全文获取类型
收费全文 | 285篇 |
免费 | 16篇 |
出版年
2024年 | 2篇 |
2022年 | 4篇 |
2021年 | 4篇 |
2019年 | 5篇 |
2018年 | 8篇 |
2017年 | 2篇 |
2016年 | 16篇 |
2015年 | 9篇 |
2014年 | 8篇 |
2013年 | 13篇 |
2012年 | 26篇 |
2011年 | 9篇 |
2010年 | 9篇 |
2009年 | 6篇 |
2008年 | 14篇 |
2007年 | 18篇 |
2006年 | 8篇 |
2005年 | 9篇 |
2004年 | 11篇 |
2003年 | 12篇 |
2002年 | 10篇 |
2001年 | 9篇 |
2000年 | 15篇 |
1999年 | 10篇 |
1998年 | 8篇 |
1997年 | 5篇 |
1996年 | 3篇 |
1995年 | 3篇 |
1992年 | 2篇 |
1991年 | 3篇 |
1990年 | 4篇 |
1989年 | 5篇 |
1988年 | 1篇 |
1987年 | 2篇 |
1986年 | 1篇 |
1985年 | 2篇 |
1984年 | 2篇 |
1983年 | 1篇 |
1982年 | 1篇 |
1981年 | 1篇 |
1980年 | 2篇 |
1978年 | 1篇 |
1977年 | 1篇 |
1975年 | 1篇 |
1974年 | 3篇 |
1972年 | 1篇 |
1971年 | 1篇 |
1970年 | 4篇 |
1969年 | 2篇 |
1968年 | 1篇 |
排序方式: 共有301条查询结果,搜索用时 15 毫秒
71.
Zoran Rankovic Jiaqiang Cai Jennifer Kerr Xavier Fradera John Robinson Ashvin Mistry Emma Hamilton George McGarry Fiona Andrews Wilson Caulfield Iain Cumming Maureen Dempster John Waller Paul Scullion Iain Martin Ann Mitchell Clive Long Mark Baugh Paul Westwood Emma Kinghorn Eric Nicolai 《Bioorganic & medicinal chemistry letters》2010,20(5):1524-1527
Morphing structural features of HTS-derived chemotypes led to the discovery of novel 2-cyano-pyrimidine inhibitors of cathepsin K with good pharmacokinetic profiles, for example, compound 20 showed high catK potency (IC50 = 4 nM), >580-fold selectivity over catL and catB, and oral bioavailability in the rat of 52%. 相似文献
72.
Bartelds GM de Groot E Nurmohamed MT Hart MH van Eede PH Wijbrandts CA Crusius JB Dijkmans BA Tak PP Aarden L Wolbink GJ 《Arthritis research & therapy》2010,12(6):R221-7
Introduction
The human monoclonal antibody adalimumab is known to induce an anti-globulin response in some adalimumab-treated patients. Antibodies against adalimumab (AAA) are associated with non-response to treatment. Immunoglobulins, such as adalimumab, carry allotypes which represent slight differences in the amino acid sequences of the constant chains of an IgG molecule. Immunoglobulins with particular IgG (Gm) allotypes are racially distributed and could be immunogenic for individuals who do not express these allotypes. Therefore, we investigated whether a mismatch in IgG allotypes between adalimumab and IgG in adalimumab-treated patients is associated with the development of AAA.Methods
This cohort study consisted of 250 adalimumab-treated rheumatoid arthritis (RA) patients. IgG allotypes were determined for adalimumab and for all patients. Anti-idiotype antibodies against adalimumab were measured with a regular radio immunoassay (RIA), and a newly developed bridging enzyme linked immunosorbent assay (ELISA) was used to measure anti-allotype antibodies against adalimumab. The association between AAA and the G1m3 and the G1m17 allotypes was determined. For differences between groups we used the independent or paired samples t-test, Mann-Whitney test or Chi square/Fisher's exact test as appropriate. To investigate the influence of confounders on the presence or absence of AAA a multiple logistic regression-analysis was used.Results
Adalimumab carries the G1m17 allotype. No anti-allotype antibodies against adalimumab were detected. Thirty-nine out of 249 patients had anti-idiotype antibodies against adalimumab (16%). IgG allotypes of RA patients were associated with the frequency of AAA: patients homozygous for G1m17 had the highest frequency of AAA (41%), patients homozygous for G1m3 the lowest frequency (10%), and heterozygous patients' AAA frequency was 14% (P = 0.0001).Conclusions
An allotype mismatch between adalimumab and IgG in adalimumab-treated patients did not lead to a higher frequency of AAA. On the contrary, patients who carried the same IgG allotype as present on the adalimumab IgG molecule, had the highest frequency of anti-adalimumab antibodies compared to patients whose IgG allotype differed from adalimumab. This suggests that the allotype of adalimumab may not be highly immunogenic. Furthermore, patients carrying the G1m17-allotype might be more prone to antibody responses. 相似文献73.
A mathematical model has been developed to describe the continuous, steady-state operation of an aqueous two-phase system for protein extraction. The model is based on steady-state mass balances of the main components and phase equilibrium data. Experimental data on the separation of thaumatin from contaminant proteins of an homogenate of E. coli in a PEG4000/Phosphate system was used. The data shows the effect of the presence and absence of NaCl which was used to carry out the extraction of thaumatin into the PEG phase and back into the PO4(-3) phase. Simulation results showing the sensitivity to key process parameters, and the effect of process variables on performance are presented and discussed. The model can be used to predict performance and thus 'robustness' of process conditions as well as predict protein recovery yield and purity. This model can also be used to implement a suitable control strategy to maintain process stability. 相似文献
74.
Roujeinikova A Levy CW Rowsell S Sedelnikova S Baker PJ Minshull CA Mistry A Colls JG Camble R Stuitje AR Slabas AR Rafferty JB Pauptit RA Viner R Rice DW 《Journal of molecular biology》1999,294(2):527-535
Molecular genetic studies with strains of Escherichia coli resistant to triclosan, an ingredient of many anti-bacterial household goods, have suggested that this compound works by acting as an inhibitor of enoyl reductase (ENR) and thereby blocking lipid biosynthesis. We present structural analyses correlated with inhibition data, on the complexes of E. coli and Brassica napus ENR with triclosan and NAD(+) which reveal how triclosan acts as a site-directed, picomolar inhibitor of the enzyme by mimicking its natural substrate. Elements of both the protein and the nucleotide cofactor play important roles in triclosan recognition, providing an explanation for the factors controlling its tight binding to the enzyme and for the emergence of triclosan resistance. 相似文献
75.
Bailey S Bolognese B Faller A Louis-Flamberg P MacPherson DT Mayer RJ Marshall LA Milner PH Mistry J Smith DG Ward JG 《Bioorganic & medicinal chemistry letters》1999,9(21):3165-3170
Using a variety of alpha-hydroxy hydroxamic acid derivatives, the size and shape of the S1' pocket for the CD23 processing metalloprotease has been explored. It has been demonstrated that a P1' 2-naphthylmethyl group occupies most of the available space and gives excellent selectivity against fibroblast collagenase (matrix metalloproteinase-1, MMP-1) and other MMPs. 相似文献
76.
77.
Cooke MS Mistry N Ahmad J Waller H Langford L Bevan RJ Evans MD Jones GD Herbert KE Griffiths HR Lunec J 《Free radical biology & medicine》2003,34(2):218-225
Oxidative DNA damage is postulated to be involved in carcinogenesis, and as a consequence, dietary antioxidants have received much interest. A recent report indicates that vitamin C facilitates the decomposition of hydroperoxides in vitro, generating reactive aldehydes. We present evidence for the in vivo generation of glyoxal, an established product of lipid peroxidation, glucose/ascorbate autoxidation, or free radical attack of deoxyribose, following supplementation of volunteers with 400 mg/d vitamin C. Utilizing a monoclonal antibody to a deoxycytidine-glyoxal adduct (gdC), we measured DNA lesion levels in peripheral blood mononuclear cells. Supplementation resulted in significant (p =.001) increases in gdC levels at weeks 11, 16, and 21, with corresponding increases in plasma malondialdehyde levels and, coupled with previous findings, is strongly suggestive of a pro-oxidative effect. However, continued supplementation revealed a highly significant (p =.0001) reduction in gdC levels. Simultaneous analysis of cyclobutane thymine dimers revealed no increase upon supplementation but, as with gdC, levels decreased. Although no single mechanism is identified, our data demonstrate a pro-oxidant event in the generation of reactive aldehydes following vitamin C supplementation in vivo. These results are also consistent with our hypothesis for a role of vitamin C in an adaptive/repair response and indicate that nucleotide excision repair specifically may be affected. 相似文献
78.
Ubiquitin-mediated proteolysis regulates the steady-state abundance of proteins and controls cellular homoeostasis by abrupt elimination of key effector proteins. A multienzyme system targets proteins for destruction through the covalent attachment of a multiubiquitin chain. The specificity and timing of protein ubiquitination is controlled by ubiquitin ligases, such as the Skp1-Cullin-F box protein complex. Cullins are major components of SCF complexes, and have been implicated in degradation of key regulatory molecules including Cyclin E, beta-catenin and Cubitus interruptus. Here, we describe the genetic identification and molecular characterisation of the Drosophila Cullin-3 homologue. Perturbation of Cullin-3 function has pleiotropic effects during development, including defects in external sensory organ development, pattern formation and cell growth and survival. Loss or overexpression of Cullin-3 causes an increase or decrease, respectively, in external sensory organ formation, implicating Cullin-3 function in regulating the commitment of cells to the neural fate. We also find that Cullin-3 function modulates Hedgehog signalling by regulating the stability of full-length Cubitus interruptus (Ci155). Loss of Cullin-3 function in eye discs but not other imaginal discs promotes cell-autonomous accumulation of Ci155. Conversely, overexpression of Cullin-3 results in a cell-autonomous stabilisation of Ci155 in wing, haltere and leg, but not eye, imaginal discs suggesting tissue-specific regulation of Cullin-3 function. The diverse nature of Cullin-3 phenotypes highlights the importance of targeted proteolysis during Drosophila development. 相似文献
79.
80.
Smooth muscle cells isolated from the secondary and tertiary branches of the rabbit mesenteric artery contain large Ca2+-dependent channels. In excised patches with symmetrical (140 mm) K+ solutions, these channels had an average slope conductance of 235 ± 3 pS, and reversed in direction at −6.1 ± 0.4 mV. The
channel showed K+ selectivity and its open probability (P
o
) was voltage-dependent. Iberiotoxin (50 nm) reversibly decreased P
o
, whereas tetraethylammonium (TEA, at 1 mm) reduced the unitary current amplitude. Apamin (200 nm) had no effect. The channel displayed sublevels around 1/3 and 1/2 of the mainstate level. The effect of [Ca2+] on P
o
was studied and data fitted to Boltzmann relationships. In 0.1, 0.3, 1.0 and 10 μm Ca2+, V
1/2 was 77.1 ± 5.3 (n= 18), 71.2 ± 4.8 (n= 16), 47.3 ± 10.1 (n= 11) and −14.9 ± 10.1 mV (n= 6), respectively. Values of k obtained in 1 and 10 μm [Ca2+] were significantly larger than that observed in 0.1 μm [Ca2+]. With 30 μm NS 1619 (a BKCa channel activator), V
1/2 values were shifted by 39 mV to the left (hyperpolarizing direction) and k values were not affected. TEA applied intracellularly, reduced the unitary current amplitude with a K
d
of 59 mm. In summary, BKCa channels show a particularly weak sensitivity to intracellular TEA and they also display large variation in V
1/2 and k. These findings suggest the possibility that different types (isoforms) of BKCa channels may exist in this vascular tissue.
Received: 22 December 1997/Revised: 27 March 1998 相似文献