全文获取类型
收费全文 | 1022篇 |
免费 | 146篇 |
出版年
2021年 | 14篇 |
2020年 | 9篇 |
2018年 | 13篇 |
2017年 | 10篇 |
2016年 | 13篇 |
2015年 | 30篇 |
2014年 | 24篇 |
2013年 | 58篇 |
2012年 | 46篇 |
2011年 | 38篇 |
2010年 | 41篇 |
2009年 | 23篇 |
2008年 | 40篇 |
2007年 | 36篇 |
2006年 | 43篇 |
2005年 | 37篇 |
2004年 | 35篇 |
2003年 | 47篇 |
2002年 | 25篇 |
2001年 | 28篇 |
2000年 | 33篇 |
1999年 | 26篇 |
1998年 | 16篇 |
1997年 | 9篇 |
1996年 | 10篇 |
1995年 | 11篇 |
1993年 | 12篇 |
1992年 | 22篇 |
1991年 | 14篇 |
1990年 | 19篇 |
1989年 | 23篇 |
1988年 | 22篇 |
1987年 | 15篇 |
1986年 | 15篇 |
1985年 | 8篇 |
1984年 | 14篇 |
1983年 | 13篇 |
1982年 | 13篇 |
1981年 | 15篇 |
1980年 | 11篇 |
1979年 | 14篇 |
1978年 | 12篇 |
1976年 | 16篇 |
1975年 | 10篇 |
1974年 | 14篇 |
1973年 | 10篇 |
1972年 | 14篇 |
1970年 | 8篇 |
1969年 | 15篇 |
1963年 | 6篇 |
排序方式: 共有1168条查询结果,搜索用时 46 毫秒
111.
112.
Jorgensen ND Andresen JM Pitt JE Swenson MA Zoghbi HY Orr HT 《Journal of neurochemistry》2007,102(6):2040-2048
Spinocerebellar ataxia type 1 (SCA1) is an inherited neurodegenerative disorder. The mutation causing SCA1 is an expansion in the polyglutamine tract of the ATXN1 protein. Previous work demonstrated that phosphorylation of mutant ATXN1 at serine 776 (S776), a putative Akt phosphorylation site, is critical for pathogenesis. To examine this pathway further, we utilized a cell-transfection system that allowed the targeting of Akt to either the cytoplasm or the nucleus. In contrast to HeLa cells, we found that Akt targeted to the cytoplasm increased the degradation of ATXN1 in Chinese hamster ovary cells. However, Akt targeted to the cytoplasm failed to destabilize ATXN1 if Hsp70/Hsc70 was present. Thus, Hsp70/Hsc70 can regulate ATXN1 levels in concert with phosphorylation of ATXN1 at S776. 相似文献
113.
Severe acute respiratory syndrome coronavirus evades antiviral signaling: role of nsp1 and rational design of an attenuated strain 总被引:3,自引:1,他引:2
下载免费PDF全文
![点击此处可从《Journal of virology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
The severe acute respiratory syndrome (SARS) epidemic was caused by the spread of a previously unrecognized infectious agent, the SARS-associated coronavirus (SARS-CoV). Here we show that SARS-CoV could inhibit both virus- and interferon (IFN)-dependent signaling, two key steps of the antiviral response. We mapped a strong inhibitory activity to SARS-CoV nonstructural protein 1 (nsp1) and show that expression of nsp1 significantly inhibited the activation of all three virus-dependent signaling pathways. We show that expression of nsp1 significantly inhibited IFN-dependent signaling by decreasing the phosphorylation levels of STAT1 while having little effect on those of STAT2, JAK1, and TYK2. We engineered an attenuated mutant of nsp1 in SARS-CoV through reverse genetics, and the resulting mutant virus was viable and replicated as efficiently as wild-type virus in cells with a defective IFN response. However, mutant virus replication was strongly attenuated in cells with an intact IFN response. Thus, nsp1 is likely a virulence factor that contributes to pathogenicity by favoring SARS-CoV replication. 相似文献
114.
Orr JA Hamilton PW 《Analytical and quantitative cytology and histology / the International Academy of Cytology [and] American Society of Cytology》2007,29(1):17-31
Chromatin phenotype is known to be significantly disrupted in cancer. This has been demonstrated in many morphologic studies on cancer and in recent years by the application of digital texture analysis for quantitative evaluation of chromatin phenotype in neoplasia. Studies have consistently demonstrated the role of chromatin phenotype as a biomarker of diagnosis and prognosis. The underlying molecular mechanisms for chromatin reorganization and its role as a biomarker are largely unknown, but epigenetic processes are likely to be a main factor that not only modify chromatin arrangement but in doing so alter gene expression profiles in a reversible fashion. Of the range of epigenetic modifications that might control chromatin phenotype, histone acetylation is a strong candidate because of its role in the direct modification of chromatin, both through local relaxation of nucleosomal structure and recruitment of chromatin remodeling complexes. The reversible nature of histone acetylation is therapeutically attractive for treatment of aberrant histone acetylation; however, it still remains to be seen whether histone deacetylase inhibitors are clinically applicable or for use primarily as valuable research tools. This review explores the role of histone acetylation in cancer development, as a potential therapeutic candidate and a potential biomarker in tissue pathology. 相似文献
115.
116.
Improved phylogenetic resolution of toxic and non-toxic Alexandrium strains using a concatenated rDNA approach 总被引:1,自引:0,他引:1
Russell J.S. Orr Anke Stüken Thomas Rundberget Wenche Eikrem Kjetill S. Jakobsen 《Harmful algae》2011,10(6):676-688
Dinoflagellates of the genus Alexandrium are known producers of paralytic shellfish toxins. Species within the genus have similar phenotypes making morphological identification problematical. The use of Alexandrium rDNA sequence data is therefore increasing, resulting in the improved resolution of evolutionary relationships by phylogenetic inferences. However, the true branching pattern within Alexandrium remains unresolved, with minimal support shown for the main phylogentic branch. The aim of this study is to improve phylogenetic resolution via a concatenated rDNA approach with a broad sample of taxa, allowing inference of the evolutionary pattern between species and toxins. 27 Alexandrium strains from 10 species were tested with HPLC for PSP toxin presence and additionally sequenced for 18S, ITS1, 5.8S, ITS2 and 28S rDNA before being phylogenetically inferred together with all available orthologous sequences from NCBI. The resulting alignment is the largest to date for the genus, in terms of both inferred characters and taxa, thus allowing for the improved phylogenetic resolution of evolutionary patterns there in. No phylogenetic pattern between PSP producing and non-producing strains could be established, however the terminal tamarense complex was shown to produce more PSP analogues than basal clades. Additionally, we distinguish a high number of polymorphic regions between the two copies of A. fundyense rDNA, thus allowing us to demonstrate the presence of chimeric sequences within GenBank, as well as a possible over estimation of diversification within the tamarense complex. 相似文献
117.
Structural colors are generated by scattering of light by variations in tissue nanostructure. They are widespread among animals and have been studied most extensively in butterflies and moths (Lepidoptera), which exhibit the widest diversity of photonic nanostructures, resultant colors, and visual effects of any extant organism. The evolution of structural coloration in lepidopterans, however, is poorly understood. Existing hypotheses based on phylogenetic and/or structural data are controversial and do not incorporate data from fossils. Here we report the first example of structurally colored scales in fossil lepidopterans; specimens are from the 47-million-year-old Messel oil shale (Germany). The preserved colors are generated by a multilayer reflector comprised of a stack of perforated laminae in the scale lumen; differently colored scales differ in their ultrastructure. The original colors were altered during fossilization but are reconstructed based upon preserved ultrastructural detail. The dorsal surface of the forewings was a yellow-green color that probably served as a dual-purpose defensive signal, i.e. aposematic during feeding and cryptic at rest. This visual signal was enhanced by suppression of iridescence (change in hue with viewing angle) achieved via two separate optical mechanisms: extensive perforation, and concave distortion, of the multilayer reflector. The fossils provide the first evidence, to our knowledge, for the function of structural color in fossils and demonstrate the feasibility of reconstructing color in non-metallic lepidopteran fossils. Plastic scale developmental processes and complex optical mechanisms for interspecific signaling had clearly evolved in lepidopterans by the mid-Eocene. 相似文献
118.
Endothelial cells in straight, unbranched segments of arteries elongate and align in the direction of flow, a feature which is highly correlated with reduced atherosclerosis in these regions. The mitogen-activated protein kinase c-Jun N-terminal kinase (JNK) is activated by flow and is linked to inflammatory gene expression and apoptosis. We previously showed that JNK activation by flow is mediated by integrins and is observed in cells plated on fibronectin but not on collagen or basement membrane proteins. We now show thatJNK2 activation in response to laminar shear stress is biphasic, with an early peak and a later peak. Activated JNK localizes to focal adhesions at the ends of actin stress fibers, correlates with integrin activation and requires integrin binding to the extracellular matrix. Reducing JNK2 activation by siRNA inhibits alignment in response to shear stress. Cells on collagen, where JNK activity is low, align slowly. These data show that an inflammatory pathway facilitates adaptation to laminar flow, thereby revealing an unexpected connection between adaptation and inflammatory pathways. 相似文献
119.
Bonnet M Pardini M Meacci F Orrù G Yesilkaya H Jarosz T Andrew PW Barer M Checchi F Rinder H Orefici G Rüsch-Gerdes S Fattorini L Oggioni MR Melzer J Niemann S Varaine F 《PloS one》2011,6(8):e23081
Introduction
Emerging antituberculosis drug resistance is a serious threat for tuberculosis (TB) control, especially in Eastern European countries.Methods
We combined drug susceptibility results and molecular strain typing data with treatment outcome reports to assess the influence of drug resistance on TB treatment outcomes in a prospective cohort of patients from Abkhazia (Georgia). Patients received individualized treatment regimens based on drug susceptibility testing (DST) results. Definitions for antituberculosis drug resistance and treatment outcomes were in line with current WHO recommendations. First and second line DST, and molecular typing were performed in a supranational laboratory for Mycobacterium tuberculosis (MTB) strains from consecutive sputum smear-positive TB patients at baseline and during treatment.Results
At baseline, MTB strains were fully drug-susceptible in 189/326 (58.0%) of patients. Resistance to at least H or R (PDR-TB) and multidrug-resistance (MDR-TB) were found in 69/326 (21.2%) and 68/326 (20.9%) of strains, respectively. Three MDR-TB strains were also extensively resistant (XDR-TB). During treatment, 3/189 (1.6%) fully susceptible patients at baseline were re-infected with a MDR-TB strain and 2/58 (3.4%) PDR-TB patients became MDR-TB due to resistance amplification. 5/47 (10.6%) MDR- patients became XDR-TB during treatment. Treatment success was observed in 161/189 (85.2%), 54/69 (78.3%) and 22/68 (32.3%) of patients with fully drug susceptible, PDR- and MDR-TB, respectively. Development of ofloxacin resistance was significantly associated with a negative treatment outcome.Conclusion
In Abkhazia, a region with high prevalence of drug resistant TB, the use of individualized MDR-TB treatment regimens resulted in poor treatment outcomes and XDR-TB amplification. Nosocomial transmission of MDR-TB emphasizes the importance of infection control in hospitals. 相似文献120.
Analysis of pressure-collapse curves of Halobacterium cells containing gas vesicles and of gas vesicles released from such cells by hypotonic lysis shows that the isolated gas vesicles are considerably weaker than those present within the cells: their mean critical collapse pressure was around 0.049-0.058 MPa, as compared to 0.082-0.095 MPa for intact cells. The hypotonic lysis procedure, which is widely used for the isolation of gas vesicles from members of the Halobacteriaceae, thus damages the mechanical properties of the vesicles. The phenomenon can possibly be attributed to the loss of one or more structural gas vesicle proteins such as GvpC, the protein that strengthens the vesicles built of GvpA subunits: Halobacterium GvpC is a highly acidic, typically "halophilic" protein, expected to denature in the absence of molar concentrations of salt. 相似文献