全文获取类型
收费全文 | 1632篇 |
免费 | 50篇 |
国内免费 | 41篇 |
出版年
2023年 | 11篇 |
2022年 | 47篇 |
2021年 | 44篇 |
2020年 | 56篇 |
2019年 | 46篇 |
2018年 | 49篇 |
2017年 | 49篇 |
2016年 | 61篇 |
2015年 | 44篇 |
2014年 | 90篇 |
2013年 | 183篇 |
2012年 | 27篇 |
2011年 | 74篇 |
2010年 | 48篇 |
2009年 | 64篇 |
2008年 | 58篇 |
2007年 | 75篇 |
2006年 | 48篇 |
2005年 | 48篇 |
2004年 | 50篇 |
2003年 | 45篇 |
2002年 | 33篇 |
2001年 | 30篇 |
2000年 | 28篇 |
1999年 | 32篇 |
1998年 | 34篇 |
1997年 | 33篇 |
1996年 | 27篇 |
1995年 | 36篇 |
1994年 | 27篇 |
1993年 | 25篇 |
1992年 | 13篇 |
1991年 | 15篇 |
1990年 | 23篇 |
1989年 | 18篇 |
1988年 | 11篇 |
1987年 | 12篇 |
1986年 | 6篇 |
1985年 | 15篇 |
1984年 | 26篇 |
1983年 | 6篇 |
1982年 | 17篇 |
1981年 | 18篇 |
1980年 | 7篇 |
1979年 | 2篇 |
1978年 | 2篇 |
1977年 | 3篇 |
1976年 | 2篇 |
1974年 | 2篇 |
1971年 | 1篇 |
排序方式: 共有1723条查询结果,搜索用时 15 毫秒
1.
2.
《Journal of molecular biology》2021,433(19):167162
Many proteins that can assemble into higher order structures termed amyloids can also concentrate into cytoplasmic inclusions via liquid–liquid phase separation. Here, we study the assembly of human Golgi-Associated plant Pathogenesis Related protein 1 (GAPR-1), an amyloidogenic protein of the Cysteine-rich secretory proteins, Antigen 5, and Pathogenesis-related 1 proteins (CAP) protein superfamily, into cytosolic inclusions in Saccharomyces cerevisiae. Overexpression of GAPR-1-GFP results in the formation GAPR-1 oligomers and fluorescent inclusions in yeast cytosol. These cytosolic inclusions are dynamic and reversible organelles that gradually increase during time of overexpression and decrease after promoter shut-off. Inclusion formation is, however, a regulated process that is influenced by factors other than protein expression levels. We identified N-myristoylation of GAPR-1 as an important determinant at early stages of inclusion formation. In addition, mutations in the conserved metal-binding site (His54 and His103) enhanced inclusion formation, suggesting that these residues prevent uncontrolled protein sequestration. In agreement with this, we find that addition of Zn2+ metal ions enhances inclusion formation. Furthermore, Zn2+ reduces GAPR-1 protein degradation, which indicates stabilization of GAPR-1 in inclusions. We propose that the properties underlying both the amyloidogenic properties and the reversible sequestration of GAPR-1 into inclusions play a role in the biological function of GAPR-1 and other CAP family members. 相似文献
3.
Giovanni Murtas 《Systems and synthetic biology》2010,4(2):85-93
One of the major properties of the semi-synthetic minimal cell, as a model for early living cells, is the ability to self-reproduce
itself, and the reproduction of the boundary layer or vesicle compartment is part of this process. A minimal bio-molecular
mechanism based on the activity of one single enzyme, the FAS-B (Fatty Acid Synthase) Type I enzyme from Brevibacterium ammoniagenes, is encapsulated in 1-palmitoyl-2oleoyl-sn-glycero-3-phosphatidylcholine (POPC) liposomes to control lipid synthesis. Consequently molecules of palmitic acid released
from the FAS catalysis, within the internal lumen, move toward the membrane compartment and become incorporated into the phospholipid
bilayer. As a result the vesicle membranes change in lipid composition and liposome growth can be monitored. Here we report
the first experiments showing vesicles growth by catalysis of one enzyme only that produces cell boundary from within. This
is the prototype of the simplest autopoietic minimal cell. 相似文献
4.
《Bioorganic & medicinal chemistry》2014,22(7):2320-2326
The therapeutic application of siRNA suffers from poor bioavailability caused by rapid degradation and elimination. The covalent attachment of PEG is a universal concept to increase molecular size and enhance the pharmacokinetic properties of biomacromolecules. We devised a facile approach for attachment of PEG molecules with a defined molecular weight, and successful purification of the resulting conjugates. We directly conjugated structurally defined PEG chains with twelve ethylene glycol units to the 3′-terminal hydroxyl group of both sense and antisense strands via an aminoalkyl linker. The conjugates were easily purified by HPLC and successful PEGylation and molecule integrity were confirmed by ESI-MS. The evaluation of in vitro gene knockdown of two different targets in MCF-7 breast cancer cells showed stable pharmacologic activity when combined with a standard transfection reagent. Sense strand PEGylation even increased the silencing potency of a CRCX4-siRNA which had modest activity in its wild-type form. The results indicate that PEG chains at the 3′-terminus of both strands of siRNA are well tolerated by the RNAi effector. The attachment of short, chemically defined PEG chains is a feasible approach to improve the pharmacokinetic properties of siRNA, and can be combined with other targeted and untargeted delivery vehicles. 相似文献
5.
John W. Wright Anita J. Bechtholt Shelley L. Chambers Joseph W. Harding 《Peptides》1996,17(8):1365-1371
The present investigation determined that native angiotensins II and III (ANG II and III) were equipotent as pressor agents when ICV infused in alert rats, whereas native angiotensin IV (ANG IV) was less potent. An analogue of each of these angiotensins was prepared with a hydroxyethylamine (HEA) amide bond replacement at the N-terminus, yielding additional resistance to degradation. These three angiotensin analogues, HEA-ANG II, HEA-ANG III, and HEA-ANG IV, were equivalent with respect to maximum elevation in pressor responses when ICV infused; and each evidenced significantly extended durations of effect compared with their respective native angiotensin. Comparing analogues, HEA-ANG II had a significantly longer effect compared with HEA-ANG III, and HEA-ANG IV, whereas the latter were equivalent. Pretreatment with the AT1 receptor subtype antagonist, Losartan (DuP753), blocked subsequent pressor responses to each of these analogues, suggesting that these responses were mediated by the AT1 receptor subtype. Pretreatment with the specific AT4 receptor subtype antagonist, Divalinal (HED 1291), failed to influence pressor responses induced by the subsequent infusion of these analogues. These results suggest an important role for Ang III, and perhaps ANG IV, in brain angiotensin pressor responses mediated by the AT1 receptor subtype. 相似文献
6.
7.
A. Gallais A. J. Wright 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》1980,57(2):81-87
Summary Genetic effects for varietal value are defined at the level of the population of k-parent synthetic varieties. A simple expression for the total variance among synthetics arises directly from these definitions. A general expression for the covariance among related synthetics is given. Genetic effects are also defined in a completely general way so as to allow for any system of testing and used to derive an expression for the genetic advance in recurrent selection for varietal value. Covariances between relatives evaluated in the system of testing and in varietal combination are introduced, allowing a direct expression of the genetic advance in varietal development when parents are selected either individually or in groups. Some general implications for plant breeding are outlined.Dedicated to Professor F.W. Schnell on the occasion of his 65th birthday 相似文献
8.
Summary The activated dimonophosphate of 3-deoxyadenosine (cordycepin) undergoes oligomerization to produce a new family of pyrophosphate-linked oligomers in which the average repeating unit involves a nine-atom structural group. The presence of a poly(U) template increase the relative yields of higher oligomers, although the template-free reaction is itself extremely efficient.For the previous paper in this series see Schwartz et al. (1987) 相似文献
9.
The effects of structural analogues, excitatory amino acids and certain drugs on spontaneous and potassium-stimulated exogenous taurine and GABA release were investigated in mouse cerebral cortex slices using a superfusion system. Spontaneous efflux of both amino acids was rather slow but could be enhanced by their uptake inhibitors. Taurine efflux was facilitated by exogenous taurine, hypotaurine, -alanine and GABA, whereas GABA, nipecotic acid and homotaurine effectively enhanced GABA release. The stimulatory potency of the analogues closely corresponded to their ability to inhibit taurine and GABA uptake, respectively, indicating that these efflux processes could be mediated by the carriers operating outwards. Glutamate induced GABA release, whereas taurine efflux was potentiated by aspartate, glutamate, cysteate, homocysteate and kainate. The centrally acting drugs, including GABA agonists and antagonists, as well as the proposed taurine antagonist TAG (6-aminomethyl-3-methyl-4H-1,2,4-benzothiadiazine-1,1-dioxide), had no marked effects on spontaneous taurine and GABA release. Potassium ions stimulated dosedependently both taurine and GABA release from the slices, the responses of taurine being strikingly slow but sustained. Exogenous GABA and nipecotic acid accelerated the potassium-stimulated GABA release, whereas picrotoxin and bicuculline were ineffective. The potassium-stimulated taurine release was unaltered or suppressed by exogenous taurine and analogues, differing in this respect from GABA release. The apparent magnitude of the depolarization-induced GABA release is thus influenced by the function of membrane transport sites, but the same conclusion cannot be drawn with regard to taurine. Haloperidol and imipramine were able to affect the evoked release of both taurine and GABA. 相似文献
10.
9-β-
-Arabinofuranosyl-2-fluoroadenine (F-ara-A) and 9-β-
-arabinofuranosyladenine (ara-A) are purine nucleoside analogues which are incorporated into nucleic acids. This study demonstrates the mutagenic properties of F-ara-A and ara-A and provides evidence for mechanisms by which the arabinosyl nucleosides induce mutation. At the drug dosages that evoked exponential cell killing, F-ara-A and ara-A caused a significant increase in the number of 6-thioguanine-resistant mutants in Chinese hamster ovary cells. Southern analyses showed that 15 of 16 drug-induced mutants had lost all or part of the HPRT gene, whereas no loss of the gene was found in 4 spontaneous mutants. We conclude that both F-ara-A and ara-A induced mutation predominantly by causing deletion of genetic method. The remarkable frequency of gene deletion among these drug-induced mutations is discussed with respect to possible mechanisms of action of arabinosyl nucleosides in mutational studies. 相似文献