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1.
Theofilos Papadopoulos Rudolf Schemm Helmut Grubmüller Nils Brose 《The Journal of biological chemistry》2015,290(13):8256-8270
Signaling at nerve cell synapses is a key determinant of proper brain function, and synaptic defects—or synaptopathies—are at the basis of many neurological and psychiatric disorders. In key areas of the mammalian brain, such as the hippocampus or the basolateral amygdala, the clustering of the scaffolding protein Gephyrin and of γ-aminobutyric acid type A receptors at inhibitory neuronal synapses is critically dependent upon the brain-specific guanine nucleotide exchange factor Collybistin (Cb). Accordingly, it was discovered recently that an R290H missense mutation in the diffuse B-cell lymphoma homology domain of Cb, which carries the guanine nucleotide exchange factor activity, leads to epilepsy and intellectual disability in human patients. In the present study, we determined the mechanism by which the CbR290H mutation perturbs inhibitory synapse formation and causes brain dysfunction. Based on a combination of biochemical, cell biological, and molecular dynamics simulation approaches, we demonstrate that the R290H mutation alters the strength of intramolecular interactions between the diffuse B-cell lymphoma homology domain and the pleckstrin homology domain of Cb. This defect reduces the phosphatidylinositol 3-phosphate binding affinity of Cb, which limits its normal synaptogenic activity. Our data indicate that impairment of the membrane lipid binding activity of Cb and a consequent defect in inhibitory synapse maturation represent a likely molecular pathomechanism of epilepsy and mental retardation in humans. 相似文献
2.
Stefano Carenini Dirk Montag Harold Cremer Melitta Schachner Rudolf Martini 《Cell and tissue research》1996,287(1):3-9
We have previously shown that mice deficient in the gene for the myelin-associated glycoprotein (MAG) develop normal myelin
in the peripheral nerves, but show axon and myelin degeneration at eight months of age, suggesting that MAG is involved in
the maintenance of axon-Schwann cell integrity. The search for molecules that might replace MAG during myelination revealed
an overexpression of the neural cell adhesion molecule (N-CAM) at those aspects where MAG is detectable in wild type mice.
To test whether N-CAM might compensate for MAG during myelination in MAG-deficient mice, double mutants deficient in both
MAG and N-CAM (MAG−/N-CAM−mice) were generated by cross-breeding the single mutants. Whereas alterations of myelin development were not detectable in
either of the single or double mutants, degeneration of myelin and axons occurred approximately 4 weeks earlier in MAG−/N-CAM−than in MAG−mutants. Furthermore, at 8 weeks of age, single fiber preparation and electron microscopy revealed that the number of profiles
indicative of degeneration was substantially increased in MAG−/N-CAM−mutants when compared to MAG−mice. These data suggest that in MAG-deficient mice N-CAM does not compensate for MAG in myelin formation but partially substitutes
for it in the maintenance of axon-myelin integrity.
Received: 20 May 1996 / Accepted: 19 July 1996 相似文献
3.
Abstract We isolated pepT from Bacillus subtilis , a gene with homology to various tripeptidases from different bacterial sources, pepT is preceded by genes encoding a two component regulatory system. Its expression is activated during stationary phase. In minimal medium this activation is boosted in the presence of phosphate. The response regulator is preceded by putative promoter consensus sequences recognized by the stationary phase specific sigma factors σ H , σ F , and σ G . This is in accordance with the initiation of expression at the beginning of stationary phase. Inactivation of pepT causes no obvious phenotype. 相似文献
4.
Ralf J. Jäger Vincent R. Harley Rudolf A. Pfeiffer Peter N. Goodfellow Gerd Scherer 《Human genetics》1992,90(4):350-355
A familial mutation in SRY, the gene coding for the testis-determining factor TDF, was identified in an XY female with gonadal dysgenesis, her father, her two brothers and her uncle. The mutation consists of a T to C transition in the region of the SRY gene coding for a protein motif known as the high mobility group (HMG) box, a protein domain known to confer DNA-binding specificity on the SRY protein. This point mutation results in the substitution, at amino acid position 109, of a serine residue for phenylalanine, a conserved aromatic residue in almost all HMG box motifs known. This F109S mutation was not found in 176 male controls. When recombinant wildtype SRY and SRYF109S mutant protein were tested in vitro for binding to the target site AAC AAAG, no differences in DNA-binding activity were observed. These results imply that the F109S mutation either is a rare neutral sequence variant, or produces an SRY protein with slightly altered in vivo activity, the resulting sex phenotype depending on the genetic back-ground or environmental factors.This paper is dedicated by G. S. to Professor Ulrich Wolf on the occasion of his 60th birthday 相似文献
5.
Werner E.C. Muller Jürgen Conrad Rudolf K. Zahn Renate Steffen Gerhard Uhlenbruck Isabel Miller 《Differentiation; research in biological diversity》1984,26(1-3):30-35
Abstract. The Hexactinellida sponge Aphrocallistes vastus contains a soluble aggregation factor (AF) whose purification has been described in this communication. It is characterized by a S°20.w value of 37 and a buoyant density of 1.45 g/cm3 . The AF is a glycoporteinaceous particle composed of three major protein species; no core structure could be visualized. In the presence of Ca2+ , the AF causes secondary aggregation of single cells. The aggregation process is temperature, pH, and ionic strength independent within a broad range. Evidence is presented indicating that two (or more) AF molecules are required for the establishment of a stable cell: cell interaction. In contrast to the AFs from demosponges, the hexactinellid AF functions species-unspecifically. 相似文献
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9.
Rudolf Heitefuss 《Journal of Phytopathology》2011,159(4):326-327
10.
The imaginal pore plates of Hymenoptera apocrita so far examined embody five or six envelope cells respectively. In early developmental stages, however, supernumerary envelope cells have been found. The results are discussed in the context of cell death as a developmental phenomenon. 相似文献