全文获取类型
收费全文 | 232篇 |
免费 | 21篇 |
专业分类
253篇 |
出版年
2022年 | 4篇 |
2021年 | 3篇 |
2020年 | 1篇 |
2019年 | 2篇 |
2018年 | 4篇 |
2017年 | 4篇 |
2016年 | 5篇 |
2015年 | 7篇 |
2014年 | 7篇 |
2013年 | 11篇 |
2012年 | 17篇 |
2011年 | 14篇 |
2010年 | 5篇 |
2009年 | 6篇 |
2008年 | 12篇 |
2007年 | 6篇 |
2006年 | 7篇 |
2005年 | 5篇 |
2004年 | 7篇 |
2003年 | 6篇 |
2002年 | 10篇 |
2001年 | 10篇 |
2000年 | 5篇 |
1999年 | 3篇 |
1998年 | 7篇 |
1997年 | 12篇 |
1996年 | 5篇 |
1995年 | 3篇 |
1994年 | 8篇 |
1993年 | 1篇 |
1992年 | 9篇 |
1991年 | 1篇 |
1990年 | 1篇 |
1989年 | 2篇 |
1988年 | 5篇 |
1987年 | 2篇 |
1986年 | 3篇 |
1985年 | 1篇 |
1980年 | 3篇 |
1979年 | 6篇 |
1978年 | 1篇 |
1976年 | 3篇 |
1975年 | 2篇 |
1974年 | 3篇 |
1973年 | 3篇 |
1972年 | 5篇 |
1971年 | 1篇 |
1970年 | 3篇 |
1968年 | 1篇 |
1959年 | 1篇 |
排序方式: 共有253条查询结果,搜索用时 15 毫秒
21.
Sergio Couoh-Cardel Elena Milgrom Stephan Wilkens 《The Journal of biological chemistry》2015,290(46):27959-27971
The membrane sector (Vo) of the proton pumping vacuolar ATPase (V-ATPase, V1Vo-ATPase) from Saccharomyces cerevisiae was purified to homogeneity, and its structure was characterized by EM of single molecules and two-dimensional crystals. Projection images of negatively stained Vo two-dimensional crystals showed a ring-like structure with a large asymmetric mass at the periphery of the ring. A cryo-EM reconstruction of Vo from single-particle images showed subunits a and d in close contact on the cytoplasmic side of the proton channel. A comparison of three-dimensional reconstructions of free Vo and Vo as part of holo V1Vo revealed that the cytoplasmic N-terminal domain of subunit a (aNT) must undergo a large conformational change upon enzyme disassembly or (re)assembly from Vo, V1, and subunit C. Isothermal titration calorimetry using recombinant subunit d and aNT revealed that the two proteins bind each other with a Kd of ∼5 μm. Treatment of the purified Vo sector with 1-palmitoyl-2-hydroxy-sn-glycero-3-[phospho-rac-(1-glycerol)] resulted in selective release of subunit d, allowing purification of a VoΔd complex. Passive proton translocation assays revealed that both Vo and VoΔd are impermeable to protons. We speculate that the structural change in subunit a upon release of V1 from Vo during reversible enzyme dissociation plays a role in blocking passive proton translocation across free Vo and that the interaction between aNT and d seen in free Vo functions to stabilize the Vo sector for efficient reassembly of V1Vo. 相似文献
22.
Wilkens MR Mrochen N Breves G Schröder B 《Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology》2011,158(3):199-207
For ruminants, marked differences to monogastric species have been described concerning the localisation and vitamin D sensitivity of gastrointestinal calcium absorption, particularly with respect to the forestomach compartment. Therefore, we investigated gastrointestinal calcium transport of sheep as influenced by a dietary calcium restriction and/or a supraphysiological dosage of exogenous calcitriol. Using the Ussing chamber technique, we determined calcium and mannitol flux rates to differentiate between para- and transcellular calcium transport in rumen, duodenum, jejunum and colon. Expression of epithelial calcium channels, calbindin-D(9K), and basolateral extrusion mechanisms was determined by quantitative RT-PCR and Western blot analysis. Active calcium transport could be demonstrated in jejunum and rumen. A significant stimulation of jejunal calcium absorption was only observed in animals treated with calcitriol. The alimentary calcium restriction alone did not result in significant effects indicating a less effective intestinal adaptation to alimentary calcium restriction than observed in monogastric animals. The observed ruminal calcium transport was not affected at all, neither by the diet nor the calcitriol treatment. Furthermore, no significant expression of epithelial calcium channels or calbindin-D(9K) could be detected in the rumen; therefore it is concluded that calcium transport in the forestomachs is probably mediated by a different, so far unknown mechanism. 相似文献
23.
Beesley J Pickett HA Johnatty SE Dunning AM Chen X Li J Michailidou K Lu Y Rider DN Palmieri RT Stutz MD Lambrechts D Despierre E Lambrechts S Vergote I Chang-Claude J Nickels S Vrieling A Flesch-Janys D Wang-Gohrke S Eilber U Bogdanova N Antonenkova N Runnebaum IB Dörk T Goodman MT Lurie G Wilkens LR Matsuno RK Kiemeney LA Aben KK Marees T Massuger LF Fridley BL Vierkant RA Bandera EV Olson SH Orlow I Rodriguez-Rodriguez L Cook LS Le ND Brooks-Wilson A Kelemen LE Campbell I Gayther SA Ramus SJ 《PloS one》2011,6(9):e24987
Genetic variation at the TERT-CLPTM1L locus at 5p15.33 is associated with susceptibility to several cancers, including epithelial ovarian cancer (EOC). We have carried out fine-mapping of this region in EOC which implicates an association with a single nucleotide polymorphism (SNP) within the TERT promoter. We demonstrate that the minor alleles at rs2736109, and at an additional TERT promoter SNP, rs2736108, are associated with decreased breast cancer risk, and that the combination of both SNPs substantially reduces TERT promoter activity. 相似文献
24.
V de Silva S Thapa L R Wilkens M G Farr K Jayasinghe J E McMahan 《Journal of biosocial science》1988,20(2):143-156
The effects of different levels of compensatory payment for vasectomy on sterilization acceptance were examined in 496 vasectomized men in urban Sri Lanka. The results indicate that compensatory payments significantly enhanced the participation of economically poor men in vasectomy programs, especially those who had already achieved a large family size. The proportion of poor acceptors (those with a monthly income of Rs 1000 or less) increased with higher levels of payment; the acceptor's level of education was negatively correlated with the compensation amount, and the mean age of the youngest child was higher among those who received higher payments. 60% of vasectomy acceptors reported using contraception immediately before the vasectomy, suggesting a high level of motivation not to have another child. Respondents cited high effectiveness, no extra expense, and no side effects for their wives as the main reasons for selecting vasectomy over other means of contraception, regardless of the amount of payment received. Only 5% said cash payment was an important reason for choosing vasectomy, and this response did not vary significantly by level of payment. There was no influence of payment level on postoperative complications or satisfaction. While compensatory payments significantly enhanced the participation of poor men in vasectomy programs, they were not effective in attracting poorer men with few children or those whose last child was relatively young. Overall, this study's findings suggest that the decision to provide compensatory payments and how much to provide should be based on economic and political factors, not on the grounds that higher compensatory payments have led to the recruitment of ineligible men or that the promotion of vasectomy has been at the expense of a loss in the quality of services provided. 相似文献
25.
Akers Donald L. Lefer David J. Chen I. Li Wilkens Robert G. Rice Janet Aurora Harmeet Osgood Thomas A. Bedi Brenda Tenaglia Alan N. Buda Andrew J. Kadowitz Philip J. McNamara Dennis B. 《Molecular and cellular biochemistry》1997,176(1-2):13-20
The effects of an anti-P-selectin monoclonal antibody (MAb, PB1.3; Cytel Corporation) on neoendothelialization; neoendothelial function, as evidenced by acetylcholine-induced relaxation (nitric oxide formation); and intimal hyperplasia following embolectomy catheter-induced injury to the rabbit thoracic aorta were investigated. Catheter injury was induced in two groups of New Zealand White rabbits. One group received no treatment, while the second group received short-term treatment with the MAb (i.p., immediately before and 12 h after induction of catheter injury). A third group underwent a sham operation and served as uninjured controls. Following sacrifice at 2 weeks after injury, aortic rings were assessed for degree of intimal hyperplasia, neoendothelial morphology (scanning electron microscopy), and acetylcholine-induced relaxation. Aortic tissue from catheter-injured animals that received treatment exhibited improved neoendothelial morphology, as compared with tissue from untreated but catheterized animals; however, no statistically significant attenuation of the hyperplastic response or improvement in the attenuated neoendothelial-dependent acetylcholine-induced relaxant response that is characteristic of neoendothelium that forms after catheter denudation was observed. These data suggest that short-term attenuation of P-selectin-mediated polymorphonuclear leukocyte (PMN)/endothelium, PMN/platelet interactions, and/or thrombin formation beneficially affects neoendothelialization of the vascular wall following balloon catheter-induced injury. 相似文献
26.
A critical point of interaction between F(1) and F(0) in the bacterial F(1)F(0)-ATP synthase is formed by the alpha and delta subunits. Previous work has shown that the N-terminal domain (residues 3-105) of the delta subunit forms a 6 alpha-helix bundle [Wilkens, S., Dunn, S. D., Chandler, J., Dahlquist, F. W., and Capaldi, R. A. (1997) Nat. Struct. Biol. 4, 198-201] and that the majority of the binding energy between delta and F(1) is provided by the interaction between the N-terminal 22 residues of the alpha- and N-terminal domain of the delta subunit [Weber, J., Muharemagic, A., Wilke-Mounts, S., and Senior, A. E. (2003) J. Biol. Chem. 278, 13623-13626]. We have now analyzed a 1:1 complex of the delta-subunit N-terminal domain and a peptide comprising the N-terminal 22 residues of the alpha subunit by heteronuclear protein NMR spectroscopy. A comparison of the chemical-shift values of delta-subunit residues with and without alpha N-terminal peptide bound indicates that the binding interface on the N-terminal domain of the delta subunit is formed by alpha helices I and V. NOE cross-peak patterns in 2D (12)C/(12)C-filtered NOESY spectra of the (13)C-labeled delta-subunit N-terminal domain in complex with unlabeled peptide verify that residues 8-18 in the alpha-subunit N-terminal peptide are folded as an alpha helix when bound to delta N-terminal domain. On the basis of intermolecular contacts observed in (12)C/(13)C-filtered NOESY experiments, we describe structural details of the interaction of the delta-subunit N-terminal domain with the alpha-subunit N-terminal alpha helix. 相似文献
27.
Intracellular blockade by quaternary ammonium (QA) molecules of many potassium channels is state dependent, where the requirement for channel opening is evidenced by a time-dependent component of block in the macroscopic record. Whether this is the case for Ca(2+)- and voltage-activated potassium (BK) channels, however, remains unclear. Previous work (Li, W., and R.W. Aldrich. 2004. J. Gen. Physiol. 124:43-57) tentatively proposed a state-dependent, trapping model, but left open the possibility of state-independent block. Here, we found BK channel blockade by a novel QA derivative, bbTBA, was time dependent, raising the possibility of state-dependent, open channel block. Alternatively, the observed voltage dependence of block could be sufficient to explain time-dependent block. We have used steady-state and kinetic measurements of bbTBA blockade in order to discriminate between these two possibilities. bbTBA did not significantly slow deactivation kinetics at potentials between -200 and -100 mV, suggesting that channels can close unhindered by bound bbTBA. We further find no evidence that bbTBA is trapped inside BK channels after closing. Measurements of steady state fractional block at +40 mV revealed a 1.3-fold change in apparent affinity for a 33-fold change in P(o), in striking contrast to the 31-fold change predicted by state-dependent block. Finally, the appearance of a third kinetic component of bbTBA blockade at high concentrations is incompatible with state-dependent block. Our results suggest that access of intracellular bbTBA to the BK channel cavity is not strictly gated by channel opening and closing, and imply that the permeation gate for BK channels may not be intracellular. 相似文献
28.
Leonie Pothmann Lon A. Wilkens Michael H. Hofmann 《Journal of comparative physiology. A, Neuroethology, sensory, neural, and behavioral physiology》2012,198(1):1-10
Paddlefish are uniquely adapted for the detection of their prey, small water fleas, by primarily using their passive electrosensory
system. In a recent anatomical study, we found two populations of secondary neurons in the electrosensory hind brain area
(dorsal octavolateral nucleus, DON). Cells in the anterior DON project to the contralateral tectum, whereas cells in the posterior
DON project bilaterally to the torus semicircularis and lateral mesencephalic nucleus. In this study, we investigated the
properties of both populations and found that they form two physiologically different populations. Cells in the posterior
DON are about one order of magnitude more sensitive and respond better to stimuli with lower frequency content than anterior
cells. The posterior cells are, therefore, better suited to detect distant prey represented by low-amplitude signals at the
receptors, along with a lower frequency spectrum, whereas cells in the anterior DON may only be able to sense nearby prey.
This suggests the existence of two distinct channels for electrosensory information processing: one for proximal signals via
the anterior DON and one for distant stimuli via the posterior DON with the sensory input fed into the appropriate ascending
channels based on the relative sensitivity of both cell populations. 相似文献
29.
Nucleotide-induced structural changes in P-glycoprotein observed by electron microscopy 总被引:3,自引:0,他引:3
P-glycoprotein (Pgp) is an ATP hydrolysis driven multidrug efflux pump, which, when overexpressed in the plasma membrane of certain cancers, can lead to the failure of chemotherapy. Previously, we have presented a projection structure of nucleotide-free mouse Pgp from electron microscopic images of lipid monolayer-generated two-dimensional crystals ( Lee, J. Y., Urbatsch, I. L., Senior, A. E., and Wilkens, S. (2002) J. Biol. Chem. 277, 40125-40131 ). Here we have analyzed the structure of cysteine-free human Pgp from two-dimensional crystals that were generated with the same lipid-monolayer technique in the absence and presence of various nucleotides. The images show that human Pgp has a similar structure to the mouse protein. Furthermore, the analysis of projection structures obtained under different nucleotide conditions suggests that Pgp can exist in at least two major conformations, one of which shows a central cavity between the N- and C-terminal halves of the molecule and another in which the two halves have moved sideways, thereby closing the central cavity. Intermediate conformations were observed for some nucleotide/vanadate combinations. A low-resolution, three-dimensional model of human Pgp was calculated from tilted specimen crystallized in the presence of the non-hydrolyzable nucleotide analog, adenosine 5'-O-(thiotriphosphate). The structural analysis presented here adds to the emerging picture that multidrug ABC transporters function by switching between two major conformations in a nucleotide-dependent manner. 相似文献
30.