全文获取类型
收费全文 | 1580篇 |
免费 | 103篇 |
国内免费 | 28篇 |
出版年
2023年 | 10篇 |
2022年 | 34篇 |
2021年 | 39篇 |
2020年 | 41篇 |
2019年 | 45篇 |
2018年 | 57篇 |
2017年 | 29篇 |
2016年 | 19篇 |
2015年 | 37篇 |
2014年 | 67篇 |
2013年 | 104篇 |
2012年 | 60篇 |
2011年 | 55篇 |
2010年 | 100篇 |
2009年 | 79篇 |
2008年 | 71篇 |
2007年 | 96篇 |
2006年 | 97篇 |
2005年 | 87篇 |
2004年 | 77篇 |
2003年 | 55篇 |
2002年 | 58篇 |
2001年 | 33篇 |
2000年 | 23篇 |
1999年 | 34篇 |
1998年 | 34篇 |
1997年 | 27篇 |
1996年 | 10篇 |
1995年 | 24篇 |
1994年 | 20篇 |
1993年 | 22篇 |
1992年 | 18篇 |
1991年 | 13篇 |
1990年 | 16篇 |
1989年 | 13篇 |
1988年 | 13篇 |
1987年 | 7篇 |
1986年 | 12篇 |
1985年 | 13篇 |
1984年 | 14篇 |
1983年 | 6篇 |
1982年 | 17篇 |
1981年 | 11篇 |
1980年 | 7篇 |
1979年 | 3篇 |
1978年 | 2篇 |
1977年 | 1篇 |
1976年 | 1篇 |
排序方式: 共有1711条查询结果,搜索用时 15 毫秒
991.
992.
P2X receptors (P2XRs) are ATP-activated calcium-permeable ligand-gated ion channels traditionally viewed as sensors of extracellular ATP during diverse physiological processes including pain, inflammation, and taste. However, in addition to a cell surface residency P2XRs also populate the membranes of intracellular compartments, including mammalian lysosomes, phagosomes, and the contractile vacuole (CV) of the amoeba Dictyostelium. The function of intracellular P2XRs is unclear and represents a major gap in our understanding of ATP signaling. Here, we exploit the genetic versatility of Dictyostelium to investigate the effects of physiological concentrations of ATP on calcium signaling in isolated CVs. Within the CV, an acidic calcium store, P2XRs are orientated to sense luminal ATP. Application of ATP to isolated vacuoles leads to luminal translocation of ATP and release of calcium. Mechanisms of luminal ATP translocation and ATP-evoked calcium release share common pharmacology, suggesting that they are linked processes. The ability of ATP to mobilize stored calcium is reduced in vacuoles isolated from P2X(A)R knock-out amoeba and ablated in cells devoid of P2XRs. Pharmacological inhibition of luminal ATP translocation or depletion of CV calcium attenuates CV function in vivo, manifesting as a loss of regulatory cell volume decrease following osmotic swelling. We propose that intracellular P2XRs regulate vacuole activity by acting as calcium release channels, activated by translocation of ATP into the vacuole lumen. 相似文献
993.
Nakamura R Nakamoto C Obama H Durward E Nakamoto M 《The Journal of biological chemistry》2012,287(5):3282-3291
Nel (neural epidermal growth factor (EGF)-like molecule) is a multimeric, multimodular extracellular glycoprotein with heparin-binding activity and structural similarities to thrombospondin-1. Nel is predominantly expressed in the nervous system and has been implicated in neuronal proliferation and differentiation, retinal axon guidance, synaptic functions, and spatial learning. The Nel protein contains an N-terminal thrombospondin-1 (TSP-N) domain, five cysteine-rich domains, and six EGF-like domains. However, little is known about the functions of specific domains of the Nel protein. In this study, we have performed structure-function analysis of Nel, by using a series of expression constructs for different regions of the Nel protein. Our studies demonstrate that the TSP-N domain is responsible for homo-multimer formation of Nel and its heparin-binding activity. In vivo, Nel and related Nell1 are expressed in several regions of the mouse central nervous system with partly overlapping patterns. When they are expressed in the same cells in vitro, Nel and Nell1 can form hetero-multimers through the TSP-N domain, but they do not hetero-oligomerize with thrombospondin-1. Whereas both the TSP-N domain and cysteine-rich domains can bind to retinal axons in vivo, only the latter causes growth cone collapse in cultured retinal axons, suggesting that cysteine-rich domains interact with and activate an inhibitory axon guidance receptor. These results suggest that Nel interacts with a range of molecules through its different domains and exerts distinct functions. 相似文献
994.
Intracellular redistribution of heme in rat liver under oxidative stress: the role of heme synthesis
Heme distribution in subcellular fractions of rat liver was studied first hours under the action of several agents causing oxidative stress in vivo. Total and post-mitochondrial heme content in liver was found to depend on both the level of hemolysis products in blood and agent's capacity to modify heme and hemoproteins. The increase of activity of 5-aminolevulinate synthase (ALAS) and/or heme accumulation in mitochondria was accompanied by increase of tryptophan-2,3-dioxygenase (TDO) heme saturation. Membrane stabilisation by tocopherol or prevention of early ALAS induction by cycloheximide prevented both mitochondrial heme accumulation and increase of TDO heme saturation. Modification of heme fully prevented the alterations of total heme content even under severe hemolysis as well as the increase of TDO heme saturation if no increase of heme synthesis occurred. Thus heme synthesis can greatly contribute to heme intracellular redistribution under oxidative stress. 相似文献
995.
The filamentous fungus Penicillium paxilli contains two distinct geranylgeranyl diphosphate (GGPP) synthases, GgsA and GgsB (PaxG). PaxG and its homologues in Neotyphodium lolii and Fusarium fujikuroi are associated with diterpene secondary metabolite gene clusters. The genomes of other filamentous fungi including Aspergillus fumigatus, Aspergillus nidulans, Aspergillus niger, Aspergillus oryzae and Fusarium graminearum also contain two or more copies of GGPP synthase genes, although the diterpene metabolite capability of these fungi is not
known. The objective of this study was to understand the biological significance of the presence of two copies of GGPP synthases
in P. paxilli by investigating their subcellular localization. Using a carotenoid complementation assay and gene deletion analysis, we
show that P. paxilli GgsA and PaxG have GGPP synthase activities and that paxG is required for paxilline biosynthesis, respectively. In the ΔpaxG mutant background ggsA was unable to complement paxilline biosynthesis. A GgsA-EGFP fusion protein was localized to punctuate organelles and the
EGFP-GRV fusion protein, containing the C-terminus tripeptide GRV of PaxG, was localized to peroxisomes. A truncated PaxG
mutant lacking the C-terminus tripeptide GRV was unable to complement a ΔpaxG mutant demonstrating that the tripeptide is functionally important for paxilline biosynthesis.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
996.
A domain of synapsin I involved with actin bundling shares immunologic cross-reactivity with villin 总被引:3,自引:0,他引:3
Synapsin I is a neuronal phosphoprotein that can bundle actin filaments in vitro. This activity is under phosphorylation control, and may be related to its putative in vivo role of regulating the clustering and release of small synaptic vesicles. We have compared human and bovine synapsin I by peptide mapping, and have used NTCB (2-nitro-5-thiocyano benzoic acid) cleavage to generate a series of peptide fragments from bovine synapsin I. After chymotryptic digestion, 88% of the tyrosine-containing fragments appear to be structurally identical in human and bovine synapsin I, as judged by their positions on high-resolution two-dimensional peptide maps. The alignment of the NTCB peptides within the parent protein have been determined by peptide mapping, and the ability of these fragments to precipitate with actin bundles has been measured. Only peptides that are derived from regions near the ends of the protein are active. One such 25-kDa peptide which sediments with actin also cross-reacts with antibodies to chicken villin, an actin binding and bundling protein derived from the intestinal microvillus. Since in other respects villin appears to be an unrelated protein, these results suggest the possibility that certain actin binding proteins may show immunologic cross-reactivity due to convergent evolution within the acting binding domain. 相似文献
997.
Jack L. Leonard Helmut Rennke Michael M. Kaplan P.Reed Larsen 《Biochimica et Biophysica Acta (BBA)/General Subjects》1982,718(1):109-119
We have examined iodothyronine deiodination in subcellular fractions of cerebral cortex obtained from hypothyroid rats. Enzymatic activities were measured at 37°C in the presence of 20 mM dithiothreitol with 125I-labeled T4 and 125I-labeled rT3 as substrate for 5′-deiodination and 131I-labeled T3 as the substrate for the 5-deiodinase. Reaction products were separated by descending paper and/or ion-exchange chromatography. Cerebral cortex subcellular fractions were also characterized by marker enzyme analysis and electron microscopy. Under optimal reaction conditions more than 80% of the 5′-deiodinase was recovered after fractionation. Both 5′-deiodinase and (Na+ +K+-ATPase showed similar subcellular distributions and were enriched approx. 3-fold in the easily sedimenting membrane fraction and nerve terminal plasma membranes. Crude microsomal membranes (6·106g·min pellet) also showed 2-fold enrichment of these enzymes. Nuclei and isolated mitochondria were devoid of deiodinating activity. T4 and T3 5-deiodinating activity was absent in the easily sedimenting membranes and present but not enriched in particulate fractions containing microsomal membranes. These data suggest that iodothyronine 5′-deiodinase is associated with plasma membrane fractions in the cerebral cortex. 相似文献
998.
Homologous structural domains in chicken egg-white ovomucoid: Characterization and acid denaturation
The primary structure of ovomucoid shows considerable sequence homology at three contiguous regions which form structural
domains I, II and III. In order to see whether or not the three domains fold similarly and acquire similar overall native
conformation/shape, two fragments A and C were obtained by controlled peptic digestion of ovomucoid. The two fragments were
investigated for their chemical composition, molecular weight, anti-tryptic activity, hydrodynamic behaviour, optical properties
and acid denaturation. Results on molecular weight, amino acid composition and inhibitory acitivity show that the fragments
A and C correspond respectively to domain I-II and domain III. Optical data suggested more exposure of tyrosine residues in
the fragments than in the intact molecule. Domain III exists in a compact and globular conformation under native conditions
whereas domain I-II and ovomucoid appear to possess asymmetric conformation. Results on acid denaturation show that the process
is thermodynamically reversible and that inter-domain separation probably precedes denaturation of domains during acidification
of ovomucoid. 相似文献
999.
Irwin M. Reich Irene A. Skipski Walter N. Scott 《Biochimica et Biophysica Acta (BBA)/General Subjects》1981,676(3):379-385
A dual-label isotope technique was used to study the effects of aldosterone upon the incorporation of amino acids into proteins of the in vitro toad urinary bladder. Following labeling, the mucosal cells were disaggregated and the mitochondria-rich and granual cells were separated. Proteins with an elevated isotope ratio were found in a plasma membrane fraction (170 000, 110 000 and 85 000 daltons) and in the cytosol (36 000 and 6 000 daltons) of the preparations enriched in mitochondria-rich cells. These effects of aldosterone were blocked by cycloheximide. There was no evidence that aldosterone had induced the incorporation of labeled amino acids into carbonic anhydrase isolated from the soluble fraction by affinity chromatography. The results suggests that the physiologic response of the toad bladder to aldosterone is related to the synthesis of both soluble and plasma membrane proteins. 相似文献
1000.
Gilles Dietrich Gérald Gaibelet Régine Capeyrou Jean-Luc Butour Frédéric Pontet Laurent J. Emorine 《Journal of neurochemistry》1998,70(5):2106-2111
Abstract: Recent studies on chimeric μ/δ-, μ/κ- and δ/κ-opioid receptors have suggested that extracellular loops of the receptors were involved in the discriminatory binding of selective ligands by controlling their entry into the transmembrane binding site. Since homochimeric opioid receptors are mostly informative in terms of selectivity, the role of extracellular loops was examined here by studying heterochimeric μ receptors where the totality or parts of extracellular loops were replaced by the corresponding regions of the receptor for angiotensin II. Chimeric μ receptors with extracellular loop EL1 or EL3 originating from the angiotensin receptor had 100-fold decreased affinities for opioids; the length of the first extracellular loop, which is one residue longer in angiotensin than μ receptors, was shown to be responsible for this situation. Substitution of the μ receptor second extracellular loop by that of the angiotensin receptor diminished by ∼10-fold the affinities for opioids. Since all chimeras had altered affinities for selective and nonselective ligands, we propose that extracellular domains of the μ receptor, particularly the first and third loops, constrain the relative positioning of the connected transmembrane domains where selective as well as nonselective contact points form the opioid binding site. 相似文献