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881.
Dörner T Kaufmann J Wegener WA Teoh N Goldenberg DM Burmester GR 《Arthritis research & therapy》2006,8(3):R74-11
B cells play an important role in the pathogenesis of systemic lupus erythematosus (SLE), so the safety and activity of anti-B
cell immunotherapy with the humanized anti-CD22 antibody epratuzumab was evaluated in SLE patients. An open-label, single-center
study of 14 patients with moderately active SLE (total British Isles Lupus Assessment Group (BILAG) score 6 to 12) was conducted.
Patients received 360 mg/m2 epratuzumab intravenously every 2 weeks for 4 doses with analgesic/antihistamine premedication (but no steroids) prior to
each dose. Evaluations at 6, 10, 18 and 32 weeks (6 months post-treatment) follow-up included safety, SLE activity (BILAG
score), blood levels of epratuzumab, B and T cells, immunoglobulins, and human anti-epratuzumab antibody (HAHA) titers. Total
BILAG scores decreased by ≥ 50% in all 14 patients at some point during the study (including 77% with a ≥ 50% decrease at
6 weeks), with 92% having decreases of various amounts continuing to at least 18 weeks (where 38% showed a ≥ 50% decrease).
Almost all patients (93%) experienced improvements in at least one BILAG B- or C-level disease activity at 6, 10 and 18 weeks.
Additionally, 3 patients with multiple BILAG B involvement at baseline had completely resolved all B-level disease activities
by 18 weeks. Epratuzumab was well tolerated, with a median infusion time of 32 minutes. Drug serum levels were measurable
for at least 4 weeks post-treatment and detectable in most samples at 18 weeks. B cell levels decreased by an average of 35%
at 18 weeks and remained depressed at 6 months post-treatment. Changes in routine safety laboratory tests were infrequent
and without any consistent pattern, and there was no evidence of immunogenicity or significant changes in T cells, immunoglobulins,
or autoantibody levels. In patients with mild to moderate active lupus, 360 mg/m2 epratuzumab was well tolerated, with evidence of clinical improvement after the first infusion and durable clinical benefit
across most body systems. As such, multicenter controlled studies are being conducted in broader patient populations. 相似文献
882.
Steinfeld SD Tant L Burmester GR Teoh NK Wegener WA Goldenberg DM Pradier O 《Arthritis research & therapy》2006,8(4):R129
This open-label, phase I/II study investigated the safety and efficacy of epratuzumab, a humanised anti-CD22 monoclonal antibody, in the treatment of patients with active primary Sj?gren's syndrome (pSS). Sixteen Caucasian patients (14 females/2 males, 33-72 years) were to receive 4 infusions of 360 mg/m2 epratuzumab once every 2 weeks, with 6 months of follow-up. A composite endpoint involving the Schirmer-I test, unstimulated whole salivary flow, fatigue, erythrocyte sedimentation rate (ESR), and immunoglobulin G (IgG) was devised to provide a clinically meaningful assessment of response, defined as a > or = 20% improvement in at least two of the aforementioned parameters, with > or = 20% reduction in ESR and/or IgG considered as a single combined criterion. Fourteen patients received all infusions without significant reactions, 1 patient received 3, and another was discontinued due to a mild acute reaction after receiving a partial infusion. Three patients showed moderately elevated levels of Human anti-human (epratuzumab) antibody not associated with clinical manifestations. B-cell levels had mean reductions of 54% and 39% at 6 and 18 weeks, respectively, but T-cell levels, immunoglobulins, and routine safety laboratory tests did not change significantly. Fifty-three percent achieved a clinical response (at > or = 20% improvement level) at 6 weeks, with 53%, 47%, and 67% responding at 10, 18, and 32 weeks, respectively. Approximately 40%-50% responded at the > or = 30% level, while 10%-45% responded at the > or = 50% level for 10-32 weeks. Additionally, statistically significant improvements were observed in fatigue, and patient and physician global assessments. Further, we determined that pSS patients have a CD22 over-expression in their peripheral B cells, which was downregulated by epratuzumab for at least 12 weeks after the therapy. Thus, epratuzumab appears to be a promising therapy in active pSS, suggesting that further studies be conducted. 相似文献
883.
884.
Letavic MA Bronk BS Bertsche CD Casavant JM Cheng H Daniel KL George DM Hayashi SF Kamicker BJ Kolosko NL Norcia LJ Oberton VD Rushing MA Santoro SL 《Bioorganic & medicinal chemistry letters》2002,12(19):2771-2774
The stereoselective synthesis of two novel series of tribasic macrocyclic antibiotics with potent in vitro activity against Pasteurella multocida and Escherichia coli strains of bacteria is described. The in vitro activity can be significantly influenced by the nature of the substituents on the C-4" aminoalcohol, with the stereochemistry of the C-4" alcohol playing a less critical role. The effect of substitution and stereochemistry on the in vivo activity in a murine model of respiratory infection is also described. 相似文献
885.
Hill J Siedlecki J Parr I Morytko M Yu X Zhang Y Silverman J Controneo N Laganas V Li T Lai JJ Keith D Shimer G Finn J 《Bioorganic & medicinal chemistry letters》2003,13(23):4187-4191
N-Acylated ornithine analogues of daptomycin were synthesized and tested for their antibacterial efficacy. 相似文献
886.
887.
The interferons (IFNs) were originally described over 50 years ago, identified by their ability to confer viral resistance to cells. We now know that they are much more than just anti-viral cytokines collectively having roles in both innate and adaptive immune responses, in tumor surveillance and defense, and modulation of immune cell function. Three types of IFN have now been described, simply referred to as type I, II and III. Distinguishable by the unique receptors that they rely on for signal transduction, the three types of IFN have specific and varied roles in the maintenance of human health and defense against pathogens. In mounting an IFN-mediated immune response, the human body has developed the ability to regulate IFN-mediated signal transduction. Like all cytokines, the ability of a cell to respond to IFN is completely dependent on the presence of its cognate receptor on the surface of the target cell. Thus, one of the major mechanisms used by the human body to regulate the strength and duration of the IFN response is through regulation of receptor levels, thereby altering the cytokine-specific responsiveness of the target cell. This review will discuss the receptor system utilized by the type I IFNs and compare it with that of the type II and III IFNs, which also regulate immune responses through controlling receptor level on the cell surface. 相似文献
888.
Karen K. Martien Robin W. Baird Nicole M. Hedrick Antoinette M. Gorgone Janet L. Thieleking Daniel J. McSweeney Kelly M. Robertson Daniel L. Webster 《Marine Mammal Science》2012,28(3):E208-E232
We used mitochondrial and nuclear genetic markers to investigate population structure of common bottlenose dolphins, Tursiops truncatus, around the main Hawaiian Islands. Though broadly distributed throughout the world's oceans, bottlenose dolphins are known to form small populations in coastal waters. Recent photo‐identification data suggest the same is true in Hawaiian waters. We found genetic differentiation among (mtDNA ΦST= 0.014–0.141, microsatellite F’ST= 0.019–0.050) and low dispersal rates between (0.17–5.77 dispersers per generation) the main Hawaiian Island groups. Our results are consistent with movement rates estimated from photo‐identification data and suggest that each island group supports a demographically independent population. Inclusion in our analyses of samples collected near Palmyra Atoll provided evidence that the Hawaiian Islands are also occasionally visited by members of a genetically distinct, pelagic population. Two of our samples exhibited evidence of partial ancestry from Indo‐Pacific bottlenose dolphins (T. aduncus), a species not known to inhabit the Hawaiian Archipelago. Our findings have important implications for the management of Hawaiian bottlenose dolphins and raise concerns about the vulnerability to human impacts of pelagic species in island ecosystems. 相似文献
889.
890.
Grosse J Wehland M Pietsch J Ma X Ulbrich C Schulz H Saar K Hübner N Hauslage J Hemmersbach R Braun M van Loon J Vagt N Infanger M Eilles C Egli M Richter P Baltz T Einspanier R Sharbati S Grimm D 《FASEB journal》2012,26(2):639-655
This study focused on the effects of short-term microgravity (22 s) on the gene expression and morphology of endothelial cells (ECs) and evaluated gravisensitive signaling elements. ECs were investigated during four German Space Agency (Deutsches Zentrum für Luft- und Raumfahrt) parabolic flight campaigns. Hoechst 33342 and acridine orange/ethidium bromide staining showed no signs of cell death in ECs after 31 parabolas (P31). Gene array analysis revealed 320 significantly regulated genes after the first parabola (P1) and P31. COL4A5, COL8A1, ITGA6, ITGA10, and ITGB3 mRNAs were down-regulated after P1. EDN1 and TNFRSF12A mRNAs were up-regulated. ADAM19, CARD8, CD40, GSN, PRKCA (all down-regulated after P1), and PRKAA1 (AMPKα1) mRNAs (up-regulated) provide a very early protective mechanism of cell survival induced by 22 s microgravity. The ABL2 gene was significantly up-regulated after P1 and P31, TUBB was slightly induced, but ACTA2 and VIM mRNAs were not changed. β-Tubulin immunofluorescence revealed a cytoplasmic rearrangement. Vibration had no effect. Hypergravity reduced CARD8, NOS3, VASH1, SERPINH1 (all P1), CAV2, ADAM19, TNFRSF12A, CD40, and ITGA6 (P31) mRNAs. These data suggest that microgravity alters the gene expression patterns and the cytoskeleton of ECs very early. Several gravisensitive signaling elements, such as AMPKα1 and integrins, are involved in the reaction of ECs to altered gravity. 相似文献