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51.
Petzer JP Steyn S Castagnoli KP Chen JF Schwarzschild MA Van der Schyf CJ Castagnoli N 《Bioorganic & medicinal chemistry》2003,11(7):1299-1310
Adenosine receptor antagonists that are selective for the A(2A) receptor subtype (A(2A) antagonists) are under investigation as possible therapeutic agents for the symptomatic treatment of the motor deficits associated with Parkinson's disease (PD). Results of recent studies in the MPTP mouse model of PD suggest that A(2A) antagonists may possess neuroprotective properties. Since monoamine oxidase B (MAO-B) inhibitors also enhance motor function and reduce MPTP neurotoxicity, we have examined the MAO-B inhibiting properties of several A(2A) antagonists and structurally related compounds in an effort to determine if inhibition of MAO-B may contribute to the observed neuroprotection. The results of these studies have established that all of the (E)-8-styrylxanthinyl derived A(2A) antagonists examined display significant MAO-B inhibitory properties in vitro with K(i) values in the low micro M to nM range. Included in this series is (E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methylxanthine (KW-6002), a potent A(2A) antagonist and neuroprotective agent that is in clinical trials. The results of these studies suggest that MAO-B inhibition may contribute to the neuroprotective potential of A(2A) receptor antagonists such as KW-6002 and open the possibility of designing dual targeting drugs that may have enhanced therapeutic potential in the treatment of PD. 相似文献
52.
Fazi B Cope MJ Douangamath A Ferracuti S Schirwitz K Zucconi A Drubin DG Wilmanns M Cesareni G Castagnoli L 《The Journal of biological chemistry》2002,277(7):5290-5298
Abp1p is an actin-binding protein that plays a central role in the organization of Saccharomyces cerevisiae actin cytoskeleton. By a combination of two-hybrid and phage-display approaches, we have identified six new ligands of the Abp1-SH3 domain. None of these SH3-mediated novel interactions was detected in recent all genome high throughput protein interaction projects. Here we show that the SH3-mediated association of Abp1p with the Ser/Thr kinases Prk1p and Ark1p is essential for their localization to actin cortical patches. The Abp1-SH3 domain has a rather unusual binding specificity, because its target peptides contain the tetrapentapeptide +XXXPXXPX+PXXL with positive charges flanking the polyproline core on both sides. Here we present the structure of the Abp1-SH3 domain solved at 1.3-A resolution. The peptide-binding pockets in the SH3 domain are flanked by two acidic residues that are uncommon at those positions in the SH3 domain family. We have shown by site-directed mutagenesis that one of these negatively charged side chains may be the key determinant for the preference for non-classical ligands. 相似文献
53.
Protein interaction domain families that modulate the formation of macromolecular complexes recognize specific sequence or structural motifs. For instance SH3 and WW domains bind to polyproline peptides while SH2 and FHA domains bind to peptides phosphorylated in Tyr and Thr respectively. Within each family, variations in the chemical characteristics of the domain binding pocket modulate a finer peptide recognition specificity and, as a consequence, determine the selection of functional protein partners in vivo. In the proteomic era there is the need for reliable inference methods to help restricting the sequence space of the putative targets to be confirmed experimentally by more laborious experimental approaches. Here we will review the published data about the peptide recognition specificity of the SH3 domain family and we will propose a classification of SH3 domains into eight classes. Finally, we will discuss whether the available information is sufficient to infer the recognition specificity of any uncharacterized SH3 domain. 相似文献
54.
S Paoluzi L Castagnoli I Lauro A E Salcini L Coda S Fre' S Confalonieri P G Pelicci P P Di Fiore G Cesareni 《The EMBO journal》1998,17(22):6541-6550
The Eps homology (EH) domain is a recently described protein binding module that is found, in multiple or single copies, in several proteins in species as diverse as human and yeast. In this work, we have investigated the molecular details of recognition specificity mediated by this domain family by characterizing the peptide-binding preference of 11 different EH domains from mammal and yeast proteins. Ten of the eleven EH domains could bind at least some peptides containing an Asn-Pro-Phe (NPF) motif. By contrast, the first EH domain of End3p preferentially binds peptides containing an His-Thr/Ser-Phe (HT/SF) motif. Domains that have a low affinity for the majority of NPF peptides reveal some affinity for a third class of peptides that contains two consecutive amino acids with aromatic side chains (FW or WW). This is the case for the third EH domain of Eps15 and for the two N-terminal domains of YBL47c. The consensus sequences derived from the peptides selected from phage-displayed peptide libraries allows for grouping of EH domains into families that are characterized by different NPF-context preference. Finally, comparison of the primary sequence of EH domains with similar or divergent specificity identifies a residue at position +3 following a conserved tryptophan, whose chemical characteristics modulate binding preference. 相似文献
55.
N-Linked glycosylation of a baculovirus-expressed recombinant glycoprotein in insect larvae and tissue culture cells 总被引:5,自引:3,他引:2
The potential of insect cell cultures and larvae infected with recombinant
baculoviruses to produce authentic recombinant glycoproteins cloned from
mammalian sources was investigated. A comparison was made of the N-linked
glycans attached to secreted alkaline phosphatase (SEAP) produced in four
species of insect larvae and their derived cell lines plus one additional
insect cell line and larvae of one additional species. These data survey
N-linked oligosaccharides produced in four families and six genera of the
order Lepidoptera. Recombinant SEAP expressed by recombinant isolates of
Autographa californica and Bombyx mori nucleopolyhedroviruses was purified
from cell culture medium, larval hemolymph or larval homogenates by
phosphate affinity chromatography. The N-linked oligosaccharides were
released with PNGase-F, labeled with 8- aminonaphthalene-1-3-6-trisulfonic
acid, fractionated by polyacrylamide gel electrophoresis, and analyzed by
fluorescence imaging. The oligosaccharide structures were confirmed with
exoglycosidase digestions. Recombinant SEAP produced in cell lines of
Lymantria dispar (IPLB-LdEIta), Heliothis virescens (IPLB-HvT1), and Bombyx
mori (BmN) and larvae of Spodoptera frugiperda, Trichoplusia ni ,
H.virescens , B.mori , and Danaus plexippus contained oligosaccharides that
were structurally identical to the 10 oligosaccharides attached to SEAP
produced in T.ni cell lines. The oligosaccharide structures were all
mannose-terminated. Structures containing two or three mannose residues,
with and without core fucosylation, constituted more than 75% of the
oligosaccharides from the cell culture and larval samples.
相似文献
56.
In situ hybridization at the electron microscope level: hybrid detection by autoradiography and colloidal gold 总被引:14,自引:4,他引:10 下载免费PDF全文
In situ hybridization has become a standard method for localizing DNA or RNA sequences in cytological preparations. We developed two methods to extend this technique to the transmission electron microscope level using mouse satellite DNA hybridization to whole mount metaphase chromosomes as the test system. The first method devised is a direct extension of standard light microscope level using mouse satellite DNA hybridization to whole mount metaphase chromosomes as the test system. The first method devised is a direct extension of standard light microscope in situ hybridization. Radioactively labeled complementary RNA (cRNA) is hybridized to metaphase chromosomes deposited on electron microscope grids and fixed in 70 percent ethanol vapor; hybridixation site are detected by autoradiography. Specific and intense labeling of chromosomal centromeric regions is observed even after relatively short exposure times. Inerphase nuclei present in some of the metaphase chromosome preparations also show defined paatterms of satellite DNA labeling which suggests that satellite-containing regions are associate with each other during interphase. The sensitivity of this method is estimated to at least as good as that at the light microscope level while the resolution is improved at least threefold. The second method, which circumvents the use of autoradiogrphic detection, uses biotin-labeled polynucleotide probes. After hybridization of these probes, either DNA or RNA, to fixed chromosomes on grids, hybrids are detected via reaction is improved at least threefold. The second method, which circumvents the use of autoradiographic detection, uses biotin-labeled polynucleotide probes. After hybridization of these probes, either DNA or RNA, to fixed chromosomes on grids, hybrids are detected via reaction with an antibody against biotin and secondary antibody adsorbed to the surface of over centromeric heterochromatin and along the associated peripheral fibers. Labeling is on average ten times that of background binding. This method is rapid and possesses the potential to allow precise ultrastructual localization of DNA sequences in chromosomes and chromatin. 相似文献
57.
Several approaches, some of which are described in this issue, have been proposed to assemble a complete protein interaction map. These are often based on high throughput methods that explore the ability of each gene product to bind any other element of the proteome of the organism. Here we propose that a large number of interactions can be inferred by revealing the rules underlying recognition specificity of a small number (a few hundreds) of families of protein recognition modules. This can be achieved through the construction and characterization of domain repertoires. A domain repertoire is assembled in a combinatorial fashion by allowing each amino acid position in the binding site of a given protein recognition domain to vary to include all the residues allowed at that position in the domain family. The repertoire is then searched by phage display techniques with any target of interest and from the primary structure of the binding site of the selected domains one derives rules that are used to infer the formation of complexes between natural proteins in the cell. 相似文献
58.
59.
In order to study combined s-dopa and s-α-methyldopa metabolism in brain, we have developed a chemical ionization mass spectrometric method for simultaneously measuring nanomole quantities of dopamine, α-methyldopamine, norepinephrine, and α-methylnorepinephrine from tissue samples dissected from rat brain. Deuterium-labeled analogs of each of the four catecholamines were synthesized and used as internal standards for quantification. Following addition of the internal standards to the tissue sections, the catecholamines were extracted and separated from amino acids by ion-exchange chromatography. Derivatization with HCl·ethanol and pentafluoropropionic anhydride produced a family of eight derivatives with unique parent masses which were applied without gas chromatographic separation to the direct inlet probe of the mass spectrometer. The mass region containing the derivatives was repetitively scanned, and the individual amines were quantified by comparing their peak heights with the deuterium-labeled internal standards. To validate the solid probe method in vivo, animals were treated with varying combinations of s-dopa and s-α-methyldopa, and their brains were analyzed for amine concentrations. Results from rat hypothalamus, brainstem, and corpus striatum are presented. 相似文献
60.