全文获取类型
收费全文 | 3504篇 |
免费 | 226篇 |
国内免费 | 133篇 |
出版年
2023年 | 48篇 |
2022年 | 51篇 |
2021年 | 59篇 |
2020年 | 94篇 |
2019年 | 134篇 |
2018年 | 115篇 |
2017年 | 107篇 |
2016年 | 130篇 |
2015年 | 96篇 |
2014年 | 178篇 |
2013年 | 230篇 |
2012年 | 147篇 |
2011年 | 194篇 |
2010年 | 111篇 |
2009年 | 170篇 |
2008年 | 193篇 |
2007年 | 206篇 |
2006年 | 168篇 |
2005年 | 118篇 |
2004年 | 129篇 |
2003年 | 109篇 |
2002年 | 115篇 |
2001年 | 68篇 |
2000年 | 69篇 |
1999年 | 55篇 |
1998年 | 77篇 |
1997年 | 47篇 |
1996年 | 50篇 |
1995年 | 63篇 |
1994年 | 49篇 |
1993年 | 52篇 |
1992年 | 48篇 |
1991年 | 31篇 |
1990年 | 29篇 |
1989年 | 27篇 |
1988年 | 24篇 |
1987年 | 17篇 |
1986年 | 15篇 |
1985年 | 45篇 |
1984年 | 49篇 |
1983年 | 43篇 |
1982年 | 39篇 |
1981年 | 21篇 |
1980年 | 17篇 |
1979年 | 7篇 |
1978年 | 4篇 |
1977年 | 5篇 |
1976年 | 3篇 |
1975年 | 2篇 |
1974年 | 4篇 |
排序方式: 共有3863条查询结果,搜索用时 15 毫秒
1.
《Bioorganic & medicinal chemistry letters》2020,30(10):127114
A lead compound with the (1,3,4-thiadiazol-2-yl)-acrylamide scaffold was discovered to have significant cytotoxicity on several tumor cell lines in an in-house cell-based screening. A total of 60 derivative compounds were then synthesized and tested in a CCK-8 cell viability assay. Some of them exhibited improved cytotoxic activities. The most potent compounds had IC50 values of 1–5 μM on two acute leukemia tumor cell lines, i.e. RS4;11 and HL-60. Flow cytometry analysis of several active compounds and detection of caspase activation indicated that they induced caspase-dependent apoptosis. It was also encouraging to observe that these compounds did not have obvious cytotoxicity on normal cells, i.e. IC50 > 50 μM on HEK-293T cells. Although the molecular targets of this class of compound are yet to be revealed, our current results suggest that this class of compound represents a new possibility for developing drug candidates against acute leukemia. 相似文献
2.
A. B. Edmundson D. L. Harris Z.-C. Fan L. W. Guddat B. T. Schley B. L. Hanson G. Tribbick H. M. Geysen 《Proteins》1993,16(3):246-267
An immunoglobulin light chain dimer with a large generic binding cavity was used as a host molecule for designing a series of peptide guest ligands. In a screening procedure peptides coupled to solid supports were systematically tested for binding activity by enzyme linked immunosorbent assays (ELISA). Key members of the binding series were synthesized in milligram quantities and diffused into crystals of the host molecule for X-ray analyses. These peptides were incrementally increased in size and affinity until they nearly filled the cavity. Progressive changes in binding patterns were mapped by comparisons of crystallo-graphically refined structures of 14 peptide–protein complexes at 2.7 Å resolution. These comparisons led to guidelines for ligand design and also suggested ways to modify previously established binding patterns. By manipulating equilibria involving histidine, for example, it was possible to abolish one important intramolecular interaction of the bound ligand and substitute another. These events triggered a change inconformation of the ligand from a compact to an extended form and a comprehensive change in the mode of binding to the protein. In dipeptides of histidine and proline, protonation of both imidazolium nitrogen atoms was used to program anend-to-end reversal of the direction in which the ligand was inserted into the binding cavity. Peptides cocrystallized with proteins produced complexes somewhat different in structure from those in which ligandswere diffused into preexisting crystals. In sucha large and malleable cavity, space utilization was thus different when a ligand was introduced before the imposition of crystal packing restraints. © 1993 Wiley-Liss, Inc. 相似文献
3.
《Microbes and infection / Institut Pasteur》2020,22(3):111-118
Diabetes has been associated with an increased risk of developing tuberculosis. The reasons related to the increased susceptibility to develop TB in type 2 diabetes mellitus (T2DM) individuals, has not been completely elucidated. However, this susceptibility has been attributed to several factors including failures and misfunctioning of the immune system. In the present study, we aimed to determine the role of anti-hyperglycemic drugs such as glyburide, insulin, and metformin to promote the killing of mycobacteria through the regulation of innate immune molecules such as host defense peptides (HDP) in lung epithelial cells and macrophages. Our results showed that metformin reduces bacillary loads in macrophages and lung epithelial cells which correlates with higher production of β-defensin-2, -3 and -4. Since β-defensins are crucial molecules for controlling Mycobacterium tuberculosis growth, the present results suggest that the use of metformin would be the first choice in the treatment for T2DM2, in patients within tuberculosis-endemic areas. 相似文献
4.
5.
A bioactive peptide of 8595 Da was purified from the cell free supernatant of Lactococcus garvieae subsp. bovis BSN307T. MALDI MS/MS peptide mapping and the data base search displayed no significant similarity to any reported antimicrobial peptide of LAB. This peptide at a dose concentration of 200 µg ml−1 inhibited the growth of both Gram-positive and Gram-negative bacteria by 58–89% and a dose of 500 µg ml−1 scavenged 50% of DPPH-free radicals generated. Interestingly, cytotoxicity assay demonstrated that 17 µg ml−1 of peptide selectively inhibited 50% proliferation of mammalian cancer cell lines HeLa and MCF-7 whereas normal H9c2 cells remained unaffected. Fluorescent microscopic analysis after DAPI nuclear staining of HeLa cells showed characteristics of apoptosis and activation of caspase-3 was ascertained by caspase-3 fluorescence assay. 相似文献
6.
《Expert review of proteomics》2013,10(5):561-572
Cystine-knot miniproteins, also known as knottins, constitute a large family of structurally related peptides with diverse amino acid sequences and biological functions. Knottins have emerged as attractive candidates for drug development as they potentially fill a niche between small molecules and protein biologics, offering drug-like properties and the ability to bind to clinical targets with high affinity and selectivity. Due to their extremely high stability and unique structural features, knottins also demonstrate promise in addressing challenging drug development goals, including the potential for oral delivery and the ability to access intracellular drug targets. Several naturally-occurring knottins have recently received approval for treating chronic pain and irritable bowel syndrome, while others are under development for tumor imaging applications. To expand beyond nature’s repertoire, rational and combinatorial protein engineering methods are generating tumor-targeting knottins for use as cancer diagnostics and therapeutics. 相似文献
7.
MDR1 P-glycoprotein transports endogenous opioid peptides 总被引:3,自引:0,他引:3
MDR1 P-glycoprotein is generally regarded as an efflux pump for amphipathic toxic compounds. The question remains, however, whether certain endogenous compounds are also substrates for this transporter. Certain peptides have been shown to interact with MDR1 Pgp as well and we have therefore investigated whether endogenous bioactive peptides are substrates. We demonstrate here that the synthetic μ-opioid peptide DAMGO is a good substrate for MDR1 Pgp. In view of its low interaction with the membrane it is an attractive ligand for measurement of MDR1 Pgp-mediated transport activity in membrane vesicles. Various linear peptides with amidated C-termini were found to inhibit MDR1 Pgp-mediated DAMGO transport. This group includes endogenous opioid peptides such as adrenorphin and endomorphin 1 and 2, as well as the neurokinin, Substance P. The latter bioactive peptides have a relatively high affinity for the transporter. Transport of endomorphin 1 and 2 could be directly demonstrated by the uptake of the radiolabeled opioid peptides in membrane vesicles from MDR1-transfected cells with a Km of 15 and 12 μM, respectively. This opens the possibility that MDR1 Pgp is involved in the elimination and/or tissue distribution of these bioactive peptides. 相似文献
8.
9.
Different series of novel thieno [2,3-d]pyrimidine derivative (9a-d,10a-f,l,m and 15a-m) were designed, synthesized and evaluated for their ability to in vitro inhibit VEGFR-2 enzyme. Also, the cytotoxicity of the final compounds was tested against a panel of 60 different human cancer cell lines by NCI. The VEGFR-2 enzyme inhibitory results revealed that compounds 10d, 15d and 15 g are among the most active inhibitors with IC50 values of 2.5, 5.48 and 2.27 µM respectively, while compound 10a remarkably showed the highest cell growth inhibition with mean growth inhibition (GI) percent of 31.57%. It exhibited broad spectrum anti-proliferative activity against several NCI cell lines specifically on human breast cancer (T7-47D) and renal cancer (A498) cell lines of 85.5% and 77.65% inhibition respectively. To investigate the mechanistic aspects underlying the activity, further biological studies like flow cytometry cell cycle together with caspase-3 colorimetric assays were carried on compound 10a. Flow cytometric analysis on both MCV-7 and PC-3 cancer cells revealed that it induced cell-cycle arrest in the G0-G1phase and reinforced apoptosis via activation of caspase-3. Furthermore, molecular modeling studies have been carried out to gain further understanding of the binding mode in the active site of VEGFR-2 enzyme and predict pharmacokinetic properties of all the synthesized inhibitors. 相似文献
10.
Dynorphin-Related Opioid Peptides in the Neurointermediate Pituitary of Rats Are Not α-N-Acetylated 总被引:1,自引:1,他引:0
Immunoreactive dynorphin in the neurointermediate pituitary of rats was found to consist of four different molecular weight forms. The three larger molecular weight forms, with apparent molecular weights of 4800, 3200, and 1700, constituted more than 80% of the total dynorphin immunoreactivity, and each liberated leucine-enkephalin but not alpha-N-acetyl-leucine-enkephalin upon enzymatic treatment with trypsin followed by carboxypeptidase B. Only a minor portion of the smallest dynorphin-related molecular weight form, dynorphin-(1-8), released alpha-N-acetyl-leucine-enkephalin upon enzymatic cleavage. This suggests that the vast majority of dynorphin-related peptides in the rat neurointermediate pituitary is not alpha-N-acetylated. The exceptionally high opiate-like activity of the molecular weight 1700 dynorphin suggests that this dynorphin-related opioid peptide may constitute the major part of opioid activity in the neurointermediate pituitary of rats. 相似文献