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991.
Cost‐effectiveness analysis of epilepsy surgery in a controlled cohort of adult patients with intractable partial epilepsy: A 5‐year follow‐up study 下载免费PDF全文
Marie‐Christine Picot Audrey Jaussent Dorine Neveu Philippe Kahane Arielle Crespel Philippe Gelisse Edouard Hirsch Philippe Derambure Sophie Dupont Elizabeth Landré Francine Chassoux Luc Valton Jean‐Pierre Vignal Cécile Marchal Catherine Lamy Franck Semah Arnaud Biraben Alexis Arzimanoglou Jérôme Petit Pierre Thomas Valérie Macioce Pierre Dujols Philippe Ryvlin 《Epilepsia》2016,57(10):1669-1679
992.
Michael C. W. Chan Denise I. T. Kuok Connie Y. H. Leung Kenrie P. Y. Hui Sophie A. Valkenburg Eric H. Y. Lau John M. Nicholls Xiaohui Fang Yi Guan Jae W. Lee Renee W. Y. Chan Robert G. Webster Michael A. Matthay J. S. Malik Peiris 《Proceedings of the National Academy of Sciences of the United States of America》2016,113(13):3621-3626
Influenza can cause acute lung injury. Because immune responses often play a role, antivirals may not ensure a successful outcome. To identify pathogenic mechanisms and potential adjunctive therapeutic options, we compared the extent to which avian influenza A/H5N1 virus and seasonal influenza A/H1N1 virus impair alveolar fluid clearance and protein permeability in an in vitro model of acute lung injury, defined the role of virus-induced soluble mediators in these injury effects, and demonstrated that the effects are prevented or reduced by bone marrow-derived multipotent mesenchymal stromal cells. We verified the in vivo relevance of these findings in mice experimentally infected with influenza A/H5N1. We found that, in vitro, the alveolar epithelium’s protein permeability and fluid clearance were dysregulated by soluble immune mediators released upon infection with avian (A/Hong Kong/483/97, H5N1) but not seasonal (A/Hong Kong/54/98, H1N1) influenza virus. The reduced alveolar fluid transport associated with down-regulation of sodium and chloride transporters was prevented or reduced by coculture with mesenchymal stromal cells. In vivo, treatment of aged H5N1-infected mice with mesenchymal stromal cells increased their likelihood of survival. We conclude that mesenchymal stromal cells significantly reduce the impairment of alveolar fluid clearance induced by A/H5N1 infection in vitro and prevent or reduce A/H5N1-associated acute lung injury in vivo. This potential adjunctive therapy for severe influenza-induced lung disease warrants rapid clinical investigation.Acute lung injury is a continuum of clinical and radiographic changes, terminating at its most severe, with acute respiratory distress syndrome. Infection with highly pathogenic avian influenza (HPAI) viruses of the H5N1 and more recent H7N9 subtypes often leads to acute lung injury whereas seasonal influenza viruses and the 2009 pandemic H1N1 influenza viruses do so more rarely. The underlying mechanisms of influenza-related acute lung injury remain unclear, and effective therapies are lacking. Viruses that are highly pathogenic to humans (e.g., H5N1 viruses) may differ intrinsically from the less pathogenic (LP) (e.g., seasonal H1N1) viruses in their replication competence, cell tropism, and/or cytokine dysregulation (1, 2). Early treatment of H5N1 disease with the antiinfluenza drug oseltamivir is helpful but does not ensure a favorable outcome (3). Thus, effective adjunctive therapies that do not compromise beneficial host defenses are needed (4).H5N1 (5) and H7N9 (6) influenza viruses target alveolar epithelial cells, which form the crucial gas exchange interface in the lung. These cells also help to maintain intraalveolar and intravascular fluid homeostasis by vectorial transport of sodium, chloride, and water from the apical to the basolateral surface of the alveolar epithelium [alveolar fluid clearance (AFC)]. Impaired AFC and increased alveolar protein permeability (APP) contribute to acute lung injury (7). Therapies that normalize alveolar fluid clearance are likely to be free of off-target effects, unlike immunomodulation, that may promote virus replication.Human bone marrow-derived multipotent mesenchymal stromal cells (MSCs) have applications in multiple clinical disorders, including sepsis, myocardial infarction, diabetes, and acute renal failure (8). Allogeneic MSC therapy has beneficial preclinical effects on endotoxin-, bacteria-, and ventilator-induced acute lung injury (9) via MSC secretion of the soluble paracrine growth factors angiopoietin-1 (Ang1) and keratinocyte growth factor (KGF) (9, 10). MSCs can also transfer mitochondria and microvesicles that modulate immunity and epithelial response to injury (11). Current clinical trials are testing MSCs as a therapy for sepsis and acute respiratory distress syndrome (12). However, little is known about the impact of MSCs on acute respiratory viral infections, including influenza, with the exception of a study in which MSCs failed to reduce influenza-induced lung injury in mice (13). Here, we showed that influenza A/H5N1 virus infection dysregulates AFC and APP in vitro by inducing infected cells to release soluble mediators that down-regulate alveolar sodium and chloride transporters. When we cocultured alveolar epithelium with MSCs, these injury mechanisms were prevented or reduced. We then treated mice infected with influenza A/H5N1 with MSCs and demonstrated a clinically significant reduction in lung pathology and increased survival in association with a modulation of these pathogenic mechanisms in vivo. 相似文献
993.
Malaria exacerbates inflammation‐associated elevation in ferritin and soluble transferrin receptor with only modest effects on iron deficiency and iron deficiency anaemia among rural Zambian children 下载免费PDF全文
994.
Performing a preliminary hazard analysis applied to administration of injectable drugs to infants 下载免费PDF全文
995.
Sophie Kerlan‐Candon Pascale Louis‐Plence Agnes Wiedemann Bernard Combe Jacques Clot Jean‐Franois Eliaou Valrie Pinet 《Arthritis \u0026amp; Rheumatology》2001,44(6):1281-1292
Objective
To compare levels of HLA–DR expression in rheumatoid arthritis (RA) patients and healthy controls for whom an ordered expression according to the DR alleles is demonstrated and to test the functional consequences of this expression on peptide presentation.Methods
Using monoclonal antibodies that recognize different DRB1 alleles, DR molecules were quantitated at the surface of the peripheral blood B cells of 23 RA patients and 17 healthy subjects. The functional consequences of the level of DR surface expression was tested using a universal model of antigen presentation and mutated peptides with variable affinities for the T cell receptor.Results
In healthy subjects, surface HLA–DR molecules were expressed at different levels according to allele (DR53, DR4, and DR11 less than DR1 less than DR7 less than DR15). In RA patients, this hierarchy was not conserved and, furthermore, the density of RA‐associated DR4 and DR1 molecules was enhanced in patients compared with the basal density in healthy individuals. We demonstrated that an increased expression of DR molecules at the surface of antigen‐presenting cells allowed a noteworthy presentation of low‐affinity peptides that under normal conditions are not efficient in generating a T cell response at physiologic surface density of the DR molecules.Conclusion
Our results suggest that the specific overexpression of RA‐associated HLA molecules could be responsible for the presentation of low‐affinity autopeptides and therefore the activation of peripheral autoreactive T cells.996.
Ward NJ Buckley SM Waddington SN Vandendriessche T Chuah MK Nathwani AC McIntosh J Tuddenham EG Kinnon C Thrasher AJ McVey JH 《Blood》2011,117(3):798-807
Gene therapy for hemophilia A would be facilitated by development of smaller expression cassettes encoding factor VIII (FVIII), which demonstrate improved biosynthesis and/or enhanced biologic properties. B domain deleted (BDD) FVIII retains full procoagulant function and is expressed at higher levels than wild-type FVIII. However, a partial BDD FVIII, leaving an N-terminal 226 amino acid stretch (N6), increases in vitro secretion of FVIII tenfold compared with BDD-FVIII. In this study, we tested various BDD constructs in the context of either wild-type or codon-optimized cDNA sequences expressed under control of the strong, ubiquitous Spleen Focus Forming Virus promoter within a self-inactivating HIV-based lentiviral vector. Transduced 293T cells in vitro demonstrated detectable FVIII activity. Hemophilic mice treated with lentiviral vectors showed expression of FVIII activity and phenotypic correction sustained over 250 days. Importantly, codon-optimized constructs achieved an unprecedented 29- to 44-fold increase in expression, yielding more than 200% normal human FVIII levels. Addition of B domain sequences to BDD-FVIII did not significantly increase in vivo expression. These significant findings demonstrate that shorter FVIII constructs that can be more easily accommodated in viral vectors can result in increased therapeutic efficacy and may deliver effective gene therapy for hemophilia A. 相似文献
997.
998.
999.
The mode of action and the structure of a herbicide in complex with its target: binding of activated hydantocidin to the feedback regulation site of adenylosuccinate synthetase. 总被引:4,自引:0,他引:4 下载免费PDF全文
R Fonné-Pfister P Chemla E Ward M Girardet K E Kreuz R B Honzatko H J Fromm H P Sch?r M G Grütter S W Cowan-Jacob 《Proceedings of the National Academy of Sciences of the United States of America》1996,93(18):9431-9436
(+)-Hydantocidin, a recently discovered natural spironucleoside with potent herbicidal activity, is shown to be a proherbicide that, after phosphorylation at the 5' position, inhibits adenylosuccinate synthetase, an enzyme involved in de novo purine synthesis. The mode of binding of hydantocidin 5'-monophosphate to the target enzyme was analyzed by determining the crystal structure of the enzyme-inhibitor complex at 2.6-A resolution. It was found that adenylosuccinate synthetase binds the phosphorylated compound in the same fashion as it does adenosine 5'-monophosphate, the natural feedback regulator of this enzyme. This work provides the first crystal structure of a herbicide-target complex reported to date. 相似文献