全文获取类型
收费全文 | 478篇 |
免费 | 64篇 |
出版年
2019年 | 5篇 |
2018年 | 10篇 |
2015年 | 4篇 |
2014年 | 13篇 |
2013年 | 10篇 |
2012年 | 21篇 |
2011年 | 17篇 |
2010年 | 9篇 |
2009年 | 6篇 |
2008年 | 13篇 |
2007年 | 12篇 |
2006年 | 13篇 |
2005年 | 21篇 |
2004年 | 15篇 |
2003年 | 18篇 |
2002年 | 18篇 |
2001年 | 21篇 |
2000年 | 13篇 |
1999年 | 13篇 |
1998年 | 10篇 |
1997年 | 10篇 |
1996年 | 5篇 |
1995年 | 5篇 |
1994年 | 4篇 |
1993年 | 7篇 |
1992年 | 16篇 |
1991年 | 14篇 |
1990年 | 19篇 |
1989年 | 14篇 |
1988年 | 9篇 |
1987年 | 9篇 |
1986年 | 12篇 |
1985年 | 12篇 |
1984年 | 8篇 |
1983年 | 6篇 |
1982年 | 5篇 |
1981年 | 7篇 |
1980年 | 4篇 |
1979年 | 11篇 |
1978年 | 6篇 |
1977年 | 11篇 |
1976年 | 6篇 |
1975年 | 16篇 |
1974年 | 8篇 |
1973年 | 7篇 |
1972年 | 6篇 |
1971年 | 5篇 |
1970年 | 4篇 |
1969年 | 4篇 |
1967年 | 6篇 |
排序方式: 共有542条查询结果,搜索用时 31 毫秒
61.
Eulenburg V Becker K Gomeza J Schmitt B Becker CM Betz H 《Biochemical and biophysical research communications》2006,348(2):400-405
Hereditary hyperekplexia is a neuromotor disorder characterized by exaggerated startle reflexes and muscle stiffness in the neonate. The disease has been associated with mutations in the glycine receptor subunit genes GLRA1 and GLRB. Here, we describe mutations within the neuronal glycine transporter 2 gene (GLYT2, or SLC6A5, ) of hyperekplexia patients, whose symptoms cannot be attributed to glycine receptor mutations. One of the GLYT2 mutations identified causes truncation of the transporter protein and a complete loss of transport function. Our results are consistent with GLYT2 being a disease gene in human hyperekplexia. 相似文献
62.
Synaptic glycine receptors (GlyRs) are hetero-pentameric chloride channels composed of α and β subunits, which are activated by agonist binding at subunit interfaces. To examine the pharmacological properties of each potential agonist-binding site, we substituted residues of the GlyR α(1) subunit by the corresponding residues of the β subunit, as deduced from sequence alignment and homology modeling based on the recently published crystal structure of the glutamate-gated chloride channel GluCl. These exchange substitutions allowed us to reproduce the βα, αβ and ββ subunit interfaces present in synaptic heteromeric GlyRs by generating recombinant homomeric receptors. When the engineered α(1) GlyR mutants were expressed in Xenopus oocytes, all subunit interface combinations were found to form functional agonist-binding sites as revealed by voltage clamp recording. The ββ-binding site displayed the most distinct pharmacological profile towards a range of agonists and modulators tested, indicating that it might be selectively targeted to modulate the activity of synaptic GlyRs. The mutational approach described here should be generally applicable to heteromeric ligand-gated ion channels composed of homologous subunits and facilitate screening efforts aimed at targeting inter-subunit specific binding sites. 相似文献
63.
NP Nguyen A Chi M Betz F Almeida P Vos R Davis B Slane M Ceizyk D Abraham L Smith-Raymond M Stevie S Jang S Gelumbauskas V Vinh-Hung 《PloS one》2012,7(8):e42729
Purpose
The study aims to assess the feasibility of intensity-modulated and image-guided radiotherapy (IMRT, and IGRT, respectively) for functional preservation in locally advanced laryngeal cancer. A retrospective review of 27 patients undergoing concurrent chemoradiation for locally advanced laryngeal cancers (8 IMRT, 19 IGRT) was undertaken. In addition to regular clinical examinations, all patients had PET imaging at 4 months and 10 months after radiotherapy, then yearly. Loco-regional control, speech quality and feeding-tube dependency were assessed during follow-up visits.Results
At a median follow-up of 20 months (range 6–57 months), four out of 27 patients (14.8%) developed local recurrence and underwent salvage total laryngectomy. One patient developed distant metastases following salvage surgery. Among the 23 patients who conserved their larynx with no sign of recurrence at last follow-up, 22 (95%) reported normal or near normal voice quality, allowing them to communicate adequately. Four patients (14.8%) had long-term tube feeding-dependency because of severe dysphagia (2 patients) and chronic aspiration (2 patients, with ensuing death from aspiration pneumonia in one patient).Conclusions and Clinical Relevance
Functional laryngeal preservation is feasible with IMRT and IGRT for locally advanced laryngeal cancer. However, dysphagia and aspiration remain serious complications, due most likely to high radiation dose delivery to the pharyngeal musculatures. 相似文献64.
Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c 总被引:1,自引:0,他引:1
Hagiwara A Cornu M Cybulski N Polak P Betz C Trapani F Terracciano L Heim MH Rüegg MA Hall MN 《Cell metabolism》2012,15(5):725-738
Mammalian target of rapamycin complex 2 (mTORC2) phosphorylates and activates AGC kinase family members, including Akt, SGK1, and PKC, in response to insulin/IGF1. The liver is a key organ in insulin-mediated regulation of metabolism. To assess the role of hepatic mTORC2, we generated liver-specific rictor knockout (LiRiKO) mice. Fed LiRiKO mice displayed loss of Akt Ser473 phosphorylation and reduced glucokinase and SREBP1c activity in the liver, leading to constitutive gluconeogenesis, and impaired glycolysis and lipogenesis, suggesting that the mTORC2-deficient liver is unable to sense satiety. These liver-specific defects resulted in systemic hyperglycemia, hyperinsulinemia, and hypolipidemia. Expression of constitutively active Akt2 in mTORC2-deficient hepatocytes restored both glucose flux and lipogenesis, whereas glucokinase overexpression rescued glucose flux but not lipogenesis. Thus, mTORC2 regulates hepatic glucose and lipid metabolism via insulin-induced Akt signaling to control whole-body metabolic homeostasis. These findings have implications for emerging drug therapies that target mTORC2. 相似文献
65.
Overmyer K Kollist H Tuominen H Betz C Langebartels C Wingsle G Kangasjärvi S Brader G Mullineaux P Kangasjärvi J 《Plant, cell & environment》2008,31(9):1237-1249
Genetically tractable model plants offer the possibility of defining the plant O3 response at the molecular level. To this end, we have isolated a collection of ozone (O3 )-sensitive mutants of Arabidopsis thaliana . Mutant phenotypes and genetics were characterized. Additionally, parameters associated with O3 sensitivity were analysed, including stomatal conductance, sensitivity to and accumulation of reactive oxygen species, antioxidants, stress gene-expression and the accumulation of stress hormones. Each mutant has a unique phenotypic profile, with O3 sensitivity caused by a unique set of alterations in these systems. O3 sensitivity in these mutants is not caused by gross deficiencies in the antioxidant pathways tested here. The rcd3 mutant exhibits misregulated stomata. All mutants exhibited changes in stress hormones consistent with the known hormonal roles in defence and cell death regulation. One mutant, dubbed re-8 , is an allele of the classic leaf development mutant reticulata and exhibits phenotypes dependent on light conditions. This study shows that O3 sensitivity can be determined by deficiencies in multiple interacting plant systems and provides genetic evidence linking these systems. 相似文献
66.
When pituitary lactotroph granules undergo exocytosis in the presence of FM1-43, their cores absorb dye and fluoresce brightly. We report that different granules fluoresce with different colors, despite being stained with a single fluorescent dye; emission spectra from individual granules show up to a 25 nm difference between the greenest and reddest granules. We found a correlation between granule color and average fluorescence intensity, suggesting that granule color depends upon dye concentration. We confirmed this in two ways: by increasing FM dye concentration in granules, which red shifted granule color, and by partially photobleaching the FM dye in granules, which green shifted granule color. Increasing stimulation intensity (by increasing KCl concentration) increased the proportion of red granules, indicating that granules exocytosing during intense stimulation bound more dye. This, perhaps, reflects differences in granule core maturation and condensation in which mature granules with condensed cores bind more FM dye but require more intense stimulation to be released. Concentration-dependent color shifts of FM dyes may be useful for monitoring aggregation processes occurring on a size scale smaller than the optical limit. 相似文献
67.
Matthew W Strobeck David N Reisman Ranjaka W Gunawardena Bryan L Betz Steven P Angus Karen E Knudsen Timothy F Kowalik Bernard E Weissman Erik S Knudsen 《The Journal of biological chemistry》2002,277(7):4782-4789
The BRG-1 subunit of the SWI-SNF complex is involved in chromatin remodeling and has been implicated in the action of the retinoblastoma tumor suppressor (RB). Given the importance of BRG-1 in RB function, germ line BRG-1 mutations in tumorigenesis may be tantamount to RB inactivation. Therefore, in this study we assessed the behavior of cells harboring discrete BRG-1 alleles for the RB-signaling pathway. Using p16ink4a, an upstream activator of endogenous RB, or a constitutively active RB construct (PSM-RB), we determined that the majority of tumor lines with germ line defects in BRG-1 were sensitive to RB-mediated cell cycle arrest. By contrast, A427 (lung carcinoma) cells were resistant to expression of p16ink4a and PSM-RB. Analysis of the SWI-SNF subunits in the different tumor lines revealed that A427 are deficient for BRG-1 and its homologue, Brm, whereas RB-sensitive cell lines retained Brm expression. Similarly, the RB-resistant SW13 and C33A cell lines were also deficient for both BRG-1/Brm. Reintroduction of either BRG-1 or Brm into A427 or C33A cells restored RB-mediated signaling to cyclin A to cause cell cycle arrest. Consistent with this compensatory role, we observed that Brm could also drive expression of CD44. We also determined that loss of these core SWI-SNF subunits renders SW13 cells resistant to activation of the RB pathway by the chemotherapeutic agent cisplatin, since reintroduction of either BRG-1 or Brm into SW13 cells restored the cisplatin DNA-damage checkpoint. Together, these data demonstrate that Brm can compensate for BRG-1 loss as pertains to RB sensitivity. 相似文献
68.
William F. Schwindinger Lauren J. Murphree Mihalcik Kathryn E. Giger Kelly S. Betz Anna Maria Stauffer Joel Linden Denis Herve Janet D. Robishaw 《The Journal of biological chemistry》2010,285(39):29787-29796
The adenosine A2A receptor (A2AR) is increasingly recognized as a novel therapeutic target in Parkinson disease. In striatopallidal neurons, the G-protein αolf subtype is required to couple this receptor to adenylyl cyclase activation. It is now well established that the βγ dimer also performs an active role in this signal transduction process. In principal, sixty distinct βγ dimers could arise from combinatorial association of the five known β and 12 γ subunit genes. However, key questions regarding which βγ subunit combinations exist and whether they perform specific signaling roles in the context of the organism remain to be answered. To explore these questions, we used a gene targeting approach to specifically ablate the G-protein γ7 subtype. Revealing a potentially new signaling paradigm, we show that the level of the γ7 protein controls the hierarchial assembly of a specific G-protein αolfβ2γ7 heterotrimer in the striatum. Providing a probable basis for the selectivity of receptor signaling, we further demonstrate that loss of this specific G-protein heterotrimer leads to reduced A2AR activation of adenylyl cyclase. Finally, substantiating an important role for this signaling pathway in pyschostimulant responsiveness, we show that mice lacking the G-protein γ7 subtype exhibit an attenuated behavioral response to caffeine. Collectively, these results further support the A2AR G-protein αolfβ2γ7 interface as a possible therapeutic target for Parkinson disease. 相似文献
69.
70.
Bone morphogenetic protein‐2 is a stronger inducer of osteogenesis within muscle tissue than heterodimeric bone morphogenetic protein‐2/6 and ‐2/7: Implications for expedited gene‐enhanced bone repair
下载免费PDF全文
![点击此处可从《The journal of gene medicine》网站下载免费的PDF全文](/ch/ext_images/free.gif)