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51.
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53.
Meloni G Sonois V Delaine T Guilloreau L Gillet A Teissié J Faller P Vasák M 《Nature chemical biology》2008,4(6):366-372
Aberrant interactions of copper and zinc ions with the amyloid-beta peptide (Abeta) potentiate Alzheimer's disease (AD) by participating in the aggregation process of Abeta and in the generation of reactive oxygen species (ROS). The ROS production and the neurotoxicity of Abeta are associated with copper binding. Metallothionein-3 (Zn(7)MT-3), an intra- and extracellularly occurring metalloprotein, is highly expressed in the brain and downregulated in AD. This protein protects, by an unknown mechanism, cultured neurons from the toxicity of Abeta. Here, we show that a metal swap between Zn(7)MT-3 and soluble and aggregated Abeta(1-40)-Cu(II) abolishes the ROS production and the related cellular toxicity. In this process, copper is reduced by the protein thiolates forming Cu(I)(4)Zn(4)MT-3, in which an air-stable Cu(I)(4)-thiolate cluster and two disulfide bonds are present. The discovered protective effect of Zn(7)MT-3 from the copper-mediated Abeta(1-40) toxicity may lead to new therapeutic strategies for treating AD. 相似文献
54.
Beswick P Charrier N Clarke B Demont E Dingwall C Dunsdon R Faller A Gleave R Hawkins J Hussain I Johnson CN MacPherson D Maile G Matico R Milner P Mosley J Naylor A O'Brien A Redshaw S Riddell D Rowland P Skidmore J Soleil V Smith KJ Stanway S Stemp G Stuart A Sweitzer S Theobald P Vesey D Walter DS Ward J Wayne G 《Bioorganic & medicinal chemistry letters》2008,18(3):1022-1026
This article is focusing on further optimization of previously described hydroxy ethylamine (HEA) BACE-1 inhibitors obtained from a focused library with the support of X-ray crystallography. Optimization of the non-prime side of our inhibitors and introduction of a 6-membered sultam substituent binding to Asn-294 as well as a fluorine in the C-2 position led to derivatives with nanomolar potency in cell-based assays. 相似文献
55.
Christine Talmard Rodrigue Leuma Yona Peter Faller 《Journal of biological inorganic chemistry》2009,14(3):449-455
The amyloidoses are a group of disorders characterized by aberrant protein folding and assembly, leading to the deposition
of insoluble protein fibrils (amyloid), which provokes cell dysfunction and later cell death. One of the physiologically relevant
environmental factors able to affect the conformation and hence the aggregation properties of amyloidogenic proteins/peptides
is metal ions. Zn(II) promotes aggregation of most amyloidogenic peptides/proteins in vitro, including amyloid β protein (Aβ),
but the underlying mechanism is not known. To better understand this mechanism the present study focused on the partially
α-helical conformer, supposed to be an intermediate in Aβ aggregation. This partially α-helical conformer is stabilized by
10–20% 2,2,2-trifluoroethanol (TFE): therefore, the influence of Zn binding on the aggregation of the amylidogenic model peptide
Aβ(1–28) (Aβ28) was investigated at different TFE concentrations. The results showed a synergistic effect of Zn(II) and 10%
TFE, i.e., that either Zn or 10% TFE accelerated Aβ28 aggregation on its own, but with them together an at least 10 times
promotion of Aβ28 aggregation was observed. Further studies by thioflavin T fluorescence spectroscopy, transmission electron
microscopy, and circular dichroism (CD) spectroscopy suggested that the aggregates of Zn-Aβ28 formed in 10%TFE contain a β-sheet
secondary structure and are more of the amyloid type. CD spectroscopy indicated that Zn binding disrupted partially the α-helical
structure of Aβ28 in TFE. Thus, we propose that the promotion of Aβ28 aggregation by Zn is based on the transformation of
the partially α-helical conformer (intermediate) towards the β-sheet amyloid structure by a destabilization of the α-helix
in the intermediate.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
相似文献
Peter FallerEmail: Email: |
56.
KARIN NORÉN ERS ANGERBJÖRN PÁLL HERSTEINSSON 《Biological journal of the Linnean Society. Linnean Society of London》2009,97(1):18-26
The genetic composition of a population reflects several aspects of the organism and its environment. The Icelandic Arctic fox population exceeds 8000 individuals and is comprised of both coastal and inland foxes. Several factors may affect within-population movement and subsequent genetic population structure. A narrow isthmus and sheep-proof fences may prevent movement between the north-western and central part and glacial rivers may reduce movement between the eastern and central part of Iceland. Moreover, population density and habitat characteristics can influence movement behaviour further. Here, we investigate the genetic structure in the Icelandic Arctic fox population ( n = 108) using 10 microsatellite loci. Despite large glacial rivers, we found low divergence between the central and eastern part, suggesting extensive movement between these areas. However, both model- and frequency-based analyses suggest that the north-western part is genetically differentiated from the rest of Iceland (FST = 0.04, DS = 0.094), corresponding to 100–200 generations of complete isolation. This suggests that the fences cannot be the sole cause of divergence. Rather, the isthmus causes limited movement between the regions, implying that protection in the Hornstrandir Nature Reserve has a minimal impact on Arctic fox population size in the rest of Iceland. © 2009 The Linnean Society of London, Biological Journal of the Linnean Society , 2009, 97 , 18–26. 相似文献
57.
Toni Gabaldón Christophe Dessimoz Julie Huxley-Jones Albert J Vilella Erik LL Sonnhammer Suzanna Lewis 《Genome biology》2009,10(9):1-3
A report of the 24th International Conference on Yeast Genetics and Molecular Biology, Manchester, UK, 19-24 July 2009. 相似文献
58.
JM Rodríguez-Domínguez LL Ríos-Lara E Tapia-Campos R Barba-Gonzalez 《Biotechnic & histochemistry》2017,92(3):159-166
Preparations that contain well-spread metaphase chromosomes are critical for plant cytogenetic analyses including chromosome counts, banding procedures, in situ hybridization, karyotyping and construction of ideograms. Chromosome spreading is difficult for plants with large and numerous chromosomes. We report here a technique for obtaining cytoplasm-free, well-spread metaphases from two Amaryllidaceae species: Sprekelia formosissima (2n = 120) and Hymenocallis howardii (2n = 96). The technique has three main steps: 1) pretreatment to cause chromosome condensation, 2) dripping onto tilted slides coated with a thin layer of pure acetic acid and 3) application of steam and acetic acid to produce cytoplasmic hydrolysis, which spreads the chromosomes. 相似文献
59.
Andrew J. Muinonen-Martin Olivia Susanto Qifeng Zhang Elizabeth Smethurst William J. Faller Douwe M. Veltman Gabriela Kalna Colin Lindsay Dorothy C. Bennett Owen J. Sansom Robert Herd Robert Jones Laura M. Machesky Michael J. O. Wakelam David A. Knecht Robert H. Insall 《PLoS biology》2014,12(10)
The high mortality of melanoma is caused by rapid spread of cancer cells, which occurs unusually early in tumour evolution. Unlike most solid tumours, thickness rather than cytological markers or differentiation is the best guide to metastatic potential. Multiple stimuli that drive melanoma cell migration have been described, but it is not clear which are responsible for invasion, nor if chemotactic gradients exist in real tumours. In a chamber-based assay for melanoma dispersal, we find that cells migrate efficiently away from one another, even in initially homogeneous medium. This dispersal is driven by positive chemotaxis rather than chemorepulsion or contact inhibition. The principal chemoattractant, unexpectedly active across all tumour stages, is the lipid agonist lysophosphatidic acid (LPA) acting through the LPA receptor LPAR1. LPA induces chemotaxis of remarkable accuracy, and is both necessary and sufficient for chemotaxis and invasion in 2-D and 3-D assays. Growth factors, often described as tumour attractants, cause negligible chemotaxis themselves, but potentiate chemotaxis to LPA. Cells rapidly break down LPA present at substantial levels in culture medium and normal skin to generate outward-facing gradients. We measure LPA gradients across the margins of melanomas in vivo, confirming the physiological importance of our results. We conclude that LPA chemotaxis provides a strong drive for melanoma cells to invade outwards. Cells create their own gradients by acting as a sink, breaking down locally present LPA, and thus forming a gradient that is low in the tumour and high in the surrounding areas. The key step is not acquisition of sensitivity to the chemoattractant, but rather the tumour growing to break down enough LPA to form a gradient. Thus the stimulus that drives cell dispersal is not the presence of LPA itself, but the self-generated, outward-directed gradient. 相似文献
60.
Expression of the IL-7 receptor α-chain (CD127) is decreased on CD8 T-cells in HIV infected patients and partially recovers in those receiving antiretroviral therapy with sustained viral suppression. We have shown that soluble HIV Tat protein down regulates CD127 expression on CD8 T-cells isolated from healthy HIV-negative individuals. Tat is taken up by CD8 T-cells via endocytosis, exits the endosome and then translocates to the inner leaflet of the cell membrane where it binds to the cytoplasmic tail of CD127 inducing receptor internalization and degradation by the proteasome. This down regulation of CD127 by Tat results in impaired CD8 T-cell function. Interestingly, suppression of CD127 by Tat is reversible and requires the continual presence of Tat in the culture media. We thus questioned whether the low IL-7 receptor expression evident on CD8 T-cells in HIV+ patients was similarly reversible and if suppression of the receptor could be maintained ex vivo by Tat protein alone. We show here that when CD8 T-cells isolated from HIV+ patients are incubated alone in fresh medium, low CD127 expression on the cell surface recovers to normal levels. This recovery of CD127, however, is completely inhibited by the addition of HIV Tat protein to the culture media. This study then provides evidence that soluble factor(s) are responsible for low CD127 expression on circulating CD8 T-cells in HIV+ individuals and further implicates Tat in suppressing this receptor essential to CD8 T-cell proliferation and function. 相似文献