全文获取类型
收费全文 | 668篇 |
免费 | 36篇 |
专业分类
704篇 |
出版年
2023年 | 1篇 |
2022年 | 10篇 |
2021年 | 17篇 |
2020年 | 7篇 |
2019年 | 8篇 |
2018年 | 21篇 |
2017年 | 13篇 |
2016年 | 23篇 |
2015年 | 30篇 |
2014年 | 41篇 |
2013年 | 30篇 |
2012年 | 57篇 |
2011年 | 65篇 |
2010年 | 36篇 |
2009年 | 39篇 |
2008年 | 41篇 |
2007年 | 48篇 |
2006年 | 37篇 |
2005年 | 32篇 |
2004年 | 41篇 |
2003年 | 33篇 |
2002年 | 28篇 |
2001年 | 9篇 |
2000年 | 3篇 |
1999年 | 4篇 |
1998年 | 2篇 |
1997年 | 1篇 |
1996年 | 4篇 |
1995年 | 3篇 |
1994年 | 1篇 |
1993年 | 2篇 |
1990年 | 1篇 |
1989年 | 1篇 |
1988年 | 1篇 |
1987年 | 1篇 |
1984年 | 3篇 |
1982年 | 1篇 |
1979年 | 2篇 |
1978年 | 2篇 |
1974年 | 1篇 |
1973年 | 1篇 |
1972年 | 2篇 |
1971年 | 1篇 |
排序方式: 共有704条查询结果,搜索用时 15 毫秒
51.
52.
Alicja. J. Copik Aleksander Baldys Khanh Nguyen Sunil Sahdeo Hoangdung Ho Alan Kosaka Paul J. Dietrich Bill Fitch John R. Raymond Anthony P. D. W. Ford Donald Button Marcos E. Milla 《PloS one》2015,10(1)
The α1A-AR is thought to couple predominantly to the Gαq/PLC pathway and lead to phosphoinositide hydrolysis and calcium mobilization, although certain agonists acting at this receptor have been reported to trigger activation of arachidonic acid formation and MAPK pathways. For several G protein-coupled receptors (GPCRs) agonists can manifest a bias for activation of particular effector signaling output, i.e. not all agonists of a given GPCR generate responses through utilization of the same signaling cascade(s). Previous work with Gαq coupling-defective variants of α1A-AR, as well as a combination of Ca2+ channel blockers, uncovered cross-talk between α1A-AR and β2-AR that leads to potentiation of a Gαq-independent signaling cascade in response to α1A-AR activation. We hypothesized that molecules exist that act as biased agonists to selectively activate this pathway. In this report, isoproterenol (Iso), typically viewed as β-AR-selective agonist, was examined with respect to activation of α1A-AR. α1A-AR selective antagonists were used to specifically block Iso evoked signaling in different cellular backgrounds and confirm its action at α1A-AR. Iso induced signaling at α1A-AR was further interrogated by probing steps along the Gαq /PLC, Gαs and MAPK/ERK pathways. In HEK-293/EBNA cells transiently transduced with α1A-AR, and CHO_α1A-AR stable cells, Iso evoked low potency ERK activity as well as Ca2+ mobilization that could be blocked by α1A-AR selective antagonists. The kinetics of Iso induced Ca2+ transients differed from typical Gαq- mediated Ca2+ mobilization, lacking both the fast IP3R mediated response and the sustained phase of Ca2+ re-entry. Moreover, no inositol phosphate (IP) accumulation could be detected in either cell line after stimulation with Iso, but activation was accompanied by receptor internalization. Data are presented that indicate that Iso represents a novel type of α1A-AR partial agonist with signaling bias toward MAPK/ERK signaling cascade that is likely independent of coupling to Gαq. 相似文献
53.
Michael R. Perkin Tara Bader Alicja R. Rudnicka David P. Strachan Christopher G. Owen 《PloS one》2015,10(11)
Objective
Allergic conjunctivitis (AC) is a common condition, especially in childhood. The extent to which it occurs concurrently with or independently from allergic rhinitis (AR) has not been well described.Aim
To examine the inter-relationship between rhinitis and conjunctivitis and the epidemiological risk factors for these conditions in a rural UK population.Methods
Cross-sectional study of rural school children (aged 5–11 years). Parental questionnaires were used to diagnose allergic outcomes (including conjunctivitis, rhinitis and rhinoconjunctivitis), and to collect data on atopic history, demographic and environmental exposures. Odds ratios of allergic outcome by exposure were examined adjusted for age, sex, breastfeeding, family history of allergy, number of older and younger siblings.Results
Prevalence of conjunctivitis was 17.5%, rhinitis 15.1% and rhinoconjunctivitis 13.0%. Seasonality of symptoms varied by condition: 64.7% of those with conjunctivitis had seasonal symptoms (April-Sept only), 46.7% of those with rhinitis and 92.2% of those with rhinoconjunctivitis. Living on a farm consistently reduced the risk of conjunctivitis (odds ratio 0.47, 95%CI 0.29–0.79, p = 0.004), rhinitis (OR 0.57, 95%CI 0.33–1.01, p = 0.05) and rhinoconjunctivitis (OR 0.57, 95%CI 0.32–1.03, p = 0.06). Exposure to farm animals (particularly in early life), current consumption of unpasteurised milk and playing in a barn or stable significantly reduced the risk of all three conditions.Conclusion
More children had parent-reported conjunctivitis than rhinitis. The majority of children with either condition also reported symptoms with the other condition. Farmers’ children have less eye and/or nasal symptoms. A number of farming variables linked with the farm microbial environment are likely to be mediating the protective effect. 相似文献54.
Jacek Wierzchowski Alicja Stachelska-Wierzchowska Beata Wielgus-Kutrowska Goran Mikleušević 《Analytical biochemistry》2014
Two nontypical nucleosides, 7-β-d-ribosyl-2,6-diamino-8-azapurine and 8-β-d-ribosyl-2,6-diamino-8-azapurine, have been found to exhibit moderately good, and selective, substrate properties toward calf and bacterial (Escherichia coli) forms of purine nucleoside phosphorylase (PNP). The former compound is effectively phosphorolysed by calf PNP and the latter by PNP from E. coli. Both compounds are fluorescent with λmax ∼ 425 to 430 nm, but the reaction product, 2,6-diamino-8-azapurine, emits in a different spectral region (λmax ∼ 363 nm) with nearly 40% yield, providing a strong fluorogenic effect at 350 to 360 nm. 相似文献
55.
56.
Robert Rutkowski Łukasz Rejt Anna Tereba Alicja Gryczyńska-Siemiątkowska Bartosz Janic 《European Journal of Wildlife Research》2010,56(3):297-305
We analysed the genetic structure of the European kestrel population of Central Poland using nine highly polymorphic microsatellite loci. Samples were collected in two urban locations (Warsaw and ?ód?) and two rural areas. Sampling locations were at nearly equal distances from each other along an east to west line. We performed genotyping in a total of 99 birds. The results revealed the presence of a genetic structure in the population investigated. Bayesian clustering indicated that samples originated from more than one population. Genetic differentiation was less pronounced among the birds nesting in Warsaw and in the two rural sites, whereas all pairwise comparisons with the ?ód? population indicated moderate and significant genetic differentiation. The observed pattern of differentiation might have been caused by two factors: changes in allele frequency between seasons and/or the founding of the urban population of ?ód? from a different source population than the urban population from Warsaw. Additionally, we found a rather high gene flow among kestrels from the Warsaw urban area and the two investigated rural areas. 相似文献
57.
Ekiel A Aptekorz M Kazek B Wiechuła B Wilk I Martirosian G 《Medycyna do?wiadczalna i mikrobiologia》2010,62(3):237-243
Autistic behavior is often accompanied by numerous disturbing symptoms on the part of gastrointestinal system, such as abdominal pain, constipation or diarrhea. These problems are often connected with deregulation of physiological microflora in intestine. The aim of this study was to determine differences in intestinal microflora of autistic and healthy children. Strains of Clostridium spp. and enterococci were isolated more frequently from stool samples of autistic children and rarely lactobacilli. Quantitative differences were observed maliny among staphylococci, Candida spp. and Clostridium perfringens. Monitoring and stabilization of intestinal microflora and knowledge about role of particular strains in etiology of autistic disorders can increase the chances for appropriate therapy. 相似文献
58.
Agnieszka Jazwa Paulina Kucharzewska Justyna Leja Anna Zagorska Aleksandra Sierpniowska Jacek Stepniewski Magdalena Kozakowska Hevidar Taha Takahiro Ochiya Rafal Derlacz Elisa Vahakangas Seppo Yla-Herttuala Alicja Jozkowicz Jozef Dulak 《Genetic vaccines and therapy》2010,8(1):1-16
Background
Impaired wound healing in diabetes is related to decreased production of growth factors. Hence, gene therapy is considered as promising treatment modality. So far, efforts concentrated on single gene therapy with particular emphasis on vascular endothelial growth factor-A (VEGF-A). However, as multiple proteins are involved in this process it is rational to test new approaches. Therefore, the aim of this study was to investigate whether single AAV vector-mediated simultaneous transfer of VEGF-A and fibroblast growth factor 4 (FGF4) coding sequences will improve the wound healing over the effect of VEGF-A in diabetic (db/db) mice.Methods
Leptin receptor-deficient db/db mice were randomized to receive intradermal injections of PBS or AAVs carrying β-galactosidase gene (AAV-LacZ), VEGF-A (AAV-VEGF-A), FGF-4 (AAV-FGF4-IRES-GFP) or both therapeutic genes (AAV-FGF4-IRES-VEGF-A). Wound healing kinetics was analyzed until day 21 when all animals were sacrificed for biochemical and histological examination.Results
Complete wound closure in animals treated with AAV-VEGF-A was achieved earlier (day 19) than in control mice or animals injected with AAV harboring FGF4 (both on day 21). However, the fastest healing was observed in mice injected with bicistronic AAV-FGF4-IRES-VEGF-A vector (day 17). This was paralleled by significantly increased granulation tissue formation, vascularity and dermal matrix deposition. Mechanistically, as shown in vitro, FGF4 stimulated matrix metalloproteinase-9 (MMP-9) and VEGF receptor-1 expression in mouse dermal fibroblasts and when delivered in combination with VEGF-A, enhanced their migration.Conclusion
Combined gene transfer of VEGF-A and FGF4 can improve reparative processes in the wounded skin of diabetic mice better than single agent treatment. 相似文献59.
60.
Ulrich Dobramysl Iris Katharina Jarsch Yoshiko Inoue Hanae Shimo Benjamin Richier Jonathan R. Gadsby Julia Mason Alicja Szaapak Pantelis Savvas Ioannou Guilherme Pereira Correia Astrid Walrant Richard Butler Edouard Hannezo Benjamin D. Simons Jennifer L. Gallop 《The Journal of cell biology》2021,220(4)
Assemblies of actin and its regulators underlie the dynamic morphology of all eukaryotic cells. To understand how actin regulatory proteins work together to generate actin-rich structures such as filopodia, we analyzed the localization of diverse actin regulators within filopodia in Drosophila embryos and in a complementary in vitro system of filopodia-like structures (FLSs). We found that the composition of the regulatory protein complex where actin is incorporated (the filopodial tip complex) is remarkably heterogeneous both in vivo and in vitro. Our data reveal that different pairs of proteins correlate with each other and with actin bundle length, suggesting the presence of functional subcomplexes. This is consistent with a theoretical framework where three or more redundant subcomplexes join the tip complex stochastically, with any two being sufficient to drive filopodia formation. We provide an explanation for the observed heterogeneity and suggest that a mechanism based on multiple components allows stereotypical filopodial dynamics to arise from diverse upstream signaling pathways. 相似文献