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Multidrug resistance (MDR) occurs when bacteria simultaneously acquire resistance to a broad spectrum of structurally dissimilar compounds to which they have not previously been exposed. MDR is principally a consequence of the active transport of drugs out of the cell by proteins that are integral membrane transporters. We characterised and purified the putative Escherichia coli MDR transporter, MdtM, a 410 amino acid residue protein that belongs to the large and ubiquitous major facilitator superfamily. Functional characterisation of MdtM using growth inhibition and whole cell transport assays revealed its role in intrinsic resistance of E. coli cells to the antimicrobials ethidium bromide and chloramphenicol. Site-directed mutagenesis studies implied that the MdtM aspartate 22 residue and the highly conserved arginine at position 108 play a role in proton recognition. MdtM was homologously overexpressed and purified to homogeneity in dodecyl-β-D-maltopyranoside detergent solution and the oligomeric state and stability of the protein in a variety of detergent solutions was investigated using size-exclusion HPLC. Purified MdtM is monomeric and stable in dodecyl-β-D-maltopyranoside solution and binds chloramphenicol with nanomolar affinity in the same detergent. This work provides a firm foundation for structural studies on this class of multidrug transporter protein. 相似文献
74.
Techniques for studying RNA-protein interactions have lagged behind those for DNA-protein complexes as a consequence of the complexities associated with working with RNA. Here we present a method for the modification of the existing In Situ Hybridisation–Proximity Ligation Assay (ISH-PLA) protocol to adapt it to the study of RNA regulation (rISH-PLA). As proof of principle we used the well-characterised interaction of the Xenopus laevis Staufen RNA binding protein with Vg1 mRNA, the complex of which co-localises to the vegetal pole of Xenopus oocytes. The applicability of both the Stau1 antibody and the Locked Nucleic Acid probe (LNA) recognising Vg1 mRNA were independently validated by whole-mount Immunohistochemistry and whole-mount in situ hybridisation assays respectively prior to combining them in the rISH-PLA assay. The rISH-PLA assay allows the identification of a given RNA-protein complex at subcellular and single cell resolution, thus avoiding the lack of spatial resolution and sensitivity associated with assaying heterogenous cell populations from which conventional RNA-protein interaction detection techniques suffer. This technique will be particularly usefully for studying the activity of RNA binding proteins (RBPs) in complex mixtures of cells, for example tissue sections or whole embryos. 相似文献
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Nancy J Ganson Susan J Kelly Edna Scarlett John S Sundy Michael S Hershfield 《Arthritis research & therapy》2005,8(1):R12
PEG-modified recombinant mammalian urate oxidase (PEG-uricase) is being developed as a treatment for patients with chronic
gout who are intolerant of, or refractory to, available therapy for controlling hyperuricemia. In an open-label phase I trial,
single subcutaneous injections of PEG-uricase (4 to 24 mg) were administered to 13 such subjects (11 had tophaceous gout),
whose plasma uric acid concentration (pUAc) was 11.3 ± 2.1 mg/dl (mean ± SD). By day seven after injection of PEG-uricase,
pUAc had declined by an average of 7.9 mg/dl and had normalized in 11 subjects, whose mean pUAc decreased to 2.8 ± 2.2 mg/dl.
At doses of 8, 12, and 24 mg, the mean pUAc at 21 days after injection remained no more than 6 mg/dl. In eight subjects, plasma
uricase activity was still measurable at 21 days after injection (half-life 10.5 to 19.9 days). In the other five subjects,
plasma uricase activity could not be detected beyond ten days after injection; this was associated with the appearance of
relatively low-titer IgM and IgG antibodies against PEG-uricase. Unexpectedly, these antibodies were directed against PEG
itself rather than the uricase protein. Three PEG antibody-positive subjects had injection-site reactions at 8 to 9 days after
injection. Gout flares in six subjects were the only other significant adverse reactions, and PEG-uricase was otherwise well
tolerated. A prolonged circulating life and the ability to normalize plasma uric acid in markedly hyperuricemic subjects suggest
that PEG-uricase could be effective in depleting expanded tissue stores of uric acid in subjects with chronic or tophaceous
gout. The development of anti-PEG antibodies, which may limit efficacy in some patients, is contrary to the general assumption
that PEG is non-immunogenic. PEG immunogenicity deserves further investigation, because it has potential implications for
other PEGylated therapeutic agents in clinical use. 相似文献
77.
Two Southern Ocean diatoms are more sensitive to ocean acidification and changes in irradiance than the prymnesiophyte Phaeocystis antarctica
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Scarlett Trimborn Silke Thoms Tina Brenneis Jasmin P. Heiden Sara Beszteri Kai Bischof 《Physiologia plantarum》2017,160(2):155-170
To better understand the impact of ocean acidification (OA) and changes in light availability on Southern Ocean phytoplankton physiology, we investigated the effects of pCO2 (380 and 800 µatm) in combination with low and high irradiance (20 or 50 and 200 µmol photons m?2 s?1) on growth, particulate organic carbon (POC) fixation and photophysiology in the three ecologically relevant species Chaetoceros debilis, Fragilariopsis kerguelensis and Phaeocystis antarctica. Irrespective of the light scenario, neither growth nor POC per cell was stimulated by OA in any of the tested species and the two diatoms even displayed negative responses in growth (e.g. C. debilis) or POC content (e.g. F. kerguelensis) under OA in conjunction with high light. For both diatoms, also maximum quantum yields of photosystem II (Fv/Fm) were decreased under these conditions, indicating lowered photochemical efficiencies. To counteract the negative effects by OA and high light, the two diatoms showed diverging photoacclimation strategies. While cellular chlorophyll a (Chl a) and fucoxanthin contents were enhanced in C. debilis to potentially maximize light absorption, F. kerguelensis exhibited reduced Chl a per cell, increased disconnection of antennae from photosystem II reaction centers and strongly lowered absolute electron transport rates (ETR). The decline in ETRs in F. kerguelensis might be explained in terms of different species‐specific strategies for tuning the available flux of adenosine triphosphate and nicotinamide adenine dinucleotide phosphate. Overall, our results revealed that P. antarctica was more tolerant to OA and changes in irradiance than the two diatoms, which may have important implications for biogeochemical cycling. 相似文献
78.
Jun Han Ryan M. Danell Jayanti R. Patel Dmitry R. Gumerov Cameron O. Scarlett J. Paul Speir Carol E. Parker Ivan Rusyn Steven Zeisel Christoph H. Borchers 《Metabolomics : Official journal of the Metabolomic Society》2008,4(2):128-140
With unmatched mass resolution, mass accuracy, and exceptional detection sensitivity, Fourier Transform Ion Cyclotron Resonance
Mass Spectrometry (FTICR-MS) has the potential to be a powerful new technique for high-throughput metabolomic analysis. In
this study, we examine the properties of an ultrahigh-field 12-Tesla (12T) FTICR-MS for the identification and absolute quantitation
of human plasma metabolites, and for the untargeted metabolic fingerprinting of inbred-strain mouse serum by direct infusion
(DI). Using internal mass calibration (mass error ≤1 ppm), we determined the rational elemental compositions (incorporating
unlimited C, H, N and O, and a maximum of two S, three P, two Na, and one K per formula) of approximately 250 out of 570 metabolite
features detected in a 3-min infusion analysis of aqueous extract of human plasma, and were able to identify more than 100
metabolites. Using isotopically-labeled internal standards, we were able to obtain excellent calibration curves for the absolute
quantitation of choline with sub-pmol sensitivity, using 500 times less sample than previous LC/MS analyses. Under optimized
serum dilution conditions, chemical compounds spiked into mouse serum as metabolite mimics showed a linear response over a
600-fold concentration range. DI/FTICR-MS analysis of serum from 26 mice from 2 inbred strains, with and without acute trichloroethylene
(TCE) treatment, gave a relative standard deviation (RSD) of 4.5%. Finally, we extended this method to the metabolomic fingerprinting
of serum samples from 49 mice from 5 inbred strains involved in an acute alcohol toxicity study, using both positive and negative
electrospray ionization (ESI). Using these samples, we demonstrated the utility of this method for high-throughput metabolomics,
with more than 400 metabolites profiled in only 24 h. Our experiments demonstrate that DI/FTICR-MS is well-suited for high-throughput
metabolomic analysis.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
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A J Barker K H Gibson W Grundy A A Godfrey J J Barlow M P Healy J R Woodburn S E Ashton B J Curry L Scarlett L Henthorn L Richards 《Bioorganic & medicinal chemistry letters》2001,11(14):1911-1914
This paper describes the development of the epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 from a lead series of 4-anilinoquinazoline compounds. ZD1839 has suitable properties for use as a clinically effective drug and shows activity against human tumours. In particular, the use of pharmacokinetic data in the development of ZD1839 is discussed. 相似文献