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41.
Talley TT Harel M Hibbs RE Radic Z Tomizawa M Casida JE Taylor P 《Proceedings of the National Academy of Sciences of the United States of America》2008,105(21):7606-7611
Acetylcholine-binding proteins (AChBPs) from mollusks are suitable structural and functional surrogates of the nicotinic acetylcholine receptors when combined with transmembrane spans of the nicotinic receptor. These proteins assemble as a pentamer with identical ACh binding sites at the subunit interfaces and show ligand specificities resembling those of the nicotinic receptor for agonists and antagonists. A subset of ligands, termed the neonicotinoids, exhibit specificity for insect nicotinic receptors and selective toxicity as insecticides. AChBPs are of neither mammalian nor insect origin and exhibit a distinctive pattern of selectivity for the neonicotinoid ligands. We define here the binding orientation and determinants of differential molecular recognition for the neonicotinoids and classical nicotinoids by estimates of kinetic and equilibrium binding parameters and crystallographic analysis. Neonicotinoid complex formation is rapid and accompanied by quenching of the AChBP tryptophan fluorescence. Comparisons of the neonicotinoids imidacloprid and thiacloprid in the binding site from Aplysia californica AChBP at 2.48 and 1.94 A in resolution reveal a single conformation of the bound ligands with four of the five sites occupied in the pentameric crystal structure. The neonicotinoid electronegative pharmacophore is nestled in an inverted direction compared with the nicotinoid cationic functionality at the subunit interfacial binding pocket. Characteristic of several agonists, loop C largely envelops the ligand, positioning aromatic side chains to interact optimally with conjugated and hydrophobic regions of the neonicotinoid. This template defines the association of interacting amino acids and their energetic contributions to the distinctive interactions of neonicotinoids. 相似文献
42.
Maruyama Y Nishida M Sugimoto Y Tanabe S Turner JH Kozasa T Wada T Nagao T Kurose H 《Circulation research》2002,91(10):961-969
In neonatal cardiomyocytes, activation of the G(q)-coupled alpha(1)-adrenergic receptor (alpha(1)AR) induces hypertrophy by activating mitogen-activated protein kinases, including c-Jun NH(2)-terminal kinase (JNK). Here, we show that JNK activation is essential for alpha(1)AR-induced hypertrophy, in that alpha(1)AR-induced hypertrophic responses, such as reorganization of the actin cytoskeleton and increased protein synthesis, could be blocked by expressing the JNK-binding domain of JNK-interacting protein-1, a specific inhibitor of JNK. We also identified the classes and subunits of G proteins that mediate alpha(1)AR-induced JNK activation and hypertrophic responses by generating several recombinant adenoviruses that express polypeptides capable of inhibiting the function of specific G-protein subunits. alpha(1)AR-induced JNK activation was inhibited by the expression of carboxyl terminal regions of Galpha(q), Galpha(12), and Galpha(13). JNK activation was also inhibited by the Galpha(q/11)- or Galpha(12/13)-specific regulator of G-protein signaling (RGS) domains and by C3 toxin but was not affected by treatment with pertussis toxin or by expression of the carboxyl terminal region of G protein-coupled receptor kinase 2, a polypeptide that sequesters Gbetagamma. alpha(1)AR-induced hypertrophic responses were inhibited by Galpha(q/11)- and Galpha(12/13)-specific RGS domains, C3 toxin, and the carboxyl terminal region of G protein-coupled receptor kinase 2 but not by pertussis toxin. Activation of Rho was inhibited by carboxyl terminal regions of Galpha(12) and Galpha(13) but not by Galpha(q). Our findings suggest that alpha(1)AR-induced hypertrophic responses are mediated in part by a Galpha(12/13)-Rho-JNK pathway, in part by a G(q/11)-JNK pathway that is Rho independent, and in part by a Gbetagamma pathway that is JNK independent. 相似文献
43.
Kazuhiro Kitajima Shingo Yamamoto Yusuke Kawanaka Hisashi Komoto Kimihiro Shimatani Takeshi Hanasaki Motohiro Taguchi Seiji Nagasawa Yusuke Yamada Akihiro Kanematsu Koichiro Yamakado 《Medicine》2021,100(23)
This study aimed to evaluate the clinical use of choline-PET/CT for discriminating viable progressive osteoblastic bone metastasis from benign osteoblastic change induced by the treatment effect and evaluating the response of bone metastasis to treatment in metastatic castration-resistant prostate cancer (mCRPC) patients. Thirty patients with mCRPC underwent a total of 56 11C-choline-PET/CT scans for restaging, because 4 patients received 1 scan and 26 had 2 scans. Using 2 (pre- and post-treatment) 11C-choline-PET/CT examinations per patient, treatment response was assessed according to European Organization for Research and Treatment of Cancer (EORTC) criteria in 20 situations, in which only bony metastases were observed on 11C-choline-PET/CT scans. Viable bone metastases and osteoblastic change induced by the treatment effect were identified in 53 (94.6%) and 29 (51.8%) of 56 11C-choline-PET/CT scans, respectively. In 27 cases (48.2%), 11C-choline-PET/CT scans could discriminate the 2 entities. The mean SUVmax of the metastatic bony lesions was 5.82 ± 3.21, 5.95 ± 3.96, 6.73 ± 5.04, and 7.91 ± 3.25 for the osteoblastic, osteolytic, mixed, and invisible types, respectively. Of the 20 situations analyzed, CMR, PMR, SMD, and PMD, as determined by the EORTC, were seen in 1, 2, 3, and 14 cases, respectively. Of the 13 patients with increasing PSA trend, all 13 showed PMD. Of the 2 patients with PSA response of <50%, both 2 showed SMD. Of the 5 patients with PSA response of ≥50%, 1 showed CMR, 2 showed PMR, 1 showed SMD, and 1 showed PMD. Choline-PET/CT is very useful to discriminate viable progressive osteoblastic bone metastasis from osteoblastic change, and assess treatment response of bone metastases in mCRPC. 相似文献
44.
45.
Protein C activation in NIDDM patients 总被引:6,自引:0,他引:6
E. C. Gabazza H. Takeya H. Deguchi Y. Sumida O. Taguchi K. Murata K. Nakatani Y. Yano M. Mohri M. Sata T. Shima J. Nishioka K. Suzuki 《Diabetologia》1996,39(12):1455-1461
Summary Enhanced activation of the clotting system has been recently implicated in the pathogenesis of vascular complications in
patients with diabetes mellitus. Abnormalities of the anticoagulant system may constitute a potential trigger factor for the
haemostatic activation observed in diabetic subjects. The current study aimed to evaluate anticoagulant activity in diabetic
patients by assessing the plasma levels of activated protein C-protein C inhibitor complex; and by measuring the anticoagulant
response to exogenous thrombomodulin. This study comprised 61 patients (34 men, 27 women) with non-insulin-dependent diabetes
mellitus (NIDDM) of whom 22 showed microalbuminuria and 39 normoalbuminuria. Data obtained in 31 non-obese and non-diabetic
subjects were available for comparison. The plasma levels of fibrinogen (p < 0.02), prothrombin fragment 1 + 2 (p < 0.05), fibrin monomer (p < 0.0001), protein C antigen (p < 0.005), total protein S antigen (p < 0.02), soluble thrombomodulin (p < 0.005) and soluble E-selectin (p < 0.005) were significantly higher in diabetic patients than in healthy subjects. The plasma level of activated protein C-protein
C inhibitor complex (7.4 ± 3.8 vs 3.0 ± 0.4 pmol/l) was significantly higher (p < 0.0001) and the anticoagulant response to exogenous thrombomodulin (23.4 ± 2.6 vs 35.3 ± 3.0 ng/ml) was markedly lower
(p = 0.005) in all diabetic patients than in healthy subjects. Cases with microalbuminuria presented low plasma levels of activated
protein C-protein C inhibitor complex (5.5 ± 0.6 vs 8.6 ± 0.7 pmol/l, p < 0.05) and significantly decreased values of the anticoagulant response to exogenous thrombomodulin (16.5 ± 2.9 vs 23.4
± 2.6 %, p = 0.03) as compared to those with normoalbuminuria. The present study suggests that the hyper-coagulable state in NIDDM is
associated with an increased activation of protein C but with a poor plasma reactivity to the anticoagulant effect of thrombomodulin.
[Diabetologia (1996) 39: 1455–1461]
Received: 27 February 1996 and in revised form: 3 June 1996 相似文献
46.
Keisuke Kidoguchi Yasushi Kubota Shun Fujimoto Yasuhisa Sakata Haruna Kizuka-Sano Kyosuke Yamaguchi Hiroshi Ureshino Hiroo Katsuya Toshihiko Ando Motohiro Esaki Shinya Kimura 《Internal medicine (Tokyo, Japan)》2021,60(10):1601
Cronkhite-Canada syndrome (CCS) is a rare polyposis disorder accompanied by alopecia and onychodystrophy. A 63-year-old man with a history of CCS and repeated embolism developed progressive thrombocytopenia and mild anemia. Laboratory testing, a bone marrow examination, and magnetic resonance imaging of the spine resulted in a diagnosis of concurrent aplastic anemia (AA). Paroxysmal nocturnal hemoglobinuria (PNH)-type cells were detected in a peripheral blood specimen. In addition, human leukocyte antigen (HLA) included DRB1*15:01 and DRB1*15:02. Mesalazine was discontinued in consideration of possible drug-induced pancytopenia. Immunosuppressive therapy ameliorated both the gastrointestinal symptoms of CCS and pancytopenia. A common autoimmune abnormality might underlie both CCS and AA. 相似文献
47.
Lehtolainen P Takeya M Ylä-Herttuala S 《Arteriosclerosis, thrombosis, and vascular biology》2000,20(1):52-60
The type II, class A macrophage scavenger receptor (SR-A) plays an important role in the pathogenesis of atherosclerosis and foam cell formation. However, its role in nonmacrophage cell lines remains unknown. To test the hypothesis that SR-A activity leads to proatherogenic changes in nonmacrophage cell lines, we generated Moloney murine leukemia virus- and vesicular stomatitis virus G protein-pseudotyped retroviruses containing SR-A type II cDNA, which were used for stable transfection of SR-A activity into mouse fibroblasts and rabbit aortic smooth muscle cells (SMCs). beta-Galactosidase-transfected cell lines were used as controls. Transfected cell lines expressed functional SR-A mRNA and protein. Expression of SR-A activity was stable for at least 9 months. By electron microscopy, transfected receptors were located in coated pits and in intracellular structures resembling endocytotic vesicles. Expression of SR-A on the cell surface was verified by flow cytometry and by uptake and degradation of (125)I-labeled acetylated low density lipoprotein (LDL). Increases of 5- to 25-fold and of 6- to 8-fold in the rate of acetylated LDL degradation were observed in transfected fibroblasts and SMCs, respectively, compared with beta-galactosidase-transfected control cell lines. Incubation of the transfected SMCs and fibroblasts with acetylated or oxidized LDL led to foam cell formation. Incubation with oxidized LDL also led to increased apoptosis and cell death. An altered morphology with increased cell size and granularity was observed in the most active SR-A SMC clones. It is concluded that stable overexpression of SR-A leads to foam cell formation and other proatherogenic changes in nonmacrophage cell lines. Stable SMC and fibroblast cell lines can be used as models for foam cell formation. The results also suggest that increased SR activity may play an important role in SMC-related pathology in atherosclerotic arteries. 相似文献
48.
Lymphoepithelioma-like carcinoma (LELC) of the lung is an undifferentiated carcinoma with prominent lymphoid stroma. We encountered a case of synchronous primary lung cancers of LELC and papillary adenocarcinoma in a 67-year-old Japanese woman. By in situ hybridization, Epstein-Barr virus (EBV) genome was detected in malignant epithelial cells of LELC but not in the papillary adenocarcinoma. Tumor-infiltrating lymphocytes in LELC were predominantly CD8+ and T cell intracytoplasmic antigen (TIA-1)+ cytotoxic T cells with closely associated with HLA-DR-positive LELC cells by double immunostaining. These data indicate that the exaggerated lymphoid infiltration in and around the EBV-infected carcinoma cells may represent the enhanced tumor immunity, suggesting a better prognostic indicator. 相似文献
49.
50.
A novel technique using three‐dimensionally documented biopsy mapping allows precise re‐visiting of prostate cancer foci with serial surveillance of cell cycle progression gene panel 下载免费PDF全文