全文获取类型
收费全文 | 1731篇 |
免费 | 160篇 |
国内免费 | 4篇 |
专业分类
1895篇 |
出版年
2023年 | 5篇 |
2022年 | 11篇 |
2021年 | 34篇 |
2020年 | 11篇 |
2019年 | 15篇 |
2018年 | 33篇 |
2017年 | 24篇 |
2016年 | 42篇 |
2015年 | 72篇 |
2014年 | 72篇 |
2013年 | 130篇 |
2012年 | 125篇 |
2011年 | 105篇 |
2010年 | 78篇 |
2009年 | 82篇 |
2008年 | 104篇 |
2007年 | 122篇 |
2006年 | 100篇 |
2005年 | 112篇 |
2004年 | 97篇 |
2003年 | 87篇 |
2002年 | 90篇 |
2001年 | 14篇 |
2000年 | 9篇 |
1999年 | 18篇 |
1998年 | 19篇 |
1997年 | 21篇 |
1996年 | 6篇 |
1995年 | 14篇 |
1994年 | 19篇 |
1993年 | 13篇 |
1992年 | 10篇 |
1991年 | 11篇 |
1990年 | 21篇 |
1989年 | 22篇 |
1988年 | 12篇 |
1987年 | 11篇 |
1986年 | 6篇 |
1985年 | 11篇 |
1984年 | 10篇 |
1983年 | 11篇 |
1982年 | 6篇 |
1981年 | 7篇 |
1980年 | 7篇 |
1979年 | 5篇 |
1978年 | 5篇 |
1977年 | 6篇 |
1976年 | 6篇 |
1974年 | 8篇 |
1968年 | 4篇 |
排序方式: 共有1895条查询结果,搜索用时 15 毫秒
101.
Jeffrey D. Carter Estrella G. Gonzales Xi Huang Adam N. Smith Ian Mitchelle S. de Vera Peter W. D’Amore James R. Rocca Maureen M. Goodenow Ben M. Dunn Gail E. Fanucci 《FEBS letters》2014
Conformational sampling of pre- and post-therapy subtype B HIV-1 protease sequences derived from a pediatric subject infected via maternal transmission with HIV-1 were characterized by double electron–electron resonance spectroscopy. The conformational ensemble of the PRE construct resembles native-like inhibitor bound states. In contrast, the POST construct, which contains accumulated drug-pressure selected mutations, has a predominantly semi-open conformational ensemble, with increased populations of open-like states. The single point mutant L63P, which is contained in PRE and POST, has decreased dynamics, particularly in the flap region, and also displays a closed-like conformation of inhibitor-bound states. These findings support our hypothesis that secondary mutations accumulate in HIV-1 protease to shift conformational sampling to stabilize open-like conformations, while maintaining the predominant semi-open conformation for activity. 相似文献
102.
Elham Sadeqzadeh Charles E. de Bock Maureen R. O’Donnell Anna Timofeeva Gordon F. Burns Rick F. Thorne 《FEBS letters》2014
The interaction between the Drosophila cadherins fat and dachsous is regulated by phosphorylation of their respective ectodomains, a process catalysed by the atypical kinase four-jointed. Given that many signalling functions are conserved between Drosophila and vertebrate Fat cadherins, we sought to determine whether ectodomain phosphorylation is conserved in FAT1 cadherin, and also whether FJX1, the vertebrate orthologue of four-jointed, was involved in such phosphorylation events. Potential Fj consensus phosphorylation motifs were identified in FAT1 and biochemical experiments revealed the presence of phosphoserine and phosphothreonine residues in its extracellular domain. However, silencing FJX1 did not influence the levels of FAT1 ectodomain phosphorylation, indicating that other mechanisms are likely responsible. 相似文献
103.
Robert Fitzgerald Breann DeSantiago Danielle Y. Lee Guangdong Yang Jae Yeon Kim D. Brian Foster Yee Chan-Li Maureen R. Horton Reynold A. Panettieri Rui Wang Steven S. An 《Biochemical and biophysical research communications》2014
Here we explored the impact of hydrogen sulfide (H2S) on biophysical properties of the primary human airway smooth muscle (ASM)–the end effector of acute airway narrowing in asthma. Using magnetic twisting cytometry (MTC), we measured dynamic changes in the stiffness of isolated ASM, at the single-cell level, in response to varying doses of GYY4137 (1–10 mM). GYY4137 slowly released appreciable levels of H2S in the range of 10–275 μM, and H2S released was long lived. In isolated human ASM cells, GYY4137 acutely decreased stiffness (i.e. an indicator of the single-cell relaxation) in a dose-dependent fashion, and stiffness decreases were sustained in culture for 24 h. Human ASM cells showed protein expressions of cystathionine-γ-lyase (CSE; a H2S synthesizing enzyme) and ATP-sensitive potassium (KATP) channels. The KATP channel opener pinacidil effectively relaxed isolated ASM cells. In addition, pinacidil-induced ASM relaxation was completely inhibited by the treatment of cells with the KATP channel blocker glibenclamide. Glibenclamide also markedly attenuated GYY4137-mediated relaxation of isolated human ASM cells. Taken together, our findings demonstrate that H2S causes the relaxation of human ASM and implicate as well the role for sarcolemmal KATP channels. Finally, given that ASM cells express intrinsic enzymatic machinery of generating H2S, we suggest thereby this class of gasotransmitter can be further exploited for potential therapy against obstructive lung disease. 相似文献
104.
Xuefei Tan Richland W. Tester Gregory R. Luedtke Sarvajit Chakravarty Babu J. Mavunkel John J. Perumattam Qing Lu Imad Nashashibi Joon Jung Jie Hu Albert Liclican Ramona Almirez Jocelyn Tabora Vinh Tran Maureen Laney Daniel E. Levy Sundeep Dugar 《Bioorganic & medicinal chemistry letters》2010,20(3):828-831
Derivatives of the 4-fluorobenzyl dimethylpiperazine-indole class of p38α MAP kinase inhibitors are described. Biological evaluation of these compounds focused on maintaining activity while improving pharmacokinetic (PK) properties. Improved properties were observed for structures bearing substitutions on the benzylic methylene. 相似文献
105.
Francesca Avogadri Taha Merghoub Maureen F. Maughan Daniel Hirschhorn-Cymerman John Morris Erika Ritter Robert Olmsted Alan N. Houghton Jedd D. Wolchok 《PloS one》2010,5(9)
Background
Malignant melanoma is the deadliest form of skin cancer and is refractory to conventional chemotherapy and radiotherapy. Therefore alternative approaches to treat this disease, such as immunotherapy, are needed. Melanoma vaccine design has mainly focused on targeting CD8+ T cells. Activation of effector CD8+ T cells has been achieved in patients, but provided limited clinical benefit, due to immune-escape mechanisms established by advanced tumors. We have previously shown that alphavirus-based virus-like replicon particles (VRP) simultaneously activate strong cellular and humoral immunity against the weakly immunogenic melanoma differentiation antigen (MDA) tyrosinase. Here we further investigate the antitumor effect and the immune mechanisms of VRP encoding different MDAs.Methodology/Principal Findings
VRP encoding different MDAs were screened for their ability to prevent the growth of the B16 mouse transplantable melanoma. The immunologic mechanisms of efficacy were investigated for the most effective vaccine identified, focusing on CD8+ T cells and humoral responses. To this end, ex vivo immune assays and transgenic mice lacking specific immune effector functions were used. The studies identified a potent therapeutic VRP vaccine, encoding tyrosinase related protein 2 (TRP-2), which provided a durable anti-tumor effect. The efficacy of VRP-TRP2 relies on a novel immune mechanism of action requiring the activation of both IgG and CD8+ T cell effector responses, and depends on signaling through activating Fcγ receptors.Conclusions/Significance
This study identifies a VRP-based vaccine able to elicit humoral immunity against TRP-2, which plays a role in melanoma immunotherapy and synergizes with tumor-specific CD8+ T cell responses. These findings will aid in the rational design of future immunotherapy clinical trials. 相似文献106.
Mazz Marry Keith Roberts S. Juliet Jopson I. Max Huxham Michael C. Jarvis Julia Corsar Eoin Robertson Maureen C. McCann 《Physiologia plantarum》2006,126(2):243-256
Multicellular plants depend for their integrity on effective adhesion between their component cells. This adhesion depends upon various cross-links; ionic, covalent or weak interactions between the macromolecules of the adjacent cell walls. In sugar-beet ( Beta vulgaris L. Aztec) root parenchyma, cell-cell adhesion is disrupted by successive extractions with a calcium-chelating agent (imidazole) and a de-esterifying agent (sodium carbonate) but not by the calcium-chelating agent or the de-esterifying agent alone. Cell-cell adhesion in sugar-beet parenchyma thus depends upon both ester and Ca2+ cross-linked polymers. Pectic polysaccharides are removed by these treatments. Both parallel-electron energy-loss spectroscopy (PEELS) and Image-EELS show that calcium-binding sites are removed from the wall by imidazole. Using a monoclonal antibody that recognizes a relatively unesterified epitope of homogalacturonan, JIM 5, we show that a subset of JIM 5-reactive antigens remain in the middle lamella after Ca2+ chelation and that this subset is removed by cold (4° C) Na2 CO3 -induced breakage of ester bonds. Fourier transform infrared, nuclear magnetic resonance, and spectrophotometric assays show that methyl and feruloyl esters are removed from the wall by Na2 CO3 but acetyl esters remain. Sodium carbonate extraction at 20° C removes cell wall autofluorescence and most of the feruloylated moieties from the wall. We propose that the chelator-resistant subset of ester-linked JIM 5-reactive pectins are important for cell-cell adhesion. 相似文献
107.
108.
Alastair J. King Marc R. Arnone Maureen R. Bleam Katherine G. Moss Jingsong Yang Kelly E. Fedorowicz Kimberly N. Smitheman Joseph A. Erhardt Angela Hughes-Earle Laurie S. Kane-Carson Robert H. Sinnamon Hongwei Qi Tara R. Rheault David E. Uehling Sylvie G. Laquerre 《PloS one》2013,8(7)
Mitogen-Activated Protein Kinase (MAPK) pathway activation has been implicated in many types of human cancer. BRAF mutations that constitutively activate MAPK signalling and bypass the need for upstream stimuli occur with high prevalence in melanoma, colorectal carcinoma, ovarian cancer, papillary thyroid carcinoma, and cholangiocarcinoma. In this report we characterize the novel, potent, and selective BRAF inhibitor, dabrafenib (GSK2118436). Cellular inhibition of BRAFV600E kinase activity by dabrafenib resulted in decreased MEK and ERK phosphorylation and inhibition of cell proliferation through an initial G1 cell cycle arrest, followed by cell death. In a BRAFV600E-containing xenograft model of human melanoma, orally administered dabrafenib inhibited ERK activation, downregulated Ki67, and upregulated p27, leading to tumor growth inhibition. However, as reported for other BRAF inhibitors, dabrafenib also induced MAPK pathway activation in wild-type BRAF cells through CRAF (RAF1) signalling, potentially explaining the squamous cell carcinomas and keratoacanthomas arising in patients treated with BRAF inhibitors. In addressing this issue, we showed that concomitant administration of BRAF and MEK inhibitors abrogated paradoxical BRAF inhibitor-induced MAPK signalling in cells, reduced the occurrence of skin lesions in rats, and enhanced the inhibition of human tumor xenograft growth in mouse models. Taken together, our findings offer preclinical proof of concept for dabrafenib as a specific and highly efficacious BRAF inhibitor and provide evidence for its potential clinical benefits when used in combination with a MEK inhibitor. 相似文献
109.
The Mouse GalR2 Galanin Receptor: Genomic Organization, cDNA Cloning, and Functional Characterization 总被引:1,自引:1,他引:1
Ling Pang Tanaz Hashemi Hu-Jung J. Lee Maureen Maguire Michael P. Graziano Marvin Bayne Brian Hawes Gwendolyn Wong Suke Wang 《Journal of neurochemistry》1998,71(6):2252-2259
Abstract: The diverse physiological actions of galanin are thought to be mediated through activation of galanin receptors (GalRs). We report the genomic and cDNA cloning of a mouse GalR that possesses a genomic structure distinct from that of GalR1 and encodes a functional galanin receptor. The mouse GalR gene consists of two exons separated by a single intron within the protein-coding region. The splicing site for the intron is located at the junction between the third transmembrane domain and the second intracellular loop. The cDNA encodes a 370-amino acid putative G protein-coupled receptor that is markedly different from human GalR1 and rat GalR3 (38 and 57%) but shares high homology with rat GalR2 (94%). In binding studies utilizing membranes from COS-7 cells transfected with mouse GalR2 cDNA, the receptor displayed high affinity ( K D = 0.47 n M ) and saturable binding with 125 I-galanin ( B max = 670 fmol/mg). The radioligand binding can be displaced by galanin and its analogues in a rank order: galanin ⋍ M40 ⋍ M15 ⋍ M35 ⋍ C7 ⋍ galanin (2–29) ⋍ galanin (1–16) ≫ galanin (10–29) ⋍ galanin (3–29), which resembles the pharmacological profile of the rat GalR2. Receptor activation by galanin in COS-7 cells stimulated phosphoinositide metabolism, which was not reversed by pertussis toxin. Thus, the galanin receptor encoded in the cloned mouse GalR gene is the type 2 galanin receptor and is active in both ligand binding and signaling assays. 相似文献
110.
Daniela Bellicoso Maureen Trudeau Margaret I. Fitch Martin R. Ralph 《Chronobiology international》2017,34(6):808-818
Primary caregivers for victims of chronic illness and or trauma experience both positive and negative emotional consequences. These are broadly classified as compassion satisfaction (CS) and compassion fatigue (CF). Because one of the components of CF, burnout, varies with chronotype and sleep quality, we assessed the influence of chronobiological features on the broader constructs of CS and CF. Responses from primary ambulatory care oncology staff working dayshifts were assessed for potential relationships of chronotype and sleep quality with CS and CF using the professional quality of life scale. These were analyzed further in a multivariate model that included personality and job satisfaction as cofactors. We found that sleep quality was a key contributor to CS development and CF reduction. Morningness was positively linked to CS, but the univariate association was masked in the multivariate model. Job satisfaction (contingent rewards, nature of work and operating procedures) heavily influenced CS and CF development. Agreeableness and openness showed positive correlations with CS and negative with burnout, while emotional stability was linked to reduced CF. While job satisfaction and personality predictably played roles in the development of CS and CF, sleep quality and chronotype contributed significantly to benefits and negative consequences of providing care. 相似文献