全文获取类型
收费全文 | 1902篇 |
免费 | 165篇 |
国内免费 | 1篇 |
出版年
2022年 | 12篇 |
2021年 | 18篇 |
2020年 | 9篇 |
2019年 | 10篇 |
2018年 | 15篇 |
2017年 | 18篇 |
2016年 | 37篇 |
2015年 | 60篇 |
2014年 | 69篇 |
2013年 | 98篇 |
2012年 | 125篇 |
2011年 | 131篇 |
2010年 | 91篇 |
2009年 | 80篇 |
2008年 | 114篇 |
2007年 | 130篇 |
2006年 | 88篇 |
2005年 | 120篇 |
2004年 | 136篇 |
2003年 | 102篇 |
2002年 | 123篇 |
2001年 | 26篇 |
2000年 | 14篇 |
1999年 | 22篇 |
1998年 | 31篇 |
1997年 | 27篇 |
1996年 | 25篇 |
1995年 | 20篇 |
1994年 | 18篇 |
1993年 | 21篇 |
1992年 | 16篇 |
1991年 | 18篇 |
1990年 | 15篇 |
1989年 | 15篇 |
1988年 | 15篇 |
1987年 | 15篇 |
1986年 | 9篇 |
1985年 | 24篇 |
1984年 | 15篇 |
1983年 | 18篇 |
1982年 | 15篇 |
1981年 | 8篇 |
1980年 | 8篇 |
1979年 | 6篇 |
1978年 | 10篇 |
1977年 | 13篇 |
1976年 | 11篇 |
1975年 | 5篇 |
1974年 | 7篇 |
1967年 | 5篇 |
排序方式: 共有2068条查询结果,搜索用时 31 毫秒
991.
Richard L. Elliott Kimberly O. Cameron Janice E. Chin Jeremy A. Bartlett Elena E. Beretta Yue Chen Paul Da Silva Jardine Jeffrey S. Dubins Melissa L. Gillaspy Diane M. Hargrove Amit S. Kalgutkar Janet A. LaFlamme Mary E. Lame Kelly A. Martin Tristan S. Maurer Nancy A. Nardone Robert M. Oliver Dennis O. Scott Dexue Sun Andrew G. Swick Yingxin Zhang 《Bioorganic & medicinal chemistry letters》2010,20(22):6797-6801
We describe the design, synthesis, and structure–activity relationships of triazolobenzodiazepinone CCK1 receptor agonists. Analogs in this series demonstrate potent agonist activity as measured by in vitro and in vivo assays for CCK1 agonism. Our efforts resulted in the identification of compound 4a which significantly reduced food intake with minimal systemic exposure in rodents. 相似文献
992.
Nicholas Stock Christopher Baccei Gretchen Bain Alex Broadhead Charles Chapman Janice Darlington Christopher King Catherine Lee Yiwei Li Daniel S. Lorrain Pat Prodanovich Haojing Rong Angelina Santini Jasmine Zunic Jilly F. Evans John H. Hutchinson Peppi Prasit 《Bioorganic & medicinal chemistry letters》2010,20(1):213-217
A series of potent 5-lipoxygenase-activating protein (FLAP) inhibitors are herein described. SAR studies focused on the discovery of novel alicyclic moieties appended to an indole core to optimize potency, physical properties and off-target activities. Subsequent SAR on the N-benzyl substituent of the indole led to the discovery of compound 39 (AM679) which showed potent inhibition of leukotrienes in human blood and in a rodent bronchoalvelolar lavage (BAL) challenge model. 相似文献
993.
Bogachan Sahin Janice W Kansy Angus C Nairn Jozef Spychala Steven E Ealick Allen A Fienberg Robert W Greene James A Bibb 《European journal of biochemistry》2004,271(17):3547-3555
The regulation of adenosine kinase (AK) activity has the potential to control intracellular and interstitial adenosine (Ado) concentrations. In an effort to study the role of AK in Ado homeostasis in the central nervous system, two isoforms of the enzyme were cloned from a mouse brain cDNA library. Following overexpression in bacterial cells, the corresponding proteins were purified to homogeneity. Both isoforms were enzymatically active and found to possess K(m) and V(max) values in agreement with kinetic parameters described for other forms of AK. The distribution of AK in discrete brain regions and various peripheral tissues was defined. To investigate the possibility that AK activity is regulated by protein phosphorylation, a panel of protein kinases was screened for ability to phosphorylate recombinant mouse AK. Data from these in vitro phosphorylation studies suggest that AK is most likely not an efficient substrate for PKA, PKG, CaMKII, CK1, CK2, MAPK, Cdk1, or Cdk5. PKC was found to phosphorylate recombinant AK efficiently in vitro. Further analysis revealed, however, that this PKC-dependent phosphorylation occurred at one or more serine residues associated with the N-terminal affinity tag used for protein purification. 相似文献
994.
Mary E. Irwin Laura D. Nelson Janice M. Santiago-O’Farrill Phillip D. Knouse Claudia P. Miller Shana L. Palla Doris R. Siwak Gordon B. Mills Zeev Estrov Shulin Li Steven M. Kornblau Dennis P. Hughes Joya Chandra 《PloS one》2013,8(8)
The presence of the Philadelphia chromosome in patients with acute lymphoblastic leukemia (Ph+ALL) is a negative prognostic indicator. Tyrosine kinase inhibitors (TKI) that target BCR/ABL, such as imatinib, have improved treatment of Ph+ALL and are generally incorporated into induction regimens. This approach has improved clinical responses, but molecular remissions are seen in less than 50% of patients leaving few treatment options in the event of relapse. Thus, identification of additional targets for therapeutic intervention has potential to improve outcomes for Ph+ALL. The human epidermal growth factor receptor 2 (ErbB2) is expressed in ∼30% of B-ALLs, and numerous small molecule inhibitors are available to prevent its activation. We analyzed a cohort of 129 ALL patient samples using reverse phase protein array (RPPA) with ErbB2 and phospho-ErbB2 antibodies and found that activity of ErbB2 was elevated in 56% of Ph+ALL as compared to just 4.8% of Ph−ALL. In two human Ph+ALL cell lines, inhibition of ErbB kinase activity with canertinib resulted in a dose-dependent decrease in the phosphorylation of an ErbB kinase signaling target p70S6-kinase T389 (by 60% in Z119 and 39% in Z181 cells at 3 µM). Downstream, phosphorylation of S6-kinase was also diminished in both cell lines in a dose-dependent manner (by 91% in both cell lines at 3 µM). Canertinib treatment increased expression of the pro-apoptotic protein Bim by as much as 144% in Z119 cells and 49% in Z181 cells, and further produced caspase-3 activation and consequent apoptotic cell death. Both canertinib and the FDA-approved ErbB1/2-directed TKI lapatinib abrogated proliferation and increased sensitivity to BCR/ABL-directed TKIs at clinically relevant doses. Our results suggest that ErbB signaling is an additional molecular target in Ph+ALL and encourage the development of clinical strategies combining ErbB and BCR/ABL kinase inhibitors for this subset of ALL patients. 相似文献
995.
996.
997.
Ian M. Campbell Mitchell Rao Sean D. Arredondo Seema R. Lalani Zhilian Xia Sung-Hae L. Kang Weimin Bi Amy M. Breman Janice L. Smith Carlos A. Bacino Arthur L. Beaudet Ankita Patel Sau Wai Cheung James R. Lupski Pawe? Stankiewicz Melissa B. Ramocki Chad A. Shaw 《PLoS genetics》2013,9(9)
Curation and interpretation of copy number variants identified by genome-wide testing is challenged by the large number of events harbored in each personal genome. Conventional determination of phenotypic relevance relies on patterns of higher frequency in affected individuals versus controls; however, an increasing amount of ascertained variation is rare or private to clans. Consequently, frequency data have less utility to resolve pathogenic from benign. One solution is disease-specific algorithms that leverage gene knowledge together with variant frequency to aid prioritization. We used large-scale resources including Gene Ontology, protein-protein interactions and other annotation systems together with a broad set of 83 genes with known associations to epilepsy to construct a pathogenicity score for the phenotype. We evaluated the score for all annotated human genes and applied Bayesian methods to combine the derived pathogenicity score with frequency information from our diagnostic laboratory. Analysis determined Bayes factors and posterior distributions for each gene. We applied our method to subjects with abnormal chromosomal microarray results and confirmed epilepsy diagnoses gathered by electronic medical record review. Genes deleted in our subjects with epilepsy had significantly higher pathogenicity scores and Bayes factors compared to subjects referred for non-neurologic indications. We also applied our scores to identify a recently validated epilepsy gene in a complex genomic region and to reveal candidate genes for epilepsy. We propose a potential use in clinical decision support for our results in the context of genome-wide screening. Our approach demonstrates the utility of integrative data in medical genomics. 相似文献
998.
InÊs C. GonÇalves Daniela M. Takiya Frederico F. Salles Janice G. Peters Jorge L. Nessimian 《分类学与生物多样性》2013,11(6):564-581
A morphological comparison of type and non-type material of species of Campylocia, including their junior synonyms, was conducted, in addition to neighbour joining based on K2P distances and Bayesian inference analyses of 376?bp of the mitochondrial gene cytochrome oxidase I (COI) of recently collected specimens. Results revealed the lack of distinguishing characters between C. bocainensis and C. dochmia supported by the molecular analysis, where the overlap of intra- and interspecific genetic divergences suggested genetic flow among individuals. Campylocia burmeisteri is revalidated as a senior synonym of Brazilian south-eastern species C. bocainensis and C. dochmia and of E. guntheri, formerly a synonym of C. anceps. Campylocia burmeisteri is redescribed based on material from its type-locality, Nova Friburgo, Rio de Janeiro State. Two new species, C. demoulini sp. nov. and C. araca sp. nov., are described from the Amazon rain forest and a third species, C. orosi sp. nov., is described from Costa Rica. Possible cryptic species and the utility of egg morphology in the taxonomy of Campylocia are discussed for the first time for the genus. A key to the identification of adult stages of Campylocia is provided based on male genitalia and egg morphologyhttp://zoobank.org/urn:lsid:zoobank.org:pub:6779DC2C-DB98-41DF-8C52-FF97366AAF7A 相似文献
999.
Janice R. Sufrin Arthur J. Spiess John F. Karny Debora L. Kramer Robert G. Hughes Jr Ralph J. Bernacki 《Nucleosides, nucleotides & nucleic acids》2013,32(4):505-514
Abstract A novel synthesis of the nucleoside analog, 5′-deoxy-5′-(cyclopropylmethylthio)adenosine (CPMTA, 1) has been developed. CPMTA is a closely related structural analog of 5′-deoxy-5′-(isobutylthio)-adenosine (SIBA, 2), which has been widely studied and shown to exert a multitude of biological effects. The in vitro and in vivo antitumor (L1210 leukemia) activity of CPMTA has been found to be comparable to that of SIBA, whereas its in vitro antiviral (HSV and VSV) activity is diminished. These agents are being developed as inhibitors of methylation and/or polyamine synthesis. 相似文献
1000.
Russell S. Taichman Lalit R. Patel Rachel Bedenis Jingcheng Wang Savannah Weidner Taibriana Schumann Kenji Yumoto Janice E. Berry Yusuke Shiozawa Kenneth J. Pienta 《PloS one》2013,8(4)
Disseminated tumor cells (DTCs) are believed to lie dormant in the marrow before they can be activated to form metastases. How DTCs become dormant in the marrow and how dormant DTCs escape dormancy remains unclear. Recent work has shown that prostate cancer (PCa) cell lines express the growth-arrest specific 6 (GAS6) receptors Axl, Tyro3, and Mer, and become growth arrested in response to GAS6. We therefore hypothesized that GAS6 signaling regulates the proliferative activity of DTCs in the marrow. To explore this possibility, in vivo studies were performed where it was observed that when Tyro3 expression levels exceed Axl expression, the PCa cells exhibit rapid growth. When when Axl levels predominate, PCa cells remain largely quiescent. These findings suggest that a balance between the expression of Axl and Tyro3 is associated with a molecular switch between a dormant and a proliferative phenotype in PCa metastases. 相似文献