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71.
Büttner F Bergemann S Guénard D Gust R Seitz G Thoret S 《Bioorganic & medicinal chemistry》2005,13(10):3497-3511
Two new attractive series of allocolchicinoids were designed as inhibitors of tubulin assembly using the potent ketone 4 and the tetracyclic, pyrazole annulated NCME variant 7 (NCME = N-acetyl colchinol-O-methylether (2)) as lead structures. The first group of inhibitors of type 6 with novel oxepine and azepine B-ring structures belongs to the NCME-series and was synthesized via a multistep total synthesis starting from simple and cheap 3-methoxybenzaldehyde (12) and 3,4,5-trimethoxybenzaldehyde (13). Biaryl-coupling of the starting materials 12 and 13 was accomplished via Ziegler-Ullmann-reaction to furnish the biphenyl 11 equipped with two carbaldehyde functions. The subsequent Cannizzaro reaction of this dicarbaldehyde 11 proceeded with high regioselectivity to yield almost exclusively the key compound, the hydroxymethyl carboxylic acid 9. Ring closure to the o,o'-bridged biphenyls was accomplished by two routes: on the one hand, treatment of 9 with aqueous hydrochloric acid yielded the lactone 15. On the other hand, a four step sequence starting from the isomeric mixture 9/10 furnished the constitutionally isomeric lactams 23 and 24; these could be converted to the corresponding thiolactams 25 and 26 and to the tetrazole annulated NCME-type derivatives 27 and 28. The second series of bioactive compounds are congeners of allocolchicine (3). The well known desacetyl allocolchicine (29) was easily oxidized to the oxime 30, which was further transformed to the corresponding ketone 31. This served as key precursor for the syntheses of various tetracyclic allocolchicine modifications 33-36 annulated with a pyrazole, isoxazole, pyrimidine or 2-aminopyrimidine heterocycle, respectively. Unexpectedly, all the NCME-variants with a substituent in position 7 like in NCME (2) inhibited the tubulin assembly only moderately. In contrast, the new series of allocolchicine modifications proved to be highly potent antimicrotubule agents. Inhibition of tubulin assembly occurred at lower concentrations compared to those measured for the reference colchicine (1). Surprisingly, these promising results could not be confirmed in the cytotoxicity tests against the human MCF-7 breast cancer cell line, where an unexpected loss of effectiveness compared to the corresponding NCME-derivatives was observed. 相似文献
72.
Plasmacytoid dendritic cells control TLR7 sensitivity of naive B cells via type I IFN 总被引:8,自引:0,他引:8
Bekeredjian-Ding IB Berkeredjian-Ding IB Wagner M Hornung V Giese T Schnurr M Endres S Hartmann G 《Journal of immunology (Baltimore, Md. : 1950)》2005,174(7):4043-4050
Detailed information of human B cell activation via TLR may lead to a better understanding of B cell involvement in autoimmunity and malignancy. In this study we identified a fundamental difference in the regulation of TLR7- and TLR9-mediated B cell stimulation: whereas the induction of polyclonal naive B cell proliferation by the TLR7 ligands resiquimod (R848) and loxoribine required the presence of plasmacytoid dendritic cells (PDCs), activation via the TLR9 ligand CpG was independent of PDCs. We found that PDC-derived type I IFN enhanced TLR7 sensitivity of B cells by selectively up-regulating TLR7 expression. In contrast the expression levels of TLR9 and of other TLRs studied remained unchanged. In the presence of type I IFN, TLR7 ligation triggered polyclonal B cell expansion and B cell differentiation toward Ig-producing plasma cells; notably, this occurred independently of T cell help and B cell Ag. Human B cells did not respond to ligands of other TLRs including TLR2, TLR4 and TLR6 with and without type I IFN. In conclusion, our results reveal a distinct regulation of TLR7 and TLR9 function in human B cells and highlight TLR7 and TLR9 as unique targets for therapeutic intervention in B cell-mediated immunity and disease. 相似文献
73.
74.
Analysis of the phosphoproteome of Chlamydomonas reinhardtii provides new insights into various cellular pathways
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Wagner V Gessner G Heiland I Kaminski M Hawat S Scheffler K Mittag M 《Eukaryotic cell》2006,5(3):457-468
The unicellular flagellated green alga Chlamydomonas reinhardtii has emerged as a model organism for the study of a variety of cellular processes. Posttranslational control via protein phosphorylation plays a key role in signal transduction, regulation of gene expression, and control of metabolism. Thus, analysis of the phosphoproteome of C. reinhardtii can significantly enhance our understanding of various regulatory pathways. In this study, we have grown C. reinhardtii cultures in the presence of an inhibitor of Ser/Thr phosphatases to increase the phosphoprotein pool. Phosphopeptides from these cells were enriched by immobilized metal-ion affinity chromatography and analyzed by nano-liquid chromatography-electrospray ionization-mass spectrometry (MS) with MS-MS as well as neutral-loss-triggered MS-MS-MS spectra. In this way, we were able to identify 360 phosphopeptides from 328 different phosphoproteins of C. reinhardtii, thus providing new insights into a variety of cellular processes, including metabolic and signaling pathways. Comparative analysis of the phosphoproteome also yielded new functional information on proteins controlled by redox regulation (thioredoxin target proteins) and proteins of the chloroplast 70S ribosome, the centriole, and especially the flagella, for which 32 phosphoproteins were identified. The high yield of phosphoproteins of the latter correlates well with the presence of several flagellar kinases and indicates that phosphorylation/dephosphorylation represents one of the key regulatory mechanisms of eukaryotic cilia. Our data also provide new insights into certain cilium-related mammalian diseases. 相似文献
75.
Carlos Reding Pablo Cataln Gunther Jansen Tobias Bergmiller Emily Wood Phillip Rosenstiel Hinrich Schulenburg Ivana Gudelj Robert Beardmore 《Molecular biology and evolution》2021,38(9):3847
To determine the dosage at which antibiotic resistance evolution is most rapid, we treated Escherichia coli in vitro, deploying the antibiotic erythromycin at dosages ranging from zero to high. Adaptation was fastest just below erythromycin’s minimal inhibitory concentration (MIC) and genotype-phenotype correlations determined from whole genome sequencing revealed the molecular basis: simultaneous selection for copy number variation in three resistance mechanisms which exhibited an “inverted-U” pattern of dose-dependence, as did several insertion sequences and an integron. Many genes did not conform to this pattern, however, reflecting changes in selection as dose increased: putative media adaptation polymorphisms at zero antibiotic dosage gave way to drug target (ribosomal RNA operon) amplification at mid dosages whereas prophage-mediated drug efflux amplifications dominated at the highest dosages. All treatments exhibited E. coli increases in the copy number of efflux operons acrAB and emrE at rates that correlated with increases in population density. For strains where the inverted-U was no longer observed following the genetic manipulation of acrAB, it could be recovered by prolonging the antibiotic treatment at subMIC dosages. 相似文献
76.
Vargo-Gogola T Heckman BM Gunther EJ Chodosh LA Rosen JM 《Molecular endocrinology (Baltimore, Md.)》2006,20(6):1391-1405
p190-B Rho GTPase activating protein is essential for mammary gland development because p190-B deficiency prevents ductal morphogenesis. To investigate the role of p190-B during distinct stages of mammary gland development, tetracycline-regulatable p190-B-overexpressing mice were generated. Short-term induction of p190-B in the developing mammary gland results in abnormal terminal end buds (TEBs) that exhibit aberrant budding off the neck, histological anomalies, and a markedly thickened stroma. Overexpression of p190-B throughout postnatal development results in increased branching, delayed ductal elongation, and disorganization of the ductal tree. Interestingly, overexpression of p190-B during pregnancy results in hyperplastic lesions. Several cellular and molecular alterations detected within the aberrant TEBs may contribute to these phenotypes. Signaling through the IGF pathway is altered, and the myoepithelial cell layer is discontinuous at sites of aberrant budding. An increase in collagen and extensive infiltration of macrophages, which have recently been implicated in branching morphogenesis, is observed in the stroma surrounding the p190-B-overexpressing TEBs. We propose that the stromal response, disruption of the myoepithelial layer, and alterations in IGF signaling in the p190-B-overexpressing mice impact the TEB architecture, leading to disorganization and increased branching of the ductal tree. Moreover, we suggest that alterations in tissue architecture and the adjacent stroma as a consequence of p190-B overexpression during pregnancy leads to loss of growth control and the formation of hyperplasia. These data demonstrate that precise control of p190-B Rho GTPase-activating protein activity is critical for normal branching morphogenesis during mammary gland development. 相似文献
77.
Gunther NW Nuñez A Fortis L Solaiman DK 《Journal of industrial microbiology & biotechnology》2006,33(11):914-920
We recently reported that a strain of the non-pathogenic bacterial species Pseudomonas chlororaphis was capable of producing the biosurfactant molecule, rhamnolipids. Previous to this report the organisms known to produce rhamnolipids were almost exclusively pathogens. The newly described P. chlororaphis strain produced rhamnolipids at room temperature in static minimal media, as opposed to previous reports of rhamnolipid production which occurred at elevated temperatures with mechanical agitation. The non-pathogenic nature and energy conserving production conditions make the P. chlororaphis strain an attractive candidate for commercial rhamnolipid production. However, little characterization of molecular/biochemical processes in P. chlororaphis have been reported. In order to achieve a greater understanding of the process by which P. chlororaphis produces rhamnolipids, a survey of proteins differentially expressed during rhamnolipid production was performed. Separation and measurement of the bacteria’s proteome was achieved using Beckman Coulter’s Proteome Lab PF2D packed column-based protein fractionation system. Statistical analysis of the data identified differentially expressed proteins and known orthologues of those proteins were identified using an AB 4700 Proteomics Analyzer mass spectrometer system. A list of proteins differentially expressed by P. chlororaphis strain NRRL B-30761 during rhamnolipid production was generated, and confirmed through a repetition of the entire separation process.Mention of trade names or commercial products in this publication is solely for the purpose of providing specific information and does not imply recommendation or endorsement by the U.S. Department of Agriculture. 相似文献
78.
Contact of T lymphocytes with nicotinamide adenine dinucleotide (NAD) or ATP causes cell death that requires expression of purinergic receptor P2X(7) (P2X(7)R). T cell subsets differ in their responses to NAD and ATP, which awaits a mechanistic explanation. Here, we show that sensitivity to ATP correlates with P2X(7)R expression levels in CD4 cells, CD8 cells and CD4(+)CD25(+) cells from both C57BL/6 and BALB/c mice. But P2X(7)R ligands do not only induce cell death but also shedding of CD62L. It is shown here that in CD62L(high) T cells, CD62L shedding correlates with low expression of P2X(7)Rs and lower cell death, whereas in CD62L(low) cells P2X(7)R expression and death are higher. The possibility is therefore investigated that P2X(7)Rs induce T cell activation. Experiments show that spontaneous T cell proliferation is somewhat higher in cells expressing P2X(7)Rs, but this effect we suggest is caused by P2X(7)R expression on accessory cells. 相似文献
79.
Nathaniel R. Bowersock Andrea R. Litt Michael A. Sawaya Kerry A. Gunther Frank T. van Manen 《The Journal of wildlife management》2024,88(1):e22497
The quality and availability of resources are known to influence spatial patterns of animal density. In Yellowstone National Park, relationships between the availability of resources and the distribution of grizzly bears (Ursus arctos) have been explored but have yet to be examined in American black bears (Ursus americanus). We conducted non-invasive genetic sampling during 2017–2018 (mid-May to mid-July) and applied spatially explicit capture-recapture models to estimate density of black bears and examine associations with landscape features. In both years, density estimates were higher in forested vegetation communities, which provide food resources and thermal and security cover preferred by black bears, compared with non-forested areas. In 2017, density also varied by sex, with female densities being higher than males. Based on our estimates, the northern range of Yellowstone National Park supports one of the highest densities of black bears (20 black bears/100 km2) in the northern Rocky Mountains (6–12 black bears/100 km2 in other regions). Given these high densities, black bears could influence other wildlife populations more than previously thought, such as through displacement of sympatric predators from kills. Our study provides the first spatially explicit estimates of density for black bears within an ecosystem that contains the majority of North America's large mammal species. Our density estimates provide a baseline that can be used for future research and management decisions of black bears, including efforts to reduce human–bear conflicts. 相似文献
80.
Klich M Mendoza C Mullaney E Keller N Bennett JW 《Systematic and applied microbiology》2001,24(1):131-138
An unusual, sterigmatocystin-producing taxon with characteristics of both Emericella nidulans (anamorph Aspergillus nidulans) and Emericella rugulosa (anamorph Aspergillus rugulovalvus, formerly A. rugulosus) was isolated repeatedly during a mycofloral survey of desert cotton field soils where aflatoxin is a chronic problem. Members of this taxon had ascospores with smooth convex walls like E. nidulans but grew slowly like E. rugulosa; moreover, they were similar to an industrial echinocandin B-producing strain which had been classified as "Aspergillus nidulans var. roseus." These new desert isolates were compared with "A. nidulans var. roseus" and representative wild-type isolates of E. nidulans and E. rugulosa using traditional morphological characters, secondary metabolite profiles of mycelial extracts, and Southern blot analysis of genomic DNA. The desert isolates and "A. nidulans var. roseus shared morphological, physiological and molecular characters with E. rugulosa. These isolates constitute a new non-rugulose variant of E. rugulosa. 相似文献