全文获取类型
收费全文 | 229篇 |
免费 | 17篇 |
出版年
2021年 | 2篇 |
2020年 | 2篇 |
2019年 | 5篇 |
2018年 | 2篇 |
2017年 | 2篇 |
2016年 | 8篇 |
2015年 | 6篇 |
2014年 | 6篇 |
2013年 | 7篇 |
2012年 | 10篇 |
2011年 | 10篇 |
2010年 | 10篇 |
2009年 | 11篇 |
2008年 | 12篇 |
2007年 | 15篇 |
2006年 | 20篇 |
2005年 | 12篇 |
2004年 | 11篇 |
2003年 | 18篇 |
2002年 | 9篇 |
2001年 | 6篇 |
2000年 | 5篇 |
1999年 | 3篇 |
1998年 | 5篇 |
1997年 | 3篇 |
1996年 | 1篇 |
1995年 | 2篇 |
1994年 | 3篇 |
1992年 | 1篇 |
1991年 | 1篇 |
1990年 | 3篇 |
1989年 | 3篇 |
1988年 | 2篇 |
1987年 | 1篇 |
1985年 | 8篇 |
1984年 | 5篇 |
1983年 | 4篇 |
1982年 | 1篇 |
1980年 | 2篇 |
1979年 | 1篇 |
1977年 | 1篇 |
1976年 | 1篇 |
1974年 | 1篇 |
1972年 | 1篇 |
1971年 | 1篇 |
1968年 | 1篇 |
1960年 | 1篇 |
1933年 | 1篇 |
排序方式: 共有246条查询结果,搜索用时 15 毫秒
121.
Enno D. Wildschut Matthijs de Hoog Maurice J. Ahsman Dick Tibboel Albert D. M. E. Osterhaus Pieter L. A. Fraaij 《PloS one》2010,5(6)
Introduction
To evaluate the effect of extracorporeal membrane oxygenation (ECMO) support on pharmacokinetics of oseltamivir and oseltamivir carboxylate (OC) in children.Methodology
Steady state 0–12 hour pharmacokinetic sampling was performed in new influenza A (H1N1) infected children treated with oseltamivir while on ECMO support. Cmax, Cmin and AUC0–12 h were calculated. The age-specific oseltamivir dosage was doubled to counter expected decreased plasma drug concentrations due to increased volume of distribution on ECMO support.Principal Findings
Three patients were enrolled aged 15, 6 and 14 years in this pharmacokinetic case series. For two children the OC plasma concentrations were higher than those found in children and adults not on ECMO. These increased plasma concentrations related to the increased oseltamivir dosage and decreased kidney function. In one patient suboptimal plasma concentrations coincided with a decreased gastric motility.Conclusion
Oseltamivir pharmacokinetics do not appear to be significantly influenced by ECMO support. Caution is required in case of nasogastric administration and decreased gastric motility. Due to the limited number of (paediatric) patients available further multicenter studies are warranted. 相似文献122.
McSorley T Stefan E Henn V Wiesner B Baillie GS Houslay MD Rosenthal W Klussmann E 《European journal of cell biology》2006,85(7):673-678
A plethora of stimuli including hormones and neurotransmitters mediate a rise of the cellular level of cAMP and thereby activation of protein kinase A (PKA). PKA phosphorylates and thereby modulates the activity of a wide range of cellular targets. It is now appreciated that different stimuli induce the activation of PKA at specific sites where the kinase phosphorylates particular substrates in close proximity. The tethering of PKA to cellular compartments is facilitated by A kinase-anchoring proteins (AKAPs). The incorporation of phosphodiesterases (PDEs) into AKAP-based signalling complexes provides gradients of cAMP that regulate PKA activity locally. An example for a process depending on compartmentalised cAMP/PKA signalling is the arginine-vasopressin (AVP)-mediated water reabsorption in renal collecting duct principal cells. Upon activation through AVP, PKA phosphorylates the water channel aquaporin-2 (AQP-2) located on intracellular vesicles. The phosphorylation triggers the redistribution of AQP2 to the plasma membrane. AKAP-anchored PKA has been shown to be involved in AQP2 shuttling. Here, AKAP18 isoforms and members of the PDE4 family of PDEs are shown to be differentially localised in renal principal cells. 相似文献
123.
Stavru F Hülsmann BB Spang A Hartmann E Cordes VC Görlich D 《The Journal of cell biology》2006,174(4):509-519
POM121 and gp210 were, until this point, the only known membrane-integral nucleoporins (Nups) of vertebrates and, thus, the only candidate anchors for nuclear pore complexes (NPCs) within the nuclear membrane. In an accompanying study (Stavru et al.), we provided evidence that NPCs can exist independently of POM121 and gp210, and we predicted that vertebrate NPCs contain additional membrane-integral constituents. We identify such an additional membrane protein in the NPCs of mammals, frogs, insects, and nematodes as the orthologue to yeast Ndc1p/Cut11p. Human NDC1 (hNDC1) likely possesses six transmembrane segments, and it is located at the nuclear pore wall. Depletion of hNDC1 from human HeLa cells interferes with the assembly of phenylalanine-glycine repeat Nups into NPCs. The loss of NDC1 function in Caenorhabditis elegans also causes severe NPC defects and very high larval and embryonic mortality. However, it is not ultimately lethal. Instead, homozygous NDC1-deficient worms can be propagated. This indicates that none of the membrane-integral Nups is universally essential for NPC assembly, and suggests that NPC biogenesis is an extremely fault-tolerant process. 相似文献
124.
den Hertog AL van Marle J Veerman EC Valentijn-Benz M Nazmi K Kalay H Grün CH Van't Hof W Bolscher JG Nieuw Amerongen AV 《Biological chemistry》2006,387(10-11):1495-1502
The human cathelicidin peptide LL-37 and several truncated variants differ in their capability to transmigrate over the plasma membrane of Candida albicans. We investigated whether retention at the cell perimeter or membrane transmigration affects their membrane-disrupting activities and candidacidal properties. Using fluorescein-labeled peptides, we demonstrate that LL-37 and its C-terminally truncated peptide LL-31 remain permanently associated with the perimeter of the cell. The N-terminally truncated peptide RK-31 initially accumulated at the cell boundary, but transmigrated into the cytoplasm within 30 min. The C-terminally truncated peptide LL-25 transmigrated instantaneously into the cytoplasm. The ultrastructural effects on the plasma membrane were studied by freeze-fracture electron microscopy combined with filipin cytochemistry. All peptides, whether they transmigrated over the plasma membrane or not, induced phase separation in the plasma membrane. All peptides induced leakage of cell components, including nucleotides and proteins. Proteins were identified by SDS-PAGE in combination with mass spectrometry, which revealed that predominantly proteins smaller than 50 kDa had leaked out of C. albicans. 相似文献
125.
Gabriel M Nazmi K Veerman EC Nieuw Amerongen AV Zentner A 《Bioconjugate chemistry》2006,17(2):548-550
Modification of material surfaces aimed at bestowing them with antimicrobial properties is a promising approach in the development of new biomaterials. Antimicrobial peptides (AMPs) are an attractive alternative to conventional antibiotics because of lack of toxicity, inherently high selectivity, and absence of immune response. As the antimicrobial mode of action of the AMP cathelin LL37 is formation of pores and disruption of microbial membrane, the purpose of the present study was to develop and test a method of covalent immobilization of LL37 on titanium surface. The application of a flexible hydrophilic poly(ethylene glycol) spacer and selective N-terminal conjugation of LL37 resulted in a surface peptide layer which was capable of killing bacteria on contact. 相似文献
126.
The responses of antennal taste sensilla of the ground beetle Pterostichus aethiops to 100mM Na(+)-salts and their mixtures with 1 and 10mM NaOH were compared. An increase in pH by 0.3-0.6 units in 100mM Na(+)-salt solutions, caused by the content of 1mM NaOH, was too small, except for alkaline Na(2)HPO(4), to influence the firing rate of the cation cell and pH cell significantly. However, different sensitivity of the two cells to increased pH was clearly demonstrated when the concentration of NaOH in 100mM stimulating salt solutions was increased to 10mM. Increasing pH by 1.2-2 units caused the 1st s firing rate to increase by 140-1050% and 0-26% in the pH cell and cation cell, respectively. Compared to the buffer series method used for identification of the pH receptors in ground beetles earlier, considerably stronger responses of the pH cell to a similar increase in pH were observed when the NaOH method was used for testing. At the same time, undesirable changes in salt ions concentration that occur when stimulating solutions differing by 1-2 pH units are prepared were much smaller using the latter method. Behavioural and ecological relevance of the results is discussed. 相似文献
127.
Stefan Tukaj Konrad Kleszczyński Katerina Vafia Stephanie Groth Damian Meyersburg Piotr Trzonkowski Ralf J. Ludwig Detlef Zillikens Enno Schmidt Tobias W. Fischer Michael Kasperkiewicz 《PloS one》2013,8(7)
The cell stress chaperone heat shock protein 90 (Hsp90) has been implicated in inflammatory responses and its inhibition has proven successful in different mouse models of autoimmune diseases, including epidermolysis bullosa acquisita. Here, we investigated expression levels and secretory responses of Hsp90 in patients with bullous pemphigoid (BP), the most common subepidermal autoimmune blistering skin disease. In comparison to healthy controls, the following observations were made: (i) Hsp90 was highly expressed in the skin of BP patients, whereas its serum levels were decreased and inversely associated with IgG autoantibody levels against the NC16A immunodominant region of the BP180 autoantigen, (ii) in contrast, neither aberrant levels of circulating Hsp90 nor any correlation of this protein with serum autoantibodies was found in a control cohort of autoimmune bullous disease patients with pemphigus vulgaris, (iii) Hsp90 was highly expressed in and restrictedly released from peripheral blood mononuclear cells of BP patients, and (iv) Hsp90 was potently induced in and restrictedly secreted from human keratinocyte (HaCaT) cells by BP serum and isolated anti-BP180 NC16A IgG autoantibodies, respectively. Our results reveal an upregulated Hsp90 expression at the site of inflammation and an autoantibody-mediated dysregulation of the intracellular and extracellular distribution of this chaperone in BP patients. These findings suggest that Hsp90 may play a pathophysiological role and represent a novel potential treatment target in BP. 相似文献
128.
Rainer Kurre Nadzeya Kouzel Kanimozhi Ramakrishnan Enno R. Oldewurtel Berenike Maier 《PloS one》2013,8(6)
Bacterial type IV pili are essential for adhesion to surfaces, motility, microcolony formation, and horizontal gene transfer in many bacterial species. These polymers are strong molecular motors that can retract at two different speeds. In the human pathogen Neisseria gonorrhoeae speed switching of single pili from 2 µm/s to 1 µm/s can be triggered by oxygen depletion. Here, we address the question how proton motive force (PMF) influences motor speed. Using pHluorin expression in combination with dyes that are sensitive to transmembrane ΔpH gradient or transmembrane potential ΔΨ, we measured both components of the PMF at varying external pH. Depletion of PMF using uncouplers reversibly triggered switching into the low speed mode. Reduction of the PMF by ≈ 35 mV was enough to trigger speed switching. Reducing ATP levels by inhibition of the ATP synthase did not induce speed switching. Furthermore, we showed that the strictly aerobic Myxococcus xanthus failed to move upon depletion of PMF or oxygen, indicating that although the mechanical properties of the motor are conserved, its regulatory inputs have evolved differently. We conclude that depletion of PMF triggers speed switching of gonococcal pili. Although ATP is required for gonococcal pilus retraction, our data indicate that PMF is an independent additional energy source driving the high speed mode. 相似文献
129.
Hirose M Recke A Beckmann T Shimizu A Ishiko A Bieber K Westermann J Zillikens D Schmidt E Ludwig RJ 《Journal of immunology (Baltimore, Md. : 1950)》2011,187(3):1176-1183
Bullous pemphigoid (BP) is a subepidermal autoimmune blistering disease of the elderly associated with considerable morbidity and mortality. As unspecific immunosuppressants are still the mainstay of BP therapy, several animal models, based on the passive transfer of autoantibodies or immune cells, have been developed to obtain a better understanding of the pathogenesis of BP and evaluate novel therapeutic interventions. We describe in this study an experimental model inducing BP by immunization of immunocompetent mice with a recombinant form of the immunodominant 15th noncollagenous domain of murine BP180 (type XVII collagen). The homologous noncollagenous 16A domain of human BP180 has previously been identified as an immunodominant region in human BP. Immunization of female SJL/J mice with the murine peptide led to clinical disease within 14 wk in 56% of mice. In contrast, none of the other strains developed blisters despite the presence of autoantibodies. The clinical disease manifested for at least 8 wk without further manipulation. This novel immunization-induced model reflects key immunopathological characteristics of human BP, including binding of complement-fixing autoantibodies along the dermal-epidermal junction, elevated total IgE serum levels, and infiltration of skin lesions with eosinophilic granulocytes. The use of immunocompetent mice and the induction of sustained clinical disease not requiring additional interventions make this immunization-induced mouse model most suitable to further explore the pathogenesis of BP and novel therapeutic interventions for this and other autoantibody-mediated diseases. 相似文献
130.
Tony HP Burmester G Schulze-Koops H Grunke M Henes J Kötter I Haas J Unger L Lovric S Haubitz M Fischer-Betz R Chehab G Rubbert-Roth A Specker C Weinerth J Holle J Müller-Ladner U König R Fiehn C Burgwinkel P Budde K Sörensen H Meurer M Aringer M Kieseier B Erfurt-Berge C Sticherling M Veelken R Ziemann U Strutz F von Wussow P Meier FM Hunzelmann N Schmidt E Bergner R Schwarting A Eming R Hertl M Stadler R Schwarz-Eywill M Wassenberg S Fleck M Metzler C Zettl U Westphal J Heitmann S Herzog AL 《Arthritis research & therapy》2011,13(3):R75