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71.
Background
The interactions of the voltage-gated Ca2+ channel (VGCC) with syntaxin 1A (Sx 1A), Synaptosome-associated protein of 25 kD (SNAP-25), and synaptotagmin, couple electrical excitation to evoked secretion. Two vicinal Cys residues, Cys 271 and Cys 272 in the Sx 1A transmembrane domain, are highly conserved and participate in modulating channel kinetics. Each of the Sx1A Cys mutants, differently modify the kinetics of Cav1.2, and neuronal Cav2.2 calcium channel.Methodology/Principle Findings
We examined the effects of various Sx1A Cys mutants and the syntaxin isoforms 2, 3, and 4 each of which lack vicinal Cys residues, on evoked secretion, monitoring capacitance transients in a functional release assay. Membrane capacitance in Xenopus oocytes co-expressing Cav1.2, Sx1A, SNAP-25 and synaptotagmin, which is Bot C- and Bot A-sensitive, was elicited by a double 500 ms depolarizing pulse to 0 mV. The evoked-release was obliterated when a single Cys Sx1A mutant or either one of the Sx isoforms were substituted for Sx 1A, demonstrating the essential role of vicinal Cys residues in the depolarization mediated process. Protein expression and confocal imaging established the level of the mutated proteins in the cell and their targeting to the plasma membrane.Conclusions/Significance
We propose a model whereby the two adjacent transmembranal Cys residues of Sx 1A, lash two calcium channels. Consistent with the necessity of a minimal fusion complex termed the excitosome, each Sx1A is in a complex with SNAP-25, Syt1, and the Ca2+ channel. A Hill coefficient >2 imply that at least three excitosome complexes are required for generating a secreting hetero-oligomer protein complex. This working model suggests that a fusion pore that opens during membrane depolarization could be lined by alternating transmembrane segments of Sx1A and VGCC. The functional coupling of distinct amino acids of Sx 1A with VGCC appears to be essential for depolarization-evoked secretion. 相似文献72.
Tetranychus turkestani Ugarov and Nikolskii and Tetranychus urticae Koch RF (red form) (Acari: Tetranychidae) are closely related species. Previously, the two species were found in separate
agricultural habitats in Israel. Here, additional collections were undertaken and mixed populations of the two species were
found. Manipulation experiments were conducted in order to test whether sexual interactions occur when T. turkestani and T. urticae RF share the same host. Interspecific crosses showed that the two species are capable of producing viable F1 females, but that these females are sterile as their F2 eggs failed to hatch. This indicates a post-zygotic reproductive barrier, supporting the current placement of T. turkestani as a separate taxon. Mating behavior parameters revealed that males of both species courted virgin conspecific and heterospecific
females at the same rate and readily tried to copulate with them. Female mate recognition seemed to be more reliable in T. turkestani than in T. urticae RF as the number of copulations was significantly higher and their duration significantly shorter in the T. turkestani interspecific (T. turkestani ♀ × T. urticae RF ♂) as compared to the intraspecific crosses, a phenomenon not observed in T. urticae RF. In mixed cultures, a significant reduction in female production was observed for T. urticae RF but not for T. turkestani, suggesting an asymmetric reproductive interference effect in favor of T. turkestani. The long term outcome of this effect is yet to be determined since additional reproductive factors such as oviposition rate
and progeny survival to adulthood may reduce the probability of demographic displacement of one species by the other in overlapping
niches. 相似文献
73.
Monitoring of tumor response to chemotherapy in vivo by a novel small-molecule detector of apoptosis 总被引:1,自引:0,他引:1
Hagit Grimberg Galit Levin Anat Shirvan Avi Cohen Merav Yogev-Falach Ayelet Reshef Ilan Ziv 《Apoptosis : an international journal on programmed cell death》2009,14(3):257-267
Utilization of molecular imaging of apoptosis for clinical monitoring of tumor response to anti-cancer treatments in vivo
is highly desirable. To address this need, we now present ML-9 (butyl-2-methyl-malonic acid; MW = 173), a rationally designed
small-molecule detector of apoptosis, based on a novel alkyl-malonate motif. In proof-of-concept studies, induction of apoptosis
in tumor cells by various triggers both in vitro and in vivo was associated with marked uptake of 3H-ML-9 administered in vivo, in correlation with the apoptotic hallmarks of DNA fragmentation, caspase-3 activation and membrane
phospholipid scrambling, and with correlative tumor regression. ML-9 uptake following chemotherapy was tumor-specific, with
rapid clearance of the tracer from the blood and other non-target organs. Excess of non-labeled “cold” compound competitively
blocked ML-9 tumor uptake, thus demonstrating the specificity of ML-9 binding. ML-9 may therefore serve as a platform for
a novel class of small-molecule imaging agents for apoptosis, useful for assessment of tumor responsiveness to treatment.
H. Grimberg, G. Levin and A. Shirvan contributed equally to this article. 相似文献
74.
Elizabeth A. Flaherty Merav Ben-David Winston P. Smith 《Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology》2010,180(7):1067-1078
Gliding allows mammals to exploit canopy habitats of old-growth forests possibly as a means to save energy. To assess costs
of quadrupedal locomotion for a gliding arboreal mammal, we used open-flow respirometry and a variable-speed treadmill to
measure oxygen consumption and to calculate cost of transport, excess exercise oxygen consumption, and excess post-exercise
oxygen consumption for nine northern flying squirrels (Glaucomys sabrinus) and four fox squirrels (Sciurus niger). Our results indicate that oxygen consumption during exercise by flying squirrels was 1.26–1.65 times higher than predicted
based on body mass, and exponentially increased with velocity (from 0.84 ± 0.03 ml O2 kg−1 s−1 at 0.40 m s−1 to 1.55 ± 0.03 ml O2 kg−1 s−1 at 0.67 m s−1). Also, cost of transport in flying squirrels increased with velocity, although excess exercise oxygen consumption and excess
post-exercise oxygen consumption did not. In contrast, oxygen consumption during exercise for fox squirrels was similar to
predicted, varying from 0.51 (±0.02) ml O2 kg−1 s−1 at 0.63 m s−1 to 0.54 (±0.03) ml O2 kg−1 s−1 at 1.25 m s−1. In addition, the cost of transport for fox squirrels decreased with velocity, while excess exercise oxygen consumption and
excess post-exercise oxygen consumption did not. Collectively, these observations suggest that unlike fox squirrels, flying
squirrels are poorly adapted to prolonged bouts of quadrupedal locomotion. The evolution of skeletal adaptations to climbing,
leaping, and landing and the development of a gliding membrane likely has increased the cost of quadrupedal locomotion by
>50% while resulting in energy savings during gliding and reduction in travel time between foraging patches. 相似文献
75.
Yael Pewzner-Jung Ori Brenner Svantje Braun Elad L. Laviad Shifra Ben-Dor Ester Feldmesser Shirley Horn-Saban Daniela Amann-Zalcenstein Calanit Raanan Tamara Berkutzki Racheli Erez-Roman Oshrit Ben-David Michal Levy Dorin Holzman Hyejung Park Abraham Nyska Alfred H. Merrill Jr. Anthony H. Futerman 《The Journal of biological chemistry》2010,285(14):10911-10923
76.
Milko E. van der Boom Shyh-Yeon Liou Yehoshoa Ben-David 《Inorganica chimica acta》2004,357(13):4015-4023
Reaction of NiI2 with the PCP-ligand {1-Et-2,6-(CH2PiPr2)2-C6H3} (1) results in selective activation of the strong sp2-sp3 aryl-ethyl bond to afford the aryl-nickel complex [Ni{2,6-(CH2PiPr2)2-C6H3}I] (2), whereas reaction of NiI2 with {1,3,5-(CH3)3-2,6-(CH2PiPr2)2-C6H} (4) leads to the formation of the benzylic complex [Ni{1-CH2-2,6-(CH2PiPr2)2-3,5-(CH3)2-C6H}I] (5) by selective C-H bond activation. Thermolysis of 5 results in formation of [Ni{2,6-(CH2PiPr2)2-3,5-(CH3)2-C6H}I] (6) by activation of the sp2-sp3 C-C bond. The identity of the new 16-electron complexes 2 and 6 was confirmed by reaction of NiI2 with {1,3-(CH2PiPr2)2-C6H4} (3) and {1,3-(CH3)2-4,6-(CH2PiPr2)2-C6H2} (7), respectively, lacking the aryl-alkyl groups between the “phosphines arms” (alkyl=ethyl, methyl). Complexes 2 and 5 have been fully characterized by X-ray analysis. Nickel-based activation of an unstrained C-O single bond was observed as well. Reaction of the aryl-methoxy bisphosphine {1-OMe-2,6-(CH2PiPr2)2-C6H3} (8) with NiI2 results in the formation of the phenoxy complex [Ni{1-O-2,6-(CH2PiPr2)2-C6H3}I] (9) by selective sp3-sp3 C-O bond activation. 相似文献
77.
Milko E. van der Boom Mark A. Iron Linda J.W. Shimon Yehoshoa Ben-David Jan M.L. Martin David Milstein 《Inorganica chimica acta》2004,357(6):1854-1864
Halide abstraction from the 18 electron Ru(II) complex RuCl(CO)2[2,6-(CH2PtBu2)2C6H3] (2) with AgPF6 results in the exclusive formation of the cationic complex {Ru(CO)2[2,6-(CH2PtBu2)2C6H3]}+PF6− (3). The molecular structures of 2 and 3 were determined by complete single-crystal diffraction studies. X-ray crystallographic analysis of 3 reveals that the “open” coordination site is occupied by an agostic interaction between the metal center and an sp3 C-H bond of a tert-butyl substituent. DFT gas phase calculations (B97-1/SDD) show the necessity of two sterically demanding tert-butyl substituents on one P donor atom for the agostic interaction to occur. The reaction of 3 with H2 results in the quantitative conversion to {Ru(H)(CO)2[2,6-(CH2PtBu2)2C6H4]}+PF6− (4) where the aromatic Cipso-H bond is η2-coordinated to the metal center. Treatment of the agostic complex 4 with Et3N results in the formation of the neutral complex Ru(H)(CO)2[2,6-(CH2PtBu2)2C6H3] (5). The mechanistic details of 3 + H2 → 4 were investigated by DFT calculations at the B97-1/SDB-cc-pVDZ//B97-1/SDD level of theory. 相似文献
78.
Seiler C Ben-David O Sidi S Hendrich O Rusch A Burnside B Avraham KB Nicolson T 《Developmental biology》2004,272(2):328-338
Unconventional myosins have been associated with hearing loss in humans, mice, and zebrafish. Mutations in myosin VI cause both recessive and dominant forms of nonsyndromic deafness in humans and deafness in Snell's waltzer mice associated with abnormal fusion of hair cell stereocilia. Although myosin VI has been implicated in diverse cellular processes such as vesicle trafficking and epithelial morphogenesis, the role of this protein in the sensory hair cells remains unclear. To investigate the function of myosin VI in zebrafish, we cloned and examined the expression pattern of myosin VI, which is duplicated in the zebrafish genome. One duplicate, myo6a, is expressed in a ubiquitous pattern during early development and at later stages, and is highly expressed in the brain, gut, and kidney. myo6b, on the other hand, is predominantly expressed in the sensory epithelium of the ear and lateral line at all developmental stages examined. Both molecules have different splice variants expressed in these tissues. Using a candidate gene approach, we show that myo6b is satellite, a gene responsible for auditory/vestibular defects in zebrafish larvae. Examination of hair cells in satellite mutants revealed that stereociliary bundles are irregular and disorganized. At the ultrastructural level, we observed that the apical surface of satellite mutant hair cells abnormally protrudes above the epithelium and the membrane near the base of the stereocilia is raised. At later stages, stereocilia fused together. We conclude that zebrafish myo6b is required for maintaining the integrity of the apical surface of hair cells, suggesting a conserved role for myosin VI in regulation of actin-based interactions with the plasma membrane. 相似文献
79.
Shacham S Marantz Y Bar-Haim S Kalid O Warshaviak D Avisar N Inbal B Heifetz A Fichman M Topf M Naor Z Noiman S Becker OM 《Proteins》2004,57(1):51-86
G-protein coupled receptors (GPCRs) are a major group of drug targets for which only one x-ray structure is known (the nondrugable rhodopsin), limiting the application of structure-based drug discovery to GPCRs. In this paper we present the details of PREDICT, a new algorithmic approach for modeling the 3D structure of GPCRs without relying on homology to rhodopsin. PREDICT, which focuses on the transmembrane domain of GPCRs, starts from the primary sequence of the receptor, simultaneously optimizing multiple 'decoy' conformations of the protein in order to find its most stable structure, culminating in a virtual receptor-ligand complex. In this paper we present a comprehensive analysis of three PREDICT models for the dopamine D2, neurokinin NK1, and neuropeptide Y Y1 receptors. A shorter discussion of the CCR3 receptor model is also included. All models were found to be in good agreement with a large body of experimental data. The quality of the PREDICT models, at least for drug discovery purposes, was evaluated by their successful utilization in in-silico screening. Virtual screening using all three PREDICT models yielded enrichment factors 9-fold to 44-fold better than random screening. Namely, the PREDICT models can be used to identify active small-molecule ligands embedded in large compound libraries with an efficiency comparable to that obtained using crystal structures for non-GPCR targets. 相似文献
80.
Nuclear pore protein gp210 is essential for viability in HeLa cells and Caenorhabditis elegans 总被引:3,自引:0,他引:3 下载免费PDF全文
Gp210 is an evolutionarily conserved membrane protein of the nuclear pore complex (NPC). We studied the phenotypes produced by RNAi-induced downregulation of gp210 in both human (HeLa) cells and Caenorhabditis elegans embryos. HeLa cell viability requires Gp210 activity. The dying cells accumulated clustered NPCs and aberrant membrane structures at the nuclear envelope, suggesting that gp210 is required directly or indirectly for nuclear pore formation and dilation as well as the anchoring or structural integrity of mature NPCs. Essential roles for gp210 were confirmed in C. elegans, where RNAi-induced reduction of gp210 caused embryonic lethality. The nuclear envelopes of embryos with reduced gp210 also had aberrant nuclear membrane structures and clustered NPCs, confirming that gp210 plays critical roles at the nuclear membrane through mechanisms that are conserved from nematodes to humans. 相似文献