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991.
Antonia Kalushkova M?rten Frykn?s Miguel Lemaire Charlotte Fristedt Prasoon Agarwal Maria Eriksson Sarah Deleu Peter Atadja Anders ?sterborg Kenneth Nilsson Karin Vanderkerken Fredrik ?berg Helena Jernberg-Wiklund 《PloS one》2010,5(7)
Multiple myeloma (MM) is a genetically heterogeneous disease, which to date remains fatal. Finding a common mechanism for initiation and progression of MM continues to be challenging. By means of integrative genomics, we identified an underexpressed gene signature in MM patient cells compared to normal counterpart plasma cells. This profile was enriched for previously defined H3K27-tri-methylated genes, targets of the Polycomb group (PcG) proteins in human embryonic fibroblasts. Additionally, the silenced gene signature was more pronounced in ISS stage III MM compared to stage I and II. Using chromatin immunoprecipitation (ChIP) assay on purified CD138+ cells from four MM patients and on two MM cell lines, we found enrichment of H3K27me3 at genes selected from the profile. As the data implied that the Polycomb-targeted gene profile would be highly relevant for pharmacological treatment of MM, we used two compounds to chemically revert the H3K27-tri-methylation mediated gene silencing. The S-adenosylhomocysteine hydrolase inhibitor 3-Deazaneplanocin (DZNep) and the histone deacetylase inhibitor LBH589 (Panobinostat), reactivated the expression of genes repressed by H3K27me3, depleted cells from the PRC2 component EZH2 and induced apoptosis in human MM cell lines. In the immunocompetent 5T33MM in vivo model for MM, treatment with LBH589 resulted in gene upregulation, reduced tumor load and increased overall survival. Taken together, our results reveal a common gene signature in MM, mediated by gene silencing via the Polycomb repressor complex. The importance of the underexpressed gene profile in MM tumor initiation and progression should be subjected to further studies. 相似文献
992.
Background
Natural selection should favour the ability of mothers to adjust the sex ratio of offspring in relation to the offspring''s potential reproductive success. In polygynous species, mothers in good condition would be advantaged by giving birth to more sons. While studies on mammals in general provide support for the hypothesis, studies on humans provide particularly inconsistent results, possibly because the assumptions of the model do not apply.Methodology/Principal Findings
Here, we take a subset of humans in very good condition: the Forbe''s billionaire list. First, we test if the assumptions of the model apply, and show that mothers leave more grandchildren through their sons than through their daughters. We then show that billionaires have 60% sons, which is significantly different from the general population, consistent with our hypothesis. However, women who themselves are billionaires have fewer sons than women having children with billionaires, suggesting that maternal testosterone does not explain the observed variation. Furthermore, paternal masculinity as indexed by achievement, could not explain the variation, since there was no variation in sex ratio between self-made or inherited billionaires.Conclusions/Significance
Humans in the highest economic bracket leave more grandchildren through sons than through daughters. Therefore, adaptive variation in sex ratios is expected, and human mothers in the highest economic bracket do give birth to more sons, suggesting similar sex ratio manipulation as seen in other mammals. 相似文献993.
Maria Swanberg Karin Harnesk Mikael Str?m Margarita Diez Olle Lidman Fredrik Piehl 《PloS one》2009,4(6)
Background
Damage to nerve cells and axons leading to neurodegeneration is a characteristic feature of many neurological diseases. The degree of genetic influence on susceptibility to axotomy-induced neuronal death has so far been unknown. We have examined two gene regions, Vra1 and Vra2, previously linked to nerve cell loss after ventral root avulsion in a rat F2 intercross between the DA and PVG inbred rat strains.Methodology/Principal Findings
In this study, we use two generations (G8 and G10 cohorts) of an advanced intercross line between DA and PVGav1 to reproduce linkage to Vra1 and to fine-map this region. By isolating the effect from Vra1 in congenic strains, we demonstrate that Vra1 significantly regulates the loss of motoneurons after avulsion. The regulatory effect mediated by Vra1 thus resides in a congenic fragment of 9 megabases. Furthermore, we have used the advanced intercross lines to give more support to Vra2, originally detected as a suggestive QTL.Conclusions/Significance
The results demonstrated here show that naturally occurring allelic variations affect susceptibility to axotomy-induced nerve cell death. Vra1 and Vra2 represent the first quantitative trait loci regulating this phenotype that are characterized and fine mapped in an advanced intercross line. In addition, congenic strains provide experimental evidence for the Vra1 effect on the extent of injury-induced neurodegeneration. Identification of the underlying genetic variations will increase our understanding of the regulation and mechanisms of neurodegeneration. 相似文献994.
995.
996.
Fredrik Jernerén 《Archives of biochemistry and biophysics》2010,495(1):67-73
Oxygenation of linoleic acid by Aspergillus terreus was studied with LC-MS/MS. 9(R)-Hydroperoxy-10(E),12(Z)-octadecadienoic acid (9R-HpODE) was identified along with 10(R)-hydroxy-8(E),12(Z)-octadecadienoic acid and variable amounts of 8(R)-hydroxy-9(Z),12(Z)-octadecadienoic acid. 9R-HpODE was formed from [11S-2H]18:2n − 6 with loss of the deuterium label, suggesting antarafacial hydrogen abstraction and oxygenation. Two polar metabolites were identified as 9-hydroxy-10-oxo-12(Z)-octadecenoic acid (α-ketol) and 13-hydroxy-10-oxo-11(E)-octadecenoic acid (γ-ketol), likely formed by spontaneous hydrolysis of an unstable allene oxide, 9(R),10-epoxy-10,12(Z)-octadecadienoic acid. α-Linolenic acid and 20:2n − 6 were oxidized to hydroperoxy fatty acids at C-9 and C-11, respectively, but α- and γ-ketols of these fatty acids could not be detected. The genome of A. terreus lacks lipoxygenases, but contains genes homologous to 5,8-linoleate diol synthases and linoleate 10R-dioxygenases of aspergilli. Our results demonstrate that linoleate 9R-dioxygenase linked to allene oxide synthase activities can be expressed in fungi. 相似文献
997.
Olson FJ Sihlbom C Davidsson P Hulthe J Fagerberg B Bergström G 《Biochemical and biophysical research communications》2010,401(4):574-580
Identifying proteins associated with a complicated atherosclerotic plaque phenotype would provide potential biomarkers for detection of patients at elevated risk for clinically overt disease. We hypothesized that the protein content of carotid atherosclerotic tissue differs between complicated segments located in the internal carotid artery (ICA) and more stable segments in the common carotid artery (CCA). Using differential proteomics, we aimed to identify proteins differentially expressed between these segments of symptomatic carotid plaques. Ten snap-frozen human endarterectomies were divided into ICA and CCA segments and compared using two-dimensional differential gel electrophoresis and liquid chromatography-mass spectrometry. This study setup allowed pair-wise comparison of complicated and more stable atherosclerotic tissue from the same individual. We identified 19 proteins with differential distribution between ICA and CCA segments. Among the proteins more abundant in ICA were S100A10, ferritin light chain and fibrinogen. Among the proteins more abundant in CCA were ApoE, actin and l-lactate dehydrogenase B. Immunohistochemical staining revealed that S100A10 was expressed in endothelial cells, in clusters of macrophages and foam cells, and co-localized with the urokinase-type plasminogen activator receptor, uPAR. In conclusion, the results support the concept of comparing segments within plaques. The identified proteins constitute potential markers of complicated atherosclerotic lesions. The previously reported function of S100A10 to regulate plasmin activity affecting both angiogenesis and macrophage invasion, together with our observation of its accumulation in complicated plaque segments, warrants further studies of its potential role as a drug target for treatment of advanced atherosclerosis. 相似文献
998.
Thorén FB Romero AI Hellstrand K 《Journal of immunology (Baltimore, Md. : 1950)》2006,176(12):7301-7307
Cytotoxic T cells and NK cells will acquire features of apoptosis when exposed to oxygen radicals, but the molecular mechanisms underlying this phenomenon are incompletely understood. We have investigated the role of two enzyme systems responsible for execution of cell death, caspases and the poly(ADP-ribose) polymerase (PARP). We report that although human cytotoxic lymphocytes were only marginally protected by caspase inhibitors, PARP inhibitors completely protected lymphocytes from radical-induced apoptosis and restored their cytotoxic function. The radical-induced, PARP-dependent cell death was accompanied by nuclear accumulation of apoptosis-inducing factor and a characteristic pattern of large-fragment DNA degradation. It is concluded that the PARP/apoptosis-inducing factor axis is critically involved in oxygen radical-induced apoptosis in cytotoxic lymphocytes. 相似文献
999.
An important property of the bacterial surface is its conductivity. To obtain reliable conductivity values, it is essential
to handle the cells as gently as possible during the measurement procedure. We have developed a method where a standard conductivity
meter is used in combination with cross-flow filtration, thus avoiding repeated centrifugation and resuspension. With this
method, the conductivity of Bacillus subtilis was determined to be 7000 μS/cm, which is a deviation from previously published data by almost an order of a magnitude. 相似文献
1000.
Katrine Worsaae Arne Nygren Greg W. Rouse Gonzalo Giribet Jenny Persson Per Sundberg & Fredrik Pleijel 《Zoologica scripta》2005,34(3):313-328
The phylogenetic position of the most speciose meiofaunal polychaete family, Nerillidae, has remained contentious. Recent hypotheses have generally focused on the fact that Nerillidae shares with Aciculata (a major polychaete subgroup) features such as compound chaetae, ventral buccal organ and short ventrolateral palps. Here we present the first phylogenetic analysis of Aciculata, together with Nerillidae, combining morphological and molecular data. We also include Aberrantidae, previously referred to or placed near to spiomorph polychaetes, but recently referred to Aciculata, possibly close to Nerillidae. The data sets of 24 terminals contain 53 morphological characters and nearly complete sequences of 18S rRNA. The sequences were analysed simultaneously with the morphological data by direct optimization in the program POY with a variety of parameter settings (costs of gaps: transversions: transitions). The various settings resulted in markedly different phylogenetic hypotheses, but on the basis of congruence (ILD) the results of two parameter settings were chosen. In all analyses, the three included nerillid species constituted a monophyletic group. Only two analyses provided fully resolved cladograms. The morphological analysis gave poor resolution and the position of the nerillids was equivocal. The two molecular‐based cladograms (minimizing ILD) were also poorly resolved, but one provided a position for nerillids next to Eunice pennata and Nothria conchilega, from the subgroup Eunicida within Aciculata. The two cladograms of the combined analyses (minimizing ILD) were fully resolved and placed nerillids in a terminal position next to Aberranta sp., within a clade of eunicidan species. The study showed that the analytical conditions for the homology assignment of 18S rRNA strongly influenced the phylogenetic results. The various previous proposals on the phylogenetic position of the Nerillidae are reviewed, some of which are in accordance with the results of the present study. 相似文献