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31.
Balachandar Venkatesan Sumanth D. Prabhu Kaliyamurthi Venkatachalam Srinivas Mummidi Anthony J. Valente Robert A. Clark Patrice Delafontaine Bysani Chandrasekar 《Cellular signalling》2010,22(5):809-820
The anthracycline antibiotic doxorubicin (DOX) is a potent cancer chemotherapeutic agent that exerts both acute and chronic cardiotoxicity. Here we show that in adult mouse cardiomyocytes, DOX activates (i) the pro-apoptotic p53, (ii) p38MAPK and JNK, (iii) Bax translocation, (iv) cytochrome c release, and (v) caspase 3. Further, it (vi) inhibits expression of anti-apoptotic Akt, Bcl-2 and Bcl-xL, and (vii) induces internucleosomal degradation and cell death. WNT1-inducible signaling pathway protein-1 (WISP1), a CCN family member and a matricellular protein, inhibits DOX-mediated cardiomyocyte death. WISP1 inhibits DOX-induced p53 activation, p38 MAPK and JNK phosphorylation, Bax translocation to mitochondria, and cytochrome c release into cytoplasm. Additionally, WISP1 reverses DOX-induced suppression of Bcl-2 and Bcl-xL expression and Akt inhibition. The pro-survival effects of WISP1 were recapitulated by the forced expression of mutant p53, wild-type Bcl-2, wild-type Bcl-xL, or constitutively active Akt prior to DOX treatment. WISP1 also induces the pro-survival factor Survivin via PI3K/Akt signaling. Overexpression of wild-type, but not mutant Survivin, blunts DOX cytotoxicity. Further, WISP1 stimulates PI3K–Akt-dependent GSK3β phosphorylation and β-catenin nuclear translocation. Importantly, WISP1 induces its own expression. Together, these results provide important insights into the cytoprotective effects of WISP1 in cardiomyocytes, and suggest a potential therapeutic role for WISP1 in DOX-induced cardiotoxicity. 相似文献
32.
Adam M. Gilbert Pawel Nowak Natasja Brooijmans Matthew G. Bursavich Christoph Dehnhardt Efren Delos Santos Larry R. Feldberg Irwin Hollander Stephen Kim Sabrina Lombardi Kaapjoo Park Aranapakam M. Venkatesan Robert Mallon 《Bioorganic & medicinal chemistry letters》2010,20(2):636-639
Series of purine and pyrazolo[3,4-d]pyrimidine inhibitors of phosphatidylinositol-3-kinases (PI3K) have been prepared. The optimized purine inhibitors show good potency in a PI3K p110α (PI3K-α) fluorescence polarization assay with good selectivity versus PI3K p110γ (PI3K-γ) and the mammalian target of rapamycin (mTOR). The related pyrazolo[3,4-d]pyrimidines show potent PI3K-α and mTOR inhibition with good selectivity versus PI3K-γ. Representative compounds showed activity in a cellular proliferation assay against Caco-2 colorectal, LoVo colorectal and PC3MM2 prostate adenocarcinoma cancer cells. Signaling through the PI3K pathway was confirmed via inhibition of phospho-AKT in MDA-361 cells. 相似文献
33.
Aranapakam M. Venkatesan O. Dos Santos John Ellingboe Deborah A. Evrard Boyd L. Harrison Deborah L. Smith Rosemary Scerni Geoffrey A. Hornby Lee E. Schechter Terrence H. Andree 《Bioorganic & medicinal chemistry letters》2010,20(3):824-827
Several benzofuran derivatives linked to a 3-indoletetrahydropyridine through an alkyl chain were prepared and evaluated for serotonin transporter and 5-HT1A receptor affinities. Their design, synthesis and structure–activity relationships are described. 相似文献
34.
Aranapakam M. Venkatesan Zecheng Chen Osvaldo Dos Santos Christoph Dehnhardt Efren Delos Santos Semiramis Ayral-Kaloustian Robert Mallon Irwin Hollander Larry Feldberg Judy Lucas Ker Yu Inder Chaudhary Tarek S. Mansour 《Bioorganic & medicinal chemistry letters》2010,20(19):5869-5873
A series of mono-morpholino 1,3,5-triazine derivatives (8a–8q) bearing a 3-oxa-8-azabicyclo[3.2.1]octane were prepared and evaluated for PI3-kinase/mTOR activity. Replacement of one of the bis-morpholines in lead compound 1 (PKI-587) with 3-oxa-8-azabicyclo[3.2.1]octane and reduction of the molecular weight yielded 8m (PKI-179), an orally efficacious dual PI3-kinase/mTOR inhibitor. The in vitro activity, in vivo efficacy, and PK properties of 8m are discussed. 相似文献
35.
36.
Cancers are thought to originate in stem cells through the accumulation of multiple mutations. Some of these mutations result in a loss of heterozygosity (LOH). A recent report demonstrates that exposure of mouse embryonic stem cells to nontoxic amounts of mutagens triggers a marked increase in the frequency of LOH. Thus, mutagen induction of LOH in embryonic stem cells suggests a new pathway to account for the multiple homozygous mutations in human tumors. This induction could mimic early mutagenic events that generate cancers in human tissue stem cells. 相似文献
37.
Lamesch P Li N Milstein S Fan C Hao T Szabo G Hu Z Venkatesan K Bethel G Martin P Rogers J Lawlor S McLaren S Dricot A Borick H Cusick ME Vandenhaute J Dunham I Hill DE Vidal M 《Genomics》2007,89(3):307-315
Complete sets of cloned protein-encoding open reading frames (ORFs), or ORFeomes, are essential tools for large-scale proteomics and systems biology studies. Here we describe human ORFeome version 3.1 (hORFeome v3.1), currently the largest publicly available resource of full-length human ORFs (available at ). Generated by Gateway recombinational cloning, this collection contains 12,212 ORFs, representing 10,214 human genes, and corresponds to a 51% expansion of the original hORFeome v1.1. An online human ORFeome database, hORFDB, was built and serves as the central repository for all cloned human ORFs (http://horfdb.dfci.harvard.edu). This expansion of the original ORFeome resource greatly increases the potential experimental search space for large-scale proteomics studies, which will lead to the generation of more comprehensive datasets. 相似文献
38.
Alhazzani Khalid Venkatesan Thiagarajan Natarajan Umamaheswari Algahtani Mohammad Alaseem Ali Alobid Saad Rathinavelu Appu 《Biotechnology letters》2022,44(5-6):787-801
Biotechnology Letters - Colorectal cancer (CRC) is the third most prevalent type of cancer in the United States. The treatment options for cancer include surgery, chemotherapy, radiation,... 相似文献
39.
Gowdhami Balakrishnan Manojkumar Yesaiyan Vimala R. T. V. Ramya Venkatesan Karthiyayini Balakrishnan Kadalmani Balamuthu Akbarsha Mohammad Abdulkader 《Biometals》2022,35(1):67-85
BioMetals - Increasing cancer drug chemo-resistance, especially in the treatment of breast and lung cancers, alarms the immediate need of newer and effective anticancer drugs. Until now,... 相似文献
40.