全文获取类型
收费全文 | 7266篇 |
免费 | 549篇 |
国内免费 | 566篇 |
出版年
2024年 | 16篇 |
2023年 | 207篇 |
2022年 | 206篇 |
2021年 | 328篇 |
2020年 | 358篇 |
2019年 | 449篇 |
2018年 | 379篇 |
2017年 | 362篇 |
2016年 | 360篇 |
2015年 | 362篇 |
2014年 | 510篇 |
2013年 | 773篇 |
2012年 | 275篇 |
2011年 | 389篇 |
2010年 | 270篇 |
2009年 | 332篇 |
2008年 | 331篇 |
2007年 | 330篇 |
2006年 | 298篇 |
2005年 | 259篇 |
2004年 | 238篇 |
2003年 | 198篇 |
2002年 | 201篇 |
2001年 | 114篇 |
2000年 | 79篇 |
1999年 | 88篇 |
1998年 | 93篇 |
1997年 | 87篇 |
1996年 | 52篇 |
1995年 | 56篇 |
1994年 | 51篇 |
1993年 | 47篇 |
1992年 | 36篇 |
1991年 | 33篇 |
1990年 | 29篇 |
1989年 | 23篇 |
1988年 | 11篇 |
1987年 | 17篇 |
1986年 | 17篇 |
1985年 | 24篇 |
1984年 | 29篇 |
1983年 | 18篇 |
1982年 | 7篇 |
1981年 | 9篇 |
1980年 | 8篇 |
1979年 | 6篇 |
1978年 | 5篇 |
1977年 | 4篇 |
1976年 | 4篇 |
1971年 | 1篇 |
排序方式: 共有8381条查询结果,搜索用时 390 毫秒
1.
2.
3.
Ulrich Weser Karl-Heinz Sellinger Edmund Lengfelder Walther Werner Joachim Strähle 《Biochimica et Biophysica Acta (BBA)/General Subjects》1980,631(2):232-245
The copper complex of indomethacin (1-(p-chlorobenzoyl)-5-methoxy-2-methyl-indole acetate), a common anti-inflammatory drug, was prepared and characterized. Crystal structure determination revealed the dimeric form of the 1:2 complex, namely Cu2(indomethacin)4 · L2, in the unit cell. Suprisingly, the copper-copper distance (263 pm) was very close to metallic copper (256 pm). The two coordination sites in the copper-copper axis can be readily replaced by superoxide. An intriguing similarity to Cu2(acetate)4 was seen.Due to the lipophilic nature of the indomethacin ligand, this copper complex reacted with superoxide in aprotic solvents. The superoxide dismutating activity was successfully demonstrated in Me2SO/water and acetonitrile/water mixtures using the nitro-blue tetrazolium assay and pulse radiolysis. The second-order rate constant of 6 · 109 M?1 · s?1 in strictly aqueous systems dropped only slightly to 1.1 · 109 M?1 · s?1 when aprotic solvents were used. This is the fastest rate constant ever observed for a copper-dependent dismutation of superoxide. The KO2-induced lipid peroxidation in both erythrocytes and liver microsomes was suppressed by 70% in the presence of 1 · 10?10 mol · ml?1 of Cu2(indomethacin)4. The inhibitory action dropped to 25% when Cu2Zn2superoxide dismutase was employed. The formation of copper · indomethacin in rat serum after administration of indomethacin was shown in vitro and in vivo. 相似文献
4.
《Bioorganic & medicinal chemistry》2016,24(18):4444-4451
Nowadays, AT1 receptor (AT1R) antagonists (ARBs) constitute the one of the most prevalent classes of antihypertensive drugs that modulate the renin-angiotensin system (RAS). Their main uses include also treatment of diabetic nephropathy (kidney damage due to diabetes) and congestive heart failure. Towards this direction, our study has been focused on the discovery of novel agents bearing different scaffolds which may evolve as a new class of AT1 receptor antagonists. To fulfill this aim, a combination of computational approaches and biological assays were implemented. Particularly, a pharmacophore model was established and served as a 3D search query to screen the ChEMBL15 database. The reliability and accuracy of virtual screening results were improved by using molecular docking studies. In total, 4 compounds with completely diverse chemical scaffolds from potential ARBs, were picked and tested for their binding affinity to AT1 receptor. Results revealed high nanomolar to micromolar affinity (IC50) for all the compounds. Especially, compound 4 exhibited a binding affinity of 199 nM. Molecular dynamics simulations were utilized in an effort to provide a molecular basis of their binding to AT1R in accordance to their biological activities. 相似文献
5.
Current and emerging commercial optical biosensors. 总被引:5,自引:0,他引:5
The field of commercial optical biosensors is rapidly evolving, with new systems and detection methods being developed each year. This review outlines the currently available biosensor hardware and highlights unique features of each platform. Affinity-based biosensor technology, with its high sensitivity, wide versatility and high throughput, is playing a significant role in basic research, pharmaceutical development, and the food and environmental sciences. Likewise, the increasing popularity of biosensors is prompting manufacturers to develop new instrumentation for dedicated applications. We provide a preview of some of the emerging commercial systems that are dedicated to drug discovery, proteomics, clinical diagnostics and routine biomolecular interaction analysis. 相似文献
6.
Prasert Akkaramongkolporn Tanasait Ngawhirunpat Praneet Opanasopit 《AAPS PharmSciTech》2009,10(2):641-648
The differently sulfonated styrene–divinylbenzene cross-linked copolymer cationic exchange resins were prepared by oil-in-water
polymerization and varied degrees of sulfonation. Several characteristics of the obtained resins were evaluated, i.e., Fourier
transform infrared spectra, the ion-exchange capacity, microscopic morphology, size, and swelling. The resin characteristics
were altered in relation to the degree of sulfonation, proving that differently sulfonated resins could be prepared. The behavior
of chlorpheniramine (CPM) loading and in vitro release in the USP simulated gastric (SGF) and intestinal fluids (SIF) of the obtained resins were also evaluated. The CPM
loaded in the resinates (drug-loaded resins) increased with the increasing degree of sulfonic group and hence the drug binding
site in the employed resins. The CPM release was lower from the resins with the higher degree of sulfonic group due to the
increase in the diffusive path depth. The CPM release was obviously lower in SGF than SIF because CPM, a weak base drug, ionized
to a greater extent in SGF and then preferred binding with rather than releasing from the resins. In conclusion, the differently
sulfonated resins could be utilized as novel carriers for drug delivery. 相似文献
7.
Mahsa Zahiri Maryam Babaei Khalil Abnous Seyed Mohammad Taghdisi Mohammad Ramezani Mona Alibolandi 《Journal of cellular physiology》2020,235(2):1036-1050
In this study, the chemical features of dendritic mesoporous silica nanoparticles (DMSNs) provided the opportunity to design a nanostructure with the capability to intelligently transport the payload to the tumor cells. In this regard, doxorubicin (DOX)-encapsulated DMSNs was electrostatically surface-coated with polycarboxylic acid dextran (PCAD) to provide biocompatible dextran-capped DMSNs (PCAD-DMSN@DOX) with controlled pH-dependent drug release. Moreover, a RNA aptamer against a cancer stem cell (CSC) marker, CD133 was covalently attached to the carboxyl groups of DEX to produce a CD133-PCAD-DMSN@DOX. Then, the fabricated nanosystem was utilized to efficiently deliver DOX to CD133+ colorectal cancer cells (HT29). The in vitro evaluation in terms of cellular uptake and cytotoxicity demonstrated that the CD133-PCAD-DMSN@DOX specifically targets HT29 as a CD133 overexpressed cancer cells confirmed by flow cytometry and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay. The potentially promising intelligent-targeted platform suggests that targeted dextran-capped DMSNs may find impressive application in cancer therapy. 相似文献
8.
In searching for differentially expressed genes in human uterine leiomyomas (ULs), suppression sub-tractive hybridization was used to construct an UL up-regulated library, which turned out to represent 88genes. After two rounds of screening by reverse Northern analysis, twenty genes were proved to be up-regulated, including seventeen known genes and three genes with unknown function. All these genes werefirstly associated with UL. Three genes with notable difference were selected for Northern confirmationOur results proved the authenticity of the twenty genes. One gene named Phospholipase A2 (PLA2) showedup-regulation in 4/6 of the patients and investigation of tissue distribution indicated that it had obviousexpression in prostate, testis, liver, heart and skeletal muscle. 相似文献
9.
Fátima H. Vaz Patrícia M. Machado Rita D. Brand?o Cátia T. Laranjeira Joana S. Eugénio Aires H. Fernandes Saudade P. André 《The journal of histochemistry and cytochemistry》2007,55(11):1105-1113
Only 20-25% of families screened for BRCA1/2 mutations are found positive. Because only a positive result is informative, we studied the role of BRCA1/2 immunohistochemistry as an additional method for patient selection. From 53 high-risk-affected probands, 18 (34%) had available paraffin blocks of their tumors and were selected for this study. Mutation screening was done by conformation-sensitive gel electrophoresis and multiplex ligation-dependent probe amplification. For immunohistochemistry, 21 neoplastic specimens (15 breast carcinomas, 5 ovary neoplasms, and 1 rectal adenocarcinoma) were analyzed with BRCA1 (monoclonal antibody, Ab-1, oncogene) and BRCA2 (polyclonal antibody, Ab-2, oncogene) antibodies. Absence of the BRCA1 protein was confirmed in negative tumors by Western blotting. Seven patients were positive for BRCA1/2 mutations: 5 for BRCA1 and 2 for BRCA2. Four out of five positive patients had tumors negative for BRCA1 immunostaining, and the remaining 13 BRCA1-negative patients had positive BRCA1 immunostaining in all tumor samples. Sensitivity to predict for BRCA1 mutation carriers was 80%, and specificity was 100%, with a positive predictive value of 100% and a negative predictive value of 93%. This correlation was statistically significant (p=0.001). No correlation was observed for BRCA2. If larger studies confirm these results, high-risk patients with BRCA1-negative tumors should be screened first for this gene. 相似文献
10.
Spinal muscular atrophy (SMA) is the most common genetic disease that causes infant mortality. Its treatment and prevention represent the paradigmatic example of the ethical dilemmas of 21st-century medicine. New therapies (nusinersen and AVXS-101) hold the promise of being able to treat, but not cure, the condition. Alternatively, genomic analysis could identify carriers, and carriers could be offered in vitro fertilization and preimplantation genetic diagnosis. In the future, gene editing could prevent the condition at the embryonic stage. How should these different options be evaluated and compared within a health system? In this paper, we discuss the ethical considerations that bear on the question of how to prioritize the different treatments and preventive options for SMA, at a policy level. We argue that despite the tremendous value of what we call ‘ex-post’ approaches to treating SMA (such as using pharmacological agents or gene therapy), there is a moral imperative to pursue ‘ex-ante’ interventions (such as carrier screening in combination with prenatal testing and preimplantation genetic diagnosis, or gene editing) to reduce the incidence of SMA. There are moral reasons relating to autonomy, beneficence and justice to prioritize ex-ante methods over ex-post methods. 相似文献