known how activity exerts its effects. Here we show that neurotransmission-evoked calcium (Ca(2+)) release from intracellular stores stabilizes dendrites during the period of synapse formation. Using a ballistic labelling method to load cells with Ca(2+) indicator dyes, we simultaneously monitored dendritic activity and structure in the intact retina. Two distinct patterns of spontaneous Ca(2+) increases occurred in developing retinal ganglion cells--global increases throughout the arborization, and local 'flashes' of activity restricted to small dendritic segments. Blockade of local, but not global, activity caused rapid retraction of dendrites. This retraction was prevented locally by focal uncaging of caged Ca(2+) that triggered Ca(2+) release from internal stores. Thus, local Ca(2+) release is a mechanism by which afferent activity can selectively and differentially regulate dendritic structure across the developing arborization. 相似文献
957.
Rice LB 《Cellular and molecular life sciences : CMLS》2002,59(12):2023-2032
Among the more important problems in modern hospitals is the prevalence of bacterial pathogens expressing resistance to multiple
antimicrobial agents. The frequency of multiresistance suggests mechanisms by which bacterial species can concentrate and
efficiently exchange a variety of resistance determinants. Mechanisms by which this occurs include insertion of transposons
within transposons, coalescence through the activity of insertion sequences and the employment of integrons. In some instances,
more than one of these mechanisms is involved in creating large multiresistance genetic elements. The association of the elements
with transferable elements or transposons may promote rapid dissemination among clinical strains, and create further opportunities
for inclusion of additional resistance determinants. 相似文献
958.
The copines are a novel family of ubiquitous Ca(2+)-dependent, phospholipid-binding proteins. They contain two Ca(2+)- and phospholipid-binding domains known as 'C2 domains' present in proteins such as protein kinase C, phospholipase C and synaptotagmin. Copines are thought to be involved in membrane-trafficking phenomena because of their phospholipid-binding properties. They may also be involved in protein-protein interactions since they contain a domain similar to the protein-binding 'A domain' of integrins. The biochemistry, gene structure, tissue distribution and possible biological roles of copines are discussed, including recent observations with Arabidopsis that indicate that copines may be involved in cell division and growth. 相似文献
959.
Bignold LP 《Cellular and molecular life sciences : CMLS》2002,59(6):950-958
Almost all solid malignancies exhibit complex cytological and architectural abnormalities, which vary from cell to cell and
area to area within the same tumour, and between tumours of the same type. The degrees of these abnormalities do not correlate
perfectly with the biological behaviour (especially growth rate and metastatic potential) among the various tumour types.
These features of tumours have long been considered to invalidate simple mutational or 'abnormal gene expression' (epigenetic)
theories of carcinogenesis. The 'mutator phenotype/clonal selection' hypothesis is based on the now well-established phenomenon
of genetic instability of cancer cells, and proposes that this instability is an essential requirement for the development
of tumours, and not an irrelevant side-effect of some other process. This paper argues that this hypothesis can provide a
satisfactory explanation for the diverse histological and biological features of solid malignancies. Further, because virtually
all solid tumours are histologically abnormal, genetic instability is likely to be essential for the malignant process. The
concepts of mutator phenotype and clonal selection are therefore supported.
Received 8 April 2002; accepted 25 April 2002 相似文献
960.
Rosenberg MJ Agarwala R Bouffard G Davis J Fiermonte G Hilliard MS Koch T Kalikin LM Makalowska I Morton DH Petty EM Weber JL Palmieri F Kelley RI Schäffer AA Biesecker LG 《Nature genetics》2002,32(1):175-179
The disorder Amish microcephaly (MCPHA) is characterized by severe congenital microcephaly, elevated levels of alpha-ketoglutarate in the urine and premature death. The disorder is inherited in an autosomal recessive pattern and has been observed only in Old Order Amish families whose ancestors lived in Lancaster County, Pennsylvania. Here we show, by using a genealogy database and automated pedigree software, that 23 nuclear families affected with MCPHA are connected to a single ancestral couple. Through a whole-genome scan, fine mapping and haplotype analysis, we localized the gene affected in MCPHA to a region of 3 cM, or 2 Mb, on chromosome 17q25. We constructed a map of contiguous genomic clones spanning this region. One of the genes in this region, SLC25A19, which encodes a nuclear mitochondrial deoxynucleotide carrier (DNC), contains a substitution that segregates with the disease in affected individuals and alters an amino acid that is highly conserved in similar proteins. Functional analysis shows that the mutant DNC protein lacks the normal transport activity, implying that failed deoxynucleotide transport across the inner mitochondrial membrane causes MCPHA. Our data indicate that mitochondrial deoxynucleotide transport may be essential for prenatal brain growth. 相似文献