全文获取类型
收费全文 | 5340篇 |
免费 | 407篇 |
专业分类
5747篇 |
出版年
2024年 | 3篇 |
2023年 | 37篇 |
2022年 | 83篇 |
2021年 | 148篇 |
2020年 | 68篇 |
2019年 | 116篇 |
2018年 | 137篇 |
2017年 | 128篇 |
2016年 | 196篇 |
2015年 | 300篇 |
2014年 | 333篇 |
2013年 | 436篇 |
2012年 | 512篇 |
2011年 | 490篇 |
2010年 | 299篇 |
2009年 | 243篇 |
2008年 | 334篇 |
2007年 | 337篇 |
2006年 | 309篇 |
2005年 | 249篇 |
2004年 | 245篇 |
2003年 | 217篇 |
2002年 | 193篇 |
2001年 | 32篇 |
2000年 | 20篇 |
1999年 | 32篇 |
1998年 | 44篇 |
1997年 | 18篇 |
1996年 | 24篇 |
1995年 | 20篇 |
1994年 | 13篇 |
1993年 | 13篇 |
1992年 | 26篇 |
1991年 | 12篇 |
1990年 | 8篇 |
1989年 | 7篇 |
1988年 | 9篇 |
1987年 | 5篇 |
1986年 | 7篇 |
1985年 | 7篇 |
1984年 | 3篇 |
1983年 | 5篇 |
1982年 | 4篇 |
1981年 | 4篇 |
1980年 | 3篇 |
1979年 | 4篇 |
1978年 | 4篇 |
1977年 | 2篇 |
1975年 | 2篇 |
1939年 | 1篇 |
排序方式: 共有5747条查询结果,搜索用时 15 毫秒
51.
Ammazzalorso A Amoroso R Baraldi M Bettoni G Braghiroli D De Filippis B Duranti A Moretti M Tortorella P Tricca ML Vezzalini F 《Bioorganic & medicinal chemistry letters》2002,12(5):817-821
The chiral analogues of gemfibrozil 5-(2,5-dimethylphenoxy)-2-methylpentanoic acid and 5-(2,5-dimethylphenoxy)-2-ethylpentanoic acid were synthesized in optically active form using (S)-4-(1-methylethyl)-2-oxazolidinone as chiral auxiliary. All compounds inhibit human platelet aggregation. From these data, one can surmise that all tested compounds and gemfibrozil act at the platelet level with different mechanism than that of ASA, even if with a different potency. 相似文献
52.
Gelmi ML Caputo F Clerici F Pellegrino S Giannaccini G Betti L Fabbrini L Schmid L Palego L Lucacchini A 《Bioorganic & medicinal chemistry》2007,15(24):7581-7589
Enantiopure constrained 1-aminocyclopentane-1,2,4-tricarboxylic acids containing the glutamic acid skeleton were prepared as two diastereomers characterized by having the carboxylic groups in position two and four cis-oriented to each other and trans with respect to 1-carboxylic group and all cis-oriented carboxylic groups, respectively. A biochemical screening of activity of the above amino acids was investigated on glutamate and 5-HT receptors to find a possible metabotropic agonist, acting on the serotoninergic system. 相似文献
53.
Francesca Pretto Giuliano Elia Nadia Castioni Dario Neri 《Cancer immunology, immunotherapy : CII》2014,63(9):901-910
Antibody-cytokine fusion proteins (“immunocytokines”) represent a promising class of armed antibody products, which allow the selective delivery of potent pro-inflammatory payloads at the tumor site. The antibody-based selective delivery of interleukin-2 (IL2) is particularly attractive for the treatment of metastatic melanoma, an indication for which this cytokine received marketing approval from the US Food and drug administration. We used the K1735M2 immunocompetent syngeneic model of murine melanoma to study the therapeutic activity of F8–IL2, an immunocytokine based on the F8 antibody in diabody format, fused to human IL2. F8–IL2 was shown to selectively localize at the tumor site in vivo, following intravenous administration, and to mediate tumor growth retardation, which was potentiated by the combination with paclitaxel or dacarbazine. Combination treatment led to a substantially more effective tumor growth inhibition, compared to the cytotoxic drugs used as single agents, without additional toxicity. Analysis of the immune infiltrate revealed a significant accumulation of CD4+ T cells 24 h after the administration of the combination. The fusion proteins F8–IL2 and L19–IL2, specific to the alternatively spliced extra domain A and extra domain B of fibronectin respectively, were also studied in combination with tumor necrosis factor (TNF)-based immunocytokines. The combination treatment was superior to the action of the individual immunocytokines and was able to eradicate neoplastic lesions after a single intratumoral injection, a procedure that is being clinically used for the treatment of Stage IIIC melanoma. Collectively, these data reinforce the rationale for the use of IL2-based immunocytokines in combination with cytotoxic agents or TNF-based immunotherapy for the treatment of melanoma patients. 相似文献
54.
Francesca Chiarini Francesca Paganelli Tommaso Balestra Cristina Capanni Antonietta Fazio Maria Cristina Manara Lorena Landuzzi Stefania Petrini Camilla Evangelisti Pier-Luigi Lollini Alberto M. Martelli Giovanna Lattanzi Katia Scotlandi 《Cell death & disease》2022,13(4)
Lamin A, a main constituent of the nuclear lamina, is involved in mechanosignaling and cell migration through dynamic interactions with the LINC complex, formed by the nuclear envelope proteins SUN1, SUN2 and the nesprins. Here, we investigated lamin A role in Ewing Sarcoma (EWS), an aggressive bone tumor affecting children and young adults. In patients affected by EWS, we found a significant inverse correlation between LMNA gene expression and tumor aggressiveness. Accordingly, in experimental in vitro models, low lamin A expression correlated with enhanced cell migration and invasiveness and, in vivo, with an increased metastatic load. At the molecular level, this condition was linked to altered expression and anchorage of nuclear envelope proteins and increased nuclear retention of YAP/TAZ, a mechanosignaling effector. Conversely, overexpression of lamin A rescued LINC complex organization, thus reducing YAP/TAZ nuclear recruitment and preventing cell invasiveness. These effects were also obtained through modulation of lamin A maturation by a statin-based pharmacological treatment that further elicited a more differentiated phenotype in EWS cells. These results demonstrate that drugs inducing nuclear envelope remodeling could be exploited to improve therapeutic strategies for EWS.Subject terms: Nuclear organization, Cancer 相似文献
55.
56.
57.
Francesca Zito Demian Koop Maria Byrne Valeria Matranga 《Development, growth & differentiation》2015,57(7):507-514
Carbonic anhydrases (CAs) are a family of widely distributed metalloenzymes, involved in diverse physiological processes. These enzymes catalyse the reversible conversion of carbon dioxide to protons and bicarbonate. At least 19 genes encoding for CAs have been identified in the sea urchin genome, with one of these localized to the skeletogenic mesoderm (primary mesenchyme cells, PMCs). We investigated the effects of a specific inhibitor of CA, acetazolamide (AZ), on development of two sea urchin species with contrasting investment in skeleton production, Paracentrotus lividus and Heliocidaris tuberculata, to determine the role of CA on PMC differentiation, skeletogenesis and on non‐skeletogenic mesodermal (NSM) cells. Embryos were cultured in the presence of AZ from the blastula stage prior to skeleton formation and development to the larval stage was monitored. At the dose of 8 mmol/L AZ, 98% and 90% of P. lividus and H. tuberculata embryos lacked skeleton, respectively. Nevertheless, an almost normal PMC differentiation was indicated by the expression of msp130, a PMC‐specific marker. Strikingly, the AZ‐treated embryos also lacked the echinochrome pigment produced by the pigment cells, a subpopulation of NSM cells with immune activities within the larva. Conversely, all ectoderm and endoderm derivatives and other subpopulations of mesoderm developed normally. The inhibitory effects of AZ were completely reversed after removal of the inhibitor from the medium. Our data, together with new information concerning the involvement of CA on skeleton formation, provide evidence for the first time of a possible role of the CAs in larval immune pigment cells. 相似文献
58.
Lara A Gruijs da Silva Francesca Simonetti Saskia Hutten Henrick Riemenschneider Erin L Sternburg Lisa M Pietrek Jakob Gebel Volker Dtsch Dieter Edbauer Gerhard Hummer Lukas S Stelzl Dorothee Dormann 《The EMBO journal》2022,41(8)
Post‐translational modifications (PTMs) have emerged as key modulators of protein phase separation and have been linked to protein aggregation in neurodegenerative disorders. The major aggregating protein in amyotrophic lateral sclerosis and frontotemporal dementia, the RNA‐binding protein TAR DNA‐binding protein (TDP‐43), is hyperphosphorylated in disease on several C‐terminal serine residues, a process generally believed to promote TDP‐43 aggregation. Here, we however find that Casein kinase 1δ‐mediated TDP‐43 hyperphosphorylation or C‐terminal phosphomimetic mutations reduce TDP‐43 phase separation and aggregation, and instead render TDP‐43 condensates more liquid‐like and dynamic. Multi‐scale molecular dynamics simulations reveal reduced homotypic interactions of TDP‐43 low‐complexity domains through enhanced solvation of phosphomimetic residues. Cellular experiments show that phosphomimetic substitutions do not affect nuclear import or RNA regulatory functions of TDP‐43, but suppress accumulation of TDP‐43 in membrane‐less organelles and promote its solubility in neurons. We speculate that TDP‐43 hyperphosphorylation may be a protective cellular response to counteract TDP‐43 aggregation. 相似文献
59.
Magdalena Brzezowska Francesca Bernardi Nicola Gaggelli Gianni Valensin 《Journal of inorganic biochemistry》2010,104(2):193-198
Teicoplanin, a member of the “last chance” antibiotic family has a similar structure and the same mechanism of action as parent drug vancomycin, which is proved to be an effective binder of Cu(II) ions. However, the potentiometric and spectroscopic studies (UV-visible, CD, NMR) have shown that the modification of the N-terminal structure of the peptide backbone in teicoplanin affects considerably the binding ability towards Cu(II) ions. While vancomycin forms almost instantly the stable 3 N complex species involving the N-terminal and two amide nitrogen donors, in case of teicoplanin only two nitrogen donors derived from the N-terminal amino group and adjacent peptide bond are coordinated to Cu(II) ion within the whole pH range studied. The major factor influencing the binding mode is most likely the structure of the N-terminus of the peptide unit in the antibiotic ligand. 相似文献
60.
Antonio Rescigno Francesca Sollai Brunella Pisu Augusto Rinaldi Enrico Sanjust 《Journal of enzyme inhibition and medicinal chemistry》2013,28(4):207-218
The active site of tyrosinase is described with a view to depicting its interactions with substrates and inhibitors. Occurrence and mechanism(s) of tyrosinase-mediated browning of agrofood products are reviewed, with regard to both enzymic and chemical reactions, and their control, modulation, and inhibition. Technical and applicational implications are discussed. 相似文献