全文获取类型
收费全文 | 227篇 |
免费 | 34篇 |
国内免费 | 1篇 |
出版年
2018年 | 2篇 |
2016年 | 3篇 |
2015年 | 8篇 |
2014年 | 10篇 |
2013年 | 11篇 |
2012年 | 14篇 |
2011年 | 10篇 |
2010年 | 9篇 |
2009年 | 5篇 |
2008年 | 10篇 |
2007年 | 13篇 |
2006年 | 9篇 |
2005年 | 11篇 |
2004年 | 9篇 |
2003年 | 9篇 |
2002年 | 7篇 |
2001年 | 10篇 |
2000年 | 10篇 |
1999年 | 9篇 |
1998年 | 5篇 |
1997年 | 5篇 |
1996年 | 4篇 |
1995年 | 2篇 |
1994年 | 1篇 |
1993年 | 2篇 |
1992年 | 7篇 |
1991年 | 6篇 |
1990年 | 6篇 |
1989年 | 2篇 |
1988年 | 6篇 |
1987年 | 5篇 |
1986年 | 7篇 |
1985年 | 4篇 |
1984年 | 7篇 |
1983年 | 10篇 |
1982年 | 5篇 |
1980年 | 2篇 |
1979年 | 3篇 |
1978年 | 1篇 |
1977年 | 2篇 |
1975年 | 1篇 |
排序方式: 共有262条查询结果,搜索用时 15 毫秒
31.
Membrane localization of v-ErbB is required but not sufficient for ligand-independent transformation
Danielsen AJ Christensen TA Lovejoy CA Adelsman MA Connolly DC Maihle NJ 《Experimental cell research》2004,296(2):285-293
The v-ErbB retroviral oncogene is a transduced, mutated copy of the avian EGF receptor gene, and its expression is sufficient to induce tumor formation in vivo. The structural alterations that release the oncogenic potential of the v-ErbB oncogene are similar to EGFR gene mutations described in human tumors. Thus, the study of v-ErbB tumor biology offers a useful model through which we can gain insight into the mechanism of EGFR-induced malignancies. Despite years of study, however, questions remain regarding the domains of v-ErbB required for oncogenicity. We sought to clarify the role of the transmembrane domain of v-ErbB during transformation using S3-v-ErbB, an acutely transforming retroviral oncogene isolated from avian sarcomas. Infection of primary fibroblasts with a retroviral vector containing S3-v-ErbB results in the formation of a transformation-associated phosphoprotein signaling complex, soft agar colony formation, and the rapid induction of highly vascularized sarcomas in vivo. To address contribution of the transmembrane domain of S3-v-ErbB during these processes, we constructed a mutant version of this oncogene with a precise deletion in this domain. Specifically, the S3-v-ErbB-TM- mutant was created through an in-frame deletion of the entire transmembrane domain. Primary fibroblasts expressing this S3-v-ErbB-TM- mutant fail to form a characteristic transformation-associated phosphoprotein complex and do not grow in an anchorage-independent manner. In addition, day-old chicks injected with a helper-independent retrovirus expressing the S3-v-ErbB-TM- mutant exhibit only limited tumor formation in vivo. These results demonstrate that the transmembrane domain and, consequently membrane localization, are essential for S3-v-ErbB-mediated transformation. 相似文献
32.
Force spectroscopy of collagen fibers to investigate their mechanical properties and structural organization 下载免费PDF全文
Gutsmann T Fantner GE Kindt JH Venturoni M Danielsen S Hansma PK 《Biophysical journal》2004,86(5):3186-3193
Tendons are composed of collagen and other molecules in a highly organized hierarchical assembly, leading to extraordinary mechanical properties. To probe the cross-links on the lower level of organization, we used a cantilever to pull substructures out of the assembly. Advanced force probe technology, using small cantilevers (length <20 microm), improved the force resolution into the sub-10 pN range. In the force versus extension curves, we found an exponential increase in force and two different periodic rupture events, one with strong bonds (jumps in force of several hundred pN) with a periodicity of 78 nm and one with weak bonds (jumps in force of <7 pN) with a periodicity of 22 nm. We demonstrate a good correlation between the measured mechanical behavior of collagen fibers and their appearance in the micrographs taken with the atomic force microscope. 相似文献
33.
Acquisition of passive immunity by endocytosis of intact immunoglobulins (Ig) from colostrum is critical for prevention of intestinal and systemic diseases in neonatal mammals. We compared proteome patterns of healthy and inflamed gut tissues from pre-term piglets to investigate the effect of inflammation on acquisition of passive immunity. A clear difference in the two-dimensional gel electrophoresis protein patterns between healthy and inflamed intestinal tissues was observed, suggesting that inflamed tissues failed to absorb and transfer Ig from colostrum to epithelial cells. We have mapped and identified the Ig proteins that are taken up by healthy intestinal tissues, and found that isoforms of the IgA and IgG heavy chain and Ig kappa and lambda light chains were internalized. Our results indicate that colostrum protein uptake in the porcine gut is a selective process that is obstructed in inflamed pre-term gut. 相似文献
34.
Dorthe Helena Larsen Catherine Poinsignon Thorkell Gudjonsson Christoffel Dinant Mark R. Payne Flurina J. Hari Jannie M. Rendtlew Danielsen Patrice Menard Jette Christensen Sand Manuel Stucki Claudia Lukas Jiri Bartek Jens S. Andersen Jiri Lukas 《The Journal of cell biology》2010,190(5):731-740
In response to ionizing radiation (IR), cells delay cell cycle progression and activate DNA repair. Both processes are vital for genome integrity, but the mechanisms involved in their coordination are not fully understood. In a mass spectrometry screen, we identified the adenosine triphosphate–dependent chromatin-remodeling protein CHD4 (chromodomain helicase DNA-binding protein 4) as a factor that becomes transiently immobilized on chromatin after IR. Knockdown of CHD4 triggers enhanced Cdc25A degradation and p21Cip1 accumulation, which lead to more pronounced cyclin-dependent kinase inhibition and extended cell cycle delay. At DNA double-strand breaks, depletion of CHD4 disrupts the chromatin response at the level of the RNF168 ubiquitin ligase, which in turn impairs local ubiquitylation and BRCA1 assembly. These cell cycle and chromatin defects are accompanied by elevated spontaneous and IR-induced DNA breakage, reduced efficiency of DNA repair, and decreased clonogenic survival. Thus, CHD4 emerges as a novel genome caretaker and a factor that facilitates both checkpoint signaling and repair events after DNA damage. 相似文献
35.
A bifunctional activity label (8) for directed molecular evolution of lipolytic enzymes has been designed and synthesized. The structure is composed of a 4-nitrophenyl activated phosphonate, that is, a suicide substrate of lipases/esterases, connected to a biotin moiety through a spacer containing a disulfide bridge. The phosphonate (3) was prepared by Michaelis-Arbuzov reaction of trimethylsilyl-protected 11-bromoundecanol (2) with triethyl phosphite. The deprotected omega-hydroxyalkylphosphonate (4) was transformed into an active N-hydroxysuccinimide carbonate (5) followed by 4-nitrophenyl activation of the phosphonate using standard procedures. The biotinylated phosphonate inhibitor (8) was then synthesised by coupling the phosphonate inhibitor (6) to the epsilon-amino-caproic acid and cystamine containing biotinyl spacer (7). The function of all relevant groups of the final activity label (8) (biotin-label, cleavable disulfide bridge, phosphonate-inhibitor) have been successfully tested with the commercial lipase Lipolase (Novo Nordisk). Hence, a tool for directed molecular evolution of lipolytic enzymes has been developed. 相似文献
36.
Loft S Danielsen P Løhr M Jantzen K Hemmingsen JG Roursgaard M Karotki DG Møller P 《Archives of biochemistry and biophysics》2012,518(2):142-150
Oxidatively damaged DNA may be important in carcinogenesis. 8-Oxo-7,8-dihydroguanine (8-oxoGua) is an abundant and mutagenic lesion excised by oxoguanine DNA glycosylase 1 (OGG1) and measurable in urine or plasma by chromatographic methods with electrochemical or mass spectrometric detectors, reflecting the rate of damage in steady state. A common genetic OGG1 variant may affect the activity and was associated with increased levels of oxidized purines in leukocytes without apparent effect on 8-oxoGua excretion or major change in cancer risk. 8-OxoGua excretion has been associated with exposure to air pollution, toxic metals, tobacco smoke and low plasma antioxidant levels, whereas fruit and vegetable intake or dietary interventions showed no association. In rodent studies some types of feed may be source of 8-oxoGua in collected urine. Of cancer therapies, cisplatin increased 8-oxoGua excretion, whereas radiotherapy only showed such effects in experimental animals. Case-control studies found high excretion of 8-oxoGua in relation to cancer, dementia and celiac disease but not hemochromatosis, although associations could be a consequence rather than reflecting causality of disease. One prospective study found increased risk of developing lung cancer among non-smokers associated with high excretion of 8-oxoGua. Urinary excretion of 8-oxoGua is a promising biomarker of oxidatively damaged DNA. 相似文献
37.
While long-term fixation and storage of specimens is common and useful for many research projects, it is particularly important for space flight investigations where samples may not be returned to Earth for several months (International Space Station) or years (manned mission to Mars). We examined two critical challenges of space flight experimentation: the effect of long-term fixation on the quality of mouse bone preservation and the preservation of antigens and enzymes for both histochemical and immunohistochemical analyses, and how the animal/sample processing affects the preservation. We show that long-term fixation minimally affects standard histological staining, but that enzyme histochemistry and immunolabeling are greatly compromised. Further, we demonstrate that whole animal preservation is not as suitable as whole leg or stripped leg preservation for long-term fixation and all histological analyses. Overall, we recommend whole leg processing for long-term storage of bone specimens in fixative prior to embedding in plastic for histological examination. 相似文献
38.
39.
EO Ogueji CD Nwani SC Iheanacho CE Mbah CO Okeke A Yaji 《African Journal of Aquatic Science》2018,43(3):293-303
Indiscriminate discharge of pharmaceutical waste into the aquatic ecosystem may pose serious health challenges to aquatic biota. The effect of acute exposure to ibuprofen was evaluated using changes in behaviour and haematological parameters under static bio-assay method in Clarias gariepinus. Test specimens were exposed to acute concentrations of ibuprofen (0.28, 0.33, 0.38, 0.43 and 0.48 mg l?1) for 24, 48, 72 and 96 h durations respectively. Behavioural and phenotypic changes were observed in surviving fish. There were significant (p < 0.05) concentration and duration-dependent increases in erythrocyte (RBC), haemoglobin (Hb), pack cell volume (PCV) and leukocytes (WBC) in treated fish compared to the control. Insignificant decreases (p > 0.05) in mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH) and mean corpuscular haemoglobin concentration (MCHC) were observed in treated fish compared to the control. Ibuprofen elicited dose and duration- dependent decrease in neutrophil counts with the decreases being significant (p < 0.05) in the higher doses of 0.43 and 0.48 mg l?1. Ibuprofen did not elicit any significant changes in monocytes, basophils and eosinophils. Changes observed in this study showed that ibuprofen negatively affected the health of the fish and we recommend that discharge of ibuprofen into the aquatic environment should be monitored and controlled. 相似文献
40.