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31.
Pimthanya Wanichawan Tandekile Lubelwana Hafver Kjetil Hodne Jan Magnus Aronsen Ida Gjervold Lunde Bj?rn Dalhus Marianne Lunde Heidi Kval?y William Edward Louch Theis T?nnessen Ivar Sjaastad Ole Mathias Sejersted Cathrine Rein Carlson 《The Journal of biological chemistry》2014,289(49):33984-33998
Cardiac sodium (Na+)-calcium (Ca2+) exchanger 1 (NCX1) is central to the maintenance of normal Ca2+ homeostasis and contraction. Studies indicate that the Ca2+-activated protease calpain cleaves NCX1. We hypothesized that calpain is an important regulator of NCX1 in response to pressure overload and aimed to identify molecular mechanisms and functional consequences of calpain binding and cleavage of NCX1 in the heart. NCX1 full-length protein and a 75-kDa NCX1 fragment along with calpain were up-regulated in aortic stenosis patients and rats with heart failure. Patients with coronary artery disease and sham-operated rats were used as controls. Calpain co-localized, co-fractionated, and co-immunoprecipitated with NCX1 in rat cardiomyocytes and left ventricle lysate. Immunoprecipitations, pull-down experiments, and extensive use of peptide arrays indicated that calpain domain III anchored to the first Ca2+ binding domain in NCX1, whereas the calpain catalytic region bound to the catenin-like domain in NCX1. The use of bioinformatics, mutational analyses, a substrate competitor peptide, and a specific NCX1-Met369 antibody identified a novel calpain cleavage site at Met369. Engineering NCX1-Met369 into a tobacco etch virus protease cleavage site revealed that specific cleavage at Met369 inhibited NCX1 activity (both forward and reverse mode). Finally, a short peptide fragment containing the NCX1-Met369 cleavage site was modeled into the narrow active cleft of human calpain. Inhibition of NCX1 activity, such as we have observed here following calpain-induced NCX1 cleavage, might be beneficial in pathophysiological conditions where increased NCX1 activity contributes to cardiac dysfunction. 相似文献
32.
Johannes G.M. Rack Magali R. VanLinden Timo Lutter Rein Aasland Mathias Ziegler 《Journal of molecular biology》2014
Sirtuin-2 (SIRT2), the cytoplasmic member of the sirtuin family, has been implicated in the deacetylation of nuclear proteins. Although the enzyme has been reported to be located to the nucleus during G2/M phase, its spectrum of targets suggests functions in the nucleus throughout the cell cycle. While a nucleocytoplasmic shuttling mechanism has been proposed for SIRT2, recent studies have indicated the presence of a constitutively nuclear isoform. Here we report the identification of a novel splice variant (isoform 5) of SIRT2 that lacks a nuclear export signal and encodes a predominantly nuclear isoform. This novel isoform 5 fails to show deacetylase activity using several assays, both in vitro and in vivo, and we are led to conclude that this isoform is catalytically inactive. Nevertheless, it retains the ability to interact with p300, a known interaction partner. Moreover, changes in intrinsic tryptophan fluorescence upon denaturation indicate that the protein is properly folded. These data, together with computational analyses, confirm the structural integrity of the catalytic domain. Our results suggest an activity-independent nuclear function of the novel isoform. 相似文献
33.
Inken Padberg Erik Peter Sandra González-Maldonado Henning Witt Matthias Mueller Tanja Weis Bianca Bethan Volker Liebenberg Jan Wiemer Hugo A. Katus Dietrich Rein Philipp Schatz 《PloS one》2014,9(1)
Objective
The objective of the current study was to find a metabolic signature associated with the early manifestations of type-2 diabetes mellitus.Research Design and Method
Modern metabolic profiling technology (MxP™ Broad Profiling) was applied to find early alterations in the plasma metabolome of type-2 diabetic patients. The results were validated in an independent study. Eicosanoid and single inon monitoring analysis (MxP™ Eicosanoid and MxP™ SIM analysis) were performed in subsets of samples.Results
A metabolic signature including significantly increased levels of glyoxylate as a potential novel marker for early detection of type-2 diabetes mellitus was identified in an initial study (Study1). The signature was significantly altered in fasted diabetic and pre-diabetic subjects and in non-fasted subjects up to three years prior to the diagnosis of type-2 diabetes; most alterations were also consistently found in an independent patient group (Study 2). In Study 2 diabetic and most control subjects suffered from heart failure. In Study 1 a subgroup of diabetic subjects, with a history of use of anti-hypertensive medication further showed a more pronounced increase of glyoxylate levels, compared to a non-diabetic control group when tested in a hyperglycemic state. In the context of a prior history of anti-hypertensive medication, alterations in hexosamine and eicosanoid levels were also found.Conclusion
A metabolic signature including glyoxylate was associated with type-2 diabetes mellitus, independent of the fasting status and of occurrence of another major disease. The same signature was also found to be associated with pre-diabetic subjects. Glyoxylate levels further showed a specifically strong increase in a subgroup of diabetic subjects. It could represent a new marker for the detection of medical subgroups of diabetic subjects. 相似文献34.
A molecular dynamics (MD) study of (dG)6.(dC)6 including counter ions and 292 water molecules was made. The hydrogen bonding pattern and propeller twist angles for the mini-helix are reported as averages for times spanning 21-30, 31-40, 41-50, and 51-60 ps. The propeller twist angles range from 18 degrees to 38 degrees. Bifurcated and interstrand neighboring base (twisted) hydrogen bonding patterns were found. 相似文献
35.
Poorly expressed endogenous ecotropic provirus of DBA/2 mice encodes a mutant Pr65gag protein that is not myristylated. 总被引:12,自引:11,他引:1 下载免费PDF全文
N G Copeland N A Jenkins B Nex A M Schultz A Rein T Mikkelsen P Jrgensen 《Journal of virology》1988,62(2):479-487
DBA/2 mice carry a single endogenous ecotropic murine leukemia provirus designated Emv-3. Although this provirus appears to be nondefective by genomic restriction enzyme mapping, weanling mice do not produce virus and only about one-third of adult mice ever express virus. 5-Iododeoxyuridine and 5-azacytidine, two potent inducers of ecotropic virus expression, are relatively ineffective at inducing Emv-3 expression. However, the chemical carcinogen 7,12-dimethylbenz(a)anthracene can induce ecotropic virus expression in approximately 95% of treated DBA/2 mice. Previous experiments involving DNA transfection and marker rescue analysis of molecularly cloned Emv-3 DNA suggested that Emv-3 carries a small defect(s) in the gag gene, not detectable by restriction enzyme mapping, that inhibits virus expression in vivo and in vitro. Using a combination of approaches, including DNA sequencing, peptide mapping, and metabolic labeling of cells with [3H]myristate, we have demonstrated that the defect in Emv-3 most likely results from a single nucleotide substitution within the gene for p15gag that inhibits myristylation of the Pr65gag N terminus. Myristylation of Pr65gag is thought to be required for this protein to associate with the plasma membrane and is essential for virus particle formation. These results provide a conceptual framework for understanding how Emv-3 expression is regulated during development and after chemical induction. 相似文献
36.
Simian virus 40 rapidly lowers cAMP levels in mouse cells 总被引:4,自引:0,他引:4
A Rein R A Carchman G S Johnson I Pastan 《Biochemical and biophysical research communications》1973,52(3):899-904
The addition of SV40 to contact inhibited cells causes a 2-fold decrease in intracellular cAMP levels. The levels reach a minimum 3 hours after virus addition, and after a few hours begin to rise toward normal. No significant changes in cAMP levels are observed after cells are exposed to UV-inactivated virus or are mock-infected. This is the earliest known effect of SV40 infection. We propose that SV40 induces host DNA synthesis by lowering cAMP levels. 相似文献
37.
38.
Richard P. Shefferson Tiiu Kull Michael J. Hutchings Marc‐André Selosse Hans Jacquemyn Kimberly M. Kellett Eric S. Menges Richard B. Primack Juha Tuomi Kirsi Alahuhta Sonja Hurskainen Helen M. Alexander Derek S. Anderson Rein Brys Emilia Brzosko Slavomir Dostálik Katharine Gregg Zdeněk Ipser Anne Jäkäläniemi Jana Jersáková W. Dean Kettle Melissa K. McCormick Ana Mendoza Michael T. Miller Asbjørn Moen Dag‐Inge Øien Ülle Püttsepp Mélanie Roy Nancy Sather Nina Sletvold Zuzana Štípková Kadri Tali Robert J. Warren II Dennis F. Whigham 《Ecology letters》2018,21(5):724-733
Vegetative dormancy, that is the temporary absence of aboveground growth for ≥ 1 year, is paradoxical, because plants cannot photosynthesise or flower during dormant periods. We test ecological and evolutionary hypotheses for its widespread persistence. We show that dormancy has evolved numerous times. Most species displaying dormancy exhibit life‐history costs of sprouting, and of dormancy. Short‐lived and mycoheterotrophic species have higher proportions of dormant plants than long‐lived species and species with other nutritional modes. Foliage loss is associated with higher future dormancy levels, suggesting that carbon limitation promotes dormancy. Maximum dormancy duration is shorter under higher precipitation and at higher latitudes, the latter suggesting an important role for competition or herbivory. Study length affects estimates of some demographic parameters. Our results identify life historical and environmental drivers of dormancy. We also highlight the evolutionary importance of the little understood costs of sprouting and growth, latitudinal stress gradients and mixed nutritional modes. 相似文献
39.
Tandekile Lubelwana Hafver Kjetil Hodne Pimthanya Wanichawan Jan Magnus Aronsen Bj?rn Dalhus Per Kristian Lunde Marianne Lunde Marita Martinsen Ulla Helene Enger William Fuller Ivar Sjaastad William Edward Louch Ole Mathias Sejersted Cathrine Rein Carlson 《The Journal of biological chemistry》2016,291(9):4561-4579
The sodium (Na+)-calcium (Ca2+) exchanger 1 (NCX1) is an important regulator of intracellular Ca2+ homeostasis. Serine 68-phosphorylated phospholemman (pSer-68-PLM) inhibits NCX1 activity. In the context of Na+/K+-ATPase (NKA) regulation, pSer-68-PLM is dephosphorylated by protein phosphatase 1 (PP1). PP1 also associates with NCX1; however, the molecular basis of this association is unknown. In this study, we aimed to analyze the mechanisms of PP1 targeting to the NCX1-pSer-68-PLM complex and hypothesized that a direct and functional NCX1-PP1 interaction is a prerequisite for pSer-68-PLM dephosphorylation. Using a variety of molecular techniques, we show that PP1 catalytic subunit (PP1c) co-localized, co-fractionated, and co-immunoprecipitated with NCX1 in rat cardiomyocytes, left ventricle lysates, and HEK293 cells. Bioinformatic analysis, immunoprecipitations, mutagenesis, pulldown experiments, and peptide arrays constrained PP1c anchoring to the K(I/V)FF motif in the first Ca2+ binding domain (CBD) 1 in NCX1. This binding site is also partially in agreement with the extended PP1-binding motif K(V/I)FF-X5–8Φ1Φ2-X8–9-R. The cytosolic loop of NCX1, containing the K(I/V)FF motif, had no effect on PP1 activity in an in vitro assay. Dephosphorylation of pSer-68-PLM in HEK293 cells was not observed when NCX1 was absent, when the K(I/V)FF motif was mutated, or when the PLM- and PP1c-binding sites were separated (mimicking calpain cleavage of NCX1). Co-expression of PLM and NCX1 inhibited NCX1 current (both modes). Moreover, co-expression of PLM with NCX1(F407P) (mutated K(I/V)FF motif) resulted in the current being completely abolished. In conclusion, NCX1 is a substrate-specifying PP1c regulator protein, indirectly regulating NCX1 activity through pSer-68-PLM dephosphorylation. 相似文献
40.
In distylous, self-incompatible plants, clonal propagation, unbalanced floral morph frequencies, and reduced population size can interfere with the functioning of distyly by compromising legitimate intermorph pollinations, resulting in reduced reproductive output. Here, we examined the mating system and the impact of mate availability, population size, and spatial aggregation of morphs on reproductive output in the distylous, clonal, aquatic plant Hottonia palustris. Controlled pollinations under greenhouse conditions detected no spontaneous selfing without the action of a pollen vector (autonomous autogamy) and demonstrated very low fruit and seed development after self-pollination. Intermorph (legitimate) crossings resulted in high reproductive output in both floral morphs (long- and short-styled individuals), whereas intramorph (illegitimate) crossings decreased fruit and seed development by more than 50%, indicating that the species has partial intramorph-incompatibility. In natural populations, small population size and increasing deviation of floral morph frequencies negatively affected reproductive outcome. Individuals of the majority morph type developed significantly fewer fruit and seeds than individuals of the minority morph type. This rapid decline in fecundity was symmetrical, indicating that regardless of which morph was in the majority, the same patterns of negative frequency-dependent mating occurred. Increasing spatial isolation between compatible morphs significantly reduced fruit and seed set in both morphs similarly. This study provides clear indications of frequency- and context-dependent mating in natural populations of a distylous plant species. 相似文献