全文获取类型
收费全文 | 1318篇 |
免费 | 87篇 |
国内免费 | 47篇 |
出版年
2024年 | 5篇 |
2023年 | 32篇 |
2022年 | 36篇 |
2021年 | 46篇 |
2020年 | 32篇 |
2019年 | 40篇 |
2018年 | 39篇 |
2017年 | 24篇 |
2016年 | 28篇 |
2015年 | 36篇 |
2014年 | 68篇 |
2013年 | 65篇 |
2012年 | 52篇 |
2011年 | 83篇 |
2010年 | 69篇 |
2009年 | 61篇 |
2008年 | 69篇 |
2007年 | 121篇 |
2006年 | 72篇 |
2005年 | 59篇 |
2004年 | 52篇 |
2003年 | 46篇 |
2002年 | 33篇 |
2001年 | 28篇 |
2000年 | 18篇 |
1999年 | 18篇 |
1998年 | 21篇 |
1997年 | 12篇 |
1996年 | 18篇 |
1995年 | 14篇 |
1994年 | 8篇 |
1993年 | 9篇 |
1992年 | 9篇 |
1991年 | 10篇 |
1990年 | 8篇 |
1989年 | 4篇 |
1988年 | 4篇 |
1987年 | 4篇 |
1985年 | 10篇 |
1984年 | 11篇 |
1983年 | 11篇 |
1982年 | 12篇 |
1981年 | 6篇 |
1980年 | 6篇 |
1979年 | 7篇 |
1978年 | 10篇 |
1977年 | 6篇 |
1976年 | 5篇 |
1975年 | 5篇 |
1974年 | 5篇 |
排序方式: 共有1452条查询结果,搜索用时 15 毫秒
121.
This work presents an example of a cooperative system of truncated linear recursions in which the interaction between species
causes one of the species to have an anomalous spreading speed. By this we mean that this species spreads at a speed which
is strictly greater than its spreading speed in isolation from the other species and the speeds at which all the other species
actually spread. An ecological implication of this example is discussed in Sect. 5. Our example shows that the formula for
the fastest spreading speed given in Lemma 2.3 of our paper (Weinberger et al. in J Math Biol 45:183–218, 2002) is incorrect.
However, we find an extra hypothesis under which the formula for the faster spreading speed given in (Weinberger et al. in
J Math Biol 45:183–218, 2002) is valid. We also show that the hypotheses of all but one of the theorems of (Weinberger et al.
in J Math Biol 45:183–218, 2002) whose proofs rely on Lemma 2.3 imply this extra hypothesis, so that all but one of the theorems
of (Weinberger et al. in J Math Biol 45:183–218, 2002) and all the examples given there are valid as they stand. 相似文献
122.
We have investigated the tumour therapeutic efficacy of homologous and heterologous prime-boost vaccine strategies against the 5T4 oncofoetal antigen, using both replication defective adenovirus expressing human 5T4 (Ad5T4), and retrovirally transduced DC lines (DCh5T4) in a subcutaneous B16 melanoma model (B16h5T4). In naïve mice we show that all vaccine combinations tested can provide significant tumour growth delay. While DCh5T4/Adh5T4 sequence is the best prophylactic regimen (P > 0.0001), it does not demonstrate any therapeutic efficacy in mice with established tumours. In active therapy the Adh5T4/DCh5T4 vaccination sequence is the best treatment regimen (P = 0.0045). In active therapy, we demonstrate that B16h5T4 tumour growth per se induces Th2 polarising immune responses against 5T4, and the success of subsequent vaccination is dependant on altering the polarizing immune responses from Th2 to Th1. We show that the first immunization with Adh5T4 can condition the mice to induce 5T4 specific Th1 immune responses, which can be sustained and subsequently boosted with DCh5T4. In contrast immunisation with DCh5T4 augments Th2 immune responses, such that a subsequent vaccination with Adh5T4 cannot rescue tumour growth. In this case the depletion of CD25+ regulatory cells after tumour challenge but before immunization can restore therapeutic efficacy. This study highlights that all vaccine vectors are not equal at generating TAA immune responses; in tumour bearing mice the capability of different vaccines to activate the most appropriate anti-tumour immune responses is greatly altered compared to what is found in naïve mice. 相似文献
123.
Yamamoto K Choi M Abe D Shimizu M Yamada S 《The Journal of steroid biochemistry and molecular biology》2007,103(3-5):282-285
We achieved exhaustive alanine scanning mutational analysis of the amino acid residues lining the ligand binding pocket of the Vitamin D receptor to investigate the mechanism of the ligand recognition by the receptor. This is the first exhaustive analysis in the nuclear receptor superfamily. Our results demonstrated the role and importance of all the residues lining the ligand binding pocket. In addition, this analysis was found to indicate ligand-specific ligand-protein interactions, which have key importance in determining the transactivation potency of the individual ligands. Thus, the analysis using 1beta-methyl-1alpha,25-dihydroxyvitamin D(3) revealed the specific van der Waals interactions of 1beta-methyl group with the receptor. 相似文献
124.
25-Hydroxyvitamin D requirement for maintaining skeletal health utilising a Sprague-Dawley rat model
Anderson PH Sawyer RK May BK O'Loughlin PD Morris HA 《The Journal of steroid biochemistry and molecular biology》2007,103(3-5):592-595
To study the role of vitamin D to optimise bone architecture, we have developed an animal model to investigate the effects of frank vitamin D-deficiency as well as graded depletion of circulating 25-hydroxyvitamin D(3) (25D) levels on the skeleton. Rats fed on dietary vitamin D levels from 0 to 500 ng/day achieved diet-dependent circulating levels of 25D ranging from 11 to 115 nmol/L. Levels of serum 1,25-dihydroxyvitamin D(3) (1,25D) increased as dietary vitamin D increased between 0 and 200 ng/day at which point a maximum level was achieved and retained with higher vitamin D intakes. The renal levels of 25-hydroxyvitamin D-1alpha-hydroxylase (CYP27B1) mRNA were highest in animal groups fed on vitamin D between 0 and 300 ng/day. In contrast, renal 25-hydroxyvitamin D 24-hydroxylase (CYP24) mRNA levels increased as dietary vitamin D increased achieving maximum levels in animals receiving 500 ng vitamin D/day. This animal model of vitamin D depletion is suitable to provide invaluable information on the serum levels of 25D and dietary calcium intake necessary for optimal bone structure. Such information is essential for developing nutritional recommendations to reduce the incidence of osteoporotic hip fractures. 相似文献
125.
Zvi Schwartz Bryan F. Bell Liping Wang Ge Zhao Rene Olivares-Navarrete Barbara D. Boyan 《The Journal of steroid biochemistry and molecular biology》2007,103(3-5):606
Surface micron-scale and submicron scale features increase osteoblast differentiation and enhance responses of osteoblasts to 1,25-dihydroxyvitamin D3 [1α,25(OH)2D3]. β1 integrin expression is increased in osteoblasts grown on Ti substrates with rough microarchitecture, and it is regulated by 1α,25(OH)2D3 in a surface-dependent manner. To determine if β1 has a role in mediating osteoblast response, we silenced β1 expression in MG63 human osteoblast-like cells using small interfering RNA (siRNA). In addition, MG63 cells were treated with two different monoclonal antibodies to human β1 to block ligand binding. β1-silenced MG63 cells grown on a tissue culture plastic had reduced alkaline phosphatase activity and levels of osteocalcin, transforming growth factor β1, prostaglandin E2, and osteoprotegerin in comparison with control cells. Moreover, β1-silencing inhibited the effects of surface roughness on these parameters and partially inhibited effects of 1α,25(OH)2D3. Anti β1 antibodies decreased alkaline phosphatase but increase osteocalcin; effects of 1α,25(OH)2D3 on cell number and alkaline phosphatase were reduced and effects on osteocalcin were increased. These findings indicate that β1 plays a major and complex role in osteoblastic differentiation modulated by either surface microarchitecture or 1α,25(OH)2D3. The results also show that β1 mediates, in part, the synergistic effects of surface roughness and 1α,25(OH)2D3. 相似文献
126.
127.
Mutations in the helix termination motif of mouse type I IRS keratin genes impair the assembly of keratin intermediate filament 总被引:1,自引:0,他引:1
Tanaka S Miura I Yoshiki A Kato Y Yokoyama H Shinogi A Masuya H Wakana S Tamura M Shiroishi T 《Genomics》2007,90(6):703-711
Two classical mouse hair coat mutations, Rex (Re) and Rex wavy coat (Re(wc)), are linked to the type I inner root sheath (IRS) keratin genes of chromosome 11. An N-ethyl-N-nitrosourea-induced mutation, M100573, also maps close to the type I IRS keratin genes. In this study, we demonstrate that Re and M100573 mice bear mutations in the type I IRS gene Krt25; Re(wc) mice bear an additional mutation in the type I IRS gene Krt27. These three mutations are located in the helix termination motif of the 2B alpha-helical rod domain of a type I IRS keratin protein. Immunohistological analysis revealed abnormal foam-like immunoreactivity with an antibody raised to type II IRS keratin K71 in the IRS of Re/+ mice. These results suggest that the helix termination motif is essential for the proper assembly of types I and II IRS keratin protein complexes and the formation of keratin intermediate filaments. 相似文献
128.
129.
Molecular dissection of the interactions of an antitumor interleukin‐2‐derived mutein on a phage display‐based platform
下载免费PDF全文
![点击此处可从《Journal of molecular recognition : JMR》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Gertrudis Rojas Tania Carmenate Kalet Leon 《Journal of molecular recognition : JMR》2015,28(4):261-268
A mutein with stronger antitumor activity and lower toxicity than wild‐type human interleukin‐2 (IL‐2) has been recently described. The rationale behind its design was to reinforce the immunostimulatory potential through the introduction of four mutations that would selectively disrupt the interaction with the IL‐2 receptor alpha chain (thought to be critical for both IL‐2‐driven expansion of T regulatory cells and IL‐2‐mediated toxic effects). Despite the successful results of the mutein in several tumor models, characterization of its interactions was still to be performed. The current work, based on phage display of IL‐2‐derived variants, showed the individual contribution of each mutation to the impairment of alpha chain binding. A more sensitive assay, based on the ability of phage‐displayed IL‐2 variants to induce proliferation of the IL‐2‐dependent CTLL‐2 cell line, revealed differences between the mutated variants. The results validated the mutein design, highlighting the importance of the combined effects of the four mutations. The developed phage display‐based platform is robust and sensitive, allows a fast comparative evaluation of multiple variants, and could be broadly used to engineer IL‐2 and related cytokines, accelerating the development of cytokine‐derived therapeutics. Copyright © 2015 John Wiley & Sons, Ltd. 相似文献
130.
Dalil Hannani Marie Vétizou David Enot Sylvie Rusakiewicz Nathalie Chaput David Klatzmann Melanie Desbois Nicolas Jacquelot Nadège Vimond Salem Chouaib Christine Mateus James P Allison Antoni Ribas Jedd D Wolchok Jianda Yuan Philip Wong Michael Postow Andrzej Mackiewicz Jacek Mackiewicz Dirk Schadendorff Dirk Jaeger Alan J Korman Keith Bahjat Michele Maio Luana Calabro Michele WL Teng Mark J Smyth Alexander Eggermont Caroline Robert Guido Kroemer Laurence Zitvogel 《Cell research》2015,25(2):208-224
The cytotoxic T lymphocyte antigen-4 (CTLA-4)-blocking antibody ipilimumab induces immune-mediated long-term control of metastatic melanoma in a fraction of patients. Although ipilimumab undoubtedly exerts its therapeutic effects via immunostimulation, thus far clinically useful, immunologically relevant biomarkers that predict treatment efficiency have been elusive. Here, we show that neutralization of IL-2 or blocking the α and β subunits of the IL-2 receptor (CD25 and CD122, respectively) abolished the antitumor effects and the accompanying improvement of the ratio of intratumoral T effector versus regulatory cells (Tregs), which were otherwise induced by CTLA-4 blockade in preclinical mouse models. CTLA-4 blockade led to the reduction of a suppressive CD4+ T cell subset expressing Lag3, ICOS, IL-10 and Egr2 with a concomitant rise in IL-2-producing effector cells that lost FoxP3 expression and accumulated in regressing tumors. While recombinant IL-2 improved the therapeutic efficacy of CTLA-4 blockade, the decoy IL-2 receptor α (IL-2Rα, sCD25) inhibited the anticancer effects of CTLA-4 blockade. In 262 metastatic melanoma patients receiving ipilimumab, baseline serum concentrations of sCD25 represented an independent indicator of overall survival, with high levels predicting resistance to therapy. Altogether, these results unravel a role for IL-2 and IL-2 receptors in the anticancer activity of CTLA-4 blockade. Importantly, our study provides the first immunologically relevant biomarker, namely elevated serum sCD25, that predicts resistance to CTLA-4 blockade in patients with melanoma. 相似文献