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61.
Urbahns K Härter M Albers M Schmidt D Stelte-Ludwig B Brüggemeier U Vaupel A Keldenich J Lustig K Tsujishita H Gerdes C 《Bioorganic & medicinal chemistry letters》2007,17(22):6151-6154
Vitronectin receptor (alpha(V)beta(3)) antagonists have been implicated as a possible new treatment of restenosis following balloon angioplasty. In this work we investigate a series of novel arginine mimetic scaffolds leading to new insight of the alpha(V)beta(3)/ligand interaction. Squaric acid amide 10 is a subnanomolar alpha(V)beta(3) antagonist with improved potency on human smooth muscle cell migration. 相似文献
62.
Eriksson U Hilfinger JM Kim JS Mitchell S Kijek P Borysko KZ Breitenbach JM Drach JC Kashemirov BA McKenna CE 《Bioorganic & medicinal chemistry letters》2007,17(3):583-586
Cidofovir (HPMPC) is a broad-spectrum anti-viral agent whose potential, particularly in biodefense scenarios, is limited by its low oral bioavailability. Two prodrugs (3 and 4) created by conjugating ethylene glycol-linked amino acids (L-Val, L-Phe) with the cyclic form of cidofovir (cHPMPC) via a P-O ester bond were synthesized and their pH-dependent stability (3 and 4), potential for in vivo reconversion to drug (3), and oral bioavailability (3) were evaluated. The prodrugs were stable in buffer between pH 3 and 5, but underwent rapid hydrolysis in liver (t(1/2) = 3.7 min), intestinal (t(1/2) = 12.5 min), and Caco-2 cell homogenates (t(1/2) = 20.2 min). In vivo (rat), prodrug 3 was >90% reconverted to cHPMPC. The prodrug was 4x more active than ganciclovir (IC50 value, 0.68 microM vs 3.0 microM) in a HCMV plaque reduction assay. However, its oral bioavailability in a rat model was similar to the parent drug. The contrast between the promising activation properties and unenhanced transport of the prodrug is briefly discussed. 相似文献
63.
Calpains are cytoplasmic Ca(2+)-regulated cysteine proteases that may regulate insulin-like growth factor (IGF)-independent actions of insulin-like growth factor binding proteins (IGFBPs) through IGFBP proteolysis. In this study, [(125)I]-labeled IGFBP-2 and -3, but not IGFBP-1, were proteolyzed by Ca(2+)-activated m-calpain in vitro. Degradation of higher concentrations of the recombinant proteins IGFBP-2 and -3 by m-calpain was dose-dependent, but was terminated within 20 min by autolysis. By subjecting proteolytic fragments to N-terminal amino acid sequence analysis, the primary cleavage sites in IGFBP-2 and -3 were localized to the non-conserved central linker regions. Using the biosensor technique, in vitro binding of m-calpain to IGFBP-3 was demonstrated to be a Ca(2+)-dependent reaction with a rapid on/off rate. 相似文献
64.
Activation of astrocytes accompanies many brain pathologies. Reactive astrocytes have a beneficial role in acute neurotrauma but later on might inhibit regeneration. 2D-gel electrophoresis and mass spectrometry were applied to study the proteome difference in denervated hippocampus in wildtype mice and mice lacking intermediate filament proteins glial fibrillary acidic protein (GFAP) and vimentin (GFAP-/-Vim-/-) that show attenuated reactive gliosis and enhanced posttraumatic regeneration. Proteomic data and immunohistochemical analyses showed upregulation of the adapter protein 14-3-3 four days postlesion and suggested that 14-3-3 upregulation after injury is triggered by reactive gliosis. Culture-derived isotope tags (CDIT) and mass spectrometry demonstrated that 14-3-3 epsilon was the major isoform upregulated in denervated hippocampus and that its upregulation was attenuated in GFAP-/-Vim-/- mice and thus most likely connected to reactive gliosis. 相似文献
65.
Annica Andersson Alexandra Stubelius Merja Nurkkala Karlsson Cecilia Engdahl Malin Erlandsson Louise Grahnemo Marie K Lagerquist Ulrika Islander 《Arthritis research & therapy》2015,17(1)
IntroductionThe incidence and progression of many autoimmune diseases are sex-biased, which might be explained by the immunomodulating properties of endocrine hormones. Treatment with estradiol potently inhibits experimental autoimmune arthritis. Interleukin-17-producing T helper cells (Th17) are key players in several autoimmune diseases, particularly in rheumatoid arthritis. The aim of this study was to investigate the effects of estrogen on Th17 cells in experimental arthritis.MethodsOvariectomized DBA/1 mice treated with 17β-estradiol (E2) or placebo were subjected to collagen-induced arthritis (CIA), and arthritis development was assessed. Th17 cells in joints and lymph nodes were studied by flow cytometry. Lymph node Th17 cells were also examined in ovariectomized estrogen receptor α–knockout mice (ERα−/−) and wild-type littermates, treated with E2 or placebo and subjected to antigen-induced arthritis.ResultsE2-treated mice with established CIA showed reduced severity of arthritis and fewer Th17 cells in joints compared with controls. Interestingly, E2-treated mice displayed increased Th17 cells in lymph nodes during the early phase of the disease, dependent on ERα. E2 increased the expression of C-C chemokine receptor 6 (CCR6) on lymph node Th17 cells as well as the expression of the corresponding C-C chemokine ligand 20 (CCL20) within lymph nodes.ConclusionsThis is the first study in which the effects of E2 on Th17 cells have been characterized in experimental autoimmune arthritis. We report that E2 treatment results in an increase of Th17 cells in lymph nodes during the early phase of arthritis development, but leads to a decrease of Th17 in joints during established arthritis. Our data suggest that this may be caused by interference with the CCR6-CCL20 pathway, which is important for Th17 cell migration. This study contributes to the understanding of the role of estrogen in the development of autoimmune arthritis and opens up new fields for research concerning the sex bias in autoimmune disease.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-015-0548-y) contains supplementary material, which is available to authorized users. 相似文献66.
An integrated UASB-sludge digester system for raw domestic wastewater treatment in temperate climates 总被引:1,自引:0,他引:1
To improve the performance of an upflow anaerobic sludge blanket (UASB) reactor treating raw domestic wastewater under temperate climates conditions, the addition of a sludge digester to the process was investigated. With the decrease in temperature, the COD removal decreased from 78% at 28 °C to 42% at 10 °C for the UASB reactor operating alone at a hydraulic retention time of 6 h. The decrease was attributed to low hydrolytic activity at lower temperatures that reduced suspended matter degradation and resulted in solids accumulation in the top of the sludge blanket. Solids removed from the upper part of the UASB sludge were treated in an anaerobic digester. Based on sludge degradation kinetics at 30 °C, a digester of 0.66 l per liter of UASB reactor was design operating at a 3.20 days retention time. Methane produced by the sludge digester is sufficient to maintain the temperature at 30 °C. 相似文献
67.
68.
69.
Omprakash Sarkar Ulrika Rova Paul Christakopoulos Leonidas Matsakas 《Engineering in Life Science》2022,22(10):650
The present study reports the mixed culture acidogenic production of biohydrogen and carboxylic acids (CA) from brewery spent grains (BSG) in the presence of high concentrations of cobalt, iron, nickel, and zinc. The metals enhanced biohydrogen output by 2.39 times along with CA biosynthesis by 1.73 times. Cobalt and iron promoted the acetate and butyrate pathways, leading to the accumulation of 5.14 gCOD/L of acetic and 11.36 gCOD/L of butyric acid. The production of solvents (ethanol + butanol) was higher with zinc (4.68 gCOD/L) and cobalt (4.45 gCOD/L). A combination of all four metals further enhanced CA accumulation to 42.98 gCOD/L, thus surpassing the benefits accrued from supplementation with individual metals. Additionally, 0.36 and 0.31 mol green ammonium were obtained from protein‐rich brewery spent grain upon supplementation with iron and cobalt, respectively. Metagenomic analysis revealed the high relative abundance of Firmicutes (>90%), of which 85.02% were Clostridium, in mixed metal‐containing reactors. Finally, a significant correlation of dehydrogenase activity with CA and biohydrogen evolution was observed upon metal addition. 相似文献
70.
Jochems C Islander U Erlandsson M Verdrengh M Ohlsson C Carlsten H 《Arthritis research & therapy》2005,7(4):R837-R843
Generalized osteoporosis in postmenopausal rheumatoid arthritis (RA) is caused both by estrogen deficiency and by the inflammatory
disease. The relative importance of each of these factors is unknown. The aim of this study was to establish a murine model
of osteoporosis in postmenopausal RA, and to evaluate the relative importance and mechanisms of menopause and arthritis-related
osteoporosis. To mimic postmenopausal RA, DBA/1 mice were ovariectomized, followed by the induction of type II collagen-induced
arthritis. After the mice had been killed, paws were collected for histology, one femur for bone mineral density (BMD) and
sera for analyses of markers of bone resorption (RatLaps; type I collagen cross-links, bone formation (osteocalcin) and cartilage
destruction (cartilage oligomeric matrix protein), and for the evaluation of antigen-specific and innate immune responsiveness.
Ovariectomized mice displayed more severe arthritis than sham-operated controls. At termination of the experiment, arthritic
control mice and non-arthritic ovariectomized mice displayed trabecular bone losses of 26% and 22%, respectively. Ovariectomized
mice with arthritis had as much as 58% decrease in trabecular BMD. Interestingly, cortical BMD was decreased by arthritis
but was not affected by hormonal status. In addition, markers of bone resorption and cartilage destruction were increased
in arthritic mice, whereas markers of bone formation were increased in ovariectomized mice. This study demonstrates that the
loss of endogenous estrogen and inflammation contribute additively and equally to osteoporosis in experimental postmenopausal
polyarthritis. Markers of bone remodeling and bone marrow lymphocyte phenotypes indicate different mechanisms for the development
of osteoporosis caused by ovariectomy and arthritis in this model. 相似文献