全文获取类型
收费全文 | 203篇 |
免费 | 16篇 |
出版年
2021年 | 3篇 |
2019年 | 4篇 |
2018年 | 2篇 |
2017年 | 5篇 |
2016年 | 7篇 |
2015年 | 15篇 |
2014年 | 10篇 |
2013年 | 10篇 |
2012年 | 12篇 |
2011年 | 9篇 |
2010年 | 10篇 |
2009年 | 6篇 |
2008年 | 11篇 |
2007年 | 15篇 |
2006年 | 4篇 |
2005年 | 5篇 |
2004年 | 7篇 |
2003年 | 6篇 |
2002年 | 8篇 |
2001年 | 4篇 |
2000年 | 3篇 |
1999年 | 4篇 |
1998年 | 3篇 |
1997年 | 2篇 |
1994年 | 3篇 |
1993年 | 3篇 |
1991年 | 2篇 |
1990年 | 2篇 |
1988年 | 2篇 |
1987年 | 2篇 |
1986年 | 4篇 |
1985年 | 2篇 |
1980年 | 2篇 |
1973年 | 1篇 |
1971年 | 1篇 |
1970年 | 1篇 |
1968年 | 1篇 |
1967年 | 1篇 |
1964年 | 1篇 |
1960年 | 1篇 |
1958年 | 1篇 |
1954年 | 2篇 |
1951年 | 1篇 |
1949年 | 1篇 |
1947年 | 2篇 |
1946年 | 1篇 |
1943年 | 1篇 |
1942年 | 1篇 |
1933年 | 1篇 |
1909年 | 1篇 |
排序方式: 共有219条查询结果,搜索用时 31 毫秒
81.
82.
Dipeptidyl peptidase IV, a kidney brush-border serine peptidase. 总被引:11,自引:11,他引:0
A J Kenny A G Booth S G George J Ingram D Kershaw E J Wood A R Young 《The Biochemical journal》1976,157(1):169-182
Dipeptidyl peptidase IV, an enzyme that releases dipeptides from substrates with N-terminal sequences of the forms X-Pro-Y or X-Ala-Y, was purified 300-fold from pig kidney cortex. The kidney is the main source of the enzyme, where it is one of the major microvillus-membrane proteins. Several other tissues contained demonstrable activity against the usual assay substrate glycylproline 2-naphthylamide. In the small intestine this activity was greatly enriched in the microvillus fraction. In all tissues examined, the activity was extremely sensitive to inhibition by di-isopropyl phosphorofluoridate (Dip-F), but relatively resistant to inhibition by phenylmethylsulphonyl fluoride. It is a serine proteinase which may be covalently labelled with [32P]Dip-F, and is the only enzyme of this class in the microvillus membrane. The apparent subunit mol.wt. estimated by sodium dodecyl-sulphate/polyacrylamide-gel electrophoresis and by titration with [32P]Dip-F was 130 000. Gel-filtration and sedimentation-equilibrium methods gave values in the region of 280 000, which is consistent with a dimeric structure, a conclusion supported by electron micrographs of the purified enzyme. Among other well-characterized serine proteinases, this enzyme is unique in its membrane location and its large subunit size. Investigation of the mode of attack of the peptidase on oligopeptides revealed that it could hydrolyse certain N-blocked peptides, e.g. Z-Gly-Pro-Leu-Gly-Pro. In this respect it is acting as an endopeptidase and as such may merit reclassification and renaming as microvillus-membrane serine peptidase. 相似文献
83.
Tempo and mode of concerted evolution in the L1 repeat family of mice 总被引:10,自引:0,他引:10
Martin SL; Voliva CF; Hardies SC; Edgell MH; Hutchison CA d 《Molecular biology and evolution》1985,2(2):127-140
A 300-bp DNA sequence has been determined for 30 (10 from each of three
species of mice) random isolates of a subset of the long interspersed
repeat family L1. From these data we conclude that members of the L1 family
are evolving in concert at the DNA sequence level in Mus domesticus, Mus
caroli, and Mus platythrix. The mechanism responsible for this phenomenon
may be either duplicative transposition, gene conversion, or a combination
of the two. The amount of intraspecies divergence averages 4.4%, although
between species base substitutions accumulate at the rate of approximately
0.85%/Myr to a maximum divergence of 9.1% between M. platythrix and both M.
domesticus and M. caroli. Parsimony analysis reveals that the M. platythrix
L1 family has evolved into a distinct clade in the 10-12 Myr since M.
platythrix last shared a common ancestor with M. domesticus and M. caroli.
The parsimony tree also provides a means to derive the average half-life of
L1 sequences in the genome. The rates of gain and loss of individual copies
of L1 were estimated to be approximately equal, such that approximately
one-half of them turn over every 3.3 Myr.
相似文献
84.
Hof D Cheung K de Rooij DJ van den Hoogen FH Pruijn GJ van Venrooij WJ Raats JM 《Arthritis research & therapy》2005,7(2):R302-R309
Modifications occurring on autoantigens during cell death have been proposed to have a role in the initiation of autoimmune
diseases. Patients suffering from mixed connective tissue disease (MCTD) produce autoantibodies directed to U1 small nuclear
ribonucleoprotein (snRNP), and antibodies against a 70 kDa protein component, the U1-70K (70K) protein, are the most prominent.
During apoptosis, 70K is cleaved by caspase-3 to a 40 kDa product, which remains associated with the complex. Autoantibodies
preferentially recognizing the apoptotic form of 70K have been described previously, and an apoptosis-specific epitope on
70K has been identified. This study shows that 29 of 53 (54%) MCTD sera preferentially recognize the apoptotic form of 70K
over intact 70K. Moreover, we show that antibodies directed to an apoptosis-specific epitope on 70K are more specifically
associated with MCTD than other anti-70K antibodies, suggesting that apoptotic 70K is a better antigen for the detection of
these antibodies in MCTD patients. Longitudinal analysis of 12 MCTD patients showed in several patients that early sera are
relatively enriched with antibodies recognizing an apoptosis-specific epitope, and that the levels of these apoptosis-specific
antibodies decrease in time. These findings indicate that the early detection of apoptotic 70K is of considerable interest
for anti-U1 snRNP-positive patients. 相似文献
85.
Pimanda JE Ganderton T Maekawa A Yap CL Lawler J Kershaw G Chesterman CN Hogg PJ 《The Journal of biological chemistry》2004,279(20):21439-21448
Plasma von Willebrand factor (VWF) is a multimeric glycoprotein from endothelial cells and platelets that mediates adhesion of platelets to sites of vascular injury. In the shear force of flowing blood, however, only the very large VWF multimers are effective in capturing platelets. The multimeric size of VWF can be controlled by proteolysis at the Tyr(842)-Met(843) peptide bond by ADAMTS13 or cleavage of the disulfide bonds that hold VWF multimers together by thrombospondin-1 (TSP-1). The average multimer size of plasma VWF in TSP-1 null mice was significantly smaller than in wild type mice. In addition, the multimer size of VWF released from endothelium in vivo was reduced more rapidly in TSP-1 null mice than in wild type mice. TSP-1, like ADAMTS13, bound to the VWF A3 domain. TSP-1 in the wild type mice, therefore, may compete with ADAMTS13 for interaction with the A3 domain and slow the rate of VWF proteolysis. TSP-1 is stored in platelet alpha-granules and is released upon platelet activation. Significantly, platelet VWF multimer size was reduced upon lysis or activation of wild type murine platelets but not TSP-1 null platelets. This difference had functional consequences in that there was an increase in collagen- and VWF-mediated aggregation of the TSP-1 null platelets under both static and shear conditions. These findings indicate that TSP-1 influences plasma and platelet VWF multimeric size differently and may be more relevant for control of the VWF released from platelets. 相似文献
86.
87.
Effects of thymoquinone on liver miRNAs and oxidative stress in Ehrlich acid mouse solid tumor model
I Meral M Pala F Akbas S Ustunova C Yildiz MH Demirel 《Biotechnic & histochemistry》2018,93(4):301-308
We investigated the effects of thymoquinone (TQ) on the expression of liver microRNAs (miRNAs), liver histopathology and oxidative stress in Ehrlich acid solid tumor model induced mice. We used 24 male BALB/c mice divided randomly into three groups. Control (C) group mice were injected intraperitoneally (i.p.) with 0.5 ml saline for four weeks. Tumor (T) group mice were injected i.p. with 0.5 ml saline for four weeks, then Ehrlich acid tumor cells were injected subcutaneously into the neck to induce solid tumor formation. TQ (T + Tq) group mice injected i.p. with 10 mg/kg TQ for four weeks, then Ehrlich acid tumor cells were injected subcutaneously into the neck of the mice in this group to induce solid tumor formation. At the end of the study, liver from all groups were removed for histopathological and miRNAs analysis, and oxidative stress measurement. We found that the expression of miR-206b-3p was up-regulated and the oxidative stress and necrosis increased in the liver tissue of mice with Ehrlich acid solid tumor. TQ application decreased the oxidative stress, prevented necrosis, increased regeneration and down-regulated the expression of miR-206b-3p in the liver tissue. 相似文献
88.
Aimée Little Benjamin Elliott Chantal Conneller Diederik Pomstra Adrian A. Evans Laura C. Fitton Andrew Holland Robert Davis Rachel Kershaw Sonia O’Connor Terry O’Connor Thomas Sparrow Andrew S. Wilson Peter Jordan Matthew J. Collins André Carlo Colonese Oliver E. Craig Rebecca Knight Alexandre J. A. Lucquin Barry Taylor Nicky Milner 《PloS one》2016,11(4)
Shamanic belief systems represent the first form of religious practice visible within the global archaeological record. Here we report on the earliest known evidence of shamanic costume: modified red deer crania headdresses from the Early Holocene site of Star Carr (c. 11 kya). More than 90% of the examples from prehistoric Europe come from this one site, establishing it as a place of outstanding shamanistic/cosmological significance. Our work, involving a programme of experimental replication, analysis of macroscopic traces, organic residue analysis and 3D image acquisition, metrology and visualisation, represents the first attempt to understand the manufacturing processes used to create these artefacts. The results produced were unexpected—rather than being carefully crafted objects, elements of their production can only be described as expedient. 相似文献
89.
Hollie J. Pegram Nicole M. Haynes Mark J. Smyth Michael H. Kershaw Phillip K. Darcy 《Cancer immunology, immunotherapy : CII》2010,59(8):1235-1246
Natural killer (NK) cells represent a promising cell type to utilize for effective adoptive immunotherapy. However, little
is known about the important cytolytic molecules and signaling pathways used by NK cells in the adoptive transfer setting.
To address this issue, we developed a novel mouse model to investigate the trafficking and mechanism of action of these cells.
We demonstrate that methylcholanthrene-induced RKIK sarcoma cells were susceptible to NK cell-mediated lysis in vitro and
in vivo following adoptive transfer of NK cells in C57BL/6 RAG-2−/−γc−/− mice. Cytotoxic molecules perforin, granzymes B and M as well as the death ligand TRAIL and pro-inflammatory cytokine IFN-γ
were found to be important in the anti-tumor effect mediated by adoptively transferred NK cells. Importantly, we demonstrate
that adoptively transferred NK cells could traffic to the tumor site and persisted in vivo which correlated with the anti-tumor
effect observed. Overall, the results of this study have important implications for enhancing NK cell-based immunotherapies. 相似文献
90.
Leda Mirbahai Rachael M. Kershaw Richard M. Green Rachel E. Hayden Rosalind A. Meldrum Nikolas J. Hodges 《DNA Repair》2010,9(2):144-152
An abundant form of DNA damage caused by reactive oxygen species is 8-oxo-7,8-dihydroguanine for which the base excision repair protein 8-oxoguanine-DNA glycosylase 1 (OGG1) is a major repair enzyme. To assess the location and intracellular activity of the OGG1 protein in response to oxidative stress, we have utilised a fluorescence–quench molecular beacon switch containing a 8-oxo-dG:C base pair and a fluorescent and quencher molecule at opposite ends of a hairpin oligonucleotide. Oxidative stress was induced by treatment with potassium bromate. Flow cytometry demonstrated a concentration-dependent increase in the activity of OGG1 that was detected by the fluorescence produced when the oligonucleotide was cleaved in the cells treated with potassium bromate. This signal is highly specific and not detectable in OGG1 knock out cells. Induction of OGG1 activity is not a result of induction of OGG1 gene expression as assessed by qPCR suggesting a role for protein stabilisation or increased OGG1 catalytic activity. High resolution confocal microscopy pinpointed the location of the fluorescent molecular beacon in live cells to perinuclear regions that were identified as mitochondria by co-staining with mitotracker dye. There is no evidence of cut beacon within the nuclear compartment of the cell. Control experiments with a positive control beacon (G:C base pair and lacking the DAB quencher) did not result in mitochondrial localisation of fluorescence signal indicating that the dye does not accumulate in mitochondria independent of OGG1 activity. Furthermore, faint nuclear staining was apparent confirming that the beacon structure is able to enter the nucleus. In conclusion, these data indicate that the mitochondria are the major site for OGG1 repair activity under conditions of oxidative stress. 相似文献