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121.
Metzger S Bauer P Tomiuk J Laccone F Didonato S Gellera C Mariotti C Lange HW Weirich-Schwaiger H Wenning GK Seppi K Melegh B Havasi V Balikó L Wieczorek S Zaremba J Hoffman-Zacharska D Sulek A Basak AN Soydan E Zidovska J Kebrdlova V Pandolfo M Ribaï P Kadasi L Kvasnicova M Weber BH Kreuz F Dose M Stuhrmann M Riess O 《Human genetics》2006,120(2):285-292
The expansion of a polymorphic CAG repeat in the HD gene encoding huntingtin has been identified as the major cause of Huntington’s disease (HD) and determines 42–73% of the variance in the age-at-onset of the disease. Polymorphisms in huntingtin interacting or associated genes are thought to modify the course of the disease. To identify genetic modifiers influencing the age at disease onset, we searched for polymorphic markers in the GRIK2, TBP, BDNF, HIP1 and ZDHHC17 genes and analysed seven of them by association studies in 980 independent European HD patients. Screening for unknown sequence variations we found besides several silent variations three polymorphisms in the ZDHHC17 gene. These and polymorphisms in the GRIK2, TBP and BDNF genes were analysed with respect to their association with the HD age-at-onset. Although some of the factors have been defined as genetic modifier factors in previous studies, none of the genes encoding GRIK2, TBP, BDNF and ZDHHC17 could be identified as a genetic modifier for HD.Electronic Supplementary Material Supplementary material is available to authorised users in the online version of this article at . 相似文献
122.
Betti M Ciacci C Lorusso LC Canonico B Falcioni T Gallo G Canesi L 《Biology of the cell / under the auspices of the European Cell Biology Organization》2006,98(4):233-244
BACKGROUND INFORMATION: Many studies indicate that innate immunity in invertebrates can be modulated by a cytokine network like in vertebrates. In molluscs, the immune response is carried out by circulating haemocytes and soluble haemolymph factors. In the present study, the effects of heterologous TNFalpha (tumour necrosis factor alpha) on cell signalling and function in the haemocytes of the bivalve Mytilus galloprovincialis Lam. were investigated. RESULTS AND CONCLUSIONS: Addition of TNFalpha in the absence of haemolymph serum [in ASW (artificial sea water)] induced cellular stress, as indicated by lysosomal destabilization, and decreased phagocytosis; on the other hand, in the presence of serum, TNFalpha did not affect lysosomal stability and even stimulated phagocytosis. TNFalpha induced rapid phosphorylation of the stress-activated p38 and JNK (c-Jun N-terminal kinase) MAPKs (mitogen-activated protein kinases); both effects were persistent in ASW but transient in serum. Activation of p38 and JNKs in mediating the effects of TNFalpha was confirmed by the use of specific MAPK inhibitors. Moreover, flow cytometric analysis indicated that TNFalpha in the presence of serum induced transient phosphatidylserine exposure on the haemocyte surface, evaluated as annexin V binding; in ASW, the cytokine resulted in a stable increase in the percentage of both annexin- and propidium iodide-positive cells, indicating possible apoptotic/necrotic processes. The results indicate that TNFalpha can affect the function of bivalve haemocytes through conserved transduction pathways involving stress-activated MAPKs and suggest that the haemocyte response to the cytokine is influenced by soluble haemolymph components. 相似文献
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124.
Placido A Damiano F Sciancalepore M De Benedetto C Rainaldi G Gallerani R 《Biochimica et biophysica acta》2006,1757(9-10):1207-1216
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126.
Levantesi C Rossetti S Thelen K Kragelund C Krooneman J Eikelboom D Nielsen PH Tandoi V 《Environmental microbiology》2006,8(9):1552-1563
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128.
Michio Hirano Caterina Garone Catarina M. Quinzii 《Biochimica et Biophysica Acta (BBA)/General Subjects》2012
Background
Although causative mutations have been identified for numerous mitochondrial disorders, few disease-modifying treatments are available. Two examples of treatable mitochondrial disorders are coenzyme Q10 (CoQ10 or ubiquinone) deficiency and mitochondrial neurogastrointestinal encephalomyopathy (MNGIE).Scope of review
Here, we describe clinical and molecular features of CoQ10 deficiencies and MNGIE and explain how understanding their pathomechanisms have led to rationale therapies. Primary CoQ10 deficiencies, due to mutations in genes required for ubiquinone biosynthesis, and secondary deficiencies, caused by genetic defects not directly related to CoQ10 biosynthesis, often improve with CoQ10 supplementation. In vitro and in vivo studies of CoQ10 deficiencies have revealed biochemical alterations that may account for phenotypic differences among patients and variable responses to therapy. In contrast to the heterogeneous CoQ10 deficiencies, MNGIE is a single autosomal recessive disease due to mutations in the TYMP gene encoding thymidine phosphorylase (TP). In MNGIE, loss of TP activity causes toxic accumulations of the nucleosides thymidine and deoxyuridine that are incorporated by the mitochondrial pyrimidine salvage pathway and cause deoxynucleoside triphosphate pool imbalances, which, in turn cause mtDNA instability. Allogeneic hematopoetic stem cell transplantation to restore TP activity and eliminate toxic metabolites is a promising therapy for MNGIE.Major conclusions
CoQ10 deficiencies and MNGIE demonstrate the feasibility of treating specific mitochondrial disorders through replacement of deficient metabolites or via elimination of excessive toxic molecules.General significance
Studies of CoQ10 deficiencies and MNGIE illustrate how understanding the pathogenic mechanisms of mitochondrial diseases can lead to meaningful therapies. This article is part of a Special Issue entitled: Biochemistry of Mitochondria, Life and Intervention 2010. 相似文献129.
Viggiano E Passavanti MB Pace MC Sansone P Spaziano G Viggiano A Aurilio C Monda M Viggiano A Pota V De Luca B De Luca E 《Journal of cellular physiology》2012,227(5):1988-1991
Glutamine (gln) is the most abundant free amino acid in the blood. It is involved in important metabolic and biochemical processes, like cell proliferation and oxidative stress. Previous studies have demonstrated that gln concentration in human plasma decreases in several conditions such as sepsis, ischemia-reperfusion, trauma, major surgery and burn. The aim of the present work was to compare the acute effects of different types of surgical interventions and of anesthetization on blood gln concentration. Plasma samples from 88 subjects (30 males and 58 females) were collected before and after major or minor surgery and the gln concentration was analyzed with high-performance liquid chromatography. The results showed that plasma gln concentration after surgery was lower than pre-surgery values and that in major surgery the decrease of gln was higher than in minor surgery. No significant effect was shown for sex or type of anesthesia. These results demonstrate the importance of a gln supplementation before a surgical intervention and show that the amount of gln supplementation should also be adjusted based on the type of surgery. 相似文献
130.
Basile A Pascale M Franceschelli S Nieddu E Mazzei MT Fossa P Turco MC Mazzei M 《Journal of cellular physiology》2012,227(9):3317-3323
Cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-dependent Cl(-) channel located in the plasma membrane, and its malfunction results in cystic fibrosis (CF), the most common lethal genetic disease in Caucasians. Most CF patients carry the deletion of Phe508 (ΔF508 mutation); this mutation prevents the delivery of the CFTR to its correct cellular location, the apical (lumen-facing) membrane of epithelial cells. Molecular chaperones play a central role in determining the fate of ΔF508-CFTR. In this report, we show that the Matrine, a quinolizidine alkaloid, downregulates the expression of the molecular chaperone HSC70 and increases the protein levels of ΔF508-CFTR in human alveolar basal epithelial cells (A549 cell line), stably transfected with a ΔF508-CFTR-expressing construct. Moreover, Matrine induced ΔF508-CFTR release from endoplasmic reticulum to cell cytosol and its localization on the cell membrane. Interestingly, downregulation of HSC70 resulted in increased levels of ΔF508-CFTR complexes with the co-chaperone BAG3 that in addition appeared to co-localize with the mutated protein on the cell surface. These results shed new light on ΔF508-CFTR interactions with proteins of the chaperones/co-chaperones system and could be useful in strategies for future medical treatments for CF. 相似文献