全文获取类型
收费全文 | 649篇 |
免费 | 39篇 |
出版年
2022年 | 6篇 |
2021年 | 8篇 |
2020年 | 2篇 |
2019年 | 8篇 |
2018年 | 16篇 |
2017年 | 10篇 |
2016年 | 15篇 |
2015年 | 37篇 |
2014年 | 26篇 |
2013年 | 41篇 |
2012年 | 53篇 |
2011年 | 46篇 |
2010年 | 36篇 |
2009年 | 27篇 |
2008年 | 40篇 |
2007年 | 54篇 |
2006年 | 40篇 |
2005年 | 37篇 |
2004年 | 28篇 |
2003年 | 30篇 |
2002年 | 29篇 |
2001年 | 5篇 |
2000年 | 2篇 |
1999年 | 6篇 |
1998年 | 7篇 |
1997年 | 2篇 |
1996年 | 9篇 |
1995年 | 5篇 |
1994年 | 6篇 |
1993年 | 6篇 |
1992年 | 3篇 |
1991年 | 4篇 |
1990年 | 3篇 |
1988年 | 1篇 |
1987年 | 1篇 |
1986年 | 1篇 |
1985年 | 2篇 |
1984年 | 2篇 |
1983年 | 4篇 |
1981年 | 3篇 |
1980年 | 1篇 |
1978年 | 1篇 |
1977年 | 2篇 |
1976年 | 1篇 |
1973年 | 1篇 |
1971年 | 1篇 |
1966年 | 1篇 |
1940年 | 1篇 |
1939年 | 6篇 |
1938年 | 10篇 |
排序方式: 共有688条查询结果,搜索用时 390 毫秒
51.
Theis JF Irene C Dershowitz A Brost RL Tobin ML di Sanzo FM Wang JY Boone C Newlon CS 《PLoS genetics》2010,6(12):e1001227
In eukaryotic chromosomes, DNA replication initiates at multiple origins. Large inter-origin gaps arise when several adjacent origins fail to fire. Little is known about how cells cope with this situation. We created a derivative of Saccharomyces cerevisiae chromosome III lacking all efficient origins, the 5ORIΔ-ΔR fragment, as a model for chromosomes with large inter-origin gaps. We used this construct in a modified synthetic genetic array screen to identify genes whose products facilitate replication of long inter-origin gaps. Genes identified are enriched in components of the DNA damage and replication stress signaling pathways. Mrc1p is activated by replication stress and mediates transduction of the replication stress signal to downstream proteins; however, the response-defective mrc1(AQ) allele did not affect 5ORIΔ-ΔR fragment maintenance, indicating that this pathway does not contribute to its stability. Deletions of genes encoding the DNA-damage-specific mediator, Rad9p, and several components shared between the two signaling pathways preferentially destabilized the 5ORIΔ-ΔR fragment, implicating the DNA damage response pathway in its maintenance. We found unexpected differences between contributions of components of the DNA damage response pathway to maintenance of ORIΔ chromosome derivatives and their contributions to DNA repair. Of the effector kinases encoded by RAD53 and CHK1, Chk1p appears to be more important in wild-type cells for reducing chromosomal instability caused by origin depletion, while Rad53p becomes important in the absence of Chk1p. In contrast, RAD53 plays a more important role than CHK1 in cell survival and replication fork stability following treatment with DNA damaging agents and hydroxyurea. Maintenance of ORIΔ chromosomes does not depend on homologous recombination. These observations suggest that a DNA-damage-independent mechanism enhances ORIΔ chromosome stability. Thus, components of the DNA damage response pathway contribute to genome stability, not simply by detecting and responding to DNA template damage, but also by facilitating replication of large inter-origin gaps. 相似文献
52.
Giovanni Esposito Maria R Amoroso Carmela Bergamasco Elia Di Schiavi Paolo Bazzicalupo 《BMC biology》2010,8(1):138
Background
Polymodal, nociceptive sensory neurons are key cellular elements of the way animals sense aversive and painful stimuli. In Caenorhabditis elegans, the polymodal nociceptive ASH sensory neurons detect aversive stimuli and release glutamate to generate avoidance responses. They are thus useful models for the nociceptive neurons of mammals. While several molecules affecting signal generation and transduction in ASH have been identified, less is known about transmission of the signal from ASH to downstream neurons and about the molecules involved in its modulation. 相似文献53.
Villani F Casaburi A Pennacchia C Filosa L Russo F Ercolini D 《Applied and environmental microbiology》2007,73(17):5453-5463
The microbial ecology of "soppressata of Vallo di Diano," a traditional dry fermented sausage from southern Italy, was studied by using both culture-dependent and culture-independent approaches. The ripened fermented sausages were characterized by high microbial loads of both staphylococci and lactobacilli. Using PCR-denaturing gradient gel electrophoresis (PCR-DGGE) targeting the variable V3 and V1 regions of the 16S rRNA gene and direct DNA sequencing, it was possible to identify Staphylococcus xylosus, S. succinus, and S. equorum among the staphylococci and Lactobacillus sakei and L. curvatus within the lactobacilli. Moreover, Debaryomyces hansenii was the main yeast species found by targeting the yeast 26S rRNA gene by PCR-DGGE. Selected strains of S. xylosus, L. sakei, and L. curvatus were characterized for their technological properties in the ripening conditions of the fermented sausages so as to select an autochthonous starter formulation. The selection included the determination of nitrate reductase, lipolytic, and antioxidant activity and proteolysis with myofibrillar and sarcoplasmic protein fractions. Such properties were evaluated in both in vitro and in situ assays; the latter were performed by using each strain as a starter in the laboratory-scale manufacture of soppressata of Vallo di Diano and by monitoring the microbiological and chemical changes at the end of ripening. The results show differences between the in vitro and in situ selection results and indicate that in situ evaluation of the technological performance of specific strains is better suited to selecting autochthonous starter cultures for fermented-meat products than in vitro evaluation. 相似文献
54.
Filomena de Nigris Maria Luisa Balestrieri Sharon Williams-Ignarro Francesco P D'Armiento Carmela Fiorito Louis J Ignarro Claudio Napoli 《Nitric oxide》2007,17(1):50-54
Metabolic syndrome includes most widely distributed clinical conditions such as obesity, hypertension, dislipidemia, and diabetes. Pomegranate fruit extract (PFE), rich in polyphenolic antioxidants, reduces the expression of oxidation-sensitive genes at the sites of perturbed shear-stress. The aim of this study was to evaluate the effect of PFE in comparison to regular pomegranate juice (PJ) and seed oil on the biological actions of nitric oxide (NO) and the arterial function in obese Zucker rats, a model of metabolic syndrome. Our results indicated that supplementation with PFE or PJ significantly decreased the expression of vascular inflammation markers, thrombospondin (TSP), and cytokine TGFbeta1 (P<0.05), whereas seed oil supplementation had a significant effect only on TSP-1 expression (P <0.05). Plasma nitrate and nitrite (NO(x)) levels were significantly increased by PFE and PJ (P<0.05). Furthermore, the effect of PFE in increasing endothelial NO synthase (eNOS) expression was comparable to that of PJ. These data highlight possible clinical applications of PFE in metabolic syndrome. 相似文献
55.
Catania MV D'Antoni S Bonaccorso CM Aronica E Bear MF Nicoletti F 《Molecular neurobiology》2007,35(3):298-307
Group I metabotropic glutamate receptors (mGlu1 and mGlu5) are coupled to polyphosphoinositide hydrolysis and are involved
in activity-dependent forms of synaptic plasticity, both during development and in the adult life. Group I mGlu receptors
can also regulate proliferation, differentiation, and survival of neural stem/progenitor cells, which further support their
role in brain development. An exaggerated response to activation of mGlu5 receptors may underlie synaptic dysfunction in Fragile
X syndrome, the most common inherited form of mental retardation. In addition, group I mGlu receptors are overexpressed in
dysplastic neurons of focal cortical dysplasia and hemimegaloencephaly, which are disorders of cortical development associated
with chronic epilepsy. Drugs that block the activity of group I mGlu receptors (in particular, mGlu5 receptors) are potentially
helpful for the treatment of Fragile X syndrome and perhaps other neurodevelopmental disorders. 相似文献
56.
57.
Background
The evidence on the use of the oral dimethyl-fumarate after the discontinuation of treatment with natalizumab in people with Multiple Sclerosis is still little. Natalizumab discontinuation may induce the recurrence or rebound of the clinical and neuroradiological disease activity. Currently no therapeutic approach has been established to abolish disease reactivation and rebound after natalizumab interruption.Case Presentation
We describe a case of a 21-year-old woman affected from a highly active relapsing-remitting Multiple Sclerosis who developed a clinical and radiological rebound 5 months after the last infusion of natalizumab, while she was being treated with dimethyl-fumarate 240 mg twice daily. She had received a bridge “therapy” with Cyclophosphamide before staring dimethyl-fumarate.Conclusion
We report on this case to stimulate further research to establish whether new current and future drugs available for multiple sclerosis are able to halt the disease rebound after the natalizumab interruption.58.
Simard D Leblanc Y Berthelette C Zaghdane MH Molinaro C Wang Z Gallant M Lau S Thao T Hamel M Stocco R Sawyer N Sillaots S Gervais F Houle R Lévesque JF 《Bioorganic & medicinal chemistry letters》2011,21(2):841-845
A new class of 7-azaindole analogs of MK-7246 as potent and selective CRTH2 antagonists is reported. The SAR leading to the identification of the optimal azaindole regioisomer as well as the pharmacokinetics and off-target activities of the most potent antagonists are disclosed. 相似文献
59.
Zaghdane H Boyd M Colucci J Simard D Berthelette C Leblanc Y Wang Z Houle R Lévesque JF Molinaro C Hamel M Stocco R Sawyer N Sillaots S Gervais F Gallant M 《Bioorganic & medicinal chemistry letters》2011,21(11):3471-3474
A new series of indole amide acting as hCRTH2 receptor ligands had been explored and are described herein. Several amide derivatives displaying low nanomolar activity in hCRTH2 binding and whole blood assays were identified. They were found to behave as a full antagonists, exhibiting good selectivity over related prostaglandin receptors. Also, prototypical compounds in this novel series which displayed acceptable CYP profiles and were orally bioavailable in rats were identified. 相似文献
60.
Burchak ON Pihive EL Maigre L Guinchard X Bouhours P Jolivalt C Schneider D Maurin M Giglione C Meinnel T Paris JM Denis JN 《Bioorganic & medicinal chemistry》2011,19(10):3204-3215
A collection of 3-substituted indole derivatives was prepared using nucleophilic addition of indoles to nitrones. The compounds were then tested for their antibacterial activity against almost thirty bacterial strains representative of common human pathogens. Two types of indolic molecules inhibit the growth of Staphylococcus aureus, including MRSA and VISA strains, with MIC values ranging from 8 to 16 mg/L. 相似文献