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41.
Hundreds of variants clustered in genomic loci and biological pathways affect human height 总被引:2,自引:0,他引:2
Lango Allen H Estrada K Lettre G Berndt SI Weedon MN Rivadeneira F Willer CJ Jackson AU Vedantam S Raychaudhuri S Ferreira T Wood AR Weyant RJ Segrè AV Speliotes EK Wheeler E Soranzo N Park JH Yang J Gudbjartsson D Heard-Costa NL Randall JC Qi L Vernon Smith A Mägi R Pastinen T Liang L Heid IM Luan J Thorleifsson G Winkler TW Goddard ME Sin Lo K Palmer C Workalemahu T Aulchenko YS Johansson A Zillikens MC Feitosa MF Esko T Johnson T Ketkar S Kraft P Mangino M Prokopenko I Absher D Albrecht E 《Nature》2010,467(7317):832-838
Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P?0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways. 相似文献
42.
Johansson S Gullbo J Lindholm P Ek B Thunberg E Samuelsson G Larsson R Bohlin L Claeson P 《Cellular and molecular life sciences : CMLS》2003,60(1):165-175
Four novel proteins (phoratoxins C–F) have been isolated from the North American mistletoe Phoradendron tomentosum. The amino acid sequences of these phoratoxins were determined unambiguously using a combination of Edman degradation and
trypsin enzymatic digestion, and by electrospray ionization tandem mass spectrometry sequencing. Phoratoxins C, E and F consist
of 46 amino acid residues; and phoratoxin D of 41. All proteins had six cysteines, similar to the earlier described phoratoxins
A and B, which are thionins. The cytotoxicity of each protein was evaluated in a human cell line panel that represented several
cytotoxic drug-resistance mechanisms. For the half-maximal inhibitory concentrations (IC50 values) of the different cell lines in the panel, correlation with those of standard drugs was low. The most potent cytotoxic
phoratoxin C was further tested on primary cultures of human tumor cells from patients. The solid tumor samples from breast
cancer cells were 18 times more sensitive to phoratoxin C than the tested hematological tumor samples.
Received 30 September 2002; received after revision 28 October 2002; accepted 7 November 2002
RID="*"
ID="*"Corresponding author. 相似文献
43.
Matrix metalloproteinases in tumor invasion 总被引:26,自引:0,他引:26
Controlled degradation of extracellular matrix (ECM) is essential for the growth, invasion, and metastasis of malignant tumors, and for tumor-induced angiogenesis. Matrix metalloproteinases (MMPs) are a family of zinc-dependent neutral endopeptidases collectively capable of degrading essentially all ECM components and they apparently play an important role in all these aspects of tumor development. Furthermore, recent evidence suggests that MMPs also play a role in tumor cell survival. In this review, we discuss the current concept concerning the role of MMPs and their inhibitors in tumor invasion, as a basis for prognosis and targeted therapeutic intervention in cancer. 相似文献
44.
45.
Anna Rising Mona Widhe Jan Johansson My Hedhammar 《Cellular and molecular life sciences : CMLS》2011,68(2):169-184
Spider dragline silk is an outstanding material made up of unique proteins—spidroins. Analysis of the amino acid sequences
of full-length spidroins reveals a tripartite composition: an N-terminal non-repetitive domain, a highly repetitive central
part composed of approximately 100 polyalanine/glycine rich co-segments and a C-terminal non-repetitive domain. Recent molecular
data on the terminal domains suggest that these have different functions. The composite nature of spidroins allows for recombinant
production of individual and combined regions. Miniaturized spidroins designed by linking the terminal domains with a limited
number of repetitive segments recapitulate the properties of native spidroins to a surprisingly large extent, provided that
they are produced and isolated in a manner that retains water solubility until fibre formation is triggered. Biocompatibility
studies in cell culture or in vivo of native and recombinant spider silk indicate that they are surprisingly well tolerated,
suggesting that recombinant spider silk has potential for biomedical applications. 相似文献
46.
Johansson L Ekholm ME Kukkonen JP 《Cellular and molecular life sciences : CMLS》2008,65(12):1948-1956
We investigated coupling of OX(1) receptors to phospholipase activation and diacylglycerol generation in Chinese hamster ovary (CHO) cells using both biochemical and fluorescence "real-time" methods. The results indicate that at lowest orexin-A concentrations (highest potency), diacylglycerol generated results from phospholipase D activity. At 10-100-fold higher orexin-A concentrations, phospholipase C is activated, likely hydrolyzing phosphatidylinositol (PI) or phosphatidylinositol monophosphate (PIP) but not phosphatidylinositol bisphosphate (PIP(2)). At further 7-fold higher orexin-A concentrations, PIP(2) is hydrolyzed, releasing both diacylglycerol and inositol-1,4,5-trisphosphate. Thus, OX(1) orexin receptors connect to multiple phospholipase activities, apparently composed of at least one phospholipase D and two different phospholipase C activities. At low agonist concentrations, diacylglycerol and phosphatidic acid are the preferred products, and interestingly, it seems that even the primarily activated phospholipase C mainly works to increase diacylglycerol and not inositol-1,4,5-trisphosphate. 相似文献
47.
Kaj Sunesson Carl Martin Allwood Dan Paulin Ilona Heldal Mattias Roupé Mikael Johansson Brje Westerdahl Chalmers University of Technology SE- Gteborg Sweden 《清华大学学报》2008,13(Z1):255-260
The introduction of virtual reality (VR)-models in the city planning process will cause changes in the traditional roles of the involved parties. In order to better understand some of these changes, the events involving the use of VR-models in an architectural competition concerning rebuilding-proposals for the city library in a Swedish city were analyzed. The study shows that VR was introduced into the competition as an extra add-on and that the VR-presentation was experienced as useful by the jury. The transformation of the architects’ contributions into VR was experienced as problematic by the architects, partly because they lost full control over the presentation. In the future architects are likely to have to produce the VR-models for their proposals themselves. This may make it more difficult for smaller architectural firms to enter the market but their proposals will be more accessible to a wider group of stakeholders. 相似文献
48.
Most foot-propelled swimming birds sweep their webbed feet backwards in a curved path that lies in a plane aligned with the swimming direction. When the foot passes the most outward position, near the beginning of the power stroke, a tangent to the foot trajectory is parallel with the line of swimming and the foot web is perpendicular to it. But later in the stroke the foot takes an increasingly transverse direction, swinging towards the longitudinal axis of the body. Here we show that, early in the power stroke, propulsion is achieved mostly by hydrodynamic drag on the foot, whereas there is a gradual transition into lift-based propulsion later in the stroke. At the shift to lift mode, the attached vortices of the drag-based phase turn into a starting vortex, shed at the trailing edge, and into spiralling leading-edge vortices along the sides of the foot. Because of their delta shape, webbed feet can generate propulsive forces continuously through two successive modes, from drag at the beginning of the stroke, all the way through the transition to predominantly lift later in the stroke. 相似文献
49.
Materials science. The hardest known oxide 总被引:3,自引:0,他引:3
Dubrovinsky LS Dubrovinskaia NA Swamy V Muscat J Harrison NM Ahuja R Holm B Johansson B 《Nature》2001,410(6829):653-654
A material as hard as diamond or cubic boron nitride has yet to be identified, but here we report the discovery of a cotunnite-structured titanium oxide which represents the hardest oxide known. This is a new polymorph of titanium dioxide, where titanium is nine-coordinated to oxygen in the cotunnite (PbCl2) structure. The phase is synthesized at pressures above 60 gigapascals (GPa) and temperatures above 1,000 K and is one of the least compressible and hardest polycrystalline materials to be described. 相似文献
50.
A characteristic feature of induced pinocytosis in Amoeba proteus is the formation of broad channels by invagination of the cell membrane. This process, which requires Ca2+, occurs in response to depolarising cations. High Ca2+ levels reduce pinocytosis induced by cations such as Na+ and Tris+, whereas pinocytosis induced by K+ is less affected by Ca2+ (ref. 4). Agents which interfere with the calcium metabolism of the amoeba will therefore either stimulate or inhibit pinocytosis induced by Na+ (ref. 5). Among the agents which are supposed to reduce Ca2+ influx across cell membranes or otherwise decrease cellular availability of Ca2+ are the opiates and opioid peptides, high doses of which have been reported to affect the amoeba. Accordingly, Met-enkephalin, morphine and codeine potentiate the inhibition of pinocytosis caused by Ca2+-binding agents and reverse the calcium blockade of pinocytosis mediated by caffeine. In this report we show that pinocytosis induced by Na+ or Tris+ is suppressed by beta-endorphin, Metenkephalin and morphine. These effects were abolished or diminished by an opiate receptor antagonist, (-)naloxone, by increasing the Na+ concentration, or by addition of Ca2+. 相似文献