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排序方式: 共有1246条查询结果,搜索用时 15 毫秒
51.
Hippen KL Bucher C Schirm DK Bearl AM Brender T Mink KA Waggie KS Peffault de Latour R Janin A Curtsinger JM Dillon SR Miller JS Socie G Blazar BR 《Blood》2012,119(2):619-628
In rodent graft-versus-host disease (GVHD) models, anti-IL-21 neutralizing mAb treatment ameliorates lethality and is associated with decreases in Th1 cytokine production and gastrointestinal tract injury. GVHD prevention was dependent on the in vivo generation of donor-inducible regulatory T cells (Tregs). To determine whether the IL-21 pathway might be targeted for GVHD prevention, skin and colon samples obtained from patients with no GVHD or grade 2 to 4 GVHD were analyzed for IL-21 protein expression. By immunohistochemistry staining, IL-21 protein-producing cells were present in all gastrointestinal tract samples and 54% of skin samples obtained from GVHD patients but not GVHD-free controls. In a human xenogeneic GVHD model, human IL-21-secreting cells were present in the colon of GVHD recipients and were associated with elevated serum IL-21 levels. A neutralizing anti-human IL-21 mAb given prophylactically significantly reduced GVHD-associated weight loss and mortality, resulting in a concomitant increase in Tregs and a decrease in T cells secreting IFN-γ or granzyme B. Based on these findings, anti-IL-21 mAb could be considered for GVHD prevention in the clinic. 相似文献
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Anemia is very common in patients suffering from infections or chronic inflammation and can add substantially to the morbidity of the underlying disease. It is mediated by excessive production of the iron-regulatory peptide hepcidin, but the signaling pathway responsible for hepcidin up-regulation in the inflammatory context is still not understood completely. In the present study, we show that activin B has an unexpected but crucial role in the induction of hepcidin by inflammation. There is a dramatic induction of Inhbb mRNA, encoding the activin β(B)-subunit, in the livers of mice challenged with lipopolysaccharide, slightly preceding an increase in Smad1/5/8 phosphorylation and Hamp mRNA. Activin B also induces Smad1/5/8 phosphorylation in human hepatoma-derived cells and, synergistically with IL-6 and STAT-3 signaling, up-regulates hepcidin expression markedly, an observation confirmed in mouse primary hepatocytes. Pretreatment with a bone morphogenic protein type I receptor inhibitor showed that the effect of activin B on hepcidin expression is entirely attributable to its effect on bone morphogenetic protein signaling, most likely via activin receptor-like kinase 3. Activin B is therefore a novel and specific target for the treatment of anemia of inflammation. 相似文献
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Bloch-Queyrat C Fondanèche MC Chen R Yin L Relouzat F Veillette A Fischer A Latour S 《The Journal of experimental medicine》2005,202(1):181-192
SAP is an adaptor protein that is expressed in NK and T cells. It is mutated in humans who have X-linked lymphoproliferative (XLP) disease. By interacting with SLAM family receptors, SAP enables tyrosine phosphorylation signaling of these receptors by its ability to recruit the Src-related kinase, Fyn. Here, we analyzed the role of SAP in NK cell functions using the SAP-deficient mouse model. Our results showed that SAP was required for the ability of NK cells to eliminate tumor cells in vitro and in vivo. This effect strongly correlated with expression of CD48 on tumor cells, the ligand of 2B4, a SLAM-related receptor expressed in NK cells. In keeping with earlier reports that studied human NK cells, we showed that SAP was necessary for the ability of 2B4 to trigger cytotoxicity and IFN-gamma secretion. In the absence of SAP, 2B4 function was shifted toward inhibition of NK cell-mediated cytotoxicity. By analyzing mice lacking Fyn, we showed that similarly to SAP, Fyn was strictly required for 2B4 function. Taken together, these results provide evidence that the 2B4-SAP-Fyn cascade defines a potent activating pathway of natural cytotoxicity. They also could help to explain the high propensity of patients who have XLP disease to develop lymphoproliferative disorders. 相似文献
56.
Chlo Dimeglio Marine Milhes Jean-Michel Loubes Nomie Ranger Jean-Michel Mansuy Pauline Trmeaux Nicolas Jeanne Justine Latour Florence Nicot Ccile Donnadieu Jacques Izopet 《Viruses》2021,13(5)
The spread of SARS-CoV-2 and the resulting disease COVID-19 has killed over 2.6 million people as of 18 March 2021. We have used a modified susceptible, infected, recovered (SIR) epidemiological model to predict how the spread of the virus in regions of France will vary depending on the proportions of variants and on the public health strategies adopted, including anti-COVID-19 vaccination. The proportion of SARS-CoV-2 variant B.1.1.7, which was not detected in early January, increased to become 60% of the forms of SARS-CoV-2 circulating in the Toulouse urban area at the beginning of February 2021, but there was no increase in positive nucleic acid tests. Our prediction model indicates that maintaining public health measures and accelerating vaccination are efficient strategies for the sustained control of SARS-CoV-2. 相似文献
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Growing evidence supports the concept that neutrophils accumulating in reperfused ischaemic myocardium play a detrimental role in evolving infarction. Lignocaine, an antiarrhythmic drug commonly used clinically, interferes with neutrophil function in vitro and potentially in vivo. To test the hypothesis that lignocaine may influence infarct size by reducing neutrophil accumulation in reperfused ischaemic myocardium, 31 dogs underwent a 2 h occlusion of the left anterior descending coronary artery, followed by 6 h of reperfusion. One group of dogs received saline (controls) the other a perfusion of lignocaine 0.06 mg.kg-1.min-1 starting 30 min before coronary occlusion and lasting for the duration of the experiment. Blood lignocaine concentrations at the onset of reperfusion were 3.3(0.6) micrograms.ml-1. 111Indium labelled autologous neutrophils were injected at the time of occlusion and their accumulation in the myocardium measured by digital scintigraphy of heart slices. The area at risk and infarct size were evaluated by planimetry of the heart slices (7 mm) after perfusion of Evans blue dye and triphenyltetrazolium staining. Ventricular fibrillation occurred in six controls and in five dogs receiving lignocaine. The phenomenon occurred early during the occlusion period in the lignocaine group (five dogs) and at reperfusion in controls (five dogs; p less than 0.05). In the remaining 20 dogs, 10 in each group, a linear correlation was found between myocardial 111In labelled neutrophil and circulating neutrophil counts at the onset of reperfusion (r = 0.076, p less than 0.05) and with infarct size (r = 0.96 and 0.74, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
59.
Direct inhibition by nitric oxide of the transcriptional ferric uptake regulation protein via nitrosylation of the iron
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D'Autreaux B Touati D Bersch B Latour JM Michaud-Soret I 《Proceedings of the National Academy of Sciences of the United States of America》2002,99(26):16619-16624
Ferric uptake regulation protein (Fur) is a bacterial global regulator that uses iron as a cofactor to bind to specific DNA sequences. The function of Fur is not limited to iron homeostasis. A wide variety of genes involved in various mechanisms such as oxidative and acid stresses are under Fur control. Flavohemoglobin (Hmp) is an NO-detoxifying enzyme induced by NO and nitrosothiol compounds. Fur recently was found to regulate hmp in Salmonella typhimurium, and in Escherichia coli, the iron-chelating agent 2,2'-dipyridyl induces hmp expression. We now establish direct inhibition of E. coli Fur activity by NO. By using chromosomal Fur-regulated lacZ reporter fusion in E. coli, Fur activity is switched off by NO at micromolar concentration. In vitro Fur DNA-binding activity, as measured by protection of restriction site in aerobactin promoter, is directly sensitive to NO. NO reacts with Fe(II) in purified FeFur protein to form a S = 12 low-spin FeFur-NO complex with a g = 2.03 EPR signal. Appearance of the same EPR signal in NO-treated cells links nitrosylation of the iron with Fur inhibition. The nitrosylated Fur protein is still a dimer and is stable in anaerobiosis but slowly decays in air. This inhibition probably arises from a conformational switch, leading to an inactive dimeric protein. These data establish a link between control of iron metabolism and the response to NO effects. 相似文献
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