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951.
Marcuzzi A Piscianz E Girardelli M Crovella S Pontillo A 《Apoptosis : an international journal on programmed cell death》2011,16(9):882-888
The inhibition of mevalonate pathway by the aminobisphosphonate alendronate (ALD) has been previously associated with an augmented
lipopolysaccharide-induced interleukin-1beta (IL-1β) secretion in monocytes, as demonstrated in an auto-inflammatory disease
known as mevalonate kinase deficiency (MKD). In this study we investigated the effect of ALD + LPS on monocyte cell line (Raw
264.7) death. ALD strongly augmented LPS-induced programmed cell death (PCD) as well as IL-1β secretion in Raw murine monocytes,
whereas necrosis was rather unaffected. ALD + LPS induced caspase-3 activation. Inhibition of IL-1β stimulation partially
restored cell viability. These findings suggest that the inhibition of mevalonate pathway, together with a bacterial stimulus,
induce a PCD partly sustained by the caspase-3-related apoptosis and partly by caspase-1-associated pyroptosis. The involvement
of pyroptosis is a novel hit in our cell model and opens discussions about its role in inflammatory cells with chemical or
genetic inhibition of mevalonate pathway. 相似文献
952.
953.
Alonso-Perez E Suarez-Gestal M Calaza M Kwan T Majewski J Gomez-Reino JJ Gonzalez A 《Arthritis research & therapy》2011,13(3):R80
Introduction
Interferon regulatory factor 5 gene (IRF5) polymorphisms are strongly associated with several diseases, including systemic lupus erythematosus (SLE). The association includes risk and protective components. They could be due to combinations of functional polymorphisms and related to cis-regulation of IRF5 expression, but their mechanisms are still uncertain. We hypothesised that thorough testing of the relationships between IRF5 polymorphisms, expression data from multiple experiments and SLE-associated haplotypes might provide useful new information. 相似文献954.
Opitz E Koch A Klingel K Schmidt F Prokop S Rahnefeld A Sauter M Heppner FL Völker U Kandolf R Kuckelkorn U Stangl K Krüger E Kloetzel PM Voigt A 《PLoS pathogens》2011,7(9):e1002233
Proteasomes recognize and degrade poly-ubiquitinylated proteins. In infectious disease, cells activated by interferons (IFNs) express three unique catalytic subunits β1i/LMP2, β2i/MECL-1 and β5i/LMP7 forming an alternative proteasome isoform, the immunoproteasome (IP). The in vivo function of IPs in pathogen-induced inflammation is still a matter of controversy. IPs were mainly associated with MHC class I antigen processing. However, recent findings pointed to a more general function of IPs in response to cytokine stress. Here, we report on the role of IPs in acute coxsackievirus B3 (CVB3) myocarditis reflecting one of the most common viral disease entities among young people. Despite identical viral load in both control and IP-deficient mice, IP-deficiency was associated with severe acute heart muscle injury reflected by large foci of inflammatory lesions and severe myocardial tissue damage. Exacerbation of acute heart muscle injury in this host was ascribed to disequilibrium in protein homeostasis in viral heart disease as indicated by the detection of increased proteotoxic stress in cytokine-challenged cardiomyocytes and inflammatory cells from IP-deficient mice. In fact, due to IP-dependent removal of poly-ubiquitinylated protein aggregates in the injured myocardium IPs protected CVB3-challenged mice from oxidant-protein damage. Impaired NFκB activation in IP-deficient cardiomyocytes and inflammatory cells and proteotoxic stress in combination with severe inflammation in CVB3-challenged hearts from IP-deficient mice potentiated apoptotic cell death in this host, thus exacerbating acute tissue damage. Adoptive T cell transfer studies in IP-deficient mice are in agreement with data pointing towards an effective CD8 T cell immune. This study therefore demonstrates that IP formation primarily protects the target organ of CVB3 infection from excessive inflammatory tissue damage in a virus-induced proinflammatory cytokine milieu. 相似文献
955.
Human and Saccharomyces cerevisiae MutLα, and some bacterial MutL proteins, possess a metal ion-dependent endonuclease activity which is important for the in vivo function of these proteins. Conserved amino acids of the C-terminal region of human PMS2, S. cerevisiae PMS1 and of some bacterial MutL proteins have been implicated in the metal-binding/endonuclease activity. However, the contribution of individual amino acids to these activities has not yet been fully elucidated. In this work we show that Pseudomonas aeruginosa MutL protein possess an in vitro metal ion-dependent endonuclease activity. In agreement with previous published results, we observed that mutation of the aspartic acid, the first histidine or the first glutamic acid of the conserved C-terminal DMHAAHERITYE region results in nonfunctional in vivo proteins. We also determined that the arginine residue is essential for the in vivo function of this protein. However, we unexpectedly observed that although the first glutamic acid mutant derivative is not functional in vivo, its in vitro endonuclease activity is even higher than that of the wild-type protein. 相似文献
956.
Manuela T. Raimondi Elisa Bonacina Gabriele Candiani Matteo Laganà Elena Rolando Giuseppe Talò Daniele Pezzoli Roberto D’Anchise Riccardo Pietrabissa Matteo Moretti 《Biomechanics and modeling in mechanobiology》2011,10(2):259-268
We present an integrated experimental–computational mechanobiology model of chondrogenesis. The response of human articular
chondrocytes to culture medium perfusion, versus perfusion associated with cyclic pressurisation, versus non-perfused culture,
was compared in a pellet culture model, and multiphysic computation was used to quantify oxygen transport and flow dynamics
in the various culture conditions. At 2 weeks of culture, the measured cell metabolic activity and the matrix content in collagen
type II and aggrecan were greatest in the perfused+pressurised pellets. The main effects of perfusion alone, relative to static
controls, were to suppress collagen type I and GAG contents, which were greatest in the non-perfused pellets. All pellets
showed a peripheral layer of proliferating cells, which was thickest in the perfused pellets, and most pellets showed internal
gradients in cell density and matrix composition. In perfused pellets, the computed lowest oxygen concentration was 0.075 mM
(7.5% tension), the maximal oxygen flux was 477.5 nmol/m2/s and the maximal fluid shear stress, acting on the pellet surface, was 1.8 mPa (0.018 dyn/cm2). In the non-perfused pellets, the lowest oxygen concentration was 0.003 mM (0.3% tension) and the maximal oxygen flux was
102.4 nmol/m2/s. A local correlation was observed, between the gradients in pellet properties obtained from histology, and the oxygen fields
calculated with multiphysic simulation. Our results show up-regulation of hyaline matrix protein production by human chondrocytes
in response to perfusion associated with cyclic pressurisation. These results could be favourably exploited in tissue engineering
applications. 相似文献
957.
Tramentozzi E Tibaldi E Brunati AM Pagetta A Finotti P 《Journal of cellular and molecular medicine》2011,15(12):2768-2780
Previous observations showed that complexes of glucose-regulated protein94 (Grp94) with human IgG, both those isolated from plasma of diabetic subjects and complexes formed in vitro, displayed cytokine-like effects on human umbilical vein endothelial cells (HUVECs), including angiogenic-like transformation capacity that predicted an increased risk of vascular damage. The aim of the present work was to find an effective inhibitor of the angiogenic-like effect of Grp94-IgG complexes. Because this effect is mediated by an increased expression of matrix metalloprotease-9 (MMP-9), we tested the selective MMP-9 inhibitor, the cyclic decapeptide CTT (CTTHWGFTLC) at 5, 10 and 20 μM. CCT failed to inhibit any morphological alteration induced by Grp94-IgG on HUVECs, on its own displaying a paradoxical angiogenic-like activity. We identified the phosphatidylinositol 3-kinase (PI3K)/Akt pathway as the specific target activated by both Grp94-IgG and CTT for sustaining the angiogenic-like transformation of HUVECs. Functioning of the PI3K/Akt pathway was crucially dependent on functional heat-shock protein (HSP)90, and both Grp94-IgG and CTT caused and increased expression of HSP90, promoting its localization to podosomes. CTT appeared to enhance the angiogenic-like effect of Grp94-IgG by increasing the rate of secretion of both HSP90 and MMP-9. By preventing the chaperoning capacity of HSP90 with the inhibitor purine-scaffold (PU)-H71 that blocked the ATP-binding site on HSP90, it was possible to inhibit the expression of Akt and secretion of HSP90 and MMP-9 induced by Grp94-IgG, thus completely reversing the angiogenic pattern. Results reveal a fundamental role of HSP90 in the PI3K/Akt pathway-mediated angiogenic-like effect of Grp94-IgG, also questioning the capacity of CTT to serve as an effective inhibitor of the angiogenic effect. 相似文献
958.
Tiziana Montemurro Gabriella Andriolo Elisa Montelatici Gaia Weissmann Mihaela Crisan Maria Rosa Colnaghi Paolo Rebulla Fabio Mosca Bruno Péault Lorenza Lazzari 《Journal of cellular and molecular medicine》2011,15(4):796-808
Mesenchymal stem cells (MSC) have been derived from different cultured human tissues, including bone marrow, adipose tissue, amniotic fluid and umbilical cord blood. Only recently it was suggested that MSC descended from perivascular cells, the latter being defined as CD146+ neuro‐glial proteoglycan (NG)2+ platelet‐derived growth factor‐Rβ+ ALP+ CD34– CD45– von Willebrand factor (vWF)– CD144–. Herein we studied the properties of perivascular cells from a novel source, the foetal human umbilical cord (HUC) collected from pre‐term newborns. By immunohistochemistry and flow cytometry we show that pre‐term/foetal HUCs contain more perivascular cells than their full‐term counterparts (2.5%versus 0.15%). Moreover, foetal HUC perivascular cells (HUCPC) express the embryonic cell markers specific embryonic antigen‐4, Runx1 and Oct‐4 and can be cultured over the long term. To further confirm the MSC identity of these cultured perivascular cells, we also showed their expression at different passages of antigens that typify MSC. The multilineage differentiative capacity of HUCPC into osteogenic, adipogenic and myogenic cell lineages was demonstrated in culture. In the perspective of a therapeutic application in chronic lung disease of pre‐term newborns, we demonstrated the in vitro ability of HUCPC to migrate towards an alveolar type II cell line damaged with bleomycin, an anti‐cancer agent with known pulmonary toxicity. The secretory profile exhibited by foetal HUCPC in the migration assay suggested a paracrine effect that could be exploited in various clinical conditions including lung disorders. 相似文献
959.
The identification of biomarkers is one of the leading research areas in proteomics. When biomarkers have to be searched for in spot volume datasets produced by 2D gel-electrophoresis, problems may arise related to the large number of spots present in each map and the small number of samples available in each class (control/pathological). In such cases multivariate methods are usually exploited together with variable selection procedures, to provide a set of possible biomarkers: they are however usually aimed to the selection of the smallest set of variables (spots) providing the best performances in prediction. This approach seems not to be suitable for the identification of potential biomarkers since in this case all the possible candidate biomarkers have to be identified to provide a general picture of the "pathological state": in this case exhaustivity has to be preferred to provide a complete understanding of the mechanisms underlying the pathology. We propose here a ranking and classification method, "Ranking-PCA", based on Principal Component Analysis and variable selection in forward search: the method selects one variable at a time as the one providing the best separation of the two classes investigated in the space given by the relevant PCs. The method was applied to an artificial dataset and a real case-study: Ranking-PCA exhaustively identified the potential biomarkers and provided reliable and robust results. 相似文献
960.
Bisphosphonates (BP's), biologically stable analogs of naturally occurring pyrophosphates, became the treatment of choice for pathologic conditions characterized by increased osteoclast-mediated bone resorption, namely Paget's disease, osteoporosis and tumor bone disease. Moreover, the clinical success of BP's is also associated with their use in (99m)Tc-based radiopharmaceuticals for bone imaging. In addition to the successful delivery of (99m)Tc (γ-emitter) to bone, BP's have also been used to deliver β(-)-particle emitting radiometals (e.g.(153)Sm, (186/188)Re) for bone-pain palliation. The main goal of this Review is to update the most recent research efforts toward the synthesis, characterization and biological evaluation of novel BP-containing radiometal complexes and radiohalogenated compounds for diagnostic or therapeutic purposes. The structure and in vivo properties of those compounds will be discussed and compared to the clinically available ones, namely in terms of image quality and therapeutic effect. We will also mention briefly the use of BP's as carriers of multimodal nuclear and optical imaging probes. 相似文献