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Dra Szarka Grta Elekes Orsolya Berczeli Eszter Vizvri Lszl Szalay Chuanqing Ding Lszl Tlosi Edit Tth-Molnr 《Investigative ophthalmology & visual science》2020,61(14)
PurposeThe role of adrenergic innervation in the regulation of lacrimal gland (LG) ductal fluid secretion is unknown. The Aim of the present study was to investigate the effect of adrenergic stimulation on fluid secretion in isolated LG duct segments and to study the underlying intracellular mechanisms.MethodsFluid secretion of isolated mouse LG ducts was measured using video-microscopy. Effect of various adrenergic agonists (norepinephrine, phenylephrine, and isoproterenol) on fluid secretion as well as inhibitory effects of specific antagonists on adrenergic agonist-stimulated secretory response were analyzed. Changes in intracellular Ca2+ level [Ca2+i] were investigated with microfluorometry.ResultsBoth norepinephrine and phenylephrine initiated a rapid and robust fluid secretory response, whereas isoproterenol did not cause any secretion. Phenylephrine-induced secretion was completely blocked by α1D-adrenergic receptor blocker BMY-7378. The endothelial nitric oxide synthase (eNOS) inhibitor L-NAME or guanylyl cyclase inhibitor ODQ reduced but not completely abolished the phenylephrine-induced fluid secretion, whereas co-administration of Ca2+-chelator BAPTA-AM resulted in a complete blockade. Phenylephrine stimulation induced a small, but statistically significant elevation in [].ConclusionsOur results prove the direct role of α1-adrenergic stimulation on LG ductal fluid secretion. Lack of isoproterenol-induced fluid secretory response suggests the absence of β-receptor mediated pathway in mouse LG ducts. Complete blockade of phenylephrine-induced fluid secretion by BMY-7378 and predominant inhibition of the secretory response either by L-NAME or ODQ suggest that α-adrenergic agonists use the NO/cGMP pathway through α1D receptor. Ca2+ signaling independent from NO/cGMP pathway may also play an at least partial role in α-adrenergic induced ductal fluid secretion. 相似文献
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Miyazaki A Tsuda Y Fukushima S Yokoi T Vántus T Bökönyi G Szabó E Horváth A Kéri G Okada Y 《Journal of medicinal chemistry》2008,51(16):5121-5124
On the basis of the structure of somatostatin analogue TT-232 (1), which exhibited a highly potent antitumor activity, we synthesized small linear peptide derivatives and evaluated their antitumor and apoptotic activity. Of them, Boc-Tyr-D-Trp-1-adamantylamide (5) had the most potent cell antiproliferative activity in SW480 and A431 cell lines, which was supported in A431 cell lines by FACS analysis that demonstrated a major increase in DNA fragmentation in the subG1 fraction. 相似文献
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Sndor Sznt Tams Brdos Zoltn Szab Chella S. David Edit I. Buzs Katalin Mikecz Tibor T. Glant 《Arthritis \u0026amp; Rheumatology》2004,50(6):1984-1995
Objective
To determine whether the rheumatoid arthritis (RA)–predisposing class II molecules of the major histocompatibility complex (MHC) can present cartilage proteoglycan (PG) aggrecan, and if so, to determine the epitope repertoire of the human cartilage PG in HLA‐transgenic mice and determine whether HLA‐transgenic mice develop arthritis in response to immunization with human cartilage PG.Methods
Mice transgenic for HLA–DR2.Ab0, DR3.Ab0, DR4.Ab0, and DQ8.Ab0, lacking their own (mouse) class II antigens (Ab0), on the original (arthritis‐resistant) and the arthritis‐susceptible BALB/c backgrounds, were immunized with human cartilage PG. The T cell epitope repertoire presented by these class II MHC alleles was determined using a synthetic peptide library (143 peptides of the core protein of human cartilage PG), and arthritis development was monitored and compared in wild‐type and HLA‐transgenic/congenic BALB/c mice.Results
Mice of the 4 HLA‐transgenic lines, either on the original mixed, arthritis‐resistant background or DR4.Ab0‐ and DQ8.Ab0‐transgenic/congenic mice on the arthritis‐susceptible BALB/c genetic background, responded well to PG immunization (as assessed by T cell responses and antibody and cytokine production), and a number of T cell epitopes along the core protein of human cartilage PG were identified. DR4.Ab0‐ and DQ8.Ab0‐transgenic mice immunized with human cartilage PG developed arthritis, but only when these class II MHC molecules were present on the arthritis‐susceptible (BALB/c) genetic background.Conclusion
A number of human cartilage PG epitopes can be presented by HLA alleles that predispose to the development of RA, but the epitopes of the cartilage PG presented by HLA–DR4 or HLA–DQ8 can induce arthritis only in the presence of an appropriate genetic (non‐MHC) background.107.
Selective, covalent modification of β-tubulin residue Cys-239 by T138067, an antitumor agent with in vivo efficacy against multidrug-resistant tumors
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Bei Shan Julio C. Medina Edit Santha Walter P. Frankmoelle Ting-C. Chou Robert M. Learned Mathew R. Narbut Dean Stott Pengguang Wu Juan C. Jaen Terry Rosen Pieter B. M. W. M. Timmermans Holger Beckmann 《Proceedings of the National Academy of Sciences of the United States of America》1999,96(10):5686-5691
Microtubules are linear polymers of alpha- and beta-tubulin heterodimers and are the major constituents of mitotic spindles, which are essential for the separation of chromosomes during mitosis. Here we describe a synthetic compound, 2-fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene (T138067), which covalently and selectively modifies the beta1, beta2, and beta4 isotypes of beta-tubulin at a conserved cysteine residue, thereby disrupting microtubule polymerization. Cells exposed to T138067 become altered in shape, indicating a collapse of the cytoskeleton, and show an increase in chromosomal ploidy. Subsequently, these cells undergo apoptosis. Furthermore, T138067 exhibits cytotoxicity against tumor cell lines that exhibit substantial resistance to vinblastine, paclitaxel, doxorubicin, and actinomycin D. T138067 is also equally efficacious in inhibiting the growth of sensitive and multidrug-resistant human tumor xenografts in athymic nude mice. These observations suggest that T138067 may be clinically useful for the treatment of multidrug-resistant tumors. 相似文献
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109.
Klára?Piukovics Gabriella?Terhes Tímea?Gurbity-Pálfi ágnes?Bereczki Ferenc?Rárosi Judit?Deák Zita?Borbényi Edit?UrbánEmail author 《Annals of hematology》2017,96(1):125-131
Because of the widespread use of immunosuppressive drugs, CMV infection is one of the most important causes of morbidity and mortality in patients with haematological malignancies worldwide. The aim of the study was to retrospectively analyse the epidemiology of CMV infection in haematological patients. Between 2008 and 2014, 1238 quantitative CMV DNA detections from plasma specimens were performed. These specimens were collected from 271 patients with haematological malignancy. Patients were grouped on the basis of underlying diseases (lymphoid and myeloid malignancies and other haematological diseases). In the lymphoid and myeloid groups, we distinguished ASCT and non-ASCT groups. During the studied period, the majority of examined patients (82.6 %) were treated with lymphoproliferative disease. A total of 126 (46.5 %) patients underwent ASCT, while 145 (53.5 %) did not have stem cell transplantation. A total of 118 (9.5 %) of 1238 plasma specimens proved to be positive for CMV DNA; these specimens were collected from 66 (24.4 %) patients. Twenty-four (16.6 %) of 145 non-ASCT patients had CMV PCR positive specimens. Among non-ASCT patients with positive CMV PCR results, 10 patients were asymptomatic, 14 had symptomatic reactivation, while 2 had CMV disease. In the ASCT group, 42 (33.3 %) patients had CMV PCR positive samples. CMV reactivation was asymptomatic in 34 (81 %) cases, and 8 (19 %) patients had symptomatic reactivation. In the non-ASCT group, the rate of CMV infection is low. In the ASCT group, the prevalence of CMV infection was higher than in the non-ASCT group, but the majority of CMV infection was asymptomatic and only small number of patients had symptomatic reactivation. Thus, our results also showed that the use of routine CMV DNA monitoring is not necessary in patients with haematological malignancies not receiving fludarabine-containing regimen or alemtuzumab, in spite of this to decrease the mortality we have to consider the use of molecular tests in case of suspected infectious conditions. 相似文献
110.
Soltész P Kerekes G Dér H Szücs G Szántó S Kiss E Bodolay E Zeher M Timár O Szodoray P Szegedi G Szekanecz Z 《Autoimmunity reviews》2011,10(7):416-425
Numerous autoimmune-inflammatory rheumatic diseases have been associated with accelerated atherosclerosis or other types of vasculopathy leading to increased cardio- and cerebrovascular disease risk. Traditional risk factors, as well as the role of systemic inflammation including cytokines, chemokines, proteases, autoantibodies, adhesion receptors and others have been implicated in the development of these vascular pathologies. The characteristics of vasculopathies may significantly differ depending on the underlying disease. While classical accelerated atherosclerosis has been associated with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) or spondyloarthropathies (SpA), obliterative vasculopathy may rather be characteristic for systemic sclerosis (SSc) or mixed connective tissue disease (MCTD). Antiphospholipid antibodies have been implicated in vasculopathies underlying SLE, antiphospholipid syndrome (APS), RA and MCTD. There is also heterogeneity with respect to inflammatory risk factors. Cytokines, such as tumor necrosis factor-α (TNF-α) or interleukin 6 (IL-6) and immune complexes are primarily involved in arthritides, such as RA, SpA, as well as in SLE. On the other hand, autoantibodies including anti-oxLDL anti-cardiolipin and anti-β2GPI are rather involved in SLE- and APS-associated vasculopathies. Regarding the non-invasive assessment of vascular function, endothelial dysfunction, overt atherosclerosis and vascular stiffness may be indicated by brachial artery flow-mediated vasodilation (FMD), common carotid intima-media thickness (ccIMT) and aortic pulse-wave velocity (PWV), respectively. These abnormalities have been described in most inflammatory rheumatic diseases. While ccIMT and stiffness are relatively stable, FMD may be influenced by many confounding factors. In addition to traditional vasculoprotection, immunosuppressive agents including corticosteroids, traditional and biologic DMARDs may have significant vascular and metabolic effects. The official EULAR recommendations on the assessment and management of cardiovascular disease in arthritides have just been published, and similar recommendations in connective tissue diseases are to be developed soon. 相似文献