全文获取类型
收费全文 | 1349篇 |
免费 | 118篇 |
专业分类
1467篇 |
出版年
2023年 | 5篇 |
2022年 | 14篇 |
2021年 | 35篇 |
2020年 | 13篇 |
2019年 | 21篇 |
2018年 | 32篇 |
2017年 | 24篇 |
2016年 | 35篇 |
2015年 | 51篇 |
2014年 | 61篇 |
2013年 | 72篇 |
2012年 | 68篇 |
2011年 | 91篇 |
2010年 | 56篇 |
2009年 | 47篇 |
2008年 | 85篇 |
2007年 | 65篇 |
2006年 | 63篇 |
2005年 | 54篇 |
2004年 | 61篇 |
2003年 | 57篇 |
2002年 | 52篇 |
2001年 | 46篇 |
2000年 | 34篇 |
1999年 | 33篇 |
1998年 | 22篇 |
1997年 | 23篇 |
1996年 | 12篇 |
1995年 | 12篇 |
1994年 | 10篇 |
1993年 | 11篇 |
1992年 | 27篇 |
1991年 | 27篇 |
1990年 | 17篇 |
1989年 | 15篇 |
1988年 | 14篇 |
1987年 | 15篇 |
1986年 | 8篇 |
1985年 | 10篇 |
1984年 | 11篇 |
1983年 | 5篇 |
1982年 | 7篇 |
1981年 | 5篇 |
1979年 | 8篇 |
1978年 | 4篇 |
1977年 | 4篇 |
1975年 | 5篇 |
1974年 | 3篇 |
1973年 | 8篇 |
1970年 | 3篇 |
排序方式: 共有1467条查询结果,搜索用时 15 毫秒
31.
32.
Jean Guillon Anita Cohen Clotilde Boudot Alessandra Valle Vittoria Milano Rabindra Nath Das 《Journal of enzyme inhibition and medicinal chemistry》2013,28(1):432-459
Abstract A series of new 2,4-bis[(substituted-aminomethyl)phenyl]quinoline, 1,3-bis[(substituted-aminomethyl)phenyl]isoquinoline, and 2,4-bis[(substituted-aminomethyl)phenyl]quinazoline derivatives was designed, synthesised, and evaluated in?vitro against three protozoan parasites (Plasmodium falciparum, Leishmania donovani, and Trypanosoma brucei brucei). Biological results showed antiprotozoal activity with IC50 values in the µM range. In addition, the in?vitro cytotoxicity of these original molecules was assessed with human HepG2 cells. The quinoline 1c was identified as the most potent antimalarial candidate with a ratio of cytotoxic to antiparasitic activities of 97 against the P. falciparum CQ-sensitive strain 3D7. The quinazoline 3h was also identified as the most potent trypanosomal candidate with a selectivity index (SI) of 43 on T. brucei brucei strain. Moreover, as the telomeres of the parasites P. falciparum and Trypanosoma are possible targets of this kind of nitrogen heterocyclic compounds, we have also investigated stabilisation of the Plasmodium and Trypanosoma telomeric G-quadruplexes by our best compounds through FRET melting assays. 相似文献
33.
Ivan Literák Petr Heneberg Jiljí Sitko Eric J. Wetzel Jorge Manuel Cardenas Callirgos Miroslav Čapek Daniel Valle Basto Ivo Papoušek 《Parasitology international》2013,62(4):390-396
Until now, four species of eye trematodes have been found in South America. Of them, Philophthalmus lucipetus (synonymized with Philophthalmus gralli) displays a broad host spectrum, with at least 30 bird species (prevalently large water birds), five mammal species and humans serving as definitive hosts, and with snails Fagotia (Microcolpia) acicularis, Amphimelania holandri, Melanopsis praemorsa and Melanoides tuberculata serving as intermediate hosts. When examining a total of 50 birds of ten species in the wetland of Pantanos de Villa, Lima, Peru in July 2011, eye trematodes were identified visually in the edematous conjunctival sac of 11 (48%) out of 23 resident many-colored rush tyrants Tachuris rubrigastra. Based on morphometric characteristics, the trematodes were identified as P. lucipetus. ITS2 and CO1 gene of the examined specimens combined showed a 99% similarity to an Iranian isolate of Philophthalmus sp. from the intermediate host Melanoides tuberculata, an invasive freshwater snail, suggesting that these two isolates represent the same species with a wide geographical range. Moreover, the prevalence of infection with the philophthalmid cercariae was 31% in 744 Melanoides tuberculata examined in Pantanos de Villa in 2010. It is evident that P. lucipetus occurs throughout the world as well as locally, including Eurasia and South America. Here we report this trematode for the first time in Peru, and we were the first to sequence any of the South American eye trematodes. Low host specificity of P. lucipetus and the invasive character of Melanoides tuberculata as a competent intermediate host suggest that eye trematodosis caused by P. lucipetus may emerge frequently in various parts of the world, especially in the tropics. Increase of the zoonotic potential of the P. lucipetus associated with this invasive snail spreading across the world is predictable and should be of interest for further research. 相似文献
34.
Marcelo de Oliveira Barbosa Rubens Rodrigues da Silva Vanessa Carolina de Sena Correia Luana Pereira dos Santos Analía del Valle Garnero Ricardo José Gunski 《Genetics and molecular biology》2013,36(1):70-73
Cytogenetic studies in birds are still scarce compared to other vertebrates. Woodcreepers (Dendrocolaptidae) are part of a highly specialized group within the Suboscines of the New World. They are forest birds exclusive to the Neotropical region and similar to woodpeckers, at a comparable evolutionary stage. This paper describes for the first time the karyotypes of the Olivaceous and the Narrow-billed Woodcreeper using conventional staining with Giemsa and silver nitrate staining of the nucleolar organizer regions (Ag-NORs). Metaphases were obtained by fibular bone marrow culture. The chromosome number of the Olivaceous Woodcreeper was 2n = 82 and of the Narrow-billed Woodcreeper, 2n = 82. Ag-NORs in the largest macrochromosome pair and evidence of a chromosome inversion are described herein for the first time for this group. 相似文献
35.
Elena Donadio Laura Giusti Veronica Seccia Federica Ciregia Ylenia da Valle Iacopo Dallan Tiziana Ventroni Gino Giannaccini Stefano Sellari-Franceschini Antonio Lucacchini 《PloS one》2013,8(8)
Major salivary gland tumours are uncommon neoplasms of the head and neck. The increase of precise pre-operative diagnosis is crucial for their correct management and the identification of molecular markers would surely improve the required accuracy. In this study we performed a comparative proteomic analysis of fine needle aspiration fluids of the most frequent benign neoplasms of major salivary glands, namely pleomorphic adenoma and Warthin''s tumour, in order to draw their proteomic profiles and to point out their significant features. Thirty-five patients submitted to parotidectomy were included in the study, 22 were identified to have pleomorphic adenoma and 14 Warthin''s tumour. Fine needle aspiration samples were processed using a two-dimensional electrophoresis/mass spectrometry-based approach. A total of 26 differentially expressed proteins were identified. Ingenuity software was used to search the biological processes to which these proteins belong and to construct potential networks. Intriguingly, all Warthin''s tumour up-regulated proteins such as Ig gamma-1 chain C region, Ig kappa chain C region and Ig alpha-1 chain C region and S100A9 were correlated to immunological and inflammatory diseases, while pleomorphic adenomas such as annexin A1, annexin A4, macrophage-capping protein, apolipoprotein E and alpha crystalline B chain were associated with cell death, apoptosis and tumorigenesis, showing different features of two benign tumours. Overall, our results shed new light on the potential usefulness of a proteomic approach to study parotid tumours and in particular up regulated proteins are able to discriminate two types of benign parotid lesions. 相似文献
36.
Haiyan Chen Giorgia Valle Sandra Furlan Alma Nani Sandor Gyorke Michael Fill Pompeo Volpe 《The Journal of general physiology》2013,142(2):127-136
Release of Ca2+ from the sarcoplasmic reticulum (SR) drives contractile function of cardiac myocytes. Luminal Ca2+ regulation of SR Ca2+ release is fundamental not only in physiology but also in physiopathology because abnormal luminal Ca2+ regulation is known to lead to arrhythmias, catecholaminergic polymorphic ventricular tachycardia (CPVT), and/or sudden cardiac arrest, as inferred from animal model studies. Luminal Ca2+ regulates ryanodine receptor (RyR)2-mediated SR Ca2+ release through mechanisms localized inside the SR; one of these involves luminal Ca2+ interacting with calsequestrin (CASQ), triadin, and/or junctin to regulate RyR2 function.CASQ2-RyR2 regulation was examined at the single RyR2 channel level. Single RyR2s were incorporated into planar lipid bilayers by the fusion of native SR vesicles isolated from either wild-type (WT), CASQ2 knockout (KO), or R33Q-CASQ2 knock-in (KI) mice. KO and KI mice have CPVT-like phenotypes. We show that CASQ2(WT) action on RyR2 function (either activation or inhibition) was strongly influenced by the presence of cytosolic MgATP. Function of the reconstituted CASQ2(WT)–RyR2 complex was unaffected by changes in luminal free [Ca2+] (from 0.1 to 1 mM). The inhibition exerted by CASQ2(WT) association with the RyR2 determined a reduction in cytosolic Ca2+ activation sensitivity. RyR2s from KO mice were significantly more sensitive to cytosolic Ca2+ activation and had significantly longer mean open times than RyR2s from WT mice. Sensitivity of RyR2s from KI mice was in between that of RyR2 channels from KO and WT mice. Enhanced cytosolic RyR2 Ca2+ sensitivity and longer RyR2 open times likely explain the CPVT-like phenotype of both KO and KI mice. 相似文献
37.
Engineering the Substrate Specificity of a Thermophilic Penicillin Acylase from Thermus thermophilus
Leticia L. Torres ángel Cantero Mercedes del Valle Anabel Marina Fernando López-Gallego José M. Guisán José Berenguer Aurelio Hidalgo 《Applied and environmental microbiology》2013,79(5):1555-1562
A homologue of the Escherichia coli penicillin acylase is encoded in the genomes of several thermophiles, including in different Thermus thermophilus strains. Although the natural substrate of this enzyme is not known, this acylase shows a marked preference for penicillin K over penicillin G. Three-dimensional models were created in which the catalytic residues and the substrate binding pocket were identified. Through rational redesign, residues were replaced to mimic the aromatic binding site of the E. coli penicillin G acylase. A set of enzyme variants containing between one and four amino acid replacements was generated, with altered catalytic properties in the hydrolyses of penicillins K and G. The introduction of a single phenylalanine residue in position α188, α189, or β24 improved the Km for penicillin G between 9- and 12-fold, and the catalytic efficiency of these variants for penicillin G was improved up to 6.6-fold. Structural models, as well as docking analyses, can predict the positioning of penicillins G and K for catalysis and can demonstrate how binding in a productive pose is compromised when more than one bulky phenylalanine residue is introduced into the active site. 相似文献
38.
María Eugenia Sabatino Liliana del Valle Sosa Juan Pablo Petiti Jorge Humberto Mukdsi Iván Darío Mascanfroni Claudia Gabriela Pellizas Silvina Gutiérrez Alicia Inés Torres Ana Lucía De Paul 《Experimental cell research》2013
Toll like receptor 4 (TLR4) has been characterized for its ability to recognize bacterial endotoxin lipopolysaccharide (LPS). Considering that infections or inflammatory processes might contribute to the progression of pituitary tumors, we analyzed the TLR4 functional role by evaluating the LPS effect on lactotroph proliferation in primary cultures from experimental pituitary tumors, and examined the involvement of PI3K-Akt and NF-κB activation in this effect. In addition, the role of 17β-estradiol as a possible modulator of LPS-induced PRL cell proliferation was further investigated. In estrogen-induced hyperplasic pituitaries, LPS triggered lactotroph cell proliferation. However, endotoxin failed to increase the number of lactotrophs taking up BrdU in normal pituitaries. Moreover, incubation with anti-TLR4 antibody significantly reduced LPS-induced lactotroph proliferation, suggesting a functional role of this receptor. As a sign of TLR4 activation, an LPS challenge increased IL-6 release in normal and tumoral cells. By flow cytometry, TLR4 baseline expression was revealed at the plasma membrane of tumoral lactotrophs, without changes noted in the percentage of double PRL/TLR4 positive cells after LPS stimulus. Increases in TLR4 intracellular expression were detected as well as rises in CD14, p-Akt and NF-κB after an LPS challenge, as assessed by western blotting. The TLR4/PRL and PRL/NF-κB co-localization was also corroborated by immunofluorescence and the involvement of PI3K/Akt signaling in lactotroph proliferation and IL-6 release was revealed through the PI3K inhibitor Ly-294002. In addition, 17β-estradiol attenuated the LPS-evoked increase in tumoral lactotroph proliferation and IL-6 release. Collectively these results demonstrate the presence of functional TLR4 in lactotrophs from estrogen-induced hyperplasic pituitaries, which responded to the proliferative stimulation and IL-6 release induced by LPS through TLR4/CD14, with a contribution of the PI3K-Akt and NF-κB signaling pathways. 相似文献
39.
Colonization of newly created habitats is a challenge for waterbird populations in a changing world. Knowing which habitat characteristics are required by waterbird populations is a research challenge for rational management of the new ecosystems and their aquatic bird populations. Since 1989 intertidal dredge islands have been built in the lagoon of Venice using sediments coming from regular dredging of lagoon channels and inlets. Kentish Plover, a species declining in Europe, readily uses these new sites as soon as they become available. Between 2005 and 2007, 75 dredge islands were surveyed each year and the number of breeding pairs of Kentish Plover estimated. Each year about one-third of available dredge islands was used by Kentish Plover. Between 34 (in 2005) and 131 (in 2007) breeding pairs were found, and possible differences in vegetation and morphological characteristics between occupied and unoccupied sites were investigated. Only age, mean elevation above sea level and extension of bare ground were statistically different; Kentish Plover preferred younger sites, with higher elevation and with larger areas of bare ground. The largest groups of breeding pairs, up to thirty pairs, were found on islands which also supported colonies of Little Terns. In the study period dredged islands supported about 60 % of the total breeding population of the lagoon of Venice and 4–6 % of the estimated Italian population. Along coastal sites where human pressure on beaches is particularly heavy, man made habitats such as dredge islands may become a valuable alternative breeding site for this and other species of conservation concern. Management works aimed at promoting the occurrence of this species at selected dredge islands have been made in the lagoon of Venice. 相似文献
40.