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1.
Kassem Ghaddar Ahmad Merhi Elie Saliba Eva-Maria Krammer Martine Prévost Bruno André 《Molecular and cellular biology》2014,34(24):4447-4463
Many plasma membrane transporters are downregulated by ubiquitylation, endocytosis, and delivery to the lysosome in response to various stimuli. We report here that two amino acid transporters of Saccharomyces cerevisiae, the general amino acid permease (Gap1) and the arginine-specific permease (Can1), undergo ubiquitin-dependent downregulation in response to their substrates and that this downregulation is not due to intracellular accumulation of the transported amino acids but to transport catalysis itself. Following an approach based on permease structural modeling, mutagenesis, and kinetic parameter analysis, we obtained evidence that substrate-induced endocytosis requires transition of the permease to a conformational state preceding substrate release into the cell. Furthermore, this transient conformation must be stable enough, and thus sufficiently populated, for the permease to undergo efficient downregulation. Additional observations, including the constitutive downregulation of two active Gap1 mutants altered in cytosolic regions, support the model that the substrate-induced conformational transition inducing endocytosis involves remodeling of cytosolic regions of the permeases, thereby promoting their recognition by arrestin-like adaptors of the Rsp5 ubiquitin ligase. Similar mechanisms might control many other plasma membrane transporters according to the external concentrations of their substrates. 相似文献
2.
Andreas Koeberle Eva-Maria Haberl Antonietta Rossi Carlo Pergola Friederike Dehm Hinnak Northoff Reinhard Troschuetz Lidia Sautebin Oliver Werz 《Bioorganic & medicinal chemistry》2009,17(23):7924-7932
Selective inhibition of pro-inflammatory prostaglandin (PG)E2 formation via microsomal PGE2 synthase-1 (mPGES-1) might be superior over inhibition of all cyclooxygenase (COX)-derived products by non-steroidal anti-inflammatory drugs (NSAIDs) and coxibs. We recently showed that benzo[g]indol-3-carboxylates potently suppress leukotriene biosynthesis by inhibiting 5-lipoxygenase. Here, we describe the discovery of benzo[g]indol-3-carboxylates as a novel class of potent mPGES-1 inhibitors (IC50 ? 0.1 μM). Ethyl 2-(3-chlorobenzyl)-5-hydroxy-1H-benzo[g]indole-3-carboxylate (compound 7a) inhibits human mPGES-1 in a cell-free assay (IC50 = 0.6 μM) as well as in intact A549 cells (IC50 = 2 μM), and suppressed PGE2 pleural levels in rat carrageenan-induced pleurisy. Inhibition of cellular COX-1/2 activity was significantly less pronounced. Compound 7a significantly reduced inflammatory reactions in the carrageenan-induced mouse paw edema and rat pleurisy. Together, based on the select and potent inhibition of mPGES-1 and 5-lipoxygenase, benzo[g]indol-3-carboxylates possess potential as novel anti-inflammatory drugs with a valuable pharmacological profile. 相似文献
3.
Paal J Henselewski H Muth J Meksem K Menéndez CM Salamini F Ballvora A Gebhardt C 《The Plant journal : for cell and molecular biology》2004,38(2):285-297
The endoparasitic root cyst nematode Globodera rostochiensis causes considerable damage in potato cultivation. In the past, major genes for nematode resistance have been introgressed from related potato species into cultivars. Elucidating the molecular basis of resistance will contribute to the understanding of nematode-plant interactions and assist in breeding nematode-resistant cultivars. The Gro1 resistance locus to G. rostochiensis on potato chromosome VII co-localized with a resistance-gene-like (RGL) DNA marker. This marker was used to isolate from genomic libraries 15 members of a closely related candidate gene family. Analysis of inheritance, linkage mapping, and sequencing reduced the number of candidate genes to three. Complementation analysis by stable potato transformation showed that the gene Gro1-4 conferred resistance to G. rostochiensis pathotype Ro1. Gro1-4 encodes a protein of 1136 amino acids that contains Toll-interleukin 1 receptor (TIR), nucleotide-binding (NB), leucine-rich repeat (LRR) homology domains and a C-terminal domain with unknown function. The deduced Gro1-4 protein differed by 29 amino acid changes from susceptible members of the Gro1 gene family. Sequence characterization of 13 members of the Gro1 gene family revealed putative regulatory elements and a variable microsatellite in the promoter region, insertion of a retrotransposon-like element in the first intron, and a stop codon in the NB coding region of some genes. Sequence analysis of RT-PCR products showed that Gro1-4 is expressed, among other members of the family including putative pseudogenes, in non-infected roots of nematode-resistant plants. RT-PCR also demonstrated that members of the Gro1 gene family are expressed in most potato tissues. 相似文献
4.
William L. Muth Fred T. Counter Kathryn K. Richardson Lawrence F. Fisher 《Journal of industrial microbiology & biotechnology》1993,11(4):253-257
Summary The colonizing potential ofEscherichia coli K12 containing a vector coding for somidobove (bovine somatotropin) was determined. Treated male and female Fischer-344 rats were given a single oral gavage inoculum of sucrose with/without tetracycline (15 g/ml). Untreated control animals received similar drinking water regimes. All animals survived until termination. There were no clinical signs of toxicity observed and no treatment-related effect upon body weight, food consumption, or efficiency of food utilization. Fresh fecal samples were collected from each rat every 24 h following inoculation and the population of the marked strain was quantitated until no bacterial colonies were observed for two consecutive days. While all inoculated rats were positive at 24 h, by 72 and 96 h all had become negative for the test (marked) strain, as were the corresponding control group throughout the test. The frozen stock of the marked strain used as the positive control demonstrated that the agar plates were selective for the test strain. Fourteen days following inoculation, all groups of rats were killed and the gastrointestinal tracts removed and treated to recover the marked strain. There was no evidence of the marked strain in the gastrointestinal tract of any rat from any group. Thus, theE. coli K12 host/vector system used in this experiment does not colonize the gastrointestinal tract of Fischer-344 rats. 相似文献
5.
Eight of eleven ochratoxigenic isolates of Penicillium nordicum and Penicillium verrucosum produced guttation droplets when grown on Czapek yeast extract (CYA) agar for 10–14 days at 25°C. Parallel cultivation of
one strain each of P. nordicum and P. verrucosum on malt extract agar demonstrated that higher volumes of exudate are produced on this agar. However, HPLC analyses revealed
higher concentrations of ochratoxin A (OTA) and B (OTB) in droplets originating from cultures on CYA. For quantitative determination
of the mycotoxin contents, triplicates of three isolates each of P. nordicum and P. verrucosum were grown as single spot cultures on CYA for up to 14 days at 25°C. Guttation droplets were carefully collected between
day 11 and 14 with a microliter syringe from each culture. Extracts from exudates and corresponding mycelia as well as fungal
free agar were analyzed by HPLC for the occurrence of ochratoxin A (OTA) and B (OTB). Mean concentrations ranging between
92.7–8667.0 ng OTA and 159.7–2943.3 ng OTB per ml were detected in the guttation fluids. Considerably lower toxin levels were
found in corresponding samples of the underlying mycelia (9.0–819.3 ng OTA and 4.5–409.7 ng OTB/g) and fungal free agar (15.3–417.0 ng
OTA and 12.7–151.3 ng OTB/g). This is the first report which shows that high amounts of mycotoxins could be excreted from
toxigenic Penicillium isolates into guttation droplets. 相似文献
6.
Summary As a presupposition for estimating the mean tissue dose from intravascularly injected Thorotrast results of investigations on tissue distribution and steady state activity ratios of232Th and daughters in Thorotrast patients were compiled and are presented as best estimates. Special emphasis has been given to the non-uniformity of Thorotrast distribution on the organ 2and cellular level on the basis of results from animal experiments. Moreover, the variation widths of the mean tissue doses were calculated from the individual standard errors of the mean Thorotrast tissue distribution and activity ratios.According to the results of Thorotrast tissue distribution analyses about 97% of intravascularly injected colloidal ThO2 are retained by the organs of the reticulo-endothelial-system (RES) of the average Thorotrast patient (liver: 59%; spleen: 29%; bone marrow: 9%). Only 0.7 and 0.1% are distributed within the lungs and the kidneys, respectively. The fractional retention of232Th in the marrow-free skeleton proved to be 2% on the average. Considering in addition the results on the steady state activity ratios between232Th and its daughters and self-absorption of-energy in Thorotrast agglomerates the mean annual tissue doses to the liver, spleen, red bone marrow, lungs (respiratory zone), and cells on bone surface, e.g., from 30 ml intravascularly injected Thorotrast are about 30 (10–70), 80 (30–200), 10 (4–27), 4.5 (1.8–11.3), and 15 (6–38) rad. The variation widths of the mean tissue doses given in brackets are based upon an average individual standard error of the mean Thorotrast tissue distribution and activity ratios of 150%. The data on mean tissue doses, however, do not include variations of the dose due to macroscopic inhomogeneities of Thorotrast distribution on the organ level, which in the liver may go up to a factor of 50. Contrary to the mean tissue dose the local annual dose, i.e., the dose to cells adjacent to the surface of 0.1–50 µm Thorotrast aggregates is between 40 and 40,000 rad.Paper presented on the occasion of a WHO meeting of a Scientific Group on the Long-Term Effects of Radium and Thorium in Man. Geneva, Sept. 12–16, 1977Dedicated to Prof. Dr. med. F. Sommer, Homburg/Saar, on the occasion of his 65th birthday 相似文献
7.
Höhne M Lorscheider J von Bardeleben A Dufner M Scharf MA Gödel M Helmstädter M Schurek EM Zank S Gerke P Kurschat C Sivritas SH Neumann-Haefelin E Huber TB Reinhardt HC Schauss AC Schermer B Fischbach KF Benzing T 《Molecular and cellular biology》2011,31(16):3241-3251
Neph proteins are evolutionarily conserved membrane proteins of the immunoglobulin superfamily that control the formation of specific intercellular contacts. Cell recognition through these proteins is essential in diverse cellular contexts such as patterning of the compound eye in Drosophila melanogaster, neuronal connectivity in Caenorhabditis elegans, and the formation of the kidney filtration barrier in mammals. Here we identify the PDZ and BAR domain protein PICK1 (protein interacting with C-kinase 1) as a Neph-interacting protein. Binding required dimerization of PICK1, was dependent on PDZ domain protein interactions, and mediated stabilization of Neph1 at the plasma membrane. Moreover, protein kinase C (PKCα) activity facilitated the interaction through releasing Neph proteins from their binding to the multidomain scaffolding protein zonula occludens 1 (ZO-1), another PDZ domain protein. In Drosophila, the Neph homologue Roughest is essential for sorting of interommatidial precursor cells and patterning of the compound eye. RNA interference-mediated knockdown of PICK1 in the Drosophila eye imaginal disc caused a Roughest destabilization at the plasma membrane and a phenotype that resembled rst mutation. These data indicate that Neph proteins and PICK1 synergistically regulate cell recognition and contact formation. 相似文献
8.
Jeon HK Yong TS Sohn WM Chai JY Hong SJ Han ET Jeong HG Chhakda T Sinuon M Socheat D Eom KS 《The Korean journal of parasitology》2011,49(2):195-197
We collected fecal samples from 21 individuals infected with Taenia tapeworms in Koh Kong Province, Cambodia, and performed nucleotide sequencing of the cox1 gene and multiplex PCR on the eggs for DNA differential diagnosis of human Taenia tapeworms. Genomic DNA was extracted from the eggs of a minimum number of 10 isolated from fecal samples. Using oligonucleotide primers Ta7126F, Ts7313F, Tso7466F, and Rev7915, the multiplex PCR assay proved useful for differentially diagnosing Taenia solium, Taenia saginata, and Taenia asiatica based on 706, 629, and 474 bp bands, respectively. All of the Taenia specimens from Kho Kong, Cambodia, were identified as either T. saginata (n=19) or T. solium (n=2) by cox1 sequencing and multiplex PCR. 相似文献
9.
Elias Balafoutis Michael Paterakis Peter Triantafillou Guido Nerjes Peter Muth Gerhard Weikum 《Cluster computing》2003,6(1):75-86
Divisible load scenarios occur in modern media server applications since most multimedia applications typically require access to continuous and discrete data. A high performance Continuous Media (CM) server greatly depends on the ability of its disk IO subsystem to serve both types of workloads efficiently. Disk scheduling algorithms for mixed media workloads, although they play a central role in this task, have been overlooked by related research efforts. These algorithms must satisfy several stringent performance goals, such as achieving low response time and ensuring fairness, for the discrete-data workload, while at the same time guaranteeing the uninterrupted delivery of continuous data, for the continuous-data workload. The focus of this paper is on disk scheduling algorithms for mixed media workloads in a multimedia information server. We propose novel algorithms, present a taxonomy of relevant algorithms, and study their performance through experimentation. Our results show that our algorithms offer drastic improvements in discrete request average response times, are fair, serve continuous requests without interruptions, and that the disk technology trends are such that the expected performance benefits can be even greater in the future. 相似文献
10.
Pickhardt M Larbig G Khlistunova I Coksezen A Meyer B Mandelkow EM Schmidt B Mandelkow E 《Biochemistry》2007,46(35):10016-10023
One of the key pathological features of Alzheimer's disease is the aggregation of tau protein. We are therefore searching for compounds capable of inhibiting this reaction. On the basis of an initial screen of 200000 compounds [Pickhardt, M., Gazova, Z., von Bergen, M., Khlistunova, I., Wang, Y., Hascher, A., Mandelkow, E. M., Biernat, J., and Mandelkow, E. (2005) Anthraquinones inhibit tau aggregation and dissolve Alzheimer's paired helical filaments in vitro and in cells, J. Biol. Chem. 280, 3628-3635], we performed an in silico screen and predicted a new phenylthiazolyl-hydrazide (PTH) compound as a possible hit [Larbig, G., Pickhardt, M., Lloyd, D. G., Schmidt, B., and Mandelkow, E. (2007) Screening for inhibitors of tau protein aggregation into Alzheimer paired helical filaments: A ligand based approach results in successful scaffold hopping. Curr. Alzheimer Res. 4 (3), 315-323.]. Synthesis of this compound showed that it was indeed active in terms of inhibiting de novo tau aggregation and disassembling preformed aggregates (IC50 = 7.7 microM and DC50 = 10.8 microM). We have now synthesized 49 similar structures and identified the core of the PTHs to be crucial for activity, thus representing a lead structure. Analysis of the binding epitope by saturation transfer difference NMR shows strong interactions between the tau protein and the ligand in the aromatic regions of the inhibitor. By chemical variation of the core, we improved the inhibitory potency five-fold. The compounds showed a low toxicity as judged by an N2A cell model of tau aggregation and lend themselves for further development. 相似文献