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91.
A longer polyalanine expansion mutation in the ARX gene causes early infantile epileptic encephalopathy with suppression-burst pattern (Ohtahara syndrome) 总被引:1,自引:0,他引:1 下载免费PDF全文
Kato M Saitoh S Kamei A Shiraishi H Ueda Y Akasaka M Tohyama J Akasaka N Hayasaka K 《American journal of human genetics》2007,81(2):361-366
Early infantile epileptic encephalopathy with suppression-burst pattern (EIEE) is one of the most severe and earliest forms of epilepsy, often evolving into West syndrome; however, the pathogenesis of EIEE remains unclear. ARX is a crucial gene for the development of interneurons in the fetal brain, and a polyalanine expansion mutation of ARX causes mental retardation and seizures, including those of West syndrome, in males. We screened the ARX mutation and found a hemizygous, de novo, 33-bp duplication in exon 2, 298_330dupGCGGCA(GCG)9, in two of three unrelated male patients with EIEE. This mutation is thought to expand the original 16 alanine residues to 27 alanine residues (A110_A111insAAAAAAAAAAA) in the first polyalanine tract of the ARX protein. Although EIEE is mainly associated with brain malformations, ARX is the first gene found to be responsible for idiopathic EIEE. Our observation that EIEE had a longer expansion of the polyalanine tract than is seen in West syndrome is consistent with the findings of earlier onset and more-severe phenotypes in EIEE than in West syndrome. 相似文献
92.
Saitoh T Igura M Obita T Ose T Kojima R Maenaka K Endo T Kohda D 《The EMBO journal》2007,26(22):4777-4787
Most mitochondrial proteins are synthesized in the cytosol and imported into mitochondria. The N-terminal presequences of mitochondrial-precursor proteins contain a diverse consensus motif (phi chi chi phi phi, phi is hydrophobic and chi is any amino acid), which is recognized by the Tom20 protein on the mitochondrial surface. To reveal the structural basis of the broad selectivity of Tom20, the Tom20-presequence complex was crystallized. Tethering a presequence peptide to Tom20 through a disulfide bond was essential for crystallization. Unexpectedly, the two crystals with different linker designs provided unique relative orientations of the presequence with respect to Tom20, and neither configuration could fully account for the hydrophobic preference at the three hydrophobic positions of the consensus motif. We propose the existence of a dynamic equilibrium in solution among multiple states including the two bound states. In accordance, NMR 15N relaxation analyses suggested motion on a sub-millisecond timescale at the Tom20-presequence interface. We suggest that the dynamic, multiple-mode interaction is the molecular mechanism facilitating the broadly selective specificity of the Tom20 receptor toward diverse mitochondrial presequences. 相似文献
93.
Cruciform extrusion propensity of human translocation-mediating palindromic AT-rich repeats 总被引:1,自引:0,他引:1
There is an emerging consensus that secondary structures of DNA have the potential for genomic instability. Palindromic AT-rich repeats (PATRRs) are a characteristic sequence identified at each breakpoint of the recurrent constitutional t(11;22) and t(17;22) translocations in humans, named PATRR22 (~600bp), PATRR11 (~450bp) and PATRR17 (~190bp). The secondary structure-forming propensity in vitro and the instability in vivo have been experimentally evaluated for various PATRRs that differ regarding their size and symmetry. At physiological ionic strength, a cruciform structure is most frequently observed for the symmetric PATRR22, less often for the symmetric PATRR11, but not for the other PATRRs. In wild-type E. coli, only these two PATRRs undergo extensive instability, consistent with the relatively high incidence of the t(11;22) in humans. The resultant deletions are putatively mediated by central cleavage by the structure-specific endonuclease SbcCD, indicating the possibility of a cruciform conformation in vivo. Insertion of a short spacer at the centre of the PATRR22 greatly reduces both its cruciform extrusion in vitro and instability in vivo. Taken together, cruciform extrusion propensity depends on the length and central symmetry of the PATRR, and is likely to determine the instability that leads to recurrent translocations in humans. 相似文献
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The Evolutionarily Significant Unit (ESU) was conceptualized in 1986 as a conservation unit below the species level, theoretically
applicable to a wide range of taxa. The concept has gained support, and various definitions or criteria, some of which are
inconsistent with each other, have since been proposed. Recent critiques of the ESU have pointed out the dominance of definitions
biased to the identification of long-term isolation or neutral genetic variation, which has largely ignored the adaptive components.
We present here the validity of such claims and show how the ESU definitions have actually been applied in research. We surveyed
scientific journals for original papers supporting ESU designations and determined who among the proponents of ESU definitions
have gained wider support. Our results indicate that indeed there are inconsistencies with the original concept and with the
existing definitions. Although the original concept recommended both ecological and genetic data as the basis for identification
of ESUs, which reflect true evolutionary variation, recent definitions have become biased to either neutral genetic variation
or adaptive variation. The definition which uses genetic data to assess neutral genetic variation (long-term isolation) has
gained major support, and therefore validates the earlier claims. To bridge the gap between the original concept and the practical
application, we propose the use of partial ESU and full ESU designations. The application of full ESU should be limited solely
to when both information about neutral genetic variation and adaptive variation are available. In other cases, in which only
a part of the variation is examined, we should use the term partial ESU (e.g., molecular-based ESU) and continue to investigate
focal populations from other aspects of variations to designate full ESU. 相似文献
97.
Immunohistochemical detection of hypoxia in mouse liver tissues treated with pimonidazole using “in vivo cryotechnique” 总被引:2,自引:2,他引:0
Wang J Olin M Rozell B Björkhem I Einarsson C Eggertsen G Gåfvels M 《Histochemistry and cell biology》2007,127(3):253-261
To evaluate hypoxic cells in live mouse liver tissues, immunohistochemistry for protein adducts of reductively activated pimonidazole
(PARaPi) was performed using the “in vivo cryotechnique (IVCT)” followed by freeze-substitution fixation. This method was
used because cryotechniques have some merits for examining biological events in living animal organs with improved time-resolution
compared to conventional perfusion and/or immersion chemical fixation. Pimonidazole was intraperitoneally injected into living
mice, and then after various times of hypoxia, their livers were quickly frozen by IVCT. The frozen liver tissues were freeze-substituted
in acetone containing 2% paraformaldehyde, and routinely embedded in paraffin wax. De-paraffinized sections were immunostained
for PARaPi. In liver tissues of mice without hypoxia, almost no immunostained cells were detected. However, in liver tissues
with 30 s of hypoxia, some hepatocytes in the pericentral zones were strongly immunostained. After 60 s of hypoxia, many hepatocytes
were immunostained with various degrees of staining intensity in all lobular zones, indicating different reactivities of pimonidazole
in the hepatocytes to hypoxia. At this time, the general immunoreactivity also appeared to be stronger around the central
veins than other portal areas. Although many hepatocytes were immunostained for PARaPi in the liver tissues with perfusion
fixation via heart, those with perfusion via portal vein were not immunostained. Thus, IVCT is useful to detect time-dependent
hypoxic states with pimonidazole treatment in living animal organs. 相似文献
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Yamamoto H Ben S Saitoh S Kamata K Iguchi K Hoshino M 《Protein and peptide letters》2011,18(12):1204-1211
Galanin is a neuropeptide that is widely distributed in the central and peripheral nervous systems. In a previous study, we showed that a small cell lung carcinoma (SCLC) cell line, SBC-3A, released progalanin but not galanin, and that progalanin was then converted to galanin(1-20), the active form. Because the galanin(1-20) had undergone hydrolysis at Arg and Lys residues, the protease concerned was surmised to have a trypsin-like activity. The present study was performed to identify the trypsin-like protease which had previously been found to activate progalanin in this tumor tissue. The protease was isolated using chromatography and electrophoresis, and identified in tumor extracts from SBC-3A tumor-bearing mice; the major protease was found to be plasmin. We next confirmed that extracellular processing of progalanin occurs in SCLC tumor tissue (tumors produced by the implantation of SBC-3A cells into mice), and in two types of breast tumor tissue (obtained by implantation into mice of BT-549 and MDA-MB-436 cells). In cell culture, processed forms of progalanin were undetectable in SBC-3A, BT-549 or MDA-MB-436 cells. Conversely, gel filtration chromatography analysis of tumor extracts from SBC-3A, BT-549 and MDA-MB-436-bearing mice, revealed that galanin-like immunoreactivity (galanin-LI) in these tumor extracts was due to the presence of progalanin (14 kDa) and galanin(1-20) (2 kDa). Moreover, trypsin-like protease activity was elevated, and plasmin was expressed abundantly in SBC-3A, BT-549 and MDA-MB-436 tumors in mice. In addition, tranexamic acid, a plasmin inhibitor, inhibited progalanin conversion to galanin(1-20). The present study revealed that plasmin was present in tumor tissue, and that it was responsible for processing progalanin to galanin(1-20) in the extracellular environment. 相似文献