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131.
Hughes TV Emanuel SL O'Grady HR Connolly PJ Rugg C Fuentes-Pesquera AR Karnachi P Alexander R Middleton SA 《Bioorganic & medicinal chemistry letters》2008,18(18):5130-5133
A novel series of 7-[1H-indol-2-yl]-2,3-dihydro-isoindol-1-ones designed to be inhibitors of VEGF-R2 kinase was synthesized and found to potently inhibit VEGF-R2 and Aurora-A kinases. The structure-based design, synthesis, and initial SAR of the series are discussed. 相似文献
132.
Xu G Searle LL Hughes TV Beck AK Connolly PJ Abad MC Neeper MP Struble GT Springer BA Emanuel SL Gruninger RH Pandey N Adams M Moreno-Mazza S Fuentes-Pesquera AR Middleton SA Greenberger LM 《Bioorganic & medicinal chemistry letters》2008,18(12):3495-3499
We herein disclose a novel series of 4-aminopyrimidine-5-carbaldehyde oximes that are potent and selective inhibitors of both EGFR and ErbB-2 tyrosine kinases, with IC(50) values in the nanomolar range. Structure-activity relationship (SAR) studies elucidated a critical role for the 4-amino and C-6 arylamino moieties. The X-ray co-crystal structure of EGFR with 37 was determined and validated our design rationale. 相似文献
133.
Torres-Gómez H Hernández-Núñez E León-Rivera I Guerrero-Alvarez J Cedillo-Rivera R Moo-Puc R Argotte-Ramos R Rodríguez-Gutiérrez Mdel C Chan-Bacab MJ Navarrete-Vázquez G 《Bioorganic & medicinal chemistry letters》2008,18(11):3147-3151
A series of ten novel hybrids from benzimidazole and pentamidine were prepared using a short synthetic route. Each compound was tested in vitro against the protozoa Trichomonas vaginalis, Giardia lamblia, Entamoeba histolytica, Leishmania mexicana, and Plasmodium berghei, in comparison with pentamidine and metronidazole. Some analogues showed high bioactivity in the low micromolar range (IC(50)<1 microM) against the first four protozoa, which make them significantly more potent than either standard. 1,5-bis[4-(5-methoxy-1H-benzimidazole-2-yl)phenoxy]pentane (2) was 3- and 9-fold more potent againstG. lamblia than metronidazole and pentamidine, respectively. This compound was 23-, 108-, and 13-fold more active than pentamidine against T. vaginalis, E. histolytica and L. mexicana, respectively. Studying further structure-activity relationships through the use of bioisosteric substitution in these hybrids should provide new leads against protozoal diseases. 相似文献
134.
Valerie S. Calvert Yihui Tang Vince Boveia Julie Wulfkuhle Amy Schutz-Geschwender D. Michael Olive Lance A. Liotta Emanuel F. Petricoin III 《Clinical proteomics》2004,1(1):81-89
Protein microarrays have been recently employed for signal pathway profiling and high-throughput protein expression analysis.
Reversephase arrays, where the array consists of immobilized analytes and lysates has especially shown promise in low abundance
analyte detection and signal pathway profiling using phospho-specific antibodies. A limitation to current reverse phase array
methodology is the inability to multiplex proteomic-based endpoints as each array can only report one analyte endpoint. In
this study, we report on the use of a dual dye based approach that can effectively double the number of endpoints observed
per array allowing, for example, both phosphospecific and total protein levels to be measured and analyzed at once. The method
utilizes antibody bound dyes that emit in the infrared spectral region as a means of sensitive and specific detection. 相似文献
135.
Human Calmodulin-like Protein Is an Epithelial-Specific Protein Regulated during Keratinocyte Differentiation 总被引:5,自引:0,他引:5
Michael S. Rogers Teruaki Kobayashi Mark R. Pittelkow Emanuel E. Strehler 《Experimental cell research》2001,267(2):216-224
Human calmodulin-like protein (CLP) is a calcium-binding protein down-regulated in a cell culture model of mammary tumorigenesis as well as in a majority of breast cancers in vivo. CLP down-regulation may be a result of the poorly differentiated state of these cell lines and tumors, or CLP expression may be incompatible with the uncontrolled cell growth associated with tumorigenesis. To learn more about CLP expression and regulation, we determined the distribution of CLP in various human tissues by immunohistochemistry. CLP was expressed exclusively in the epithelium of the tissues surveyed and was most abundant in thyroid, breast, prostate, kidney, and skin. CLP expression appears to increase in stratified epithelium during differentiation, as illustrated in the skin where CLP staining intensified from the basal through the spinous to the granular layers. Using a normal human keratinocyte culture model, we examined CLP expression in response to various agents known to affect keratinocyte differentiation. Agents that inhibit (epidermal growth factor, EGF) or permit (keratinocyte growth factor) terminal differentiation correspondingly regulate CLP expression. Factors modulating the EGF receptor signaling pathway were particularly potent in regulating CLP expression. CLP expression correlated with an agent's ability to promote terminal differentiation regardless of the agent's effect on keratinocyte proliferation. These studies show that CLP expression is coordinately regulated by, and may be involved in, the program of terminal differentiation in human keratinocytes and, likely, other differentiating epithelial cell types. 相似文献
136.
Ann Holbourn Wolfgang Kuhnt Emanuel Soeding 《Palaeogeography, Palaeoclimatology, Palaeoecology》2001,170(3-4):171-196
Spatial distribution patterns of benthic foraminifers in upper Albian sediments from 25 DSDP/ODP sites and 31 onshore sections of the North and South Atlantic Ocean are used to generate paleobathymetric reconstructions and to identify areas of high primary production such as coastal and equatorial upwelling zones. New paleobathymetric estimates are provided for DSDP/ODP sites and onshore locations that are not situated on oceanic crust. Paleobathymetric reconstructions indicate shallow water exchange between the North and South Atlantic but show the existence of a deep-water connection between the western and eastern Tethys (>2500 m) through the Gibraltar Gateway. Strikingly, there is no evidence for a strong latitudinal gradient in deep-water benthic foraminiferal distribution during the late Albian: South Atlantic assemblages show close affinity to North Atlantic and Tethyan assemblages, exhibiting only a minor degree of provincialism. Biogeographic patterns reveal a distinct asymmetry in late Albian paleoproductivity for the North Atlantic. As for the present day, the eastern margins of the Atlantic were generally more productive than the western margins, and a belt of enhanced carbon flux export to the seafloor can be traced around the north African coast, which probably corresponded to a zone of vigorous coastal upwelling. By contrast, assemblage composition in the South Atlantic generally reflects mesotrophic to oligotrophic conditions. Benthic foraminiferal distribution patterns, thus, provide robust proxy data to test predictions from paleocirculation and paleobathymetric models for the mid-Cretaceous Atlantic Ocean and adjacent margins. 相似文献
137.
Utility of reverse phase protein arrays: applications to signalling pathways and human body arrays. 总被引:2,自引:0,他引:2
Lu Charboneau Heather Tory Heather Scott Tina Chen Mary Winters Emanuel F Petricoin Lance A Liotta Cloud P Paweletz 《Briefings in Functional Genomics and Prot》2002,1(3):305-315
Protein microarrays offer a new means by which to conduct quantitative profiling of disease-associated proteins. The knowledge gained may provide novel strategies for early detection, diagnosis and therapeutic intervention. A variety of sophisticated approaches, including gene arrays, sequencing consortiums and large-scale two-dimensional gel electrophoresis, continue to generate lists of proteins potentially linked to disease aetiology and progression. The challenge is to evaluate quantitatively promising lead protein candidates using matched normal and diseased cell populations. In contrast to the antibody array, the reverse phase protein microarrays (RPPA) do not require labelling of cellular protein lysates, and constitute a sensitive high throughput platform for marker screening, pathophysiology investigation and therapeutic monitoring. In this paper, examples will be provided using RPPAs in the study of the apoptotic signalling cascade and in the evaluation of the expression of organ-specific protein makers using microdissected human organ cell lysates configured as 'human body arrays'. 相似文献
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140.
Emanuel Miller 《BMJ (Clinical research ed.)》1936,1(3934):1112-1113