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71.
p62 Is a Common Component of Cytoplasmic Inclusions in Protein Aggregation Diseases 总被引:14,自引:0,他引:14 下载免费PDF全文
Kurt Zatloukal Cornelia Stumptner Andrea Fuchsbichler Hans Heid Martina Schnoelzer Lukas Kenner Reinhold Kleinert Marco Prinz Adriano Aguzzi Helmut Denk 《The American journal of pathology》2002,160(1):255-263
Exposure of cells to stress, particularly oxidative stress, leads to misfolding of proteins and, if they are not refolded or degraded, to cytoplasmic protein aggregates. Protein aggregates are characteristic features of a variety of chronic toxic and degenerative diseases, such as Mallory bodies (MBs) in hepatocytes in alcoholic and non-alcoholic steatohepatitis, neurofibrillary tangles in neurons in Alzheimer's, and Lewy bodies in Parkinson's disease. Using 2D gel electrophoresis and mass spectrometry, we identified p62 as a novel MB component. p62 and cytokeratins (CKs) are major MB constituents; HSP 70, HSP 25, and ubiquitinated CKs are also present. These proteins characterize MBs as a prototype of disease-associated cytoplasmic inclusions generated by stress-induced protein misfolding. As revealed by transfection of tissue culture cells overexpressed p62 did not induce aggregation of regular CK filaments but selectively bound to misfolded and ubiquitinated CKs. The general role of p62 in the cellular response to misfolded proteins was substantiated by detection of p62 in other cytoplasmic inclusions, such as neurofibrillary tangles, Lewy bodies, Rosenthal fibers, intracytoplasmic hyaline bodies in hepatocellular carcinoma, and alpha1-antitrypsin aggregates. The presence of p62 along with other stress proteins and ubiquitin in cytoplasmic inclusions indicates deposition as aggregates as a third line of defense against misfolded proteins in addition to refolding and degradation. 相似文献
72.
R. Hubert Laeng Heinz A. Gerber Thomas Schaffner Kurt H. Bürki 《Virchows Archiv : an international journal of pathology》1989,415(3):265-273
Summary The present report describes the results of a combined morphological, enzyme- and immunohistochemical analysis of nine cases of malignant non Hodgkin's lymphomas (NHL) clinically presenting as lethal midline granuloma. In a previous report written before antibodies directed against B and T lymphocytes were available, a histiocytic origin of such neoplasms had been suggested. A panel of antibodies reactive with most B cells (L26, MB1, KiB3) and a majority of T cells (MT1, UCHL1) was applied on paraffin sections of formalin fixed tissues as well as antibodies directed against leukocyte common antigen (LCA), myeloid/histiocyte antigen (MAC 387), lysozyme, alpha-1-antitrypsin, alpha-1-antichymotrypsin, S-100 protein, prekeratin and immunoglobulin light chains. Enzyme histochemistry included tests for non-specific acid esterase, acid phosphatase, betaglucuronidase and chloroacetate esterase. As a result, five T, two B and two unclassified (malignant histiocytosis probable) NHL were identified, indicating distinct heterogeneity of NHL as causative disorders in lethal midline granuloma. 相似文献
73.
CD4+ T cells are pivotal for elimination of Pneumocystis carinii from infected lungs, and alveolar macrophages are considered the main effector cells clearing the infected host of P. carinii organisms. To investigate this issue, several mutant mouse strains were used in a previously established experimental setup which facilitates natural acquisition of disease through inhalation of airborne fungal organisms. Mutant mice deficient in major histocompatibility complex class II molecules (Aβ−/−), T-cell receptor αβ cells (TCRβ−/−), or all mature T and B lymphocytes (RAG-1−/−) were naturally susceptible to P. carinii, whereas mouse mutants lacking the gamma interferon (IFN-γ) receptor (IFN-γ-R−/−) or tumor necrosis factor alpha (TNF-α) type I receptor (p55) (TNF-α-RI−/−) resisted disease acquisition. Analysis of pulmonary cytokine patterns and free radical expression revealed the presence of superoxide, nitric oxide, and interleukin-1 (IL-1) mRNA and elevated levels of IFN-γ, TNF-α, and IL-12 in diseased TCRβ−/− and RAG-1−/− mice. Pulmonary macrophages of all diseased mouse mutants expressed scavenger and mannose receptors. Morbid Aβ−/− mutants displayed significant NO levels and IL-1 mRNA only, whereas heterozygous controls did not exhibit any signs of disease. Interestingly, neither IFN-γ nor TNF-α appeared to be essential for resisting natural infection with P. carinii, nor were these cytokines sufficient for mediating resistance during established disease in the absence of CD4+ T lymphocytes. Taken together, the results indicated that an activated phagocyte system, as evidenced by cytokine and NO secretion, in diseased mutants was apparently operative but did not suffice for parasite clearance in the absence of CD4+ TCRαβ cells. Therefore, additional pathways, possibly involving interactions of inflammatory cytokines with CD4+ T lymphocytes, must contribute to successful resistance against P. carinii.Immunocompromised patients, especially those suffering from AIDS, are at elevated risk of acquiring Pneumocystis carinii pneumonia (PCP), a major cause of premature mortality among AIDS patients (8, 35, 53). Various studies have emphasized that CD4+ T lymphocytes play a pivotal role in the orchestration of resistance to P. carinii (22, 43, 45), an opportunistic fungus, but the mechanisms underlying protection remain a conundrum. Pulmonary macrophages are considered the main effector cells in clearing the immunocompetent host from invading P. carinii organisms (25). It seems conceivable, therefore, that macrophage-activating functions mediated by CD4+ T cells are central to resistance. Impaired gamma interferon (IFN-γ) production by T cells from AIDS patients is thought to enhance susceptibility to P. carinii (34, 41). This notion is supported by reports that application of exogenous IFN-γ ameliorates disease in experimental animal models (2, 45). In contrast, in vivo neutralization of IFN-γ in spleen cell-reconstituted severe combined immunodeficiency (SCID) mice by a specific monoclonal antibody (MAb) does not affect parasite clearance (5). Further studies point to a critical role of tumor necrosis factor alpha (TNF-α) (5) and interleukin-1 (IL-1) (6) in maintaining an immunocompetent state. Both cytokines are mainly produced by macrophages and induce inflammatory responses (4, 10, 26). Overall, these findings support involvement of macrophage-derived cytokines in successful host resistance against P. carinii.To analyze in more depth the role of inflammatory and Th1/Th2-related pulmonary defense mechanisms in control of aerogenically acquired PCP, we took advantage of naturally susceptible gene disruption mutant mice lacking major histocompatibility complex (MHC) class II molecules (and therefore conventional CD4+ T cells) (Aβ−/−), T-cell receptor (TCR) αβ cells (TCRβ−/−), or all mature T and B lymphocytes (RAG-1−/−) (19). We further exploited mice deficient in the IFN-γ receptor (IFN-γ-R−/−) or the TNF-α type I receptor (p55) (TNF-α-RI−/−) to analyze their capacity to cope with aerogenic P. carinii organisms.Bronchoalveolar lavage (BAL) cells of healthy and diseased mice were investigated for expression of the proinflammatory cytokines IL-1, TNF-α, IFN-γ, and IL-12, as well as IL-4, IL-5, and IL-10. The latter three cytokines counteract IFN-γ- and IL-12-mediated responses but participate in protection against certain extracellular pathogens (9). Moreover, production of superoxide (SO) and nitric oxide (NO), putative effector molecules of antimicrobial defense, was taken as a further indicator of macrophage activation. Contact with foreign material induces a rapid respiratory burst in professional phagocytes which results in SO production as a first line of defense. SO has been implicated in destruction of P. carinii (31), whereas NO produced by IFN-γ-stimulated macrophages encountering pathogens (4, 18, 30) does not appear to participate in control of P. carinii infection (47). Of further interest was the role of macrophage-expressed mannose receptors (MR) and scavenger receptors (SR). MR were previously found crucial for mediating P. carinii internalization (11, 37). The relevance of SR with respect to PCP has not been evaluated, but they are mainly expressed by tissue macrophages (36) and nonspecifically bind a large array of molecules, including surface molecules of microorganisms (39). Receptors with such broad pattern reactivity may be involved in direct differentiation of self from non-self, and recent data suggest that not only MR but also SR aid pattern recognition by macrophages and subsequent internalization of invading pathogens (27).We found that BAL cells from P. carinii-diseased RAG-1−/− and TCRβ−/− mutants secreted elevated IFN-γ, TNF-α, IL-12, NO, and SO levels and expressed IL-1 mRNA. In contrast, cells from morbid Aβ−/− mice produced IL-1 mRNA and high levels of NO only, whereas all other parameters were low to absent in these mutants. SR were expressed on pulmonary macrophages of all diseased RAG-1−/−, TCRβ−/−, and Aβ−/− mutants, whereas MR were also expressed by macrophages of healthy animals. Yet, the apparently activated phagocyte system in the lung, most pronounced in morbid TCRβ−/− and RAG-1−/− mutant mice, was insufficient for protection against natural P. carinii infection. Elevated levels of IFN-γ and TNF-α in morbid mutants (not in Aβ−/− mice) and the naturally resistant status of IFN-γ-R−/− and TNF-α-RI−/− mice further argue not only for independence from IFN-γ and TNF-α. Our findings indicate that CD4+ αβ T lymphocytes prevent and clear infection with P. carinii by mechanisms distinct from, or in addition to, pulmonary macrophage activation.(This study is part of the Ph.D. thesis of R. Hanano.) 相似文献
74.
Sequence information on the genome of porcine epidemic diarrhea virus (PEDV) has only recently been determined. In contrast, very little is known about the viral proteins. In the present report we have identified the membrane glycoprotein (M) of PEDV by use of rabbit anti-peptide sera and transient expression of the cloned M gene in Vero cells and by expression in the baculovirus system. The native M protein of PEDV is incorporated into virions, is N-glycosylated, and migrates with a relative mobility (Mr) of 27 k in polyacrylamide gels. In contrast, the M protein synthesized by recombinant baculoviruses migrates with a Mr of 23 k, that is, with identical mobility as the deglycosylated product of PEDV. Thus, it appears that M protein specified by the recombinant baculovirus is poorly, if at all, glycosylated. Using monoclonal antibodies and rabbit antipeptide sera specific for the N and C termini of the M protein, we were able to show that a 19 k band detected in PEDV-infected cells but not in virions represented a fragment of M from which the C terminus had been cleaved off. Finally, by electron microscopy and immunogold labelling, the relative orientation of M within the virion envelope was determined as NexoCcyt. In conclusion, all of these data strongly support the hypothesis that PEDV should be classified with the group I coronaviruses. 相似文献
75.
Zusammenfassung Es wird über Versuche berichtet, in denen bei freier und artefiziell behinderter Ausatmung Beziehungen zwischen Atemzeitvolumen und alveolärem CO2-Druck aufgestellt wurden. Unter Stenoseatmung werden für gleiche Änderungen des Atemzeitvolumens größere Differenzen des alveolären CO2-Druckes benötigt. Die Verschiebungen werden als Folge der bei erschwerter Atmung erhöhten Atemarbeit gedeutet und nicht auf eine Änderung der Erregbarkeit des Atemzentrums zurückgeführt. Die alveoläre Hypoventilation bei obstruktiven Ventilationsstörungen kann daher — so wird weiter gefolgert — ihren Ursprung in der vermehrten Atemarbeit haben, ohne daß zwingend eine andere pathogenetisch wirksame Ursache diskutiert werden muß. Auf die Bedeutung von Veränderungen des Atemwiderstandes bei der experimentellen Prüfung atemwirksamer Pharmaka wird hingewiesen.Mit Unterstützung der Deutschen Forschungsgemeinschaft. 相似文献
76.
Determination of Dissolved Oxygen in Heterogenous Systems Particularly in Emulsions and Oily Liquids
Foiβner Karl-Heinz Leonhardt Andreas Wegner Gerhard Heinz Bauer Kurt 《Pharmaceutical research》1985,2(1):44-46
The content of dissolved oxygen was determined by four independent methods in a series of non-aqueous or heterogenous systems. The Lex-O2-Content Analyzer represents a fast and simple apparatus that employs a coulometric oxygen assay with Hersch cell detection. A comparison of the results with different methods demonstrates the reliability of the Lex-O2 in the determination of oxygen dissolved in heterogeneous or non-aqueous systems. Therefore, this apparatus can be recommended for the measurement of oxygen in oxygenator or perfusion fluids, as well as in blood substitutes or other oxygen transporting systems. 相似文献
77.
Sotiris Mastoridis María-Carlota Londoño Ada Kurt Elisavet Kodela Elena Crespo John Mason Oriol Bestard Marc Martínez-Llordella Alberto Sánchez-Fueyo 《American journal of transplantation》2021,21(7):2387-2398
In several murine models of transplantation, the “cross-dressing” of recipient antigen presenting cells (APCs) with intact donor major histocompatibility complex (MHC) derived from allograft-released small extracellular vesicles (sEVs) has been recently described as a key mechanism in eliciting and sustaining alloimmune responses. Investigation of these processes in clinical organ transplantation has, however, been hampered by the lack of sensitivity of conventional instruments and assays. We have employed advanced imaging flow cytometry (iFCM) to explore the kinetics of allograft sEV release and the extent to which donor sEVs might induce cross-dressing following liver and kidney transplantation. We report for the first time that recipient APC cross-dressing can be transiently detected in the circulation shortly after liver, but not kidney, transplantation in association with the release of HLA-bearing allograft-derived sEVs. In liver transplant recipients the majority of circulating cells exhibiting donor HLA are indeed cross-dressed cells and not passenger leukocytes. In keeping with experimental animal data, the downstream functional consequences of the transfer of circulating sEVs harvested from human transplant recipients varies depending on the type of transplant and time posttransplant. sEVs released shortly after liver, but not kidney, transplantation exhibit immunoinhibitory effects that could influence liver allograft immunogenicity. 相似文献
78.
Hakan Özkardeş Cankon Germiyanoğlu Ümit Kurt Levent Peşkircioğlu Uğur Altuğ Demokan Erol 《Pediatric surgery international》1995,10(7):488-491
Between 1983 and 1993, 41 patients underwent a first-stage Belt-Fuqua operation for penile hypospadias repair and 39 completed the second stage. Minor complications were observed after the first stage. The primary success rate following the second stage was 82%. Major complications noted after the second stage consisted mainly of fistula formation. The surgical technique is described and alternative methods are discussed. 相似文献
79.
Claudia Hey Ignaz Wessler Kurt Racké 《Naunyn-Schmiedeberg's archives of pharmacology》1995,351(6):651-659
Alveolar macrophages were obtained by broncho-alveolar lavage of isolated rat and rabbit lungs and cultured (2.5 × 106 cells/dish) for 18 h in the absence or presence of bacterial lipopolysaccharides (LPS) alone or in combination with cytokines. Thereafter, accumulation of 3H-citrulline (NO synthase activity) and 3H-ornithine (arginase activity) were determined.During incubation of rat alveolar macrophages with 3H-arginine clear amounts of 3H-citrulline and 3H-ornithine (3.8 and 4.6% of the added 3H-arginine, respectively) were formed and most of these metabolites appeared in the incubation medium (ratios extra-/intracellular of 17 and 70 for 3H-citrulline and 3H-ornithine, respectively). When rat alveolar macrophages had been cultured with LPS the formation of 3H-citrulline was increased about 30-fold and this was accompanied by a reduction in 3H-ornithine formation of about 60%. The effects of LPS were largely attenuated by dexamethasone (10 mol/1). Inhibition of NO synthase by NG-monomethyl-l,-arginine (l-NMMA, 100 mol/1) in LPS treated alveolar macrophages reduced the formation 3H-citrulline by more than 90% and restored the 3H-ornithine formation. After culturing in the presence of LPS the ratios extra/intracellular of 3H-citrulline and 3H-ornithine were markedly enhanced and this effect was not dexamethasone sensitive. During incubation of rabbit alveolar macrophages a marked formation of 3H-ornithine (about 5.3% of the added 3H-arginine), but no significant formation of 3H-citrulline could be detected. Pretreatment with LPS tended to enhance the formation of 3H-ornithine (by 50%) without effects on 3H-citrulline. Rabbit-interferon and/or tumor necrosis factor- present together with LPS during the culture period did not result in a significant 3H-citrulline formation. Under all conditions tested, culture media of rabbit alveolar macrophages did not contain significant amounts of nitrite (less than 0.5 nmol) whereas in culture media of untreated rat alveolar macrophages 22 nmol nitrite (per 18 h) were detected, and LPS induced a 3-fold nitrite accumulation, an effect prevented by dexamethasone.In conclusion, in rabbit alveolar macrophages NO synthase activity was not detectable and could also not be induced by LPS and different cytokines, whereas in rat alveolar macrophages NO synthase was readily inducible. Alveolar macrophages of both species showed marked arginase activity. After induction of marked NO synthase activity, ornithine formation was largely reduced possibly by concomitant inhibition of arginase and/or withdrawn of arginine from arginase. 相似文献
80.