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121.
Elia Zomot Eliane Hadas Yardeni Attilio Vittorio Vargiu Heng-Keat Tam Giuliano Malloci Venkata Krishnan Ramaswamy Michal Perach Paolo Ruggerone Klaas Martinus Pos Eitan Bibi 《Journal of molecular biology》2018,430(9):1368-1385
Secondary multidrug (Mdr) transporters utilize ion concentration gradients to actively remove antibiotics and other toxic compounds from cells. The model Mdr transporter MdfA from Escherichia coli exchanges dissimilar drugs for protons. The transporter should open at the cytoplasmic side to enable access of drugs into the Mdr recognition pocket. Here we show that the cytoplasmic rim around the Mdr recognition pocket represents a previously overlooked important regulatory determinant in MdfA. We demonstrate that increasing the positive charge of the electrically asymmetric rim dramatically inhibits MdfA activity and sometimes even leads to influx of planar, positively charged compounds, resulting in drug sensitivity. Our results suggest that unlike the mutants with the electrically modified rim, the membrane-embedded wild-type MdfA exhibits a significant probability of an inward-closed conformation, which is further increased by drug binding. Since MdfA binds drugs from its inward-facing environment, these results are intriguing and raise the possibility that the transporter has a sensitive, drug-induced conformational switch, which favors an inward-closed state. 相似文献
122.
Receptor-Mediated Activation of G Proteins Is Increased in Postmortem Brains of Bipolar Affective Disorder Subjects 总被引:7,自引:2,他引:5
Abstract: Guanine nucleotide binding proteins (G proteins) have been implicated in the pathophysiology of bipolar affective disorder. In the present investigation receptor-mediated G protein activation and changes in G protein trimeric state were examined in frontal cortical membranes obtained from postmortem brains of bipolar affective disorder subjects and from age-, sex-, and postmortem interval-matched controls. Stimulation of cortical membranes with serotonin, isoproterenol, or carbachol increased guanosine 5′-O-(3-[35S]thiophosphate) ([35S]GTPγS) binding to specific Gα proteins in a receptor-selective manner. The abilities of these receptor agonists to stimulate the binding of [35S]GTPγS to the Gα proteins was enhanced in membranes from bipolar brains. Immunoblot analyses showed increases in the levels of membrane 45- and 52-kDa Gαs proteins but no changes in the amounts of Gαi, Gαo, Gαz, Gαq/11, or Gβ proteins in membrane or cytosol fractions of bipolar brain homogenates. Pertussis toxin (PTX)-activated ADP-ribosylations of Gαi and Gαo were enhanced by ~80% in membranes from bipolar compared with control brains, suggesting an increase in the levels of the trimeric state of these G proteins in bipolar disorder. Serotonin-induced, magnesium-dependent reduction in PTX-mediated ADP-ribosylation of Gαi/Gαo in cortical membranes from bipolar brains was greater than that observed in controls, providing further evidence for enhanced receptor-G protein coupling in bipolar brain membranes. In addition, the amounts of Gβ proteins that coimmunoprecipitated with the Gα proteins were also elevated in bipolar brains. The data show that in bipolar brain membrane there is enhanced receptor-G protein coupling and an increase in the trimeric state of the G proteins. These changes may contribute to produce exaggerated transmembrane signaling and to the alterations in affect that characterize bipolar affective disorder. 相似文献
123.
Leng-Chu Shi Hoau-Yan Wang Joel Horwitz Eitan Friedman 《Journal of neurochemistry》1996,67(4):1478-1484
Abstract: Platelet-activating factor (PAF) may be a neuromodulator involved in neural cell differentiation, cerebral inflammation, and ischemia. The PAF receptor is a member of the G protein-coupled receptor superfamily. In the present study, we sought to define the specific G protein(s) that mediate PAF-stimulated phosphoinositide (PI) metabolism in an immortalized hippocampal cell line, HN33.11. PAF increased the production of 3 H-labeled inositol phosphates (IPs) with EC50 values of 1.2–1.5 n M . The effect of PAF on 3 H-IPs formation was completely blocked by the PAF antagonist BN 50739 at a concentration of 300 n M . Pertussis toxin pretreatment attenuated PAF-stimulated 3 H-IPs production by 20–30% ( p < 0.05). Consistent with a role for Gi1/2 in this response, antiserum against Gαi1/2 blocked the response to a similar degree. Pretreatment of permeabilized cells with Gαq/11 antiserum attenuated the response by 70% ( p < 0.05), suggesting a role for Gq/11 in mediating the PAF response in this cell line. Stimulation with PAF increased [α-32 P]-GTP binding to both Gαq and Gαi1/2 proteins. Moreover, specific [3 H]PAF binding sites coprecipitated with Gαq and Gαi1/2 proteins. The results suggest that PAF-stimulated PI metabolism in HN33.11 cells is mediated by both Gq and Gi1/2 proteins. 相似文献
124.
Robin?DowellEmail author Aaron?Odell Phillip?Richmond Daniel?Malmer Eitan?Halper-Stromberg Beth?Bennett Colin?Larson Sonia?Leach Richard?A.?RadcliffeEmail author 《Mammalian genome》2016,27(11-12):574-586
The Inbred Long- and Short-Sleep (ILS, ISS) mouse lines were selected for differences in acute ethanol sensitivity using the loss of righting response (LORR) as the selection trait. The lines show an over tenfold difference in LORR and, along with a recombinant inbred panel derived from them (the LXS), have been widely used to dissect the genetic underpinnings of acute ethanol sensitivity. Here we have sequenced the genomes of the ILS and ISS to investigate the DNA variants that contribute to their sensitivity difference. We identified ~2.7 million high-confidence SNPs and small indels and ~7000 structural variants between the lines; variants were found to occur in 6382 annotated genes. Using a hidden Markov model, we were able to reconstruct the genome-wide ancestry patterns of the eight inbred progenitor strains from which the ILS and ISS were derived, and found that quantitative trait loci that have been mapped for LORR were slightly enriched for DNA variants. Finally, by mapping and quantifying RNA-seq reads from the ILS and ISS to their strain-specific genomes rather than to the reference genome, we found a substantial improvement in a differential expression analysis between the lines. This work will help in identifying and characterizing the DNA sequence variants that contribute to the difference in ethanol sensitivity between the ILS and ISS and will also aid in accurate quantification of RNA-seq data generated from the LXS RIs. 相似文献
125.
In greening maize leaves δ-aminolevulinic acid (ALA) was not formed from succinyl-CoA and glycine as shown by the incorporation of [14C]-labeled 相似文献
126.
127.
The temperature at which incubation with ethylene takes placehas a significant effect on the purified alcohol dehydrogenase(ADH) activity subsequently determined at room temperature.Ethylene can be separated completely from ADH on a Sephadexcolumn. Factors, such as the ionic strength of the buffer andthe presence of gelatin and NAD during the incubation with ethylenecan modify the effects of the gas. In yeast cells the effectsof ethylene on ADH activity are similar to those in the purifiedsystem. The presence of cyloheximide in the incubation mediumdid not suppress the effects of ethylene on ADH activity. Ethylenemay induce its effect, directly, through involvement in hydrophobicbonding in enzymes. (Received March 4, 1974; ) 相似文献
128.
A model of the nucleotide-binding site in tubulin 总被引:6,自引:0,他引:6
Tubulin uses GTP to regulate microtubule assembly and is thought to be a member of a class of GDP/GTP-binding proteins (G-proteins) as defined by Hughes [(1983) Febs Lett. 164, 1-8]. How tubulin is structurally related to G-proteins is not known. We use a synthesis of sequence comparisons between tubulin, other G-proteins, and ADP/ATP-binding proteins and topological arguments to identify potential regions involved in nucleotide binding. We propose that the nucleotide-binding domain in the beta-subunit of tubulin is an alpha/beta structure derived from amino acid residues approximately 60-300. Five peptide sequences are identified which we suggest exist as 'loops' that extend from beta-strands and connect alpha-helices in this structure. We argue that GDP binds to four of the five loops in an Mg2+-independent manner while GTP binds in an Mg2+-dependent manner to a different combination of four loops. We propose that this switch between loops upon GTP binding induces a conformational change essential for microtubule assembly. 相似文献
129.
Both the composition of the culture medium and the nature of the phenolic inducer determine the amount, the rate of formation and the molecular properties of extracellular laccase formed by Botrytis cinerea. Coumaric acid is shown to act as inducer in addition to gallic acid and grape juice. It is suggested that the fungus adapts to different environments by excreting different laccases. These laccases differ in pK, heat stability and substrate specificity but not in Km values to quinol and oxygen. 相似文献
130.
Moshe Shani Dina Zevin-Sonkin Ora Saxel Yoram Carmon Don Katcoff Uri Nudel David Yaffe 《Developmental biology》1981,86(2):483-492
Cloned cDNA probes were used to measure the accumulation of myosin heavy chain, myosin light chain 2, and actin mRNA during differentiation of rat skeletal muscle cell cultures. This was compared with the changes in the rate of synthesis of the corresponding proteins. Accumulation of those mRNA sequences was detectable a few hours before the onset of the phase of cell fusion; however, the main increase in hybridizable RNA occurred during the phase of rapid cell fusion. A close correlation was found between the amounts of mRNAs coding for these proteins and the rate of synthesis of the proteins. The results suggest that the activation of stored mRNA is not a major mechanism for controlling the time at which these proteins are synthesized. 相似文献