全文获取类型
收费全文 | 1463篇 |
免费 | 130篇 |
专业分类
1593篇 |
出版年
2023年 | 4篇 |
2022年 | 10篇 |
2021年 | 23篇 |
2020年 | 17篇 |
2019年 | 37篇 |
2018年 | 35篇 |
2017年 | 38篇 |
2016年 | 58篇 |
2015年 | 93篇 |
2014年 | 93篇 |
2013年 | 103篇 |
2012年 | 131篇 |
2011年 | 133篇 |
2010年 | 79篇 |
2009年 | 50篇 |
2008年 | 87篇 |
2007年 | 92篇 |
2006年 | 80篇 |
2005年 | 63篇 |
2004年 | 64篇 |
2003年 | 55篇 |
2002年 | 59篇 |
2001年 | 11篇 |
2000年 | 11篇 |
1999年 | 11篇 |
1998年 | 14篇 |
1997年 | 19篇 |
1996年 | 12篇 |
1995年 | 8篇 |
1994年 | 10篇 |
1993年 | 3篇 |
1992年 | 5篇 |
1991年 | 11篇 |
1990年 | 10篇 |
1989年 | 6篇 |
1988年 | 4篇 |
1987年 | 6篇 |
1986年 | 7篇 |
1985年 | 8篇 |
1984年 | 4篇 |
1983年 | 5篇 |
1982年 | 8篇 |
1981年 | 5篇 |
1980年 | 1篇 |
1979年 | 1篇 |
1977年 | 2篇 |
1976年 | 3篇 |
1974年 | 1篇 |
1972年 | 1篇 |
1970年 | 2篇 |
排序方式: 共有1593条查询结果,搜索用时 15 毫秒
91.
Basu U Gyrd-Hansen M Baby SM Lozynska O Krag TO Jensen CJ Frödin M Khurana TS 《FEBS letters》2007,581(22):4153-4158
Utrophin is the autosomal homolog of dystrophin, the product of the Duchenne's muscular dystrophy (DMD) locus. Utrophin is of therapeutic interest since its over-expression can compensate dystrophin's absence. Utrophin is enriched at neuromuscular junctions due to heregulin-mediated utrophin-A promoter activation. We demonstrate that heregulin activated MSK1/2 and phosphorylated histone H3 at serine 10 in cultured C2C12 muscle cells, in an ERK-dependent manner. MSK1/2 inhibition suppressed heregulin-mediated utrophin-A activation. MSK1 over-expression potentiated heregulin-mediated utrophin-A activation and chromatin remodeling at the utrophin-A promoter. These results identify MSK1/2 as key effectors modulating utrophin-A expression as well as identify novel targets for DMD therapy. 相似文献
92.
Up-regulation of cyclooxygenase-2 and apoptosis resistance by p38 MAPK in hypericin-mediated photodynamic therapy of human cancer cells 总被引:7,自引:0,他引:7
Hendrickx N Volanti C Moens U Seternes OM de Witte P Vandenheede JR Piette J Agostinis P 《The Journal of biological chemistry》2003,278(52):52231-52239
93.
Morten Frederiksen Tycho Anker‐Nilssen Grégory Beaugrand Sarah Wanless 《Global Change Biology》2013,19(2):364-372
The boreal Northeast Atlantic is strongly affected by current climate change, and large shifts in abundance and distribution of many organisms have been observed, including the dominant copepod Calanus finmarchicus, which supports the grazing food web and thus many fish populations. At the same time, large‐scale declines have been observed in many piscivorous seabirds, which depend on abundant small pelagic fish. Here, we combine predictions from a niche model of C. finmarchicus with long‐term data on seabird breeding success to link trophic levels. The niche model shows that environmental suitability for C. finmarchicus has declined in southern areas with large breeding seabird populations (e.g. the North Sea), and predicts that this decline is likely to spread northwards during the 21st century to affect populations in Iceland and the Faroes. In a North Sea colony, breeding success of three common piscivorous seabird species [black‐legged kittiwake (Rissa tridactyla), common guillemot (Uria aalge) and Atlantic puffin (Fratercula arctica)] was strongly positively correlated with local environmental suitability for C. finmarchicus, whereas this was not the case at a more northerly colony in west Norway. Large seabird populations seem only to occur where C. finmarchicus is abundant, and northward distributional shifts of common boreal seabirds are therefore expected over the coming decades. Whether or not population size can be maintained depends on the dispersal ability and inclination of these colonial breeders, and on the carrying capacity of more northerly areas in a warmer climate. 相似文献
94.
An amphipathic cyclic tetrapeptide scaffold containing halogenated β2,2‐amino acids with activity against multiresistant bacteria 下载免费PDF全文
Marianne H. Paulsen Eskil André Karlsen Dominik Ausbacher Trude Anderssen Annette Bayer Philipp Ochtrop Christian Hedberg Tor Haug Johanna U. Ericson Sollid Morten B. Strøm 《Journal of peptide science》2018,24(10)
The present study describes the synthesis and biological studies of a small series of head‐to‐tail cyclic tetrapeptides of the general structure c(Lys‐β2,2‐Xaa‐Lys) containing one lipophilic β2,2‐amino acid and Lys, Gly, Ala, or Phe as the Xaa residue in the sequence. The peptides were investigated for antimicrobial activity against gram‐positive and gram‐negative reference strains and 30 multiresistant clinical isolates including strains with extended spectrum β‐lactamase—carbapenemase (ESBL‐CARBA) production. Toxicity was determined against human red blood cells. The most potent peptides showed high activity against the gram‐positive clinical isolates with minimum inhibitory concentrations of 4–8 μg/mL and low haemolytic activity. The combination of high antimicrobial activity and low toxicity shows that these cyclic tetrapeptides containing lipophilic β2,2‐amino acids form a valuable scaffold for designing novel antimicrobial agents. 相似文献
95.
96.
Christopher Weidner Morten Rousseau Annabell Plauth Sylvia J. Wowro Cornelius Fischer Heba Abdel-Aziz Sascha Sauer 《PloS one》2016,11(4)
Massively increasing global incidences of colorectal cancer require efficient treatment and prevention strategies. Here, we report unexpected anticancerogenic effects of hydroethanolic Iberis amara extract (IAE), which is known as a widely used phytomedical product for treating gastrointestinal complaints. IAE significantly inhibited the proliferation of HT-29 and T84 colon carcinoma cells with an inhibitory concentration (IC50) of 6 and 9 μg/ml, respectively, and further generated inhibitory effects in PC-3 prostate and MCF7 breast cancer cells. Inhibition of proliferation in HT-29 cells was associated with a G2/M phase cell cycle arrest including reduced expression of various regulatory marker proteins. Notably, in HT-29 cells IAE further induced apoptosis by intracellular formation of reactive oxygen species (ROS). Consistent with predictions derived from our in vitro experiments, bidaily oral gavage of 50 mg/kg of IAE over 4 weeks resulted in significant inhibition of tumor growth in a mouse HT-29 tumor xenograft model. Taken together, Iberis amara extracts could become useful alternatives for preventing and treating the progression of colon cancer. 相似文献
97.
Karin A. W. Wadt Lauren G. Aoude Lotte Krogh Lone Sunde Anders Bojesen Karen Gr?nskov Nine Wartacz Jakob Ek Morten Tolstrup-Andersen Mette Klarskov-Andersen ?ke Borg Steffen Heegaard Jens F. Kiilgaard Thomas V. O. Hansen Kerenaftali Klein G?ran J?nsson Krzysztof T. Drzewiecki Morten Dun? Nicholas K. Hayward Anne-Marie Gerdes 《PloS one》2015,10(3)
Both environmental and host factors influence risk of cutaneous
melanoma (CM), and worldwide, the incidence varies depending on constitutional determinants of skin type and pigmentation, latitude, and patterns of sun exposure. We performed genetic analysis of CDKN2A, CDK4, BAP1, MC1R, and MITFp.E318K in Danish high-risk melanoma cases and found CDKN2A germline mutations in 11.3% of CM families with three or more affected individuals, including four previously undescribed mutations. Rare mutations were also seen in CDK4 and BAP1, while MC1R variants were common, occurring at more than twice the frequency compared to Danish controls. The MITF p.E318K variant similarly occurred at an approximately three-fold higher frequency in melanoma cases than controls. To conclude, we propose that mutation screening of CDKN2A and CDK4 in Denmark should predominantly be performed in families with at least 3 cases of CM. In addition, we recommend that testing of BAP1 should not be conducted routinely in CM families but should be reserved for families with CM and uveal melanoma, or mesothelioma. 相似文献
98.
Granum S Andersen TC Sørlie M Jørgensen M Koll L Berge T Lea T Fleckenstein B Spurkland A Sundvold-Gjerstad V 《The Journal of biological chemistry》2008,283(32):21909-21919
T cell-specific adapter protein (TSAd), encoded by the SH2D2A gene, interacts with Lck through its C terminus and thus modulates Lck activity. Here we mapped Lck phosphorylation and interaction sites on TSAd and evaluated their functional importance. The three C-terminal TSAd tyrosines Tyr(280), Tyr(290), and Tyr(305) were phosphorylated by Lck and functioned as docking sites for the Lck Src homology 2 (SH2) domain. Binding affinities of the TSAd Tyr(P)(280) and Tyr(P)(290) phosphopeptides to the isolated Lck SH2 domain were similar to that observed for the Lck Tyr(P)(505) phosphopeptide, whereas the TSAd Tyr(P)(305) peptide displayed a 10-fold higher affinity. The proline-rich Lck SH3-binding site on TSAd as well as the Lck SH2 domain were required for efficient tyrosine phosphorylation of TSAd by Lck. Interaction sites on TSAd for both Lck SH2 and Lck SH3 were necessary for TSAd-mediated modulation of proximal TCR signaling events. We found that 20-30% of TSAd molecules are phosphorylated in activated T cells and that the proportion of TSAd to Lck molecules in such cells is approximately 1:1. Therefore, in activated T cells, a considerable number of Lck molecules may potentially be engaged by TSAd. In conclusion, Lck binds to TSAd prolines and phosphorylates and interacts with the three C-terminal TSAd tyrosines. We propose that through multivalent interactions with Lck, TSAd diverts Lck from phosphorylating other substrates, thus modulating its functional activity through substrate competition. 相似文献
99.
Elmén J Lindow M Silahtaroglu A Bak M Christensen M Lind-Thomsen A Hedtjärn M Hansen JB Hansen HF Straarup EM McCullagh K Kearney P Kauppinen S 《Nucleic acids research》2008,36(4):1153-1162
MicroRNA-122 (miR-122) is an abundant liver-specific miRNA, implicated in fatty acid and cholesterol metabolism as well as hepatitis C viral replication. Here, we report that a systemically administered 16-nt, unconjugated LNA (locked nucleic acid)-antimiR oligonucleotide complementary to the 5′ end of miR-122 leads to specific, dose-dependent silencing of miR-122 and shows no hepatotoxicity in mice. Antagonism of miR-122 is due to formation of stable heteroduplexes between the LNA-antimiR and miR-122 as detected by northern analysis. Fluorescence in situ hybridization demonstrated uptake of the LNA-antimiR in mouse liver cells, which was accompanied by markedly reduced hybridization signals for mature miR-122 in treated mice. Functional antagonism of miR-122 was inferred from a low cholesterol phenotype and de-repression within 24 h of 199 liver mRNAs showing significant enrichment for miR-122 seed matches in their 3′ UTRs. Expression profiling extended to 3 weeks after the last LNA-antimiR dose revealed that most of the changes in liver gene expression were normalized to saline control levels coinciding with normalized miR-122 and plasma cholesterol levels. Combined, these data suggest that miRNA antagonists comprised of LNA are valuable tools for identifying miRNA targets in vivo and for studying the biological role of miRNAs and miRNA-associated gene-regulatory networks in a physiological context. 相似文献
100.
Mette Christoffersen Elizabeth Woodward Anders M Bojesen Stine Jacobsen Morten R Petersen Mats HT Troedsson Henrik Lehn-Jensen 《BMC veterinary research》2012,8(1):1-14