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11.
Bartkova J Rajpert-De Meyts E Skakkebaek NE Lukas J Bartek J 《APMIS : acta pathologica, microbiologica, et immunologica Scandinavica》2003,111(1):252-266
Deregulated cell cycle and defective genome-integrity checkpoints are among the hallmarks of cancer.Here we summarize our recent studies of key components of the GI/S machinery in normal human spermatogenesis, and their abnormalities in testicular germ cell tumours (TGCTs), with special emphasis on carcinoma in situ lesions (CIS). Our combined immunohistochemical and immunoblotting analyses of normal human adult and fetal testes, CIS, seminomas, embryonal carcinomas, and teratomas, revealed an 'unorthodox' spectrum of defects within the so-called RB pathway in TGCTs. The early aberrations included lack of expression of the retinoblastoma tumour suppressor (pRB) and the CDK inhibitor pl9ink4d, and overexpression of cyclin D2. Progression from CIS to invasive TGCTswas associated with loss of another two CDK inhibitors and tumour suppressors: pl6ink4a and pl8ink4c. We also found the lack of pRB and pl9ink4d in fetal gonocytes, the candidate target cell for all types of TGCTs. These findings, together with the status of the Chk2-p53 DNA-integrity checkpoint, are considered in relation to the origin, biology and pathogenesis of TGCTs, and potential implications of the GI/S defects for the curability of these tumours. 相似文献
12.
Fat in the intestine as a regulator of appetite--role of CCK 总被引:1,自引:0,他引:1
The present review summarizes the appetite-suppressing effects of intestinal fat in the regulation of food intake in humans, with a special focus on the role of cholecystokinin (CCK). Current evidence supports a role for intestinal fat (especially long-chain free fatty acids) acting via the peptide CCK as a physiological satiety pathway. The regulation of satiety is, however, complex and it is not surprising that multiple control systems exist. It is interesting to note that nutrients, such as hydrolysis products of fat in the small intestine, stimulate the release of satiety peptides, such as CCK or PYY, that serve as satiety signals. CCK, released from the gastrointestinal tract by the local action of digested food, exerts various functions: stimulation of gallbladder contraction and exocrine pancreatic secretion, inhibition of gastric emptying, and inhibition of appetite. CCK functions therefore (1) as a positive feedback signal to stimulate digestive processes and (2) as negative feedback signal to limit the amount of food consumed during an individual meal. 相似文献
13.
14.
Proximal tubular epithelial cell integrins respond to high glucose by altered cell-matrix interactions and differentially regulate matrixin expression 总被引:11,自引:0,他引:11
Karamessinis PM Tzinia AK Kitsiou PV Stetler-Stevenson WG Michael AF Fan WW Zhou B Margaritis LH Tsilibary EC 《Laboratory investigation; a journal of technical methods and pathology》2002,82(8):1081-1093
Thickening of the tubular basement membrane (TBM) occurs in diabetic nephropathy, but the effects of high glucose on the functional aspects of proximal tubular epithelial cells are not clearly understood. In the present study, we examined the effects of elevated glucose concentrations on (a) integrin expression by human proximal tubular epithelial cells (HK-2) and integrin-mediated interactions with type IV collagen (colIV) and laminin, major components of TBM; (b) the expression of matrixins/matrix metalloproteinases (MMPs), which is regulated by integrins; and (c) the expression of tissue inhibitors of metalloproteinases (TIMPs). HK-2 cells cultured in 25 mM glucose underwent a reduction of the expression of alpha3, beta1, alpha(v)beta3, and alpha5 integrin subunits, with a concomitant increase of the alpha2 subunit, compared with cells grown in 5 mM glucose. Adhesion experiments demonstrated that high glucose led to increased cell adhesion on either colIV or laminin. Experiments of competition of adhesion using anti-integrin antibodies indicated that HK-2 cells in 5 mM glucose used mainly alpha(v)beta3 and alpha5beta1 integrins to adhere to colIV, whereas in 25 mM glucose they additionally used alpha2beta1. In the case of laminin, a beta1-mediated adhesion was observed when HK-2 cells were in 5 mM glucose, whereas in 25 mM glucose, alpha2beta1 and alpha(v)beta3 were also involved. Elevated glucose concentrations resulted in decreased expression of MMP-9 and MMP-2, whereas an increase in TIMP-1 and a decrease in TIMP-2 expression were observed. We also examined which integrins mediated the expression and secretion of matrixins MMP-2 and MMP-9. Ligation of alpha3beta1 with mAbs resulted in induction of MMP-2 expression and secretion, whereas antibody ligation of alpha(v)beta3 led to down-regulation of MMP-9. The above data implicate integrins of proximal tubular epithelial cells in the regulation of MMPs and in the development of TBM thickening in diabetic nephropathy. 相似文献
15.
Hunziker L Recher M Macpherson AJ Ciurea A Freigang S Hengartner H Zinkernagel RM 《Nature immunology》2003,4(4):343-349
Polyclonal hypergammaglobulinemia is a characteristic of chronic inflammatory conditions, including persisting viral infections and autoimmune diseases. Here we have studied hypergammaglobulinemia in mice infected with lymphocytic choriomeningitis virus (LCMV), which induces nonspecific immunoglobulins as a result of switching natural IgM specificities to IgG. The process is dependent on help from CD4+ T cells that specifically recognize LCMV peptides presented by B cells on major histocompatibility complex class II molecules. Thus, hypergammaglobulinemia may arise when specific helper T cells recognize B cells that have processed viral antigens irrespective of the B cell receptor specificity. This nonspecific B cell activation may contribute to antibody-mediated autoimmunity. 相似文献
16.
In Hypocrea jecorina (anamorph: Trichoderma reesei) multiple gene deletions are limited by the number of readily available selection markers. We have therefore constructed
a blaster cassette which enables successive gene knock-outs in H. jecorina. This 3.5 kb pyr4 blaster cassette contains the H. jecorina pyr4 marker gene encoding orotidine-5′-monophosphate (OMP) decarboxylase flanked by two direct repeats of the Streptoalloteichus hindustanus bleomycin gene (Sh ble), which facilitate the excision of the blaster cassette by homologous recombination after each round of deletion. Functionality
of this pyr4 blaster cassette was demonstrated by deletion of the glk1 encoding glucokinase and hxk1 encoding hexokinase. 1.4–1.8 kb of the non-coding flanking regions of both target genes were cloned into the respective blaster
cassettes and transformation of a pyr4 negative H. jecorina strain with the two cassettes resulted in 10–13% of the transformants in the deletion of one of the two kinase genes. For
excision of the pyr4 blaster cassettes, Δglk1 strains were selected for growth in the presence of 5-fluoroorotic acid. Recombination between the two Sh ble elements resulted in uridine auxotrophic strains which retained their respective glucokinase negative phenotype. Subsequent
transformation of one of these auxotrophic Δglk1 strains with the hexokinase blaster cassette resulted in pyr4 prototrophic strains deleted in both glk1 and hxk1. Δglk1 strains showed reduced growth on d-glucose and d-fructose whereas Δhxkl strains showed reduced compact growth on d-glucose but were unable to grow on d-fructose as carbon source. The double Δglk1Δhxk1 deletion strain was completely unable to grow on either d-glucose or d-fructose.
Nucleotide sequence data reported are available in the DDBJ/EMBL/GenBank databases under the accession numbers DQ068384 (H. jecorina glk1) and DQ068385 (H. jecorina hxk1). 相似文献
17.
Race and the response to adrenergic blockade with carvedilol in patients with chronic heart failure 总被引:9,自引:0,他引:9
Yancy CW Fowler MB Colucci WS Gilbert EM Bristow MR Cohn JN Lukas MA Young ST Packer M;U.S. Carvedilol Heart Failure Study Group 《The New England journal of medicine》2001,344(18):1358-1365
BACKGROUND: The benefits of angiotensin-converting-enzyme inhibitors and beta-blockers may be smaller in black patients than in patients of other races, but it is unknown whether race influences the response to carvedilol in patients with chronic heart failure. METHODS: In the U.S. Carvedilol Heart Failure Trials Program, 217 black and 877 nonblack patients (in New York Heart Association class II, III, or IV and with a left ventricular ejection fraction of no more than 0.35) were randomly assigned to receive placebo or carvedilol (at doses of 6.25 to 50 mg twice daily) for up to 15 months. The effects of carvedilol on ejection fraction, clinical status, and major clinical events were retrospectively compared between black and nonblack patients. RESULTS: As compared with placebo, carvedilol lowered the risk of death from any cause or hospitalization for any reason by 48 percent in black patients and by 30 percent in nonblack patients. Carvedilol reduced the risk of worsening heart failure (heart failure leading to death, hospitalization, or a sustained increase in medication) by 54 percent in black patients and by 51 percent in nonblack patients. The ratios of the relative risks associated with carvedilol for these two outcome variables in black as compared with nonblack patients were 0.74 (95 percent confidence interval, 0.42 to 1.34) and 0.94 (95 percent confidence interval, 0.43 to 2.05), respectively. Carvedilol also improved functional class, ejection fraction, and the patients' and physicians' global assessments in both the black patients and the nonblack patients. For all these measures of outcome and clinical status, carvedilol was superior to placebo within each racial cohort (P<0.05 in all analyses), and there was no significant interaction between race and treatment (P> 0.05 in all analyses). CONCLUSIONS: The benefit of carvedilol was apparent and of similar magnitude in both black and nonblack patients with heart failure. 相似文献
18.
p62 Is a Common Component of Cytoplasmic Inclusions in Protein Aggregation Diseases 总被引:14,自引:0,他引:14 下载免费PDF全文
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
19.
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
20.
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