全文获取类型
收费全文 | 2468篇 |
免费 | 147篇 |
出版年
2023年 | 15篇 |
2022年 | 22篇 |
2021年 | 76篇 |
2020年 | 73篇 |
2019年 | 61篇 |
2018年 | 96篇 |
2017年 | 82篇 |
2016年 | 115篇 |
2015年 | 176篇 |
2014年 | 181篇 |
2013年 | 185篇 |
2012年 | 218篇 |
2011年 | 231篇 |
2010年 | 153篇 |
2009年 | 125篇 |
2008年 | 122篇 |
2007年 | 116篇 |
2006年 | 118篇 |
2005年 | 86篇 |
2004年 | 71篇 |
2003年 | 74篇 |
2002年 | 56篇 |
2001年 | 25篇 |
2000年 | 11篇 |
1999年 | 14篇 |
1998年 | 13篇 |
1997年 | 8篇 |
1995年 | 7篇 |
1994年 | 9篇 |
1993年 | 3篇 |
1992年 | 8篇 |
1991年 | 8篇 |
1990年 | 4篇 |
1989年 | 7篇 |
1988年 | 7篇 |
1987年 | 5篇 |
1986年 | 2篇 |
1985年 | 3篇 |
1984年 | 3篇 |
1981年 | 3篇 |
1980年 | 5篇 |
1979年 | 2篇 |
1978年 | 3篇 |
1975年 | 1篇 |
1974年 | 2篇 |
1973年 | 1篇 |
1970年 | 1篇 |
1969年 | 1篇 |
1953年 | 1篇 |
1946年 | 2篇 |
排序方式: 共有2615条查询结果,搜索用时 156 毫秒
51.
Juliana Trevisan da Rocha Simone Pinton Bibiana Mozzaquatro Gai Cristina Wayne Nogueira 《Biological trace element research》2013,154(3):372-378
Parkinson’s disease (PD) patients, in addition to motor dysfunction, also present alterations in pain sensation. The present study characterized the antinociceptive effects of diphenyl diselenide ((PhSe)2) in a model of nociception induced by unilateral, intrastriatal 6-hydroxydopamine (6-OHDA) injection in rats. Male adult Wistar rats received 20 μg/3 μl of 6-OHDA (in saline solution containing 0.02 % of ascorbic acid) or 3 μl of vehicle into the right striatum (1.0 mm anterior, 3.0 mm lateral, and 5.0 mm ventral—with respect to the bregma). Thirty days after injection, rats received (PhSe)2 intragastrically at a dose of 10 mg/kg 1 h before behavioral tests (von Frey hairs, hot plate, tail immersion, formalin, and open field). Our results demonstrated that 6-OHDA injection to rats augmented the response frequency of von Frey hairs (VHF) stimulation, besides reducing the thermal withdrawal latency in the hot plate test. Importantly, the (PhSe)2 treatment decreased the mechanical allodynia measured by the response frequency of VHF stimulation and diminished the thermal nociception in the hot plate test in 6-OHDA-injected rats. In conclusion, these results revealed that a single oral administration of (PhSe)2 1 h prior to the accomplishment of the behavioral tests was effective to attenuate the increased mechanical and thermal nociception caused by a single intrastriatal 6-OHDA injection to rats. Furthermore, other clarifying studies are warranted to improve the evidence bases for future clinical use of (PhSe)2 as a new alternative therapy for the treatment of painful symptoms associated to PD. 相似文献
52.
Nívea?Dias Amoêdo Juan?Perez Valencia Mariana?Figueiredo Rodrigues Antonio Galina Franklin?David Rumjanek 《Bioscience reports》2013,33(6)
Tumour cells thrive in environments that would be hostile to their normal cell counterparts. Survival depends on the selection of cell lines that harbour modifications of both, gene regulation that shifts the balance between the cell cycle and apoptosis and those that involve the plasticity of the metabolic machinery. With regards to metabolism, the selected phenotypes usually display enhanced anaerobic glycolysis even in the presence of oxygen, the so-called Warburg effect, and anabolic pathways that provide precursors for the synthesis of lipids, proteins and DNA. The review will discuss the original ideas of Otto Warburg and how they initially led to the notion that mitochondria of tumour cells were dysfunctional. Data will be presented to show that not only the organelles are viable and respiring, but that they are key players in tumorigenesis and metastasis. Likewise, interconnecting pathways that stand out in the tumour phenotype and that require intact mitochondria such as glutaminolysis will be addressed. Furthermore, comments will be made as to how the peculiarities of the biochemistry of tumour cells renders them amenable to new forms of treatment by highlighting possible targets for inhibitors. In this respect, a case study describing the effect of a metabolite analogue, the alkylating agent 3BP (3-bromopyruvate), on glycolytic enzyme targets will be presented. 相似文献
53.
Julia Blümer Juliana Rey Leif Dehmelt Tomá? Mazel Yao-Wen Wu Philippe Bastiaens Roger S. Goody Aymelt Itzen 《The Journal of cell biology》2013,200(3):287-300
Eukaryotic cells critically depend on the correct regulation of intracellular vesicular trafficking to transport biological material. The Rab subfamily of small guanosine triphosphatases controls these processes by acting as a molecular on/off switch. To fulfill their function, active Rab proteins need to localize to intracellular membranes via posttranslationally attached geranylgeranyl lipids. Each member of the manifold Rab family localizes specifically to a distinct membrane, but it is unclear how this specific membrane recruitment is achieved. Here, we demonstrate that Rab-activating guanosine diphosphate/guanosine triphosphate exchange factors (GEFs) display the minimal targeting machinery for recruiting Rabs from the cytosol to the correct membrane using the Rab-GEF pairs Rab5A–Rabex-5, Rab1A-DrrA, and Rab8-Rabin8 as model systems. Specific mistargeting of Rabex-5/DrrA/Rabin8 to mitochondria led to catalytic recruitment of Rab5A/Rab1A/Rab8A in a time-dependent manner that required the catalytic activity of the GEF. Therefore, RabGEFs are major determinants for specific Rab membrane targeting. 相似文献
54.
Juliana L. França Marcelo R. Pinto Malson N. Lucena Daniela P. Garçon Wagner C. Valenti John C. McNamara Francisco A. Leone 《The Journal of membrane biology》2013,246(7):529-543
The stimulation by Mg2+, Na+, K+, NH4 +, and ATP of (Na+, K+)-ATPase activity in a gill microsomal fraction from the freshwater prawn Macrobrachium rosenbergii was examined. Immunofluorescence labeling revealed that the (Na+, K+)-ATPase α-subunit is distributed predominantly within the intralamellar septum, while Western blotting revealed a single α-subunit isoform of about 108 kDa M r. Under saturating Mg2+, Na+, and K+ concentrations, the enzyme hydrolyzed ATP, obeying cooperative kinetics with V M = 115.0 ± 2.3 U mg?1, K 0.5 = 0.10 ± 0.01 mmol L?1. Stimulation by Na+ (V M = 110.0 ± 3.3 U mg?1, K 0.5 = 1.30 ± 0.03 mmol L?1), Mg2+ (V M = 115.0 ± 4.6 U mg?1, K 0.5 = 0.96 ± 0.03 mmol L?1), NH4 + (V M = 141.0 ± 5.6 U mg?1, K 0.5 = 1.90 ± 0.04 mmol L?1), and K+ (V M = 120.0 ± 2.4 U mg?1, K M = 2.74 ± 0.08 mmol L?1) followed single saturation curves and, except for K+, exhibited site–site interaction kinetics. Ouabain inhibited ATPase activity by around 73 % with K I = 12.4 ± 1.3 mol L?1. Complementary inhibition studies suggest the presence of F0F1–, Na+-, or K+-ATPases, but not V(H+)- or Ca2+-ATPases, in the gill microsomal preparation. K+ and NH4 + synergistically stimulated enzyme activity (≈25 %), suggesting that these ions bind to different sites on the molecule. We propose a mechanism for the stimulation by both NH4 +, and K+ of the gill enzyme. 相似文献
55.
Raquel Fonseca-Maldonado Davi Serradella Vieira Juliana Sanchez Alponti Eric Bonneil Pierre Thibault Richard John Ward 《The Journal of biological chemistry》2013,288(35):25522-25534
Protein glycosylation is a common post-translational modification, the effect of which on protein conformational and stability is incompletely understood. Here we have investigated the effects of glycosylation on the thermostability of Bacillus subtilis xylanase A (XynA) expressed in Pichia pastoris. Intact mass analysis of the heterologous wild-type XynA revealed two, three, or four Hex8–16GlcNAc2 modifications involving asparagine residues at positions 20, 25, 141, and 181. Molecular dynamics (MD) simulations of the XynA modified with various combinations of branched Hex9GlcNAc2 at these positions indicated a significant contribution from protein-glycan interactions to the overall energy of the glycoproteins. The effect of glycan content and glycosylation position on protein stability was evaluated by combinatorial mutagenesis of all six potential N-glycosylation sites. The majority of glycosylated enzymes expressed in P. pastoris presented increased thermostability in comparison with their unglycosylated counterparts expressed in Escherichia coli. Steric effects of multiple glycosylation events were apparent, and glycosylation position rather than the number of glycosylation events determined increases in thermostability. The MD simulations also indicated that clustered glycan chains tended to favor less stabilizing glycan-glycan interactions, whereas more dispersed glycosylation patterns favored stabilizing protein-glycan interactions. 相似文献
56.
Gabriela Turk Yanina Ghiglione Juliana Falivene María Eugenia Socias Natalia Laufer Romina Soledad Coloccini Ana María Rodriguez María Julia Ruiz María ángeles Pando Luis David Giavedoni Pedro Cahn Omar Sued Horacio Salomon María Magdalena Gherardi 《Journal of virology》2013,87(13):7445-7462
The important role of the CD8+ T-cell response on HIV control is well established. Moreover, the acute phase of infection represents a proper scenario to delineate the antiviral cellular functions that best correlate with control. Here, multiple functional aspects (specificity, ex vivo viral inhibitory activity [VIA] and polyfunctionality) of the HIV-specific CD8+ T-cell subset arising early after infection, and their association with disease progression markers, were examined. Blood samples from 44 subjects recruited within 6 months from infection (primary HIV infection [PHI] group), 16 chronically infected subjects, 11 elite controllers (EC), and 10 healthy donors were obtained. Results indicated that, although Nef dominated the anti-HIV response during acute/early infection, a higher proportion of early anti-Gag T cells correlated with delayed progression. Polyfunctional HIV-specific CD8+ T cells were detected at early time points but did not associate with virus control. Conversely, higher CD4+ T-cell set points were observed in PHI subjects with higher HIV-specific CD8+ T-cell VIA at baseline. Importantly, VIA levels correlated with the magnitude of the anti-Gag cellular response. The advantage of Gag-specific cells may result from their enhanced ability to mediate lysis of infected cells (evidenced by a higher capacity to degranulate and to mediate VIA) and to simultaneously produce IFN-γ. Finally, Gag immunodominance was associated with elevated plasma levels of interleukin 2 (IL-2) and macrophage inflammatory protein 1β (MIP-1β). All together, this study underscores the importance of CD8+ T-cell specificity in the improved control of disease progression, which was related to the capacity of Gag-specific cells to mediate both lytic and nonlytic antiviral mechanisms at early time points postinfection. 相似文献
57.
Mark J. Valencia 《Ocean Development & International Law》2013,44(4):431-445
Abstract Vietnam claims a 12‐nautical‐mile territorial sea, a 12‐nautical‐mile contiguous zone, a continental shelf, a 200‐nautical‐mile exclusive economic zone (EEZ), historical waters encompassing most of the Gulf of Tonkin, and much of the Spratly Islands area. Vietnam's claimed boundaries overlap with those of China, Indonesia, Malaysia, Thailand, and Cambodia, and, in the Spratlys, with those of China, Taiwan, the Philippines, and Malaysia. The area claimed contains significant fisheries resources, and Vietnam has stipulated provisions for access to fish by foreign vessels. Yet issues pertaining to shared and migratory stocks remain to be addressed. Similarly, Vietnam has established regulations governing foreign ships navigating in Vietnamese‐claimed waters, including those designed to protect the environment. But some of these provisions do not conform to the provisions of the 1982 U.N. Convention on the Law of the Sea (UNCLOS). This article reviews Vietnam ‘s fisheries and navigation policies and issues. 相似文献
58.
Jaqueline Raymondi Silva Larissa Campos de Medeiros Vinícius Pinho dos Reis Juliana Helena Chávez Thiago Demarchi Munhoz Gustavo Puia Borges Otavio Augusto Brioschi Soares Carlos Henrique Coelho de Campos Rosangela Zacarias Machado Cristiane Divan Baldani Maria Luana Cristiny Rodrigues Silva Joice Lara Maia Faria Edson Elias da Silva Luiz Tadeu Moraes Figueiredo 《Memórias do Instituto Oswaldo Cruz》2013,108(7):921-923
Since the emergence of West Nile virus (WNV) in North America in 1999, there have been several reports of WNV activity in Central and South American countries. To detect WNV in Brazil, we performed a serological survey of horses from different regions of Brazil using recombinant peptides from domain III of WNV. Positive samples were validated with the neutralisation test. Our results showed that of 79 ELISA-positive horses, nine expressed WNV-specific neutralising antibodies. Eight of the infected horses were from the state of Mato Grosso do Sul and one was from the state of Paraíba. Our results provide additional evidence for the emergence of WNV in Brazil and for its circulation in multiple regions of the country. 相似文献
59.
60.
Youneng Tang Aura Ontiveros‐Valencia Liang Feng Chen Zhou Rosa Krajmalnik‐Brown Bruce E. Rittmann 《Biotechnology and bioengineering》2013,110(3):763-772
This work presents a multispecies biofilm model that describes the co‐existence of nitrate‐ and sulfate‐reducing bacteria in the H2‐based membrane biofilm reactor (MBfR). The new model adapts the framework of a biofilm model for simultaneous nitrate and perchlorate removal by considering the unique metabolic and physiological characteristics of autotrophic sulfate‐reducing bacteria that use H2 as their electron donor. To evaluate the model, the simulated effluent H2, UAP (substrate‐utilization‐associated products), and BAP (biomass‐associated products) concentrations are compared to experimental results, and the simulated biomass distributions are compared to real‐time quantitative polymerase chain reaction (qPCR) data in the experiments for parameter optimization. Model outputs and experimental results match for all major trends and explain when sulfate reduction does or does not occur in parallel with denitrification. The onset of sulfate reduction occurs only when the nitrate concentration at the fiber's outer surface is low enough so that the growth rate of the denitrifying bacteria is equal to that of the sulfate‐reducing bacteria. An example shows how to use the model to design an MBfR that achieves satisfactory nitrate reduction, but suppresses sulfate reduction. Biotechnol. Bioeng. 2013; 110: 763–772. © 2012 Wiley Periodicals, Inc. 相似文献