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排序方式: 共有240条查询结果,搜索用时 250 毫秒
61.
Martial Guillaud Timon P. H. Buys Anita Carraro Jagoda Korbelik Michele Follen Michael Scheurer Karen Adler Storthz Dirk van Niekerk Calum E. MacAulay 《PloS one》2014,9(9)
Accurate cervical intra-epithelial neoplasia (CIN) lesion grading is needed for effective patient management. We applied computer-assisted scanning and analytic approaches to immuno-stained CIN lesion sections to more accurately delineate disease states and decipher cell proliferation impacts from HPV and smoking within individual epithelial layers. A patient cohort undergoing cervical screening was identified (n = 196) and biopsies of varying disease grades and with intact basement membranes and epithelial layers were obtained (n = 261). Specimens were sectioned, stained (Mib1), and scanned using a high-resolution imaging system. We achieved semi-automated delineation of proliferation status and epithelial cell layers using Otsu segmentation, manual image review, Voronoi tessellation, and immuno-staining. Data were interrogated against known status for HPV infection, smoking, and disease grade. We observed increased cell proliferation and decreased epithelial thickness with increased disease grade (when analyzing the epithelium at full thickness). Analysis within individual cell layers showed a ≥50% increase in cell proliferation for CIN2 vs. CIN1 lesions in higher epithelial layers (with minimal differences seen in basal/parabasal layers). Higher rates of proliferation for HPV-positive vs. -negative cases were seen in epithelial layers beyond the basal/parabasal layers in normal and CIN1 tissues. Comparing smokers vs. non-smokers, we observed increased cell proliferation in parabasal (low and high grade lesions) and basal layers (high grade only). In sum, we report CIN grade-specific differences in cell proliferation within individual epithelial layers. We also show HPV and smoking impacts on cell layer-specific proliferation. Our findings yield insight into CIN progression biology and demonstrate that rigorous, semi-automated imaging of histopathological specimens may be applied to improve disease grading accuracy. 相似文献
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63.
1. To assess the significance of the methylation of nucleic acids known to be caused by certain carcinogens, the metabolic fate of 7[14C]-methylguanine was studied, with special reference to its possible incorporation into RNA and DNA. 2. The major part (approx. 95%) of the dose was excreted unchanged in the urine. A small amount of N-demethylation took place, as evidenced by the formation of radioactive adenine and guanine, and expiration of 14C-labelled carbon dioxide. No evidence was obtained for the direct incorporation of 7-methylguanine into systems synthesizing nucleic acids, i.e. RNA in liver, DNA in intestine or in the foetus. 相似文献
64.
Calum X. Cunningham Christopher N. Johnson Tracey Hollings Kaely Kreger Menna E. Jones 《Ecography》2019,42(12):2053-2059
Global declines of large carnivores have reduced the ‘landscape of fear’ that constrains the behaviour of other species. In recent years, active and passive trophic rewilding have potentially begun restoring these lost top–down controls. The Tasmanian devil Sarcophilus harrisii has declined severely due to a novel transmissible cancer. In response to extinction fears, devils were introduced to the devil‐free Maria Island, where their abundance rapidly increased. We tested how this introduction influenced risk‐sensitive foraging in the common brushtail possum Trichosurus vulpecula, a major prey species for devils, using giving‐up densities (GUDs). Before the introduction of devils, possum GUDs on Maria Island were indistinguishable from the long‐diseased region of Tasmania, where devils have been rare since ~2000. Three years after devil introduction, GUDs were 64% higher on Maria Island than the control region, demonstrating that after an initial period of high mortality, possums quickly adopted risk‐sensitive foraging behaviours. Devil activity across Maria Island was variable, leading to a heterogeneous landscape of fear and highlighting that top predators must be at functional densities to elicit behavioural responses from prey. Our study provides strong evidence that top predators modify the behaviour of prey by instilling fear, causing rapid ecological change following recoveries. 相似文献
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AG Dossetter J Bowyer CR Cook JJ Crawford JE Finlayson NM Heron C Heyes AJ Highton JA Hudson A Jestel S Krapp PA Macfaul TM McGuire AD Morley JJ Morris KM Page LR Ribeiro H Sawney S Steinbacher C Smith 《Bioorganic & medicinal chemistry letters》2012,22(17):5563-5568
The discovery of nitrile compound 4, a potent inhibitor of Cathepsin K (Cat K) with good bioavailability in dog is described. The compound was used to demonstrate target engagement and inhibition of Cat K in an in vivo dog PD model. The margin to hERG ion channel inhibition was deemed too low for a clinical candidate and an optimisation program to find isosteres or substitutions on benzothiazole group led to the discovery of 20, 24 and 27; all three free from hERG inhibition. 相似文献
67.
Cole AR Causeret F Yadirgi G Hastie CJ McLauchlan H McManus EJ Hernández F Eickholt BJ Nikolic M Sutherland C 《The Journal of biological chemistry》2006,281(24):16591-16598
Collapsin response mediator proteins (CRMPs) are a family of neuron-enriched proteins that regulate neurite outgrowth and growth cone dynamics. Here, we show that Cdk5 phosphorylates CRMP1, CRMP2, and CRMP4, priming for subsequent phosphorylation by GSK3 in vitro. In contrast, DYRK2 phosphorylates and primes CRMP4 only. The Cdk5 and DYRK2 inhibitor purvalanol decreases the phosphorylation of CRMP proteins in neurons, whereas CRMP1 and CRMP2, but not CRMP4, phosphorylation is decreased in Cdk5(-/-) cortices. Stimulation of neuroblastoma cells with IGF1 or TPA decreases GSK3 activity concomitantly with CRMP2 and CRMP4 phosphorylation. Conversely, increased GSK3 activity is not sufficient to increase CRMP phosphorylation. However, the growth cone collapse-inducing protein Sema3A increases Cdk5 activity and promotes phosphorylation of CRMP2 (but not CRMP4). Therefore, inhibition of GSK3 alters phosphorylation of all CRMP isoforms; however, individual isoforms can be differentially regulated by their respective priming kinase. This is the first GSK3 substrate found to be regulated in this manner and may explain the hyperphosphorylation of CRMP2 observed in Alzheimer's disease. 相似文献
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69.
Junichi Soh Naoki Okumura William W. Lockwood Hiromasa Yamamoto Hisayuki Shigematsu Wei Zhang Raj Chari David S. Shames Ximing Tang Calum MacAulay Marileila Varella-Garcia T?nu Vooder Ignacio I. Wistuba Stephen Lam Rolf Brekken Shinichi Toyooka John D. Minna Wan L. Lam Adi F. Gazdar 《PloS one》2009,4(10)
70.
Calum MacNeil Mark Briffa Rob S. E. W. Leuven Fiona R. Gell Richard Selman 《Hydrobiologia》2010,638(1):151-159
Freshwater invasive or alien species (IAS) can have a major impact on benthic macroinvertebrate assemblage structure and diversity.
This has implications for accurate biological monitoring, the assessment of the ecological quality status of rivers and achievement
of Water Framework Directive (WFD) objectives. Although IAS constitutes a major biological pressure to WFD objectives, current
approaches to ecological status assessment tend to ignore their presence. This problem is compounded as biotic indices such
as the Biological Monitoring Working Party (BMWP) score do not distinguish between native and IAS, when IAS tend to be more
tolerant of organic pollution than the natives they replace. Biocontamination is the presence of an IAS in a system, and we
tested a new method of biocontamination assessment, designed to be used alongside current routine water quality monitoring
techniques, by applying it to biological monitoring data from the river monitoring programme of a small Island, The Isle of
Man. Although 54% of monitoring sites exhibited no biocontamination, 19% showed low or moderate biocontamination and 27% high
or severe biocontamination. Richness contamination was low (only two contaminated families being recorded), but abundance
contamination was high in some sites (87% of individuals being IAS). Sites with a greater relative abundance of IAS individuals
exhibited lower BMWP water quality. Within invaded sites BMWP monitoring was not responsive to changing chemical water quality,
whereas within uninvaded sites it was. In invaded sites, the relative abundance of IAS increased as ammonia and BOD5 increased. Our study shows current monitoring approaches mask the presence of AIS within assemblages, with some highly biocontaminated
sites registering high BMWP biological quality. This new index represents a simple way to integrate the IAS biological pressure
into established WFD monitoring programmes, to produce more comprehensive estimates of ecological quality status than are
currently being realised. 相似文献