全文获取类型
收费全文 | 1340篇 |
免费 | 95篇 |
出版年
2023年 | 7篇 |
2022年 | 22篇 |
2021年 | 50篇 |
2020年 | 27篇 |
2019年 | 28篇 |
2018年 | 43篇 |
2017年 | 33篇 |
2016年 | 62篇 |
2015年 | 58篇 |
2014年 | 85篇 |
2013年 | 94篇 |
2012年 | 118篇 |
2011年 | 122篇 |
2010年 | 64篇 |
2009年 | 62篇 |
2008年 | 63篇 |
2007年 | 72篇 |
2006年 | 64篇 |
2005年 | 51篇 |
2004年 | 48篇 |
2003年 | 34篇 |
2002年 | 30篇 |
2001年 | 37篇 |
2000年 | 33篇 |
1999年 | 22篇 |
1998年 | 12篇 |
1997年 | 8篇 |
1996年 | 4篇 |
1995年 | 7篇 |
1994年 | 4篇 |
1993年 | 4篇 |
1992年 | 10篇 |
1991年 | 7篇 |
1990年 | 3篇 |
1989年 | 9篇 |
1988年 | 7篇 |
1987年 | 7篇 |
1986年 | 4篇 |
1985年 | 4篇 |
1982年 | 1篇 |
1981年 | 1篇 |
1976年 | 1篇 |
1975年 | 1篇 |
1974年 | 2篇 |
1973年 | 1篇 |
1971年 | 1篇 |
1968年 | 2篇 |
1967年 | 1篇 |
1959年 | 2篇 |
1957年 | 1篇 |
排序方式: 共有1435条查询结果,搜索用时 125 毫秒
161.
Valquíria P. Medeiros Edgar J. Paredes‐Gamero Hugo P. Monteiro Hugo A.O. Rocha Edvaldo S. Trindade Helena B. Nader 《Journal of cellular physiology》2012,227(6):2740-2749
Endothelial cells (ECs) are a source of physiologically important molecules that are synthesized and released to the blood and/or to the subendothelial extracellular matrix such as a heparan sulfate proteoglycan (HSPG) with antithrombotic properties. Previously, we have shown that heparin stimulates the synthesis and modifies the sulfation pattern of this HSPG. Here the molecular mechanisms involved in the up‐regulation of HSPG synthesis by heparin in endothelial cells were decoded. The cells were stimulated with heparin and the expression of HSPG and intracellular pathways were evaluated by a combination of methods involving confocal microscopy, flow cytometry, Western blotting analyses, and [35S]‐sulfate metabolically labeling of the cells. We observed that the up‐regulation of HSPG synthesis evoked by heparin is dependent on the interaction of heparin with integrin since RGD peptide abolishes the effect. The activation of integrin leads to tyrosine‐phosphorylation of focal adhesion‐associated proteins such as FAK, Src, and paxillin. In addition, heparin induces ERK1/2 phosphorylation and inhibitors of Ras and MEK decreased heparin‐dependent HSPG synthesis. Moreover, heparin also induced intracellular Ca2+ release, PLCγ1 (phospholipase Cγ1) and CaMKII (calcium calmodulin kinase II) activation, as well as an increase in nitric oxide (NO) production. Finally, an intracellular Ca2+ chelator, Ca2+ signaling inhibitors, and an endothelial NO synthase inhibitor were all able to abolish the effect in heparan sulfate synthesis. In conclusion, the heparin‐induced up‐regulation of HSPG expression is associated with the phosphorylation of focal adhesion proteins and Ras/Raf/MEK/ERK MAP and Ca2+/NO pathways. J. Cell. Physiol. 227: 2740–2749, 2012. © 2011 Wiley Periodicals, Inc. 相似文献
162.
163.
dos Reis SP Tavares Lde S Costa Cde N Brígida AB de Souza CR 《Molecular biology reports》2012,39(6):6513-6519
Cassava (Manihot esculenta Crantz) is one of the world’s most important food crops. It is cultivated mainly in developing countries of tropics, since
its root is a major source of calories for low-income people due to its high productivity and resistance to many abiotic and
biotic factors. A previous study has identified a partial cDNA sequence coding for a putative RING zinc finger in cassava
storage root. The RING zinc finger protein is a specialized type of zinc finger protein found in many organisms. Here, we
isolated the full-length cDNA sequence coding for M. esculenta RZF (MeRZF) protein by a combination of 5′ and 3′ RACE assays. BLAST analysis showed that its deduced amino acid sequence
has a high level of similarity to plant proteins of RZF family. MeRZF protein contains a signature sequence motif for a RING
zinc finger at its C-terminal region. In addition, this protein showed a histidine residue at the fifth coordination site,
likely belonging to the RING-H2 subgroup, as confirmed by our phylogenetic analysis. There is also a transmembrane domain
in its N-terminal region. Finally, semi-quantitative RT-PCR assays showed that MeRZF expression is increased in detached leaves
treated with sodium chloride. Here, we report the first evidence of a RING zinc finger gene of cassava showing potential role
in response to salt stress. 相似文献
164.
165.
Monteiro SP do Brasil PE Cabello GM de Souza RV Brasil P Georg I Cabello PH De Castro L 《Memórias do Instituto Oswaldo Cruz》2012,107(2):224-230
Severe forms of dengue, such as dengue haemorrhagic fever (DHF) and dengue shock syndrome, are examples of a complex pathogenic mechanism in which the virus, environment and host immune response interact. The influence of the host's genetic predisposition to susceptibility or resistance to infectious diseases has been evidenced in several studies. The association of the human leukocyte antigen gene (HLA) class I alleles with DHF susceptibility or resistance has been reported in ethnically and geographically distinct populations. Due to these ethnic and viral strain differences, associations occur in each population, independently with a specific allele, which most likely explains the associations of several alleles with DHF. As the potential role of HLA alleles in the progression of DHF in Brazilian patients remains unknown, we then identified HLA-A alleles in 67 patients with dengue fever and 42 with DHF from Rio de Janeiro, Brazil, selected from 2002-2008 by the sequence-based typing technique. Statistical analysis revealed an association between the HLA-A*01 allele and DHF [odds ratio (OR) = 2.7, p = 0.01], while analysis of the HLA-A*31 allele (OR = 0.5, p = 0.11) suggested a potential protective role in DHF that should be further investigated. This study provides evidence that HLA class I alleles might be important risk factors for DHF in Brazilian patients. 相似文献
166.
Feres JM Monteiro M Zucchi MI Pinheiro JB Mestriner MA Alzate-Marin AL 《American journal of botany》2012,99(4):e154-e156
? Premise of the study: We developed and characterized nuclear microsatellite markers for Anadenanthera colubrina, a tropical tree species widely distributed in South America. ? Methods and Results: Leaf samples of mature A. colubrina trees, popularly called "angico," were collected from an area that is greatly impacted by agricultural practices in the region of Ribeir?o Preto in S?o Paulo State in southeastern Brazil. Twenty simple sequence repeat (SSR) markers were developed, 14 of which had polymorphic loci. A total of 96 alleles were detected with an average of 6.86 alleles per polymorphic locus. The expected heterozygosity, calculated at polymorphic loci, ranged from 0.18 to 0.83. Finally, we demonstrated that 18 loci were cross-amplified in A. peregrina. ? Conclusions: A total of 14 polymorphic markers suggest a high potential for genetic diversity, gene flow, and mating system analyses in A. colubrina. 相似文献
167.
168.
de Castro Côrtes LM de Souza Pereira MC de Oliveira FO Corte-Real S da Silva FS Pereira BA de Fátima Madeira M de Moraes MT Brazil RP Alves CR 《Parasitology》2012,139(2):200-207
Leishmaniasis is a vector-borne disease and an important public health issue. Glycosaminoglycan ligands in Leishmania parasites are potential targets for new strategies to control this disease. We report the subcellular distribution of heparin-binding proteins (HBPs) in Leishmania (Viannia) braziliensis and specific biochemical characteristics of L. (V.) braziliensis HBPs. Promastigotes were fractionated, and flagella and membrane samples were applied to HiTrap Heparin affinity chromatography columns. Heparin-bound fractions from flagella and membrane samples were designated HBP Ff and HBP Mf, respectively. Fraction HBP Ff presented a higher concentration of HBPs relative to HBP Mf, and SDS-PAGE analyses showed 2 major protein bands in both fractions (65 and 55 kDa). The 65 kDa band showed gelatinolytic activity and was sensitive to inhibition by 1,10-phenanthroline. The localization of HBPs on the promastigote surfaces was confirmed using surface plasmon resonance (SPR) biosensor analysis by binding the parasites to a heparin-coated sensor chip; that was inhibited in a dose-dependent manner by pre-incubating the parasites with variable concentrations of heparin, thus indicating distinct heparin-binding capacities for the two fractions. In conclusion, protein fractions isolated from either the flagella or membranes of L. (V.) braziliensis promastigotes have characteristics of metallo-proteinases and are able to bind to glycosaminoglycans. 相似文献
169.
de Brito AF Martins JL Fajemiroye JO Galdino PM De Lima TC Menegatti R Costa EA 《Life sciences》2012,90(23-24):910-916
AimsOur study focuses on the design and synthesis of a new piperazinic derivate, 4-(1-phenyl-1h-Pyrazol-4-Ylmethyl)-Piperazine-1-Carboxylic Acid Ethyl ester (LQFM008), and evaluation of its anxiolytic-like profile in Swiss mice.Main methodsLQFM008 was evaluated in a screening test of the central nervous system including the rota-rod, sodium pentobarbital-induced sleep, open field, elevated plus maze and light–dark box tests.Key findingsLQFM008 induced convulsions at the dose of 1.1 mmol/kg (i.p., s.c. or p.o.). LQFM008 up to 400 μmol/kg had no effect in the rota rod test. In the open field test, LQFM008 increased the number of crossings and the time spent at the central area as well as the sleeping time in sodium pentobarbital-induced sleep. In the elevated plus maze and light–dark box tests, this compound showed an anxiolytic-like activity. This anxiolytic-like activity was antagonized by NAN-190 (5-HT1A antagonist) but not by flumazenil (benzodiazepine antagonist).SignificanceThe compound LQFM008 showed anxiolytic-like activity which may involve serotonergic pathway. 相似文献
170.
Frézard F Silva H Pimenta AM Farrell N Demicheli C 《Metallomics : integrated biometal science》2012,4(5):433-440
It has been reported recently that Sb(III) competes with Zn(II) for its binding to the CCHC zinc finger domain of the HIV-1 NCp7 protein, suggesting that zinc finger proteins may be molecular targets for antimony-based drugs. Here, the interaction of Sb(III) with a CCCH zinc finger domain, which is considered to play a crucial role in the biology of kinetoplastid protozoa, has been characterized for the first time. The binding characteristics of Sb(III) were compared between a CCCH-type peptide derived from a kinetoplastid protein and two different CCHC-type zinc finger peptides. The formation of 1 : 1 Zn-peptide and Sb-peptide complexes from the different peptides was demonstrated using circular dichroism, UV absorption, fluorescence spectroscopies and ESI-MS. Titration of the Zn-peptide complexes with SbCl(3) was performed at pH 6 and 7, exploiting the intrinsic fluorescence of the peptides. The differential spectral characteristics of the peptides allowed for competition experiments between the different peptides for binding of Zn(II). The present study establishes that Sb(III) more effectively displaces Zn(II) from the CCCH peptide than CCHC ones, as a result of both the greater stability of the Sb-CCCH complex (compared to Sb-CCHC complexes) and the lower stability of the Zn-CCCH complex (compared to Zn-CCHC complexes). Comparison of the binding characteristics of Sb(III) or Zn(II) between the CCHC-type peptides with different amino acid sequences supports the model that not only the conserved zinc finger motif, but also the sequence of non-conserved amino acids determines the binding affinity of Sb(III) and Zn(II). These data suggest that the interaction of Sb(III) with CCCH-type zinc finger proteins may modulate, or even mediate, the pharmacological action of antimonial drugs. 相似文献