全文获取类型
收费全文 | 3373篇 |
免费 | 202篇 |
国内免费 | 128篇 |
出版年
2024年 | 6篇 |
2023年 | 36篇 |
2022年 | 45篇 |
2021年 | 78篇 |
2020年 | 63篇 |
2019年 | 108篇 |
2018年 | 88篇 |
2017年 | 88篇 |
2016年 | 61篇 |
2015年 | 70篇 |
2014年 | 143篇 |
2013年 | 180篇 |
2012年 | 132篇 |
2011年 | 161篇 |
2010年 | 116篇 |
2009年 | 196篇 |
2008年 | 173篇 |
2007年 | 176篇 |
2006年 | 178篇 |
2005年 | 191篇 |
2004年 | 148篇 |
2003年 | 130篇 |
2002年 | 112篇 |
2001年 | 83篇 |
2000年 | 65篇 |
1999年 | 74篇 |
1998年 | 68篇 |
1997年 | 56篇 |
1996年 | 79篇 |
1995年 | 70篇 |
1994年 | 38篇 |
1993年 | 48篇 |
1992年 | 43篇 |
1991年 | 27篇 |
1990年 | 29篇 |
1989年 | 20篇 |
1988年 | 30篇 |
1987年 | 21篇 |
1986年 | 10篇 |
1985年 | 26篇 |
1984年 | 78篇 |
1983年 | 28篇 |
1982年 | 27篇 |
1981年 | 25篇 |
1980年 | 15篇 |
1979年 | 19篇 |
1978年 | 7篇 |
1977年 | 18篇 |
1976年 | 7篇 |
1975年 | 5篇 |
排序方式: 共有3703条查询结果,搜索用时 148 毫秒
91.
Gerhard Fierlbeck Tilmann Schreiner Gernot Rassner 《Cancer immunology, immunotherapy : CII》1995,40(3):157-164
The effect of 13-cis-retinoic acid and highly purified human leukocyte interferon α (Alphaferon) therapy for metastatic melanoma was studied.
A group of 17 patients with disseminated malignant melanoma were treated over a 6-month period. They received 60 mg 13-cis-retinoic acid/day continuously and ten cycles of interferon α (IFNα). IFN was administered by subcutaneous injection, at
a daily dose of 6×106 IU Alphaferon. The 5-day treatment period was followed by an IFN-free interval of 2 weeks. We were able to observe an overall
response rate of 30% with 12% complete responses (2 out of 17 patients). Sites of response included the skin, lung, liver
and lymph nodes. All responses have now lasted over 6 months. Therapy was generally well tolerated and could be performed
on an outpatient basis. Side-effects of this combination therapy did not exceed the established side-effects of the two substances.
We also studied 2′-5′-oligoadenylate synthetase, β2-microglobulin and neopterin levels during the whole treatment course.
All patients were within the normal range before treatment and a sharp rise occurred during each IFN cycle. The maximum being
observed 24 h after the third injection. This indicates a high biological activity of IFNα administered cyclicly during the
whole treatment course. This finding also corresponds well with the absence of neutralizing antibodies before and after the
whole treatment period.
Received: 8 December 1994 / Accepted: 10 January 1995 相似文献
92.
In our previous study (A. Balogh et al, Cell. Signalling 5 (6), 795-802, 1993.), we have shown that epidermal growth factor (EGF) increased protein kinase C (PKC) activities in colon carcinoma cell line (HT29), possibly through the increased 1,2-diacylglycerol (1,2-DAG) production via phosphatidylcholine (PC). Here we investigate the effect of the well-known PKC activator 12-O-tetradecanoyl-2 phorbol-13-acetate (TPA), on the levels of 32P incorporation into EGF induced phosphatidylinositols (PI, PI4P, PI4, 5P2) and different phospholipids (PC, PA, PS) as well as on induced tyrosine kinase activity. TPA significantly decreased the effects of EGF and it had the biggest inhibitory effect on EGF induced PC level. These data support our contention that PC plays an important role in the activation of PKC via 1,2-DAG production in the EGF stimulated pathway. 相似文献
93.
Peter Allard Jüri Jarvet Anders Ehrenberg Astrid Gräslund 《Journal of biomolecular NMR》1995,5(2):133-146
Summary The peptide hormone motilin was synthesised with a 13C-enriched -carbon in the leucine at position 10. In aqueous solution, six different relaxation rates were measured for the 13C–H fragment as a function of temperature and with and without the addition of 30% (v/v) of the cosolvent d
2-1,1,1,3,3,3-hexafluoro-2-propanol (HFP). The relaxation rates were analysed employing the spectral density mapping technique introduced by Peng and Wagner [(1992) J. Magn. Reson., 98, 308–322] and using the model-free approach by Lipari and Szabo [(1982) J. Am. Chem. Soc., 104, 4546–4570]. The fit to various models of dynamics was also considered. Different procedures to evaluate the overall rotational correlation time were compared. A single exponential time correlation function was found to give a good fit to the measured spectral densities only for motilin in 30% (v/v) HFP at low temperatures, whereas at high temperatures in this solvent, and in D2O at all temperatures, none of the considered models gave an acceptable fit. A new empirical spectral density function was tested and found to accurately fit the experimental spectral density mapping points. The application of spectral density mapping based on NMR relaxation data for specific 13C–1H vector is shown to be a highly useful method to study biomolecular dynamics. Advantages are high sensitivity, high precision and uniform sampling of the spectral density function over the frequency range.Abbreviations CD
circular dichroism
- NOE
nuclear Overhauser enhancement
- NOESY
two-dimensional NOE spectroscopy
- INEPT
insensitive nuclei enhanced by polarisation transfer
- DANTE
delays alternating with nutations for tailored excitation
- WALTZ-16
wideband, alternating phase, low-power technique for zero residual splitting
- FID
Free induction decay
- ppm
parts per million
- TSPA
3-trimethylsilyl-(3,3,2,2-d)-propionic acid
- HFP
d
2-1,1,1,3,3,3-hexafluoro-2-propanol
- CPMG
Carr-Purcell-Meiboom-Gill
- TFD
time-resolved fluorescence depolarisation
- CSA
chemical shift anisotropy
Partly presented at the symposium Dynamics and Function of Biomolecules, Szeged, Hungary, July 31–August 2, 1993. 相似文献
94.
Addi R. Fadel Dan Q. Jin Gaetano T. Montelione Ronald M. Levy 《Journal of biomolecular NMR》1995,6(2):221-226
Summary Order parameters for the backbone N–H and C–H bond vectors have been calculated from a 150 ps molecular dynamics (MD) simulation of human type- transforming growth factor in H2O solvent. Two kinds of crankshaft motions of the polypeptide backbone are observed in this MD trajectory. The first involves small-amplitude rocking of the rigid peptide bond due to correlated changes in the backbone dihedral angles i–1 and i. These high-frequency librational crankshaft motions are correlated with systematically smaller values of motional order parameters for backbone N–H bond vectors compared to C–H bond vectors. In addition, infrequent crankshaft flips of the peptide bond from one local minimum to another are observed for several amino acid residues. These MD simulations demonstrate that comparisons of N–H and C–H order parameters provide a useful approach for identifying crank-shaft librational motions in proteins. 相似文献
95.
Rasmus H. Fogh Dick Schipper Rolf Boelens Robert Kaptein 《Journal of biomolecular NMR》1995,5(3):259-270
Summary The 1H, 13C and 15N NMR resonances of serine protease PB92 have been assigned using 3D tripleresonance NMR techniques. With a molecular weight of 27 kDa (269 residues) this protein is one of the largest monomeric proteins assigned so far. The side-chain assignments were based mainly on 3D H(C)CH and 3D (H)CCH COSY and TOCSY experiments. The set of assignments encompasses all backbone carbonyl and CHn carbons, all amide (NH and NH2) nitrogens and 99.2% of the amide and CHn protons. The secondary structure and general topology appear to be identical to those found in the crystal structure of serine protease PB92 [Van der Laan et al. (1992) Protein Eng., 5, 405–411], as judged by chemical shift deviations from random coil values, NH exchange data and analysis of NOEs between backbone NH groups.Abbreviations 2D/3D/4D
two-/three-/four-dimensional
- HSQC
heteronuclear single-quantum coherence
- HMQC
heteronuclear multiple-quantum coherence
- COSY
correlation spectroscopy
- TOCSY
total correlation spectroscopy
- NOE
nuclear Overhauser enhancement (connectivity)
- NOESY
2D NOE spectroscopy
Experiment nomenclature (H(C)CH, etc.) follows the conventions used elsewhere [e.g. Ikura et al. (1990) Biochemistry, 29, 4659–4667]. 相似文献
96.
M. Teresa García-López Ibon Alkorta M. José Domínguez Rosario González-Mu?iz Rosario Herranz Nils L. Johansen Kjeld Madsen Henning Th?gersen Peter Suzdak 《Letters in Peptide Science》1995,1(6):269-276
Summary In order to enforce different spatial orientations in the C-terminal hexapeptide of neurotensin (NT8–13) and to gain information about the importance of the 10–11 peptide bond for binding to NT receptors, the Pro10-Tyr11 fragment has been replaced with (2R,8S,8aR)-, (2S,8S,8aR)-, (2S,8S,8aS)-, (2S,8R,8aS)- and (2R,8R,8aS)-8-amino-2-benzyl-3-oxoindolizidine-2-carboxylic acid. Molecular dynamics calculations and energy minimization studies have shown that, contrarily to the Pro-Tyr moiety, none of these indolizidines display a tendency to adopt type I and III -turns, but those having (8S,8aR) or (8R,8aS) stereochemistry essentially adopt extended conformations and the (8S,8aS) stereoisomer prefers a nonstandard folding. The four diastereomeric NT8–13 analogues incorporating (8S,8aR) or (8R,8aS) indolizidines displayed binding affinities for the brain NT receptor similar to that of [Ala11]-NT8–13 and only five- to ninefold lower than that of the corresponding analogue, [Phe11]NT8–13. Although this slight decrease could be attributed to differences in conformational behavior between these constrained NT8–13 analogues and [Phe11]NT8–13 or NT8–13, it is not clear whether the -turn around Pro10-AA11 (AA=Phe, Tyr) is conserved upon receptor binding. An excessive restriction in the motions of the aromatic side chain, imposed by the highly steric constraint of the indolizidine moiety, emerges as an alternative explanation. The findings reported here demonstrate the possibility of replacing the Pro10-Tyr11 dipeptide in NT8–13 with a non-peptide residue without affecting considerably the affinity for brain NT receptors. 相似文献
97.
Fons A.L.J. Peters Ron H.M. Van Der Pal Robert L.A. Peters Wim J. Vredenberg Ruud Kraayenhof 《BBA》1984,766(1):169-178
This work aimed at the resolution of the multi-component electric potential changes induced by single-turnover flash illumination of Photosystem-I-enriched subchloroplast vesicles. If supplemented with ferredoxin and under carefully adjusted redox poising, these vesicles show a pronounced slow-rising and -decaying electric potential component, as monitored by endogenous and exogenous field-sensitive probes, carotenoids and oxonol VI, respectively. The fast and slow potential components can be easily discriminated without the need for computer-assisted deconvolution after selective presaturation of the slow component by preillumination or a transmembrane ΔpH, after selective suppression of the slow component by low valinomycin or uncoupler concentrations or in the absence of ferredoxin. The slow electric potential component, as compared to the fast one, is relatively sensitive to low concentrations of ionophores and uncouplers, detergent, ageing and lower temperatures (4–12°C), is associated with electrogenic proton displacements and is interpreted to respond to a field that is more located on the membrane-bulk interface. Temperature effects show transition temperatures around 20°C for both the rise and decay of the slow potential component. The results provide further evidence that the carotenoids and oxonol VI sense the same (slow) electric field, but may be differently located in the thylakoid membrane. 相似文献
98.
H.W. Gardner E.C. Nelson L.W. Tjarks R.E. England 《Chemistry and physics of lipids》1984,35(2):87-101
Acid treatment of (13S)-(9Z,11E)-13-hydroperoxy-9,11-octadecadienoic acid in tetrahydrofuran-water solvent afforded mainly (11R,12R,13S)-(Z)-12,13-epoxy-11-hydroxy-9-octadecenoic acid, diastereomeric (Z)-11,12,13-trihydroxy-9-octadecenoic acids and four isomers of (E)-9,12,13(9,10,13)-trihydroxy-10(11)-octadecenoic acid. Other minor products were oxooctadecadienoic, (E)-9(13)-hydroxy-13(9)-oxo-10(11)-octadecenoic and (E)-12-oxo-10-dodecenoic acids. A heterolytic mechanism for acid catalysis was indicated, even though most of the products characterized also have been observed as a result of homolytic decomposition of the hydroperoxide via an oxy radical. Most of the products found in this study have been observed as metabolites of (13S)-(9Z,11E)-13-hydroperoxy-9,11-octadecadenoic acid in biological systems, and analogous compounds have been reported as metabolites of (12S)-(5Z,8Z,10E, 14Z)-12-hydroperoxy-5,8,10,14-hydroperoxy-5,8,10,14-eicosatetraenoic acid in either blood platelets or lung tissue. 相似文献
99.
Hybrid recombinant human leukocyte interferon inhibits differentiation in murine B-16 melanoma cells 总被引:1,自引:0,他引:1
P B Fisher H Hermo D R Prignoli I B Weinstein S Pestka 《Biochemical and biophysical research communications》1984,119(1):108-115
We have investigated the effects of recombinant human leukocyte interferons (IFN-alpha A and IFN-alpha D) and various hybrid recombinant human leukocyte interferons on differentiation in B-16 mouse melanoma cells. Inhibition of both spontaneous and melanocyte hormone stimulated differentiation was observed with one hybrid construct, IFN-alpha A/D (Bgl) consisting of amino acids 1 to 62 from IFN-alpha A and amino acids 64 to 166 from IFN-alpha D. In contrast, the parental human interferons, IFN-alpha A and IFN-alpha D, when used alone or in combination, as well as other hybrid human leukocyte interferons, did not cause significant inhibition of melanogenesis in B-16 mouse cells. The tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) also inhibited B-16 differentiation and the combination of TPA with IFN-alpha A/D (Bgl) or mouse L-cell interferon was synergistic in delaying melanogenesis. These studies indicate that the IFN-alpha A/D (Bgl) hybrid that exhibits antiviral activity on mouse cells can also inhibit differentiation of murine cells. 相似文献
100.
Modulation of c-myc expression in the HL-60 cell line 总被引:7,自引:0,他引:7
A decrease in the expression of the myc proto-oncogene of HL-60 cells has been reported as an accompaniment of myeloid differentiation induced by either dimethylsulfoxide or retinoic acid. We report herein that several inhibitors of poly(ADP-ribose)-polymerase induced myeloid differentiation in HL-60 cultures. Studies on the expression of the c-myc gene in total cell RNA populations indicate that expression of this gene is inversely correlated with the state of differentiation, either myeloid or monocytic, of the cultured cells independent of the inducer and the rate of cell proliferation. 相似文献