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511.
Awareness of the problem of antimicrobial resistance (AMR) has escalated and drug-resistant infections are named among the most urgent problems facing clinicians today. Our experiments here identify a transporter interactome and portray its essential function in acquisition of antimicrobial resistance. By exposing E. coli cells to consecutive increasing concentrations of the fluoroquinolone norfloxacin we generated in the laboratory highly resistant strains that carry multiple mutations, most of them identical to those identified in clinical isolates. With this experimental paradigm, we show that the MDTs function in a coordinated mode to provide an essential first-line defense mechanism, preventing the drug reaching lethal concentrations, until a number of stable efficient alterations occur that allow survival. Single-component efflux transporters remove the toxic compounds from the cytoplasm to the periplasmic space where TolC-dependent transporters expel them from the cell. We postulate a close interaction between the two types of transporters to prevent rapid leak of the hydrophobic substrates back into the cell. The findings change the prevalent concept that in Gram-negative bacteria a single multidrug transporter, AcrAB-TolC type, is responsible for the resistance. The concept of a functional interactome, the process of identification of its members, the elucidation of the nature of the interactions and its role in cell physiology will change the existing paradigms in the field. We anticipate that our work will have an impact on the present strategy searching for inhibitors of AcrAB-TolC as adjuvants of existing antibiotics and provide novel targets for this urgent undertaking. 相似文献
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Jung Carina M. Carr Matthew Blakeney G. Alon Indest Karl J. 《Journal of industrial microbiology & biotechnology》2019,46(9-10):1273-1281
Journal of Industrial Microbiology & Biotechnology - Horizontal gene transfer (HGT) is the lateral movement of genetic material between organisms. The RDX explosive-degrading bacterium Gordonia... 相似文献
515.
A. Eisenthal Yechiel Goldman Yehuda Skornick Anna Gelfand Diana Buyaner Issac Kaver Alon Yellin Henry Yehoshua Beatriz Lifschitz-Mercer Amnon Gonnene M. Shinitzky 《Cancer immunology, immunotherapy : CII》1998,46(6):304-310
Hydrostatic pressure (P) combined with membrane protein crosslinking (CL) by adenosine dialdehyde (AdA) can render tumor
cells immunogenic. We have recently shown that PCL treatment of murine tumor cells augmented the presentation of MHC-restricted
tumor-associated antigens and enhanced cell-mediated immunity. In cancer patients inoculated with autologous PCL-modified
tumor cells, a significant delayed-type hypersensitivity response was elicited. Since the balance between cell-mediated immunity
and humoral immunity is reciprocally controlled by immunoregulatory cytokines, we have examined the proliferative response
and cytokine secretion pattern in cultures of human peripheral blood mononuclear cells (PBMC) stimulated by autologous PCL-modified
and unmodified tumor cells. These tumor cells were obtained from freshly resected tumor tissue of 16 patients with colon (8),
lung (4) and renal (4) carcinomas. The results demonstrated that PCL-modified tumor cells promoted an increase in PBMC proliferation
in 5 out of 8 (63%), 1 out of 4 (25%) and 4 out of 4 (100%) colon, lung and renal cell carcinomas. Fourteen of the above cultures
were also analyzed for the secretion of interleukin-10 and interferon-γ. Overall, a substantial decrease in IL-10 secretion
was detected in 9 out of 14 (64%) cultures while a reciprocal increase in interferon-γ secretion was noted in 8 out of 14
(57%) cultures. Our results confirmed that PCL-modified human tumor cells of different etiologies can modulate the pattern
of cytokines released from stimulated autologous lymphocytes. Such a procedure could prove valuable in the production of autologous
tumor vaccines.
Received: 8 January 1998 / Accepted: 9 April 1998 相似文献