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101.
Impaired immunoregulation in systemic lupus erythematosus: defective adenosine-induced suppressor T lymphocyte generation 总被引:6,自引:0,他引:6
G M Kammer R E Birch S H Polmar 《Journal of immunology (Baltimore, Md. : 1950)》1983,130(4):1706-1712
It is currently unclear whether the suppressor cell dysfunction observed during active systemic lupus erythematosus (SLE) reflects a primary T cell disorder or one that results from immunologic modulation of suppressor T cell activity by autoantibodies. To determine whether the suppressor T cell dysfunction of active SLE is the result of a primary T cell disorder, the model of adenosine-induced immunosuppression was utilized to study the suppressor T cell functions of 12 patients with SLE (seven active SLE, five inactive SLE) and 12 matched healthy controls. T lymphocyte phenotyping was performed by utilizing monoclonal antibodies directed against T cell-specific determinants. Suppressor T cell functions were assessed by two assays in parallel. The first technique tested the capacity of two suppressor T cell subsets (spontaneous suppressors, Ts; adenosine-inducible suppressors, TRA) to inhibit pokeweed mitogen- (PWM) induced B cell differentiation. In the second technique, the ability of enriched T cell preparations to suppress mitogen- and alloantigen-induced proliferation was assayed. It was demonstrated that brief treatment of the control theophylline-resistant T lymphocyte (TR) subset possessing inducer/helper activity with adenosine (10(-5) M, 30 min, 37 degrees C) triggered a rapid shift in phenotype (RFC gamma -, T-4+ leads to RFC gamma +, T-8+) in a proportion of the subset, and the development of radioresistant suppressor function. By contrast, exposure of active SLE TR to adenosine failed to induce either the switch of phenotype or suppressor activity. When compared to controls, both the TS and TRA suppressors failed to inhibit B cell differentiation (TS, p less than 0.001; TRA, p less than 0.001). Moreover, enriched T cell preparations incompletely suppressed the proliferative responses to phytohemagglutinin (p less than 0.003), PWM (p less than 0.0003), or alloantigens (p less than 0.01). During inactive SLE, the T cell responses were usually restored. Treatment of the TR subsets with adenosine induced a switch of phenotype in four of five patients and the subsequent expression of effective suppressor function. We conclude that a) during active SLE, there is impaired suppression of proliferation and B cell differentiation; b) the impaired suppression of B cell differentiation results from abnormal spontaneous (TS) and adenosine-inducible (TRA) suppressor functions; c) the defective generation of suppressor T cell function during active disease results, in part, from a block in the transition from inducer/helper to suppressor cell; and, d) the suppressor T cell dysfunction is reversible with disease remission. The investigation of immunopharmacologic events by using the adenosine-induced immuno-suppression model in T cells from normal donors and SLE patients may provide insights into the molecular basis of disordered immunoregulation in SLE. 相似文献
102.
Lukoye Atwoli Abdullah H. Baqui Thomas Benfield Raffaella Bosurgi Fiona Godlee Stephen Hancocks Richard Horton Laurie Laybourn-Langton Carlos Augusto Monteiro Ian Norman Kirsten Patrick Nigel Praities Marcel GM Olde Rikkert Eric J. Rubin Peush Sahni Richard Smith Nick Talley Sue Turale Damin Vzquez 《PLoS medicine》2021,18(9)
103.
Anton?C?van de Vusse Suzanne?GM?Stomp-van den Berg Alfons?HF?Kessels Wim?EJ?WeberEmail author 《BMC neurology》2004,4(1):13
Background
Complex Regional Pain Syndrome type one (CRPS I) or formerly Reflex Sympathetic Dystrophy (RSD) is a disabling syndrome, in which a painful limb is accompanied by varying symptoms. Neuropathic pain is a prominent feature of CRPS I, and is often refractory to treatment. Since gabapentin is an anticonvulsant with a proven analgesic effect in various neuropathic pain syndromes, we sought to study the efficacy of the anticonvulsant gabapentin as treatment for pain in patients with CRPS I. 相似文献104.
Mishra N Khan IU Tsokos GC Kammer GM 《Journal of immunology (Baltimore, Md. : 1950)》2000,165(5):2830-2840
Systemic lupus erythematosus (SLE) is an autoimmune disorder of indeterminate etiology characterized by abnormal T cell signal transduction and altered T cell effector functions. We have previously observed a profound deficiency of total protein kinase A (PKA) phosphotransferase activity in SLE T cells. Here we examined whether reduced total PKA activity in SLE T cells is in part the result of deficient type II PKA (PKA-II) isozyme activity. The mean PKA-II activity in SLE T cells was 61% of normal control T cells. The prevalence of deficient PKA-II activity in 35 SLE subjects was 37%. Deficient isozyme activity was persistent over time and was unrelated to SLE disease activity. Reduced PKA-II activity was associated with spontaneous dissociation of the cytosolic RIIbeta2C2 holoenzyme and translocation of the regulatory (RIIbeta) subunit from the cytosol to the nucleus. Confocal immunofluorescence microscopy revealed that the RIIbeta subunit was present in approximately 60% of SLE T cell nuclei compared with only 2-3% of normal and disease controls. Quantification of nuclear RIIbeta subunit protein content by immunoprecipitation and immunoblotting demonstrated a 54% increase over normal T cell nuclei. Moreover, the RIIbeta subunit was retained in SLE T cell nuclei, failed to relocate to the cytosol, and was associated with a persistent deficiency of PKA-II activity. In conclusion, we describe a novel mechanism of deficient PKA-II isozyme activity due to aberrant nuclear translocation of the RIIbeta subunit and its retention in the nucleus in SLE T cells. Deficient PKA-II activity may contribute to impaired signaling in SLE T cells. 相似文献
105.
Okitsu SL Silvie O Westerfeld N Curcic M Kammer AR Mueller MS Sauerwein RW Robinson JA Genton B Mazier D Zurbriggen R Pluschke G 《PloS one》2007,2(12):e1278
Objectives
Peptides delivered on the surface of influenza virosomes have been shown to induce solid humoral immune responses in experimental animals. High titers of peptide-specific antibodies were also induced in a phase 1a clinical trial in volunteers immunized with virosomal formulations of two peptides derived from the circumsporozoite protein (CSP) and the apical membrane antigen 1 (AMA-1) of Plasmodium falciparum. The main objective of this study was to perform a detailed immunological and functional analysis of the CSP-specific antibodies elicited in this phase 1a trial.Methodology/Principal Findings
46 healthy malaria-naïve adults were immunized with virosomal formulations of two peptide-phosphatidylethanolamine conjugates, one derived from the NANP repeat region of P. falciparum CSP (designated UK-39) the other from P. falciparum AMA-1 (designated AMA49-C1). The two antigens were delivered in two different concentrations, alone and in combination. One group was immunized with empty virosomes as control. In this report we show a detailed analysis of the antibody response against UK-39. Three vaccinations with a 10 µg dose of UK-39 induced high titers of sporozoite-binding antibodies in all volunteers. This IgG response was affinity maturated and long-lived. Co-administration of UK-39 and AMA49-C1 loaded virosomes did not interfere with the immunogenicity of UK-39. Purified total IgG from UK-39 immunized volunteers inhibited sporozoite migration and invasion of hepatocytes in vitro. Sporozoite inhibition closely correlated with titers measured in immunogenicity assays.Conclusions
Virosomal delivery of a short, conformationally constrained peptide derived from P. falciparum CSP induced a long-lived parasite-inhibitory antibody response in humans. Combination with a second virosomally-formulated peptide derived from P. falciparum AMA-1 did not interfere with the immunogenicity of either peptide, demonstrating the potential of influenza virosomes as a versatile, human-compatible antigen delivery platform for the development of multivalent subunit vaccines.Trial Registration
ClinicalTrials.gov NCT00400101相似文献106.
Stuart A Suttie Alan GK Li Martha Quinn Kenneth GM Park 《World journal of surgical oncology》2007,5(1):1-9
Background
Caveolin-1 is thought to have an important impact on both signal transduction and mediation of intracellular processes. Furthermore, it has been suggested that Caveolin-1 may contribute to certain steps of carcinogenesis in various types of cancer. We examined the potential clinical relevance of Caveolin-1 in normal, benign and malignant breast tissue specimens.Methods
Using tissue microarray (TMA) technology cases of invasive breast cancer, DCIS, benign breast disease (i.e. fibroadenoma, sclerosing adenosis, ductal hyperplasia and radial scar) and normal breast tissue were evaluated for Caveolin-1 expression. Immunohistochemical staining with an anti-Caveolin-1-antibody was performed. Staining intensity was quantified semiquantitatively. In invasive lesions staining results were correlated with clinical and pathological data.Results
No Caveolin-1 expression was observed in epithelial cells of normal breast tissue (n = 5), benign breast disease (n = 295) and DCIS (n = 108). However, Caveolin-1 expression was found in 32 of 109 cases of invasive breast carcinomas (29.4%). Caveolin-1 expression in invasive breast cancer could neither be correlated with survival parameters such as overall or disease-free survival nor with established clinical and pathological markers.Conclusion
In this study we demonstrated expression of Caveolin-1 in one third of invasive breast cancers. A significant increase in Caveolin-1 expression was observed comparing invasive breast cancer to both benign breast tissue and non-invasive breast cancer. Since inhibitors of Caveolin-1 signalling are available, targeting Caveolin-1 in breast cancer may represent a potential option for future breast cancer treatment. 相似文献107.
Principal component models for sparse functional data 总被引:5,自引:0,他引:5
108.
Decomposition of leaf litter and its incorporation into the mineral soil are key components of the C cycle in forest soils. In a 13C tracer experiment, we quantified the pathways of C from decomposing leaf litter in calcareous soils of a mixed beech forest in the Swiss Jura. Moreover, we assessed how important the cold season is for the decomposition of freshly fallen leaves. The annual C loss from the litter layer of 69–77% resulted mainly from the C mineralization (29–34% of the initial litter C) and from the transfer of litter material to the deeper mineral soil (>4 cm) by soil fauna (30%). Although only 4–5% of the initial litter C was leached as dissolved organic carbon (DOC), this pathway could be important for the C sequestration in soils in the long term: The DOC leached from the litter layer was mostly retained (95%) in the first 5 cm of the mineral soil by both physico-chemical sorption and biodegradation and, thus, it might have contributed significantly to the litter-derived C recovered in the heavy fraction (>1.6 g cm?3) at 0–4 cm depth (4% of the initial litter C). About 80% of the annual DOC leaching from the litter layer occurred during the cold season (Nov–April) due to an initial DOC flush of water-soluble substances. In contrast, the litter mineralization in winter accounted for only 25% of the annual C losses through CO2 release from the labelled litter. Nevertheless, the highest contributions (45–60%) of litter decay to the heterotrophic soil respiration were observed on warm winter days when the mineral soil was still cold and the labile litter pool only partly mineralized. Our 13C tracing also revealed that: (1) the fresh litter C only marginally primed the mineralization of older SOM (>1 year); and (2) non-litter C, such as throughfall DOC, contributed significantly to the C fluxes from the litter layer since the microbial biomass and the DOC leached from the litter layer contained 20–30% and up to 60% of unlabelled C, respectively. In summary, our study shows that significant amounts of recent leaf litter C (<1 year) are incorporated into mineral soils and that the cold season is clearly less important for the litter turnover than the warm season in this beech forest ecosystem. 相似文献
109.
110.
Alexandre Wagner Silva de Souza Johanna Westra Johan Bijzet Pieter C Limburg Coen A Stegeman Marc Bijl Cees GM Kallenberg 《Arthritis research & therapy》2013,15(5):R104