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101.
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Paul JM Savelkoul Fabrizio De Mattia Yuedan Li Erik‐Jan Kamsteeg Irene BM Konings Peter van der Sluijs Peter MT Deen 《Human mutation》2009,30(10):E891-E903
Vasopressin regulates human water homeostasis by re‐distributing homotetrameric aquaporin‐2 (AQP2) water channels from intracellular vesicles to the apical membrane of renal principal cells, a process in which phosphorylation of AQP2 at S256 by cAMP‐dependent protein kinase A (PKA) is thought to be essential. Dominant nephrogenic diabetes insipidus (NDI), a disease in which the kidney is unable to concentrate urine in response to vasopressin, is caused by AQP2 gene mutations. Here, we investigated a reported patient case of dominant NDI caused by a novel p.R254Q mutation. Expressed in oocytes, AQP2‐p.R254Q appeared to be a functional water channel, but was impaired in its transport to the cell surface to the same degree as AQP2‐p.S256A, which mimics non‐phosphorylated AQP2. In polarized MDCK cells, AQP2‐p.R254Q was retained and was distributed similarly to that of unstimulated wt‐AQP2 or AQP2‐p.S256A. Upon co‐expression, AQP2‐p.R254Q interacted with, and retained wt‐AQP2 in intracellular vesicles. In contrast to wild‐type AQP2, forskolin did not increase AQP2‐p.R254Q phosphorylation at S256 or its translocation to the apical membrane. Mimicking constitutive phosphorylation in AQP2‐p.R254Q with the p.S256D mutation, however, rescued its apical membrane expression. These date indicate that a lack of S256 phosphorylation is the sole cause of dominant NDI here, and thereby, p.R254Q is a loss of function instead of a gain of function mutation in dominant NDI. © 2009 Wiley‐Liss, Inc. 相似文献
104.
Association and linkage of allelic variants of the dopamine transporter gene in ADHD 总被引:1,自引:0,他引:1
Friedel S Saar K Sauer S Dempfle A Walitza S Renner T Romanos M Freitag C Seitz C Palmason H Scherag A Windemuth-Kieselbach C Schimmelmann BG Wewetzer C Meyer J Warnke A Lesch KP Reinhardt R Herpertz-Dahlmann B Linder M Hinney A Remschmidt H Schäfer H Konrad K Hübner N Hebebrand J 《Molecular psychiatry》2007,12(10):923-933
Previously, we had reported a genome-wide scan for attention-deficit/hyperactivity disorder (ADHD) in 102 families with affected sibs of German ancestry; the highest multipoint LOD score of 4.75 was obtained on chromosome 5p13 (parametric HLOD analysis under a dominant model) near the dopamine transporter gene (DAT1). We genotyped 30 single nucleotide polymorphisms (SNPs) in this candidate gene and its 5' region in 329 families (including the 102 initial families) with 523 affected offspring. We found that (1) SNP rs463379 was significantly associated with ADHD upon correction for multiple testing (P=0.0046); (2) the global P-value for association of haplotypes was significant for block two upon correction for all (n=3) tested blocks (P=0.0048); (3) within block two we detected a nominal P=0.000034 for one specific marker combination. This CGC haplotype showed relative risks of 1.95 and 2.43 for heterozygous and homozygous carriers, respectively; and (4) finally, our linkage data and the genotype-IBD sharing test (GIST) suggest that genetic variation at the DAT1 locus explains our linkage peak and that rs463379 (P<0.05) is the only SNP of the above haplotype that contributed to the linkage signal. In sum, we have accumulated evidence that genetic variation at the DAT1 locus underlies our ADHD linkage peak on chromosome 5; additionally solid association for a single SNP and a haplotype were shown. Future studies are required to assess if variation at this locus also explains other positive linkage results obtained for chromosome 5p. 相似文献
105.
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107.
M Duarte-Araújo C Nascimento MA Timóteo MT Magalh?es-Cardoso P Correia-de-Sá 《British journal of pharmacology》2009,156(3):519-533
Background and purpose:
The relative contribution of distinct ecto-nucleotidases to the modulation of purinergic signalling may depend on differential tissue distribution and substrate preference.Experimental approach:
Extracellular ATP catabolism (assessed by high-performance liquid chromatography) and its influence on [3H]acetylcholine ([3H]ACh) release were investigated in the myenteric plexus of rat ileum in vitro.Key results:
ATP was primarily metabolized via ecto-ATPDase (adenosine 5′-triphosphate diphosphohydrolase) into AMP, which was then dephosphorylated into adenosine by ecto-5′-nucleotidase. Alternative conversion of ATP into ADP by ecto-ATPase (adenosine 5′-triphosphatase) was more relevant at high ATP concentrations. ATP transiently increased basal [3H]ACh outflow in a 2′,3′-O-(2,4,6-trinitrophenyl)adenosine-5′-triphosphate (TNP-ATP)-dependent, tetrodotoxin-independent manner. ATP and ATPγS (adenosine 5′-[γ-thio]triphosphate), but not α,β-methyleneATP, decreased [3H]ACh release induced by electrical stimulation. ADP and ADPβS (adenosine 5′[β-thio]diphosphate) only decreased evoked [3H]ACh release. Inhibition by ADPβS was prevented by MRS 2179 (2′-deoxy-N6-methyl adenosine 3′,5′-diphosphate diammonium salt, a selective P2Y1 antagonist); blockade of ADP inhibition required co-application of MRS 2179 plus adenosine deaminase (which inactivates endogenous adenosine). Blockade of adenosine A1 receptors with 1,3-dipropyl-8-cyclopentyl xanthine enhanced ADPβS inhibition, indicating that P2Y1 stimulation is cut short by tonic adenosine A1 receptor activation. MRS 2179 facilitated evoked [3H]ACh release, an effect reversed by the ecto-ATPase inhibitor, , which delayed ATP conversion into ADP without affecting adenosine levels. ARL67156Conclusions and implications:
ATP transiently facilitated [3H]ACh release from non-stimulated nerve terminals via prejunctional P2X (probably P2X2) receptors. Hydrolysis of ATP directly into AMP by ecto-ATPDase and subsequent formation of adenosine by ecto-5′-nucleotidase reduced [3H]ACh release via inhibitory adenosine A1 receptors. Stimulation of inhibitory P2Y1 receptors by ADP generated alternatively via ecto-ATPase might be relevant in restraining ACh exocytosis when ATP saturates ecto-ATPDase activity. 相似文献108.
109.
Renner TJ Walitza S Dempfle A Eckert L Romanos M Gerlach M Schäfer H Warnke A Lesch KP Jacob C 《Journal of neural transmission (Vienna, Austria : 1996)》2008,115(2):317-321
Summary Altered neurotransmission has been suggested to be a crucial factor in the pathophysiology of attention-deficit/hyperactivity
disorder ADHD. Subsequently genes encoding for synaptic proteins have been investigated in candidate gene studies. These proteins
mediate the release of neurotransmitters into the synaptic cleft in the process of signal transduction by forming a transient
complex, enabling the junction of vesicle and synaptic membrane. One of the core proteins of this complex is the synaptosomal-associated
protein 25 (SNAP25). It is one of the most validated candidate genes in ADHD according to meta-analyses. However, differing results were observed
in previous studies, some of which were not able to observe association with ADHD. In this study we aimed to investigate association
of genetic variants of SNAP25 located in the putative promoter region of SNAP25 and a SNP in intron 8, previously reported to associated with ADHD. A family based design was applied to detect preferential
transmission of genetic variants. In our German ADHD sample no preferential transmission of either variant could be observed.
Further investigation considering sub-sample analysis regarding response to D-amphetamine could enlight the role of SNAP25 in ADHD.
Correspondence: Tobias J. Renner, Department of Child and Adolescent Psychiatry and Psychotherapy, University of Würzburg,
Füchsleinstr. 15, 97080 Würzburg, Germany 相似文献
110.
S Caserío C Gallego P Martin MT Moral CR Pallás A Galindo 《Acta paediatrica (Oslo, Norway : 1992)》2010,99(10):1571-1577
Aim: To analyse the main prenatal and postnatal features of congenital chylothorax (CC), and the outcome including mid‐term follow‐up. Methods: We searched our databases for CC diagnosed between 1990 and 2006. Data of 29 cases were retrieved and analysed. Follow‐up until 3 years of age was available for all patients. Results: Most patients were diagnosed prenatally (94%) and most cases were complicated by foetal hydrops (66.7%). The overall survival rate at 3 years was 56%. A significantly poorer outcome was observed when foetal hydrops, preterm birth < 34 weeks, large effusions and/or early‐onset pneumothorax were present. An important but not significant improvement in the survival rate was observed through the study period; while in 1990–1998, the survival rate was 41.7%, from 1999 to 2006 it was 66.7% (p = 0.19). In the mid‐term follow‐up, we did not observe any recurrence of CC and most infants remain asymptomatic. However, 27% of survivors were diagnosed as having asthma in early infancy. Conclusion: CC still carries a significant risk of perinatal mortality. However, continuous advances in foetal and neonatal medicine are improving the prognosis of these patients, and nowadays most of them are likely to survive. Beyond the neonatal period, most survivors have an uneventful outcome. 相似文献