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21.
Background
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is a facultative intracellular pathogen that can persist within the host. The bacteria are thought to be in a state of reduced replication and metabolism as part of the chronic lung infection. Many in vitro studies have dissected the hypothesized environment within the infected lung, defining the bacterial response to pH, starvation and hypoxia. While these experiments have afforded great insight, the picture remains incomplete. The only way to study the combined effects of these environmental factors and the mycobacterial response is to study the bacterial response in vivo.Methodology/Principal Findings
We used the guinea pig model of tuberculosis to examine the bacterial proteome during the early and chronic stages of disease. Lungs were harvested thirty and ninety days after aerosol challenge with Mtb, and analyzed by liquid chromatography-mass spectrometry. To date, in vivo proteomics of the tubercle bacillus has not been described and this work has generated the first large-scale shotgun proteomic data set, comprising over 500 unique protein identifications. Cell wall and cell wall processes, and intermediary metabolism and respiration were the two major functional classes of proteins represented in the infected lung. These classes of proteins displayed the greatest heterogeneity indicating important biological processes for establishment of a productive bacterial infection and its persistence. Proteins necessary for adaptation throughout infection, such as nitrate/nitrite reduction were found at both time points. The PE-PPE protein class, while not well characterized, represented the third most abundant category and showed the most consistent expression during the infection.Conclusions/Significance
Cumulatively, the results of this work may provide the basis for rational drug design – identifying numerous Mtb proteins, from essential kinases to products involved in metal regulation and cell wall remodeling, all present throughout the course of infection. 相似文献22.
P Dobos 《Journal of virology》1979,32(3):1047-1050
The genome of infectious bursal disease virus consists of two segments of double-stranded RNA of 2.5 X 10(6) and 2.2 X 10(6) molecular weight. Polyacrylamide gel electrophoresis of purified virus resolved four structural polypeptides: VP-1 (90,000), VP-2 (41,000), VP-3 (35,000), and VP-4 (28,000). Peptide map comparisons of radioiodinated virion proteins indicated no precursor-product relationship between them. The possible relationship between the size of the virus genome and the number and sizes of different viral proteins is discussed. 相似文献
23.
Virus-specific protein synthesis in cells infected by infectious pancreatic necrosis virus. 总被引:11,自引:9,他引:2 下载免费PDF全文
P Dobos 《Journal of virology》1977,21(1):242-258
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Mycobacterium tuberculosis functional network analysis by global subcellular protein profiling 总被引:3,自引:0,他引:3 下载免费PDF全文
Mawuenyega KG Forst CV Dobos KM Belisle JT Chen J Bradbury EM Bradbury AR Chen X 《Molecular biology of the cell》2005,16(1):396-404
Trends in increased tuberculosis infection and a fatality rate of approximately 23% have necessitated the search for alternative biomarkers using newly developed postgenomic approaches. Here we provide a systematic analysis of Mycobacterium tuberculosis (Mtb) by directly profiling its gene products. This analysis combines high-throughput proteomics and computational approaches to elucidate the globally expressed complements of the three subcellular compartments (the cell wall, membrane, and cytosol) of Mtb. We report the identifications of 1044 proteins and their corresponding localizations in these compartments. Genome-based computational and metabolic pathways analyses were performed and integrated with proteomics data to reconstruct response networks. From the reconstructed response networks for fatty acid degradation and lipid biosynthesis pathways in Mtb, we identified proteins whose involvements in these pathways were not previously suspected. Furthermore, the subcellular localizations of these expressed proteins provide interesting insights into the compartmentalization of these pathways, which appear to traverse from cell wall to cytoplasm. Results of this large-scale subcellular proteome profile of Mtb have confirmed and validated the computational network hypothesis that functionally related proteins work together in larger organizational structures. 相似文献
26.
Hallgas B Patonay T Kiss-Szikszai A Dobos Z Hollósy F Eros D Orfi L Kéri G Idei M 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2004,801(2):229-235
A molecule library containing 55 aurone- and thioaurone-type structures has been designed and synthesised. Reversed phase high performance liquid chromatographic (RP-HPLC) method has been developed to separate these compounds and to characterise their lipophilicity by experimental method (k'). The experimental lipophilicity data have been compared with the computer calculated lipophilicity parameters (CLOGPs) of the same molecules. In general, good correlations between the measured and calculated lipophilicities have been found with the exception of structure isomers and compounds capable for hydrogen bonding. The chromatographic method was suitable to separate the structure (ortho and para) isomers of aurone and thioaurones and was sensitive enough to differentiate their lipophilicities. Our findings suggest the usefulness of the chromatographic method in fast characterisation of the lipophilicity of structurally closely related molecules. 相似文献
27.
As more and more users access social network services from smart devices with GPS receivers, the available amount of geo-tagged information makes repeating classical experiments possible on global scales and with unprecedented precision. Inspired by the original experiments of Milgram, we simulated message routing within a representative sub-graph of the network of Twitter users with about 6 million geo-located nodes and 122 million edges. We picked pairs of users from two distant metropolitan areas and tried to find a route between them using local geographic information only; our method was to forward messages to a friend living closest to the target. We found that the examined network is navigable on large scales, but navigability breaks down at the city scale and the network becomes unnavigable on intra-city distances. This means that messages usually arrived to the close proximity of the target in only 3–6 steps, but only in about 20% of the cases was it possible to find a route all the way to the recipient, in spite of the network being connected. This phenomenon is supported by the distribution of link lengths; on larger scales the distribution behaves approximately as , which was found earlier by Kleinberg to allow efficient navigation, while on smaller scales, a fractal structure becomes apparent. The intra-city correlation dimension of the network was found to be , less than the dimension of the distribution of the population. 相似文献
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Tamás Garay István Kenessey Eszter Molnár éva Juhász Andrea Réti Viktória László Anita Rózsás Judit Dobos Balázs D?me Walter Berger Walter Klepetko József Tóvári József Tímár Balázs Heged?s 《PloS one》2015,10(2)
While targeted therapy brought a new era in the treatment of BRAF mutant melanoma, therapeutic options for non-BRAF mutant cases are still limited. In order to explore the antitumor activity of prenylation inhibition we investigated the response to zoledronic acid treatment in thirteen human melanoma cell lines with known BRAF, NRAS and PTEN mutational status. Effect of zoledronic acid on proliferation, clonogenic potential, apoptosis and migration of melanoma cells as well as the activation of downstream elements of the RAS/RAF pathway were investigated in vitro with SRB, TUNEL and PARP cleavage assays and videomicroscopy and immunoblot measurements, respectively. Subcutaneous and spleen-to-liver colonization xenograft mouse models were used to evaluate the influence of zoledronic acid treatment on primary and disseminated tumor growth of melanoma cells in vivo. Zoledronic acid more efficiently decreased short-term in vitro viability in NRAS mutant cells when compared to BRAF mutant and BRAF/NRAS wild-type cells. In line with this finding, following treatment decreased activation of ribosomal protein S6 was found in NRAS mutant cells. Zoledronic acid demonstrated no significant synergism in cell viability inhibition or apoptosis induction with cisplatin or DTIC treatment in vitro. Importantly, zoledronic acid could inhibit clonogenic growth in the majority of melanoma cell lines except in the three BRAF mutant but PTEN wild-type melanoma lines. A similar pattern was observed in apoptosis induction experiments. In vivo zoledronic acid did not inhibit the subcutaneous growth or spleen-to-liver colonization of melanoma cells. Altogether our data demonstrates that prenylation inhibition may be a novel therapeutic approach in NRAS mutant melanoma. Nevertheless, we also demonstrated that therapeutic sensitivity might be influenced by the PTEN status of BRAF mutant melanoma cells. However, further investigations are needed to identify drugs that have appropriate pharmacological properties to efficiently target prenylation in melanoma cells. 相似文献
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