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91.
Zoraghi R Worrall L See RH Strangman W Popplewell WL Gong H Samaai T Swayze RD Kaur S Vuckovic M Finlay BB Brunham RC McMaster WR Davies-Coleman MT Strynadka NC Andersen RJ Reiner NE 《The Journal of biological chemistry》2011,286(52):44716-44725
Novel classes of antimicrobials are needed to address the emergence of multidrug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA). We have recently identified pyruvate kinase (PK) as a potential novel drug target based upon it being an essential hub in the MRSA interactome (Cherkasov, A., Hsing, M., Zoraghi, R., Foster, L. J., See, R. H., Stoynov, N., Jiang, J., Kaur, S., Lian, T., Jackson, L., Gong, H., Swayze, R., Amandoron, E., Hormozdiari, F., Dao, P., Sahinalp, C., Santos-Filho, O., Axerio-Cilies, P., Byler, K., McMaster, W. R., Brunham, R. C., Finlay, B. B., and Reiner, N. E. (2011) J. Proteome Res. 10, 1139-1150; Zoraghi, R., See, R. H., Axerio-Cilies, P., Kumar, N. S., Gong, H., Moreau, A., Hsing, M., Kaur, S., Swayze, R. D., Worrall, L., Amandoron, E., Lian, T., Jackson, L., Jiang, J., Thorson, L., Labriere, C., Foster, L., Brunham, R. C., McMaster, W. R., Finlay, B. B., Strynadka, N. C., Cherkasov, A., Young, R. N., and Reiner, N. E. (2011) Antimicrob. Agents Chemother. 55, 2042-2053). Screening of an extract library of marine invertebrates against MRSA PK resulted in the identification of bis-indole alkaloids of the spongotine (A), topsentin (B, D), and hamacanthin (C) classes isolated from the Topsentia pachastrelloides as novel bacterial PK inhibitors. These compounds potently and selectively inhibited both MRSA PK enzymatic activity and S. aureus growth in vitro. The most active compounds, cis-3,4-dihyrohyrohamacanthin B (C) and bromodeoxytopsentin (D), were identified as highly potent MRSA PK inhibitors (IC(50) values of 16-60 nM) with at least 166-fold selectivity over human PK isoforms. These novel anti-PK natural compounds exhibited significant antibacterial activities against S. aureus, including MRSA (minimal inhibitory concentrations (MIC) of 12.5 and 6.25 μg/ml, respectively) with selectivity indices (CC(50)/MIC) >4. We also report the discrete structural features of the MRSA PK tetramer as determined by x-ray crystallography, which is suitable for selective targeting of the bacterial enzyme. The co-crystal structure of compound C with MRSA PK confirms that the latter is a target for bis-indole alkaloids. It elucidates the essential structural requirements for PK inhibitors in "small" interfaces that provide for tetramer rigidity and efficient catalytic activity. Our results identified a series of natural products as novel MRSA PK inhibitors, providing the basis for further development of potential novel antimicrobials. 相似文献
92.
Williamson Jennifer L. Tye Andrew Lapworth Dan J. Monteith Don Sanders Richard Mayor Daniel J. Barry Chris Bowes Mike Bowes Michael Burden Annette Callaghan Nathan Farr Gareth Felgate Stacey Fitch Alice Gibb Stuart Gilbert Pete Hargreaves Geoff Keenan Patrick Kitidis Vassilis Juergens Monika Martin Adrian Mounteney Ian Nightingale Philip D. Pereira M. Gloria Olszewska Justyna Pickard Amy Rees Andrew P. Spears Bryan Stinchcombe Mark White Debbie Williams Peter Worrall Fred Evans Chris 《Biogeochemistry》2022,160(3):423-424
93.
94.
Y Deng J Zhao D Sakurai KM Kaufman JC Edberg RP Kimberly DL Kamen GS Gilkeson CO Jacob RH Scofield CD Langefeld JA Kelly ME Alarcón-Riquelme BIOLUPUS GENLES Networks JB Harley TJ Vyse BI Freedman PM Gaffney KM Sivils JA James TB Niewold RM Cantor W Chen BH Hahn EE Brown PROFILE BP Tsao 《Arthritis research & therapy》2012,14(Z3):A5
95.
Sawyer NB Worrall LK Crowe JA Waters SL Shakesheff KM Rose FR Morgan SP 《Biotechnology and bioengineering》2008,100(1):159-167
Bioreactor systems that maintain cells and tissues in suspension are increasingly popular for culturing 3D constructs to avoid the loss of in vivo cell function associated with traditional 2D culture methods. There is a need for the online monitoring of such systems to provide better understanding and control of the processes involved and to prevent the disruption of these processes caused by offline sampling and endpoint analysis. We describe a system for the imaging and analysis of cell aggregation, over long periods, within a high aspect rotating vessel (HARV). The system exploits side illumination, using an adjustable beam pattern, to restrict the detected light to that scattered by the cell aggregates, thus eliminating the need for the fluorescent labeling of the cells. The in situ aggregation of mammalian cells (MCF-7 breast carcinoma cells) was monitored over an 8 h period and image sequences showing the growth and motion of the aggregates within the bioreactor were obtained. Detailed size and population data have been derived characterizing the development of the aggregates during this time. We show how the number of resolvable aggregates increases to reach a peak and then declines as these aggregates merge. Once formed, remaining aggregates are found to consolidate to form more tightly packed bodies, typically reducing in cross-sectional area by one third. These results provide the basis for the development of an automated feedback system to control the growth of 3D cell cultures for repeatable, reliable, and quality controlled experimentation. 相似文献
96.
Marcaida MJ Schlarb-Ridley BG Worrall JA Wastl J Evans TJ Bendall DS Luisi BF Howe CJ 《Journal of molecular biology》2006,360(5):968-977
Cytochrome c6A is a unique dithio-cytochrome present in land plants and some green algae. Its sequence and occurrence in the thylakoid lumen suggest that it is derived from cytochrome c6, which functions in photosynthetic electron transfer between the cytochrome b6f complex and photosystem I. Its known properties, however, and a strong indication that the disulfide group is not purely structural, indicate that it has a different, unidentified function. To help in the elucidation of this function the crystal structure of cytochrome c6A from Arabidopsis thaliana has been determined in the two redox states of the heme group, at resolutions of 1.2 A (ferric) and 1.4 A (ferrous). These two structures were virtually identical, leading to the functionally important conclusion that the heme and disulfide groups do not communicate by conformational change. They also show, however, that electron transfer between the reduced disulfide and the heme is feasible. We therefore suggest that the role of cytochrome c6A is to use its disulfide group to oxidize dithiol/disulfide groups of other proteins of the thylakoid lumen, followed by internal electron transfer from the dithiol to the heme, and re-oxidation of the heme by another thylakoid oxidant. Consistent with this model, we found a rapid electron transfer between ferro-cytochrome c6A and plastocyanin, with a second-order rate constant, k2=1.2 x 10(7) M(-1) s(-1). 相似文献
97.
Worrall J 《Perspectives in biology and medicine》2008,51(3):418-431
Ethics and epistemology in medicine are more closely and more interestingly intertwined than is usually recognized. To explore this relationship, I present a case study, clinical trials of extracorporeal membrane oxygenation (ECMO; an intervention for persistent pulmonary hypertension of the newborn).Three separate ethical issues that arise from this case study-whether or not it is ethical to perform a certain trial at all, whether stopping rules for trials are ethically mandated, and the issue of informed consent-are all shown to be intimately related to epistemological judgments about the weight of evidence. Although ethical issues cannot, of course, be resolved by consideration of epistemological findings, I argue that no informed view of the ethical issues that are raised can be adopted without first taking an informed view of the evidential-epistemological ones. 相似文献
98.
Maize (Zea mays L.) tortilla is the major staple food for the Mexican population. Nine tropical maize genotypes were evaluated. All samples had white grains, a common characteristic in tropical maize, and therefore they were appropriate for nixtamalized flour industry. Grain, flour, masa and tortilla characteristics of each maize genotype were evaluated. Length, width, thickness, weight of 1000 grains and hardness of grain were determined. Moisture content, proteins, fat, ash, mean particle size, water absorption index, enthalpy, and flour temperature were also evaluated. Adhesiveness and cohesiveness were evaluated in masa. Moisture content, protein, capacity to puff up, roll making, tension and cutting strength were determined in tortillas. There were significant differences (p≤0.05) in most of the evaluated characteristics. Grain length values varied between 9.26 and 11.02 mm for populations 23 and 22, respectively. Grain hardness oscillated between 11.17 (population 32) and 14.75 (landrace Mejen). According to the weight of 1000 grains most genotypes had small grains. The minimum and maximum moisture values of flour and tortillas were 8.33-9.99% and 46.20-50.36%, respectively. The texture of tortillas elaborated from population 32 and landrace Mejen had the lowest tension and cutting strength, resulting the best genotypes for making tortilla. 相似文献
99.
Evidence for a direct interaction between the tumor suppressor serpin, maspin, and types I and III collagen. 总被引:3,自引:0,他引:3
Maspin (mammary serine protease inhibitor) was originally identified as a tumor suppressor protein in human breast epithelial cells and is a member of the serine proteases inhibitor (serpin) superfamily. It inhibits tumor cell motility and angiogenesis, and although predominantly cytoplasmic, it is also localized to the cell surface. In this study we have investigated the use of the yeast two-hybrid interaction trap to identify novel maspin targets. A target human fibroblast cDNA library was screened, and the alpha-2 chain of type I collagen was identified as a potential interactant. Binding studies with isolated proteins showed interaction between recombinant maspin and types I and III collagen but not other collagen subtypes, a profile strikingly similar to mouse pigment epithelium-derived factor (caspin), which is similarly down-regulated in murine adenocarcinoma tumors and is a potent inhibitor of angiogenesis. Kinetic analysis using an IAsys resonant mirror biosensor determined the dissociation constant of maspin for collagen type I to be 0.63 microm. Further two-hybrid interactions with maspin truncation constructs suggest that collagen binding is localized to amino acids 84-112 of maspin, which aligns with the collagen-binding region of colligin. A direct interaction between exogenous or cell surface maspin and extracellular matrix collagen may contribute to a cell adhesion role in the prevention of tumor cell migration and angiogenesis. 相似文献
100.
Trends in Dissolved Organic Carbon in UK Rivers and Lakes 总被引:11,自引:6,他引:5
Fred Worrall Ron Harriman Chris D. Evans Carol D. Watts John Adamson Colin Neal Ed Tipping Tim Burt Ian Grieve Don Monteith Pam S. Naden Tom Nisbet Brian Reynolds Paul Stevens 《Biogeochemistry》2004,70(3):369-402
Several studies have highlighted an increase in DOC concentration in streams and lakes of UK upland catchments though the causal mechanisms controlling the increase have yet to be fully explained. This study, compiles a comprehensive data set of DOC concentration records for UK catchments to evaluate trends and test whether observed increases are ubiquitous over time and space. The study analysed monthly DOC time series from 198 sites, including 29 lakes, 8 water supply reservoirs and 161 rivers. The records vary in length from 8 to 42 years going back as far as 1961. Of the 198 sites, 153 (77%) show an upward trend in DOC concentration significant at the 95% level, the remaining 45 (23%) show no significant trend and no sites show a significant decrease in DOC concentration. The average annual increase in DOC concentration was 0.17 mg C/l/year. The dataset shows: (i) a spatial consistent upward trend in the DOC concentration independent of regional effects of rainfall, acid and nitrogen deposition, and local effects of land-use change; (ii) a temporally consistent increase in DOC concentration for period back as far as the 1960s; (iii) the increase in DOC concentration means an estimated DOC flux from the UK as 0.86 Mt C for the year 2002 and is increasing at 0.02 Mt C/year. Possible reasons for the increasing DOC concentration are discussed. 相似文献