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排序方式: 共有234条查询结果,搜索用时 250 毫秒
181.
Ann-Kathrin Rahm Patrick Lugenbiel Patrick A. Schweizer Hugo A. Katus Dierk Thomas 《Biophysical reviews》2018,10(4):1097-1106
Heart failure (HF) is a complication of multiple cardiac diseases and is characterized by impaired contractile and electric function. Patients with HF are not only limited by reduced contractile function but are also prone to life-threatening ventricular arrhythmias. HF itself leads to remodeling of ion channels, gap junctions, and intracellular calcium handling abnormalities that in combination with structural remodeling, e.g., fibrosis, produce a substrate for an arrhythmogenic disorders. Not only ventricular life-threatening arrhythmias contribute to increased morbidity and mortality but also atrial arrhythmias, especially atrial fibrillation (AF), are common in HF patients and contribute to morbidity and mortality. The distinct ion channel remodeling processes in HF and in channelopathies associated with HF will be discussed. Further basic research and clinical studies are needed to identify underlying molecular pathways of HF pathophysiology to provide the basis for improved patient care and individualized therapy based on individualized ion channel composition and remodeling. 相似文献
182.
A series of studies was conducted to evaluate the ability of several second messengers/second messenger systems to stimulate LH secretion from dispersed chicken pituitary cells. [Gln8]-LHRH-(cLHRH) stimulated LH secretion in a dose-dependent fashion; this effect was potentiated in the presence of the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, and was mimicked by the cAMP analog, 8-bromo-cAMP. These data indicate that the production of cAMP in response to cLHRH can stimulate LH secretion, but do not necessarily provide evidence that such production is prerequisite. The tumor-promoting phorbol ester, phorbol 12-myristate 13-acetate (PMA), and diacylglycerol analogs, 1-oleoyl-2-acetylglycerol (OAG) and 1,2-dioctanoyl-sn-glycerol (DOG), also stimulated LH release; however, only PMA (and not cLHRH or DOG) promoted an accumulation of cAMP. The putative protein kinase C inhibitor, staurosporine, completely blocked LH release stimulated by PMA, but failed to block cLHRH-induced LH secretion. Such results indicate that protein kinase C activation can promote LH secretion, but also suggest that additional second messengers may exist to fully mediate the effects of cLHRH. Both the calcium ionophore, A23187, and the intracellular calcium mobilizing agent, thapsigargin, caused a dose-dependent increase in LH secretion; furthermore, thapsigargin augmented the stimulatory effects of PMA. These data are consistent with a role for calcium in the regulation of LH release, and indicate that the mobilization of intracellular calcium alone can affect such an action.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
183.
Irene N. Kasumba Aaron Bestor Kit Tilly Patricia A. Rosa 《Applied and environmental microbiology》2015,81(3):1038-1046
Targeted mutagenesis and complementation are important tools for studying genes of unknown function in the Lyme disease spirochete Borrelia burgdorferi. A standard method of complementation is reintroduction of a wild-type copy of the targeted gene on a shuttle vector. However, shuttle vectors are present at higher copy numbers than B. burgdorferi plasmids and are potentially unstable in the absence of selection, thereby complicating analyses in the mouse-tick infectious cycle. B. burgdorferi has over 20 plasmids, with some, such as linear plasmid 25 (lp25), carrying genes required by the spirochete in vivo but relatively unstable during in vitro cultivation. We propose that complementation on an endogenous plasmid such as lp25 would overcome the copy number and in vivo stability issues of shuttle vectors. In addition, insertion of a selectable marker on lp25 could ensure its stable maintenance by spirochetes in culture. Here, we describe the construction of a multipurpose allelic-exchange vector containing a multiple-cloning site and either of two selectable markers. This suicide vector directs insertion of the complementing gene into the bbe02 locus, a site on lp25 that was previously shown to be nonessential during both in vitro and in vivo growth. We demonstrate the functional utility of this strategy by restoring infectivity to an ospC mutant through complementation at this site on lp25 and stable maintenance of the ospC gene throughout mouse infection. We conclude that this represents a convenient and widely applicable method for stable gene complementation in B. burgdorferi. 相似文献
184.
Hill M Deghmane AE Segovia M Zarantonelli ML Tilly G Blancou P Bériou G Josien R Anegon I Hong E Ruckly C Antignac A El Ghachi M Boneca IG Taha MK Cuturi MC 《PloS one》2011,6(10):e23995
Neisseria meningitidis is a human pathogen responsible for life-threatening inflammatory diseases. Meningococcal penicillin-binding proteins (PBPs) and particularly PBP2 are involved in bacterial resistance to β-lactams. Here we describe a novel function for PBP2 that activates human and mouse dendritic cells (DC) in a time and dose-dependent manner. PBP2 induces MHC II (LOGEC50 = 4.7 μg/ml ± 0.1), CD80 (LOGEC50 = 4.88 μg/ml ± 0.15) and CD86 (LOGEC50 = 5.36 μg/ml ± 0.1). This effect was abolished when DCs were co-treated with anti-PBP2 antibodies. PBP2-treated DCs displayed enhanced immunogenic properties in vitro and in vivo. Furthermore, proteins co-purified with PBP2 showed no effect on DC maturation. We show through different in vivo and in vitro approaches that this effect is not due to endotoxin contamination. At the mechanistic level, PBP2 induces nuclear localization of p65 NF-kB of 70.7 ± 5.1% cells versus 12 ± 2.6% in untreated DCs and needs TLR4 expression to mature DCs. Immunoprecipitation and blocking experiments showed thatPBP2 binds TLR4. In conclusion, we describe a novel function of meningococcal PBP2 as a pathogen associated molecular pattern (PAMP) at the host-pathogen interface that could be recognized by the immune system as a danger signal, promoting the development of immune responses. 相似文献
185.
Dominik von Elverfeldt Constantin von zur Muhlen Kristina Wiens Irene Neudorfer Andreas Zirlik Mirko Meissner Peg Tilly Anne-Laure Charles Christoph Bode Karlheinz Peter Jean-Etienne Fabre 《PloS one》2012,7(9)
Background
Early and non-invasive detection of platelets on micro atherothrombosis provides a means to identify unstable plaque and thereby allowing prophylactic treatment towards prevention of stroke or myocardial infarction. Molecular magnetic resonance imaging (mMRI) of activated platelets as early markers of plaque rupture using targeted contrast agents is a promising strategy. In this study, we aim to specifically image activated platelets in murine atherothrombosis by in vivo mMRI, using a dedicated animal model of plaque rupture.Methods
An antibody targeting ligand-induced binding sites (LIBS) on the glycoprotein IIb/IIIa-receptor of activated platelets was conjugated to microparticles of iron oxide (MPIO) to form the LIBS-MPIO contrast agent causing a signal-extinction in T2*-weighted MRI. ApoE−/− mice (60 weeks-old) were fed a high fat diet for 5 weeks. Using a small needle, the surface of their carotid plaques was scratched under blood flow to induce atherothrombosis. In vivo 9.4 Tesla MRI was performed before and repetitively after intravenous injection of either LIBS-MPIO versus non-targeted-MPIO.Results
LIBS-MPIO injected animals showed a significant signal extinction (p<0.05) in MRI, corresponding to the site of plaque rupture and atherothrombosis in histology. The signal attenuation was effective for atherothrombosis occupying ≥2% of the vascular lumen. Histology further confirmed significant binding of LIBS-MPIO compared to control-MPIO on the thrombus developing on the surface of ruptured plaques (p<0.01).Conclusion
in vivo mMRI detected activated platelets on mechanically ruptured atherosclerotic plaques in ApoE−/− mice with a high sensititvity. This imaging technology represents a unique opportunity for noninvasive detection of atherothrombosis and the identification of unstable atherosclerotic plaques with the ultimate promise to prevent strokes and myocardial infarctions. 相似文献186.
Alexandra C. Kraberg Kristine Carstens Silvia Peters Katharina Tilly Karen H. Wiltshire 《Helgoland Marine Research》2012,66(3):463-468
The Helgoland Roads phytoplankton long-term data set is one of the longest and the most detailed data sets in Europe, having provided continuous work-daily observations of phytoplankton abundance since 1962. These high frequency counts have undergone and are continuously subject to a high level of quality control. The Helgoland data set thus is useful in the evaluation of new records in phyto- and zooplankton. Here, we report the first appearance of the relatively recently described diatom Mediopyxis helysia in the Helgoland Roads counts. This species was first detected in Helgoland samples in March 2009. Importantly, it has rapidly become a prominent member of the Helgoland phytoplankton community. While in 2009 it only produced a moderate spring peak of 4,000 cells?l?1, it was one of the dominant diatoms in the 2010 spring bloom with Mediopyxis reaching cell densities above 300,000 cells?l?1 and total chlorophyll concentrations exceeding 40?μg?l?1. In 2010, this species was repeatedly present throughout the year. There was no clear relationship between temperature and cell abundance with all Mediopyxis cells occurring at temperatures between 3 and 12°C. However, the extensive peak in 2010 was associated with a sudden drop in salinity, which could indicate that this bloom might have been the result of inflow of low salinity water into the area. This was supported by a laboratory growth experiment in which a clonal culture of M. helysia grew fastest at a salinity of 27 and slowest at a salinity of 31.5. Further long-term observations will be required to establish whether this species will become a regular feature at Helgoland and how this might affect the local food web. 相似文献
187.
Hörnig M Markoutsa S Häfner AK George S Wisniewska JM Rödl CB Hofmann B Maier T Karas M Werz O Steinhilber D 《Biochimica et biophysica acta》2012,1821(2):279-286
U73122 which was originally identified as a phospholipase C inhibitor represents a potent direct inhibitor of purified 5-lipoxygenase (5-LO) with an IC50 value of 30 nM. 5-LO catalyzes the conversion of arachidonic acid (AA) into leukotrienes which represent mediators involved in inflammatory and allergic reactions and in host defense reactions against microorganisms. Since the efficient inhibition of the human 5-LO enzyme depended on the thiol reactivity of the maleinimide group of U73122, we used this property to identify cysteine residues in the 5-LO protein that are important for 5-LO inhibition by U73122. We found by MALDI-MS that U73122 covalently binds to cysteine residues 99, 159, 248, 264, 416 and 449. Mutation of Cys416 to serine strongly reduces inhibition of 5-LO by U73122 and the additional mutation of three cysteines close to Cys416 further impairs 5-LO inhibition by the compound. Wash out experiments with U73122 and 5-LO indicated an irreversible binding of U73122. Together, our data suggest that the area around Cys416 which is close to the proposed AA entry channel to the active site is an interesting target for the development of new 5-LO inhibitors. 相似文献
188.
Takai Y Matikainen T Jurisicova A Kim MR Trbovich AM Fujita E Nakagawa T Lemmers B Flavell RA Hakem R Momoi T Yuan J Tilly JL Perez GI 《Apoptosis : an international journal on programmed cell death》2007,12(4):791-800
Previously, we analyzed mice lacking either caspase-2 or caspase-3 and documented a role for caspase-2 in developmental and
chemotherapy-induced apoptosis of oocytes. Those data also revealed dispensability of caspase-3, although we found this caspase
critical for ovarian granulosa cell death. Because of the mutual interdependence of germ cells and granulosa cells, herein
we generated caspase-2 and -3 double-mutant (DKO) mice to evaluate how these two caspases functionally relate to each other
in orchestrating oocyte apoptosis. No difference was observed in the rate of spontaneous oocyte apoptosis between DKO and
wildtype (WT) females. In contrast, the oocytes from DKO females were more susceptible to apoptosis induced by DNA damaging
agents, compared with oocytes from WT females. This increased sensitivity to death of DKO oocytes appears to be a specific
response to DNA damage, and it was associated with a compensatory upregulation of caspase-12. Interestingly, DKO oocytes were
more resistant to apoptosis induced by methotrexate (MTX) than WT oocytes. These results revealed that in female germ cells,
insults that directly interfere with their metabolic status (e.g. MTX) require caspase-2 and caspase-3 as obligatory executioners
of the ensuing cell death cascade. However, when DNA damage is involved, and in the absence of caspase-2 and -3, caspase-12
becomes upregulated and mediates apoptosis in oocytes.
Takai and Matikainen contributed equally to this work. 相似文献
189.
Increased aminophospholipid translocase activity in human platelets during secretion 总被引:1,自引:0,他引:1
R H Tilly J M Senden P Comfurius E M Bevers R F Zwaal 《Biochimica et biophysica acta》1990,1029(1):188-190
Fluorescent labeled analogs of phosphatidylcholine (NBD-PC) and phosphatidylserine (NBD-PS) were used to study transport of phospholipids from the outer to the inner leaflet of the plasma membrane of human platelets. Platelets were stimulated with thrombin or Ca2(+)-ionophore at various extracellular [Ca2+]. No significant transport of NBD-PC could be observed either in resting or stimulated platelets. NBD-PS transport in platelets stimulated with thrombin (with or without extracellular Ca2+), or ionophore in the presence of EGTA, was enhanced 4-fold (t1/2 approximately 2 min) compared to unstimulated controls (t1/2 approximately 8 min). Stimulation with ionophore at extracellular [Ca2+] exceeding 8 microM caused a gradual decrease in inward transport of NBD-PS. At 100 microM Ca2+, NBD-PS transport becomes as slow as that of NBD-PC. We conclude that platelet activation by agonists that induce secretion without appreciable shedding is accompanied by an increase in translocase activity that maintains asymmetry during fusion which occurs during exocytosis. 相似文献
190.
Phosphatidylserine (PS) in the plasma membrane of nonactivated human platelets is almost entirely located on the cytoplasmic side. Stimulation of platelets with the Ca2+ ionophore A23187 or combined action of collagen plus thrombin results in a rapid loss of the asymmetric distribution of PS. Also, treatment with the sulfhydryl-reactive compounds diamide and pyridyldithioethylamine (PDA) causes exposure of PS at the platelet outer surface. PS exposure is sensitively measured as the catalytic potential of platelets to enhance the rate of thrombin formation by the enzyme complex factor Xa-factor Va, since this reaction is essentially dependent on the presence of a PS-containing lipid surface. In this paper we demonstrate that endogenous PS, previously exposed at the outer surface during cell activation or sulfhydryl oxidation, can be translocated back to the cytoplasmic leaflet of the membrane by addition of dithiothreitol (DTT) but not by nonpermeable reducing agents like reduced glutathione. Treatment of platelets with trypsin or chymotrypsin, prior to addition of DTT, inhibits the inward transport of exposed PS. Moreover, severe depletion of metabolic ATP, as obtained by platelet stimulation with A23187 in the presence of metabolic inhibitors, though not inhibiting PS exposure at the outer surface, blocks the translocation of endogenous PS to the internal leaflet of the plasma membrane. These results strongly indicate the involvement of a membrane protein in the inward transport of endogenous PS. Recently, an aminophospholipid-specific translocase in the platelet membrane was postulated on the basis of the inward transport of exogenously added PS (analogues) [Sune, A., Bette-Bobillo, P., Bienvenue, A., Fellmann, P., & Devaux, P.F. (1987) Biochemistry 26, 2972-2978].(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献