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51.
52.
From conversion to aggregation: protofibril formation of the prion protein 总被引:6,自引:0,他引:6 下载免费PDF全文
DeMarco ML Daggett V 《Proceedings of the National Academy of Sciences of the United States of America》2004,101(8):2293-2298
The ability to diagnose and treat prion diseases is limited by our current understanding of the conversion process of the protein from healthy to harmful isoform. Whereas the monomeric, benign species is well characterized, the misfolded conformations responsible for infectivity and neurodegeneration remain elusive. There is mounting evidence that fibrillization intermediates, or protofibrils, but not mature fibrils or plaques, are the pathogenic species in amyloid diseases. Here, we use molecular dynamics to simulate the conversion of the prion protein. Molecular dynamics simulation produces a scrapie prion protein-like conformation enriched in β-structure that is in good agreement with available experimental data. The converted conformation was then used to model a protofibril by means of the docking of hydrophobic patches of the template structure to form hydrogen-bonded sheets spanning adjacent subunits. The resulting protofibril model provides a non-branching aggregate with a 31 axis of symmetry that is in good agreement with a wide variety of experimental data; importantly, it was derived from realistic simulation of the conversion process. 相似文献
53.
Mapping the early steps in the pH-induced conformational conversion of the prion protein 总被引:1,自引:0,他引:1 下载免费PDF全文
Alonso DO DeArmond SJ Cohen FE Daggett V 《Proceedings of the National Academy of Sciences of the United States of America》2001,98(6):2985-2989
Under certain conditions, the prion protein (PrP) undergoes a conformational change from the normal cellular isoform, PrP(C), to PrP(Sc), an infectious isoform capable of causing neurodegenerative diseases in many mammals. Conversion can be triggered by low pH, and in vivo this appears to take place in an endocytic pathway and/or caveolae-like domains. It has thus far been impossible to characterize the conformational change at high resolution by experimental methods. Therefore, to investigate the effect of acidic pH on PrP conformation, we have performed 10-ns molecular dynamics simulations of PrP(C) in water at neutral and low pH. The core of the protein is well maintained at neutral pH. At low pH, however, the protein is more dynamic, and the sheet-like structure increases both by lengthening of the native beta-sheet and by addition of a portion of the N terminus to widen the sheet by another two strands. The side chain of Met-129, a polymorphic codon in humans associated with variant Creutzfeldt-Jakob disease, pulls the N terminus into the sheet. Neutralization of Asp-178 at low pH removes interactions that inhibit conversion, which is consistent with the Asp-178-Asn mutation causing human prion diseases. 相似文献
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中西医结合医院单病种的质量管理及其作用 总被引:1,自引:0,他引:1
针对中西医结合医院单病种质量评定没有现成的、规范的标准的现状,就中西医结合单病种的质量管理方法及其在中西医结合医院建设中的作用进行了论述。 相似文献
57.
Pretreatment of recipients with the monoclonal antibody (MoAb) S5 facilitates engraftment of bone marrow from mismatched, unrelated donors in the canine transplantation model. In the direct comparisons reported here, the S5 glycoprotein (gp) was found to have structural homology to CD44 that in humans has been implicated in adhesive interactions of one type of effector cell, the lymphocyte. The S5 antigen and gp90Hermes-1 exhibited codistribution on canine peripheral blood cells. Both S5 and Hermes-1 (anti-CD44) MoAbs recognized 90-Kd species in radioimmune precipitations of 125I surface-labeled canine peripheral blood lymphocytes and bone marrow cells. Competitive antibody binding experiments showed that the epitope detected by S5 was distinct from that bound by Hermes-1 but overlapped with those defined by two other known anti-CD44 reagents, IM7 and Hutch-1. Sequential immunoprecipitation with S5 and Hermes-1 indicated that the two antibodies recognize the same or overlapping subsets of membrane gps. Tryptic digestion of S5 and anti-CD44 immunoprecipitates generated two major iodinated peptides of 27 and 35 Kd in both cases, a further indication of structural homology. Similarly, after N-glycanase digestion, S5 and CD44 immunoprecipitates were resolved to a single 68- Kd species. These findings suggest that CD44-mediated adhesive events may affect the fate of transplanted hematopoietic cells. The previous implications of this gp in T-lymphocyte activation and lymphocyte adhesion to endothelium thus provide useful paradigms to analyze its function in the bone marrow transplant setting. 相似文献
58.
Expression of N-Methyl-D-Aspartate receptor subunit mRNAs in the human brain: Hippocampus and cortex
Clemens R. Scherzer G. Bernhard Landwehrmeyer Julie A. Kerner Timothy J. Counihan Christoph M. Kosinski David G. Standaert Lorrie P. Daggett Gnül Velielebi John B. Penney Anne B. Young 《The Journal of comparative neurology》1998,390(1):75-90
N-methyl-D-aspartate receptor (NR) activation in the hippocampus and neocortex plays a central role in memory and cognitive function. We analyzed the cellular expression of the five NR subunit (NR1 and NR2A-D) mRNAs in these regions with in situ hybridization and human ribonucleotide probes. Film autoradiograms demonstrated a distinct pattern of hybridization signal in the hippocampal complex and the neocortex with probes for NR1, NR2A, and NR2B mRNA. NR2C and NR2D probes yielded scattered signals without a distinct organization. At the emulsion level, the NR1 probe produced high-density hybridization signals across the hippocampal complex. NR2A mRNA was higher in dentate granule cells and pyramidal cells in CA1 and subiculum compared to hilus neurons. NR2B mRNA expression was moderate throughout, with higher expression in dentate granule cells, CA1 and CA3 pyramidal cells than in hilus neurons. In the hippocampal complex, the NR2C probe signal was not different from background in any region, whereas the NR2D probe signal resulted in low to moderate grain densities. We analyzed NR subunit mRNA expression in the prefrontal, parietal, primary visual, and motor cortices. All areas displayed strong NR1 hybridization signals. NR2A and NR2B mRNAs were expressed in cortical areas and layers. NR2C mRNA was expressed at low levels in distinct layers that differed by region and the NR2D signal was equally moderate throughout all regions. Pyramidal cells in both hippocampus and neocortex express NR1, NR2A, NR2B, and, to a lesser extent, NR2D mRNA. Interneurons or granular layer neurons and some glial cells express NR2C mRNA. J. Comp. Neurol. 390:75–90, 1998. © 1998 Wiley-Liss, Inc. 相似文献
59.
Surgical management of postinfarction ventricular septal rupture 总被引:2,自引:0,他引:2
Recognition and treatment of patients with ventricular septal rupture following infarction have improved over the past 25 years to the extent that survival with good long-term palliation is achieved in the majority of patients treated surgically for this catastrophic complication of acute myocardial infarction. The small minority of patients who, by the process of selection, are seen for surgical correction of septal rupture several weeks after infarction routinely have repair of the septal defect with an operative risk of less than 10%. With increasingly early diagnosis of septal rupture, the majority of patients are seen for consideration of surgical repair often within hours after septal rupture. Most such patients seen early after septal rupture exhibit cardiogenic shock. Refinement of operative techniques both for suture repair of freshly infarcted myocardium and for repair of defects in different anatomical locations has markedly improved survival in these critically ill patients. Deferral of operation for the patient in cardiogenic shock after septal rupture represents a failed therapeutic strategy. Conversely, emergency operation for the patient with septal rupture and cardiogenic shock has markedly improved survival in this high-risk group. Prolonged intraaortic balloon pump support and deferred operation should be reserved for the uncommon patient who, because of delayed diagnosis or referral, is seen in an advanced stage of multisystem failure in which the risks of early operative intervention involve the function of organs other than the heart. 相似文献
60.
Naegleria and Acanthamoeba infections: review 总被引:16,自引:0,他引:16
P Ma G S Visvesvara A J Martinez F H Theodore P M Daggett T K Sawyer 《Reviews of infectious diseases》1990,12(3):490-513
Infections caused by small, free-living amebas are still unfamiliar to many clinicians, pathologists, and laboratorians. As of 31 July 1989, more than 140 cases of primary amebic meningoencephalitis caused by Naegleria fowleri and more than 40 cases of granulomatous amebic encephalitis caused by Acanthamoeba species (including two cases in patients with AIDS) and possibly by other free-living amebas had occurred worldwide. The recent increase in acanthamoeba keratitis (more than 200 cases), especially in contact lens wearers, has generated new interest in this group of amebas. Effective treatment is still lacking. Risk factors, clinical manifestations, and laboratory parameters helpful in the recognition of infections of the central nervous system (i.e., granulomatous amebic encephalitis and primary amebic meningoencephalitis) and acanthamoeba keratitis are reviewed. 相似文献