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21.
p62 Is a Common Component of Cytoplasmic Inclusions in Protein Aggregation Diseases 总被引:14,自引:0,他引:14
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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
22.
Smooth muscle myosin filament assembly under control of a kinase-related protein (KRP) and caldesmon
Kudryashov DS Vorotnikov AV Dudnakova TV Stepanova OV Lukas TJ Sellers JR Watterson DM Shirinsky VP 《Journal of muscle research and cell motility》2002,23(4):341-351
Kinase-related protein (KRP) and caldesmon are abundant myosin-binding proteins of smooth muscle. KRP induces the assembly
of unphosphorylated smooth muscle myosin filaments in the presence of ATP by promoting the unfolded state of myosin. Based
upon electron microscopy data, it was suggested that caldesmon also possessed a KRP-like activity (Katayama et al., 1995, J Biol Chem 270: 3919–3925). However, the nature of its activity remains obscure since caldesmon does not affect the equilibrium between
the folded and unfolded state of myosin. Therefore, to gain some insight into this problem we compared the effects of KRP
and caldesmon, separately, and together on myosin filaments using turbidity measurements, protein sedimentation and electron
microscopy. Turbidity assays demonstrated that KRP reduced myosin filament aggregation, while caldesmon had no effect. Additionally,
neither caldesmon nor its N-terminal myosin binding domain (N152) induced myosin polymerization at subthreshold Mg2+ concentrations in the presence of ATP, whereas the filament promoting action of KRP was enhanced by Mg2+. Moreover, the amino-terminal myosin binding fragment of caldesmon, like the whole protein, antagonizes Mg2+-induced myosin filament formation. In electron microscopy experiments, caldesmon shortened myosin filaments in the presence
of Mg2+ and KRP, but N152 failed to change their appearance from control. Therefore, the primary distinction between caldesmon and
KRP appears to be that caldesmon interacts with myosin to limit filament extension, while KRP induces filament propagation
into defined polymers. Transfection of tagged-KRP into fibroblasts and overlay of fibroblast cytoskeletons with Cy3KRP demonstrated
that KRP colocalizes with myosin structures in vivo. We propose a new model that through their independent binding to myosin and differential effects on myosin dynamics, caldesmon
and KRP can, in concert, control the length and polymerization state of myosin filaments.
This revised version was published online in July 2006 with corrections to the Cover Date. 相似文献
23.
Rataj Elisabeth Fischer Jan Bogner Andreas Försterra Beatrice Schüssler Alexandra Schütt Lukas 《Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz》2021,64(2):179-186
Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz - Partizipation zu ermöglichen ist Teil des Auftrags der Offenen Kinder- und Jugendarbeit. Dazu gehört die Einbindung der... 相似文献
24.
Matthias Meyer Lukas Parik Felix Greimel Tobias Renkawitz Joachim Grifka Markus Weber 《The Journal of arthroplasty》2021,36(5):1533-1542
BackgroundModels for risk stratification and prediction of outcome, such as the Charlson Comorbidity Index (CCI), the Elixhauser Comorbidity Method (ECM), the 5-factor modified Frailty Index (mFI-5), and the Hospital Frailty Risk Score (HFRS) have been validated in orthopedic surgery. The aim of this study is to compare the predictive power of these models in total hip and knee replacement.MethodsIn a retrospective analysis of 8250 patients who had undergone total joint replacement between 2011 and 2019, CCI, ECM, mFI-5, and HFRS were calculated for each patient. Receiver operating characteristic curve plots were generated and the area under the curve (AUC) was compared between each score with regard to adverse events such as transfusion, surgical, medical, and other complications. Multivariate logistic regression models were used to assess the relationship among risk stratification models, demographic factors, and postoperative adverse events.ResultsIn prediction of surgical complications, HFRS performed best (AUC: 0.719, P < .001), followed by ECM (AUC: 0.578, P < .001), mFI-5 (AUC: 0.564, P = .003), and CCI (AUC: 0.555, P = .012). With regard to medical complications, other complications, and transfusion, HFRS also was superior to ECM, mFI-5, and CCI. Multivariate logistic regression analyses revealed HFRS as an independent risk stratification model associated with all captured adverse events (P ≤ .001).ConclusionThe HFRS is superior to current risk stratification models in the context of total joint replacement. As the HRFS derives from routinely collected administrative data, healthcare providers can identify at-risk patients without additional effort or expense. 相似文献
25.
Eva Schrezenmeier Lukas J. Lehner Marina Merkel Manuel Mayrdorfer Wiebke Duettmann Marcel G. Naik Felix Fröhlich Lutz Liefeldt Mareen Pigorsch Frank Friedersdorff Danilo Schmidt Matthias Niemann Nils Lachmann Klemens Budde Fabian Halleck 《Transplant international》2021,34(4):732-742
The number of patients returning to dialysis after graft failure increases. Surprisingly, little is known about the clinical and immunological outcomes of this cohort. We retrospectively analyzed 254 patients after kidney allograft loss between 1997 and 2017 and report clinical outcomes such as mortality, relisting, retransplantations, transplant nephrectomies, and immunization status. Of the 254 patients, 49% had died 5 years after graft loss, while 27% were relisted, 14% were on dialysis and not relisted, and only 11% were retransplanted 5 years after graft loss. In the complete observational period, 111/254 (43.7%) patients were relisted. Of these, 72.1% of patients were under 55 years of age at time of graft loss and only 13.5% of patients were ≥65 years. Age at graft loss was associated with relisting in a logistic regression analysis. In the complete observational period, 42 patients (16.5%) were retransplanted. Only 4 of those (9.5%) were ≥65 years at time of graft loss. Nephrectomy had no impact on survival, relisting, or development of dnDSA. Patients after allograft loss have a high overall mortality. Immunization contributes to long waiting times. Only a very limited number of patients are retransplanted especially when ≥65 years at time of graft loss. 相似文献
26.
Die Anaesthesiologie - Die Immunthrombozytopenie (ITP) ist eine seltene, erworbene Thrombozytopenie mit einer Inzidenz von 2–4/100.000 Personen und Jahr. Sie wird durch eine Thrombozytenzahl... 相似文献
27.
28.
D. Rehn H. Geißler U. Schönbrunn H. Lukas G. Hennings 《European journal of clinical pharmacology》1990,39(2):137-141
Summary In order to evaluate the time course of its effects, dimetindene maleate has been investigated in a histamine provocation model in man. Eight healthy male volunteers were treated i. v. with 4 mg dimetindene maleate or sodium chloride solution in a double blind, cross over study. Intracutaneous histamine injections were given at –1, 2, 5, 14, 17, 20, 23, 26, and 29 h following drug administration and the areas of flares and wheals were measured after 5, 10, 20, and 30 min. There was strong inhibition of the development both of flares and wheals, which was more pronounced for the former. Baseline adjusted areas under the curve differed significantly following drug and placebo treatment. The maximum effect was observed at 2 h.The mean residence time of the inhibitory effect was calculated to be 13 h compared to the mean residence time of dimetindene in blood of 5 h, which indicates a non-linear relationship between blood level and effect. 相似文献
29.
Eight families with the combination of cleft lip and/or cleft palate plus lower lip pits including their microforms were examined with the aim of characterization of microsymptoms. Hypodontia as a further symptom was also taken into consideration. Each of the symptoms was also noted separately in relatives of the patients and are to be considered as a genetic equivalent of the complete form of the autosomal-dominant inherited Van der Woude's syndrome. Knowledge of the variable expression of the basic gene is crucial for risk assessment in family counselling and also for distinguishing from clefts of other genesis with lower recurrence risk. 相似文献
30.
Lukas Wettstein Patrick Immenschuh Tatjana Weil Carina Conzelmann Yasser Almeida-Hernández Markus Hoffmann Amy Kempf Inga Nehlmeier Rishikesh Lotke Moritz Petersen Steffen Stenger Frank Kirchhoff Daniel Sauter Stefan Pöhlmann Elsa Sanchez-Garcia Jan Münch 《Journal of medical virology》2023,95(1):e28124
Host cell proteases such as TMPRSS2 are critical determinants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tropism and pathogenesis. Here, we show that antithrombin (AT), an endogenous serine protease inhibitor regulating coagulation, is a broad-spectrum inhibitor of coronavirus infection. Molecular docking and enzyme activity assays demonstrate that AT binds and inhibits TMPRSS2, a serine protease that primes the Spike proteins of coronaviruses for subsequent fusion. Consequently, AT blocks entry driven by the Spikes of SARS-CoV, MERS-CoV, hCoV-229E, SARS-CoV-2 and its variants of concern including Omicron, and suppresses lung cell infection with genuine SARS-CoV-2. Thus, AT is an endogenous inhibitor of SARS-CoV-2 that may be involved in COVID-19 pathogenesis. We further demonstrate that activation of AT by anticoagulants, such as heparin or fondaparinux, increases the anti-TMPRSS2 and anti-SARS-CoV-2 activity of AT, suggesting that repurposing of native and activated AT for COVID-19 treatment should be explored. 相似文献