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81.
Caveolin (Cav) proteins in the plasma membrane have numerous binding partners, but the determinants of these interactions are poorly understood. We show here that Cav-3 has a small ubiquitin-like modifier (SUMO) consensus motif (ΨKX(D/E, where Ψ is a hydrophobic residue)) near the scaffolding domain and that Cav-3 is SUMOylated in a manner that is enhanced by the SUMO E3 ligase PIASy (protein inhibitor of activated STAT-y). Site-directed mutagenesis revealed that the consensus site lysine is the preferred SUMOylation site but that mutation of all lysines is required to abolish SUMOylation. Co-expression of a SUMOylation-deficient mutant of Cav-3 with β-adrenergic receptors (βARs) alters the expression level of β(2)ARs but not β(1)ARs following agonist stimulation, thus implicating Cav-3 SUMOylation in the mechanisms for β(2)AR but not β(1)AR desensitization. Expression of endothelial nitric-oxide synthase (NOS3) was not altered by the SUMOylation-deficient mutant. Thus, SUMOylation is a covalent modification of caveolins that influence the regulation of certain signaling partners. 相似文献
82.
Head BP Hu Y Finley JC Saldana MD Bonds JA Miyanohara A Niesman IR Ali SS Murray F Insel PA Roth DM Patel HH Patel PM 《The Journal of biological chemistry》2011,286(38):33310-33321
Decreased expression of prosurvival and progrowth-stimulatory pathways, in addition to an environment that inhibits neuronal growth, contribute to the limited regenerative capacity in the central nervous system following injury or neurodegeneration. Membrane/lipid rafts, plasmalemmal microdomains enriched in cholesterol, sphingolipids, and the protein caveolin (Cav) are essential for synaptic development/stabilization and neuronal signaling. Cav-1 concentrates glutamate and neurotrophin receptors and prosurvival kinases and regulates cAMP formation. Here, we show that primary neurons that express a synapsin-driven Cav-1 vector (SynCav1) have increased raft formation, neurotransmitter and neurotrophin receptor expression, NMDA- and BDNF-mediated prosurvival kinase activation, agonist-stimulated cAMP formation, and dendritic growth. Moreover, expression of SynCav1 in Cav-1 KO neurons restores NMDA- and BDNF-mediated signaling and enhances dendritic growth. The enhanced dendritic growth occurred even in the presence of inhibitory cytokines (TNFα, IL-1β) and myelin-associated glycoproteins (MAG, Nogo). Targeting of Cav-1 to neurons thus enhances prosurvival and progrowth signaling and may be a novel means to repair the injured and neurodegenerative brain. 相似文献
83.
Caveolae (caveolin-containing lipid rafts) are plasma membrane domains that scaffold and organize a variety of important proteins in eukaryotic cells. Recent work shows that caveolins can act independently of caveolae, both in cells that lack caveolae (e.g. neurons and leukocytes) and in non-caveolar regions of cells that have caveolae (e.g. cardiac myocytes and fibroblasts). Phosphorylation of caveolins can influence the scaffolding of protein partners, and caveolins appear to participate in the protection and trafficking of proteins to and from the plasma membrane. Together, these results suggest that, despite their name, caveolins should now be thought of as proteins that scaffold signaling and other proteins in both caveolar and non-caveolar regions. 相似文献
84.
Wu WW Wang G Insel PA Hsiao CT Zou S Martin B Maudsley S Shen RF 《Journal of Proteomics》2012,75(8):2480-2487
Pulsed Q collision-induced dissociation (PQD) was developed in part to facilitate detection of low-mass reporter ions using labeling reagents (e.g. iTRAQ) on LTQ platforms. It has generally been recognized that the scan speed and sensitivity of an LTQ are superior than those of an Orbitrap using the higher-energy collisional dissociation (HCD). However, the use of PQD in quantitative proteomics is limited, primarily due to the meager reproducibility of reporter ion ratios. Optimizations of PQD for iTRAQ quantification using LTQ have been reported, but a universally applicable strategy for quantifying the less abundant proteins has not been fully established. Adjustments of the AGC target, μscan, or scan speed offer only incremental improvements in reproducibility. From our experience, however, satisfactory coefficients of variation (CVs) of reporter ion ratios were difficult to achieve using the discovery-based approach. As an alternative, we implemented a target-based approach that obviates data dependency to allow repetitive data acquisitions across chromatographic peaks. Such a strategy generates enough data points for more reliable quantification. Using cAMP treatment in S49 cell lysates and this target-based approach, we were able to validate differentially expressed proteins, which were initially identified as potential candidates using the discovery-based PQD. The target-based strategy also yielded results comparable to those obtained from HCD in an Orbitrap. Our findings should aid LTQ users who desire to explore iTRAQ quantitative proteomics but have limited access to the more costly Orbitrap or other instruments. 相似文献
85.
86.
Many types of peptide hormone and neurotransmitter receptors mediate hydrolysis of phosphoinositides (PI) and arachidonic acid and arachidonic acid metabolite (AA) release, but the relation between these responses is not clearly defined. We have characterized bradykinin (BK)-mediated AA release and PI hydrolysis in clonal Madin-Darby canine kidney cells (MDCK-D1). Both responses occurred over a similar dose range in response to the B1 and B2 receptor agonist, BK, but not in response to the B1 receptor-selective agonist des-Arg-BK. To test whether AA release occurs via a mechanism which is sequential to and dependent upon PI hydrolysis, we used the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), which activates protein kinase C. TPA treatment blocked BK-mediated PI hydrolysis in MDCK-D1 cells, while at the same time and at similar concentrations enhancing BK-mediated AA release. Thus, TPA treatment dissociated BK-mediated AA release from PI hydrolysis. In addition, treatment of MDCK-D1 cells with neomycin blocked BK-mediated hydrolysis of phosphatidylinositol bisphosphate without reducing BK-mediated AA release. BK treatment increased formation of lysophospholipids with a time course in accord with BK-mediated AA release, indicating that at least part of the BK-mediated AA release was likely derived from activation of phospholipase A2. BK-mediated lysophospholipid production was enhanced by pretreatment with TPA, suggesting that the mechanism of AA release before and after treatment with TPA was the same. BK-mediated AA release and lysophospholipid production was dependent on the presence of extracellular calcium, while the enhanced responses to BK in the presence of TPA were not dependent on the presence of extracellular calcium. TPA treatment also enhanced AA release and lysophospholipid production in response to the calcium ionophore A23187. From these data we propose that BK, acting at B2 receptors, promotes AA release in MDCK cells via a mechanism which is 1) independent of polyphosphoinositide hydrolysis by phospholipase C, 2) dependent upon influx of extracellular calcium and activation of phospholipase A2, and 3) enhanced by activation of protein kinase C. 相似文献
87.
88.
Studies in clinical and experimental hypertension have identified alterations both in intracellular [Na+] and in response to hormones and neurotransmitters. We propose a hypothesis that links these two alterations. Based on recent data showing that changes in intracellular [Na+] can alter the affinity and function of platelet alpha2-adrenergic receptors, we hypothesize that elevated intracellular [Na+] in hypertension leads to enhanced response at membrane receptors. This enhancement in response to hormones and/or neurotransmitters could then contribute to the development and maintenance of the hypertensive state. Because a variety of membrane receptors are Na+-sensitive (e.g., adrenergic, muscarinic cholinergic, opiate, angiotensin, dopamine, histamine H1), this mechanism may be operative at one or more receptor types located in tissues critical to the pathophysiology of hypertension. 相似文献
89.
Pochynyuk O Bugaj V Rieg T Insel PA Mironova E Vallon V Stockand JD 《The Journal of biological chemistry》2008,283(52):36599-36607
Growing evidence implicates a key role for extracellular nucleotides in cellular regulation, including of ion channels and renal function, but the mechanisms for such actions are inadequately defined. We investigated purinergic regulation of the epithelial Na+ channel (ENaC) in mammalian collecting duct. We find that ATP decreases ENaC activity in both mouse and rat collecting duct principal cells. ATP and other nucleotides, including UTP, decrease ENaC activity via apical P2Y2 receptors. ENaC in collecting ducts isolated from mice lacking this receptor have blunted responses to ATP. P2Y2 couples to ENaC via PLC; direct activation of PLC mimics ATP action. Tonic regulation of ENaC in the collecting duct occurs via locally released ATP; scavenging endogenous ATP and inhibiting P2 receptors, in the absence of other stimuli, rapidly increases ENaC activity. Moreover, ENaC has greater resting activity in collecting ducts from P2Y2-/- mice. Loss of collecting duct P2Y2 receptors in the knock-out mouse is the primary defect leading to increased ENaC activity based on the ability of direct PLC stimulation to decrease ENaC activity in collecting ducts from P2Y2-/- mice in a manner similar to ATP in collecting ducts from wild-type mice. These findings demonstrate that locally released ATP acts in an autocrine/paracrine manner to tonically regulate ENaC in mammalian collecting duct. Loss of this intrinsic regulation leads to ENaC hyperactivity and contributes to hypertension that occurs in P2Y2 receptor-/- mice. P2Y2 receptor activation by nucleotides thus provides physiologically important regulation of ENaC and electrolyte handling in mammalian kidney. 相似文献
90.
How do I choose a mentor? How do I decide what field of neuroscience to work in? Should I consider doing research in industry? Most students and postdoctoral researchers aiming for a successful career in neuroscience ask themselves these questions. In this article, Nature Reviews Neuroscience asks four successful neuroscientists for their thoughts on the factors one should consider when making these decisions. We hope that this Viewpoint will serve as a useful resource for junior neuroscientists who have to make important and sometimes difficult decisions that might have long-lasting consequences for their careers. 相似文献