全文获取类型
收费全文 | 12605篇 |
免费 | 1079篇 |
国内免费 | 1篇 |
出版年
2023年 | 60篇 |
2022年 | 99篇 |
2021年 | 227篇 |
2020年 | 130篇 |
2019年 | 155篇 |
2018年 | 215篇 |
2017年 | 182篇 |
2016年 | 285篇 |
2015年 | 494篇 |
2014年 | 527篇 |
2013年 | 659篇 |
2012年 | 862篇 |
2011年 | 751篇 |
2010年 | 474篇 |
2009年 | 418篇 |
2008年 | 571篇 |
2007年 | 614篇 |
2006年 | 517篇 |
2005年 | 473篇 |
2004年 | 451篇 |
2003年 | 435篇 |
2002年 | 387篇 |
2001年 | 277篇 |
2000年 | 235篇 |
1999年 | 256篇 |
1998年 | 112篇 |
1997年 | 99篇 |
1996年 | 105篇 |
1995年 | 110篇 |
1994年 | 90篇 |
1993年 | 105篇 |
1992年 | 186篇 |
1991年 | 182篇 |
1990年 | 144篇 |
1989年 | 161篇 |
1988年 | 155篇 |
1987年 | 120篇 |
1986年 | 111篇 |
1985年 | 125篇 |
1984年 | 112篇 |
1983年 | 98篇 |
1982年 | 71篇 |
1981年 | 64篇 |
1979年 | 97篇 |
1978年 | 77篇 |
1977年 | 75篇 |
1974年 | 96篇 |
1973年 | 66篇 |
1972年 | 69篇 |
1970年 | 68篇 |
排序方式: 共有10000条查询结果,搜索用时 62 毫秒
971.
Luciane A. Faine Danielle M.H. Cavalcanti Martina Rudnicki Simone Ferderbar Sandra M.D. Macedo Heraldo P. Souza Sandra H.P. Farsky Lisardo Boscá Dulcineia Saes Parra Abdalla 《The Journal of nutritional biochemistry》2010,21(2):125-132
The vascular effects of nitrolinoleate (LNO2), an endogenous product of linoleic acid (LA) nitration by nitric oxide-derived species and a potential nitrosating agent, were investigated on rat endothelial-leukocyte interactions. Confocal microscopy analysis demonstrated that LNO2 was capable to deliver free radical nitric oxide (·NO) into cells, 5 min after its administration to cultured cells, with a peak of liberation at 30 min. THP-1 monocytes incubated with LNO2 for 5 min presented nitrosation of CD40, leading to its inactivation. Other anti-inflammatory actions of LNO2 were observed in vivo by intravital microscopy assays. LNO2 decreased the number of adhered leukocytes in postcapillary venules of the mesentery network. In addition to this, LNO2 reduced mRNA and protein expression of β2-integrin in circulating leukocytes, as well as VCAM-1 in endothelial cells isolated from postcapillary venules, confirming its antiadhesive effects on both cell types. Moreover, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, a nitric oxide scavenger, partially abolished the inhibitory action of LNO2 on leukocyte-endothelium interaction, suggesting that the antiadhesion effects of LNO2 involve a dual role in leukocyte adhesion, acting as a nitric oxide donor as well as through nitric oxide-independent mechanisms. In conclusion, LNO2 inhibited adhesion molecules expression and promoted ·NO inactivation of the CD40–CD40L system, both important processes of the inflammatory response. 相似文献
972.
Paola Palozza Rossella Simone Assunta Catalano Alma Boninsegna Volker Böhm Kati Fröhlich Maria Cristina Mele Giovanni Monego Franco O. Ranelletti 《The Journal of nutritional biochemistry》2010,21(1):34-46
The present study was undertaken to examine whether lycopene is able to counteract 7-ketocholesterol (7-KC)-induced oxidative stress and apoptosis in human macrophages. Human THP-1 macrophages were exposed to 7-KC (10–25 μM) alone and in combination with lycopene (0.5–2 μM), and we monitored changes in cell oxidative status [reactive oxygen species (ROS) production, NOX-4, hsp70 and hsp90 expressions, 8-OHdG formation] and in cell proliferation and apoptosis. After 24 h of treatment, lycopene significantly reduced the increase in ROS production and in 8-OHdG formation induced by the oxysterol in a dose-dependent manner. Moreover, the carotenoid strongly prevented the increase of NOX-4, hsp70 and hsp90 expressions as well as the phosphorylation of the redox-sensitive p38, JNK and ERK1/2 induced by the oxysterol. The attenuation of 7-KC-induced oxidative stress by lycopene coincided with a normalization of cell growth in human macrophages. Lycopene prevented the arrest in G0/G1 phase of cell cycle induced by the oxysterol and counteracted the increased expression of p53 and p21. Concomitantly, it inhibited 7-KC-induced apoptosis, by limiting caspase-3 activation and the modulatory effects of 7-KC on AKT, Bcl-2, Bcl-xL and Bax. Comparing the effects of lycopene, β-carotene and (5Z)-lycopene on ROS production, cell growth and apoptosis show that lycopene and its isomer were more effective than β-carotene in counteracting the dangerous effects of 7-KC in human macrophages. Our study suggests that lycopene may act as a potential antiatherogenic agent by preventing 7-KC-induced oxidative stress and apoptosis in human macrophages. 相似文献
973.
974.
Simone Fattorini 《Biodiversity and Conservation》2010,19(12):3413-3429
The conservation status of invertebrates is usually lesser known than that of vertebrates, and strategies to identify biotopes
to preserve invertebrate diversity are typically based on a single surrogate taxon, or even on the use of vertebrates as surrogates.
Aim of this research is to illustrate a method for biotope prioritisation that can be easily adapted to different animal groups
and geographical contexts. A two-step protocol for biotope prioritisation is proposed on the basis of a multidimensional characterisation
of species vulnerability. Firstly, species vulnerability is estimated from rarity measures which include geographical range,
abundance and biotope specialisation. Then, these values of vulnerability are used to rank biotopes. The method was applied
here to the tenebrionid beetles, the butterflies, the birds and the mammals of the Central Apennines, a montane area of high
conservation concern for South Europe. This study provides evidence for the importance of including insects in conservation
decisions, because vertebrates are poor surrogates for insects. Conservation efforts in the reserves included in the study
area are mostly focused on vertebrates, for which woodlands are considered particularly important. However high altitude open
biotopes are crucial for both tenebrionids and butterflies, and preservation of such kind of biotopes would be beneficial
also for vertebrates. The approach applied here demonstrates that (1) vertebrates are poor surrogates for insects, and (2)
measures of species rarity, typically used in vertebrate conservation, can be obtained also for insects, for which a veritable
amount of data are hidden in specialised literature and museum collections. 相似文献
975.
Fabrizio Micheli Daniele Andreotti Simone Braggio Anna Checchia 《Bioorganic & medicinal chemistry letters》2010,20(15):4566-4568
A direct and specific comparison of a trifluoromethyl group with the corresponding pentafluorosulfanyl group is made in terms of primary affinity and pharmacokinetic properties. 相似文献
976.
Kerstin Sander Yvonne von Coburg Jean-Claude Camelin Xavier Ligneau Oliver Rau Manfred Schubert-Zsilavecz Jean-Charles Schwartz Holger Stark 《Bioorganic & medicinal chemistry letters》2010,20(5):1581-1584
Antagonists of the human histamine H3 receptor (hH3R) often contain a second basic moiety, which is well known to boost affinity on this histamine receptor subtype. Here, we prepared compounds with acidic moieties of different pKa values to figure out that the hH3R tolerates these functionalities when added to a common pharmacophore blueprint. Depending on the acidic, electronic and steric features the designed ligands showed hH3R affinities in the nanomolar concentration range. Additionally, selected ligands were tested but failed as dual acting hH3R/hPPAR (human peroxisome proliferator-activated receptor) ligands. 相似文献
977.
Dato L Branduardi P Passolunghi S Cattaneo D Riboldi L Frascotti G Valli M Porro D 《FEMS yeast research》2010,10(7):894-908
The nonconventional yeast Zygosaccharomyces bailii has been proposed as a new host for biotechnological processes due to convenient properties such as its resistance to high sugar concentrations, relatively high temperatures and especially to acidic environments. We describe a series of new expression vectors specific for Z. bailii and the resulting improvements in production levels. By exploiting the sequences of the endogenous plasmid pSB2, 2microm-like multicopy vectors were obtained, giving a fivefold increase in production. A specific integrative vector was developed which led to 100% stability in the absence of selective pressure; a multiple-integration vector was constructed, based on an rRNA gene unit portion cloned and sequenced for this purpose, driving the insertion of up to 80 copies of the foreign construct. Moreover, we show the construction of the first stable auxotrophic mutant of Z. bailii, obtained by targeted gene deletion applied to ZbLEU2. The development of molecular tools for the Z. bailii manipulation has now reached a level that may be compatible with its industrial exploitation; the production of organic acids is a prominent field of application. 相似文献
978.
Yvonne Meyer-Lucht Celine Otten Thomas Püttker Renata Pardini Jean Paul Metzger Simone Sommer 《Conservation Genetics》2010,11(5):2001-2013
The adaptive potential of a species to a changing environment and in disease defence is primarily based on genetic variation.
Immune genes, such as genes of the major histocompatibility complex (MHC), may thereby be of particular importance. In marsupials,
however, there is very little knowledge about natural levels and functional importance of MHC polymorphism, despite their
key role in the mammalian evolution. In a previous study, we discovered remarkable differences in the MHC class II diversity
between two species of mouse opossums (Gracilinanus microtarsus, Marmosops incanus) from the Brazilian Atlantic forest, which is one of the most endangered hotspots for biodiversity conservation. Since the
main forces in generating MHC diversity are assumed to be pathogens, we investigated in this study gastrointestinal parasite
burden and functional associations between the individual MHC constitution and parasite load. We tested two contrasting scenarios,
which might explain differences in MHC diversity between species. We predicted that a species with low MHC diversity would
either be under relaxed selection pressure by low parasite diversity (‘Evolutionary equilibrium’ scenario), or there was a recent loss in MHC diversity leading to a lack of resistance alleles and increased parasite burden
(‘Unbalanced situation’ scenario). In both species it became apparent that the MHC class II is functionally important in defence against gastrointestinal
helminths, which was shown here for the first time in marsupials. On the population level, parasite diversity did not markedly
differ between the two host species. However, we did observe considerable differences in the individual parasite load (parasite
prevalence and infection intensity): while M. incanus revealed low MHC DAB diversity and high parasite load, G. microtarsus showed a tenfold higher population wide MHC DAB diversity and lower parasite burden. These results support the second scenario
of an unbalanced situation. 相似文献
979.
Simone Fulda 《Mitochondrion》2010,10(6):598-603
Mitochondria are key regulators of many forms of cell death and often altered in human malignancies. Since the inefficacy of established cancer therapies is, at least to a large extent, the result of oncogenic blockade of cell death pathways, compounds that directly affect mitochondrial functions are considered to present a promising alternative approach to eradicate chemotherapy-resistant cancer cells. Since mitochondria-targeted drugs can directly initiate mitochondrial perturbations independent of upstream signaling events, these agents may induce cell death and overcome drug resistance under circumstances, where conventional drugs fail to act because pathways upstream of mitochondria are frequently disrupted in cancer cells. A better understanding of the fundamental mechanisms that govern the complex processes of mitochondrial apoptosis is expected to open new perspectives for cancer drug development. Hopefully, this knowledge will eventually be translated into medical application for the treatment of human cancer. 相似文献
980.
Hans von Stedingk Per Rydberg Margareta Törnqvist 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2010,878(27):2483-2490
A rapid and sensitive method using liquid chromatography–tandem mass spectrometry (LC–MS/MS) for simultaneous determination of adducts from acrylamide, glycidamide and ethylene oxide to N-terminal valines in hemoglobin (Hb) was developed. This new procedure is based on the same principles as the N-alkyl Edman procedure for analysis of adducts from electrophilic agents to N-terminal valines in Hb. The N-substituted valines can be detached, enriched and measured selectively as thiohydantoins by the use of an Edman reagent, in this case fluorescein isothiocyanate (FITC). This procedure is denoted as the “adduct FIRE procedure” as the FITC reagent is used for measurement of adducts (R) formed from electrophilic compounds with a modified Edman procedure. In this study, fluorescein thiohydantoin (FTH) analytes of N-substituted valines from acrylamide, glycidamide and ethylene oxide, as well as their corresponding hepta- and tri-deuterium-substituted analogues, were synthesized. These analytes (n = 8) were then characterized by LC–MS/MS (ESI, positive ion mode) and obtained product ions were interpreted. A considerable work with optimization of the FIRE procedure™, resulted in a procedure in which low background levels of the studied adducts could be measured from 250 μL lyzed whole blood samples (human non-smokers). The analytes were enriched and purified with solid phase extraction columns and analyzed by LC–MS/MS with LOQ down to 1 pmol adduct/g Hb. Compared to other procedures for determination of N-terminal Hb adducts, the introduction of FITC has led to a simplified procedure, where whole blood also can be used, giving new opportunities and reduced hand on time with increased sample throughput. 相似文献