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101.
A Mika SL Reynolds FC Mohlin C Willis PM Swe DA Pickering V Halilovic LC Wijeyewickrema RN Pike AM Blom DJ Kemp K Fischer 《PloS one》2012,7(7):e40489
Scabies is a parasitic infestation of the skin by the mite Sarcoptes scabiei that causes significant morbidity worldwide, in particular within socially disadvantaged populations. In order to identify mechanisms that enable the scabies mite to evade human immune defenses, we have studied molecules associated with proteolytic systems in the mite, including two novel scabies mite serine protease inhibitors (SMSs) of the serpin superfamily. Immunohistochemical studies revealed that within mite-infected human skin SMSB4 (54 kDa) and SMSB3 (47 kDa) were both localized in the mite gut and feces. Recombinant purified SMSB3 and SMSB4 did not inhibit mite serine and cysteine proteases, but did inhibit mammalian serine proteases, such as chymotrypsin, albeit inefficiently. Detailed functional analysis revealed that both serpins interfered with all three pathways of the human complement system at different stages of their activation. SMSB4 inhibited mostly the initial and progressing steps of the cascades, while SMSB3 showed the strongest effects at the C9 level in the terminal pathway. Additive effects of both serpins were shown at the C9 level in the lectin pathway. Both SMSs were able to interfere with complement factors without protease function. A range of binding assays showed direct binding between SMSB4 and seven complement proteins (C1, properdin, MBL, C4, C3, C6 and C8), while significant binding of SMSB3 occurred exclusively to complement factors without protease function (C4, C3, C8). Direct binding was observed between SMSB4 and the complement proteases C1s and C1r. However no complex formation was observed between either mite serpin and the complement serine proteases C1r, C1s, MASP-1, MASP-2 and MASP-3. No catalytic inhibition by either serpin was observed for any of these enzymes. In summary, the SMSs were acting at several levels mediating overall inhibition of the complement system and thus we propose that they may protect scabies mites from complement-mediated gut damage. 相似文献
102.
Jean-Marie Frère Jean-Marie Ghuysen Peter E. Reynolds Ramon Moreno Harold R. Perkins 《The Biochemical journal》1974,143(1):241-249
Benzylpenicillin and cephaloridine reacted with the exocellular dd-carboxypeptidase–transpeptidase from Streptomyces R39 to form equimolar and inactive antibiotic–enzyme complexes. At saturation, the molar ratio of chromogenic cephalosporin 87-312 to enzyme was 1.3:1, but this discrepancy might be due to a lack of accuracy in the measurement of the antibiotic. Spectrophotometric studies showed that binding of cephaloridine and cephalosporin 87-312 to the enzyme caused opening of their β-lactam rings. Benzylpenicillin and cephalosporin 87-312 competed for the same site on the free enzyme, suggesting that binding of benzylpenicillin also resulted in the opening of its β-lactam ring. In Tris–NaCl–MgCl2 buffer at pH7.7 and 37°C, the rate constants for the dissociation of the antibiotic–enzyme complexes were 2.8×10−6, 1.5×10−6 and 0.63×10−6s−1 (half-lives 70, 130 and 300h) for benzylpenicillin, cephalosporin 87-312 and cephaloridine respectively. During the process, the protein underwent reactivation. The enzyme that was regenerated from its complex with benzylpenicillin was as sensitive to fresh benzylpenicillin as the native enzyme. With [14C]benzylpenicillin, the released radioactive compound was neither benzylpenicillin nor benzylpenicilloic acid. The Streptomyces R39 enzyme thus behaved as a β-lactam-antibiotic-destroying enzyme but did not function as a β-lactamase. Incubation at 37°C in 0.01m-phosphate buffer, pH7.0, and in the same buffer supplemented with sodium dodecyl sulphate caused a more rapid reversion of the [14C]benzylpenicillin–enzyme complex. The rate constants were 1.6×10−5s−1 and 0.8×10−4s−1 respectively. Under these conditions, however, there was no concomitant reactivation of the enzyme and the released radioactive compound(s) appeared not to be the same as before. The Streptomyces R39 enzyme and the exocellular dd-carboxypeptidase–transpeptidase from Streptomyces R61 appeared to differ from each other with regard to the topography of their penicillin-binding site. 相似文献
103.
104.
Pathak AK Besra GS Crick D Maddry JA Morehouse CB Suling WJ Reynolds RC 《Bioorganic & medicinal chemistry》1999,7(11):2407-2413
The biochemically unique structures of sugar residues in the outer cell wall of Mycobacterium tuberculosis (MTB) make the pathways for their biosynthesis and utilization attractive targets for the development of new and selective anti-tubercular agents. A cell-free assay system for galactosyltransferase activity using UDP[14C]Gal as the glycosyl donor, as well as an in vitro colorimetric broth micro-dilution assay system, were used to determine the activities of three beta-D-gal(f)(1-->4)-alpha-L-rham(p) octyl disaccharides as substrates and antimycobacterial agents respectively. The cell-free enzymatic studies using compounds 8 and 10 suggested that these disaccharides bind to and are effective substrates for a putative mycobacterial galactosyltransferase. The modified acceptor 8 was found to be a slower but prolonged binder as compared to the less substituted analogue 10 as evidenced by their Km and Vmax values. Moderate antimycobacterial activity was observed with compounds 8 and 9 against MTB H37Ra and three clinical isolates of Mycobacterium avium complex (MAC). 相似文献
105.
Nathalie Fenner Robert Williams Hannah Toberman Steve Hughes Brian Reynolds Chris Freeman 《Hydrobiologia》2011,665(1):51-66
The hypothesis that specific components of seawater, such as particulate, dissolved and colloidal organic and inorganic material,
render virions non-infective has long been postulated, but never rigorously tested. To address this hypothesis, the plaque
assay method was used to derive infective decay rates, k, of two bacteriophages—P1 (marine host: PWH3a) and T4 (enteric host: E. coli B). We compared k values of bacteriophage suspended in serial filtrations of seawater, with and without autoclaving and UV oxidation. Both
phages exhibited reduced decay rates in particle-free water (<0.2 μm) compared to <10 μm filtrate. The largest decrease in
virion decay rates was achieved by autoclaving the 0.2 μm filtrate. UV oxidation of <0.2 μm filtrate, however, yielded higher
decay rates than observed in autoclaved treatments. The lowest k values were seen in ultra-filtered seawater (<10 kDa). Exposure to a wide range of concentrations of Pronase E (a proteolytic
enzyme), inorganic clay (kaolinite or montmorillonite), and organic particles (phytoplankton debris) did not promote phage
inactivation. P1 infective titers were also not consistently reduced by exposures to axenic cultures of a resistant host mutant
(PWH3a-R) and a non-host marine bacterium (MB-5). Finally, phage were exposed to a range of temperatures to derive activation
energies required for phage inactivation. Application of the Arrhenius model to inactivation of T4 and P1 yielded activation
energies (E
a) of 49 and 40 kJ mol−1, respectively. This is the first comprehensive analysis in which specific seawater components were assayed for their ability
to inactivate bacteriophage. Inactivation of these phage does not appear to depend on capsomere denaturation, proteolytic
extracellular enzymes, sorption to non-host bacteria, clay particles or particulate organic debris, but is accelerated by
naturally occurring particles, which include living organisms, and heat-labile colloids and macromolecules >10 kDa. 相似文献
106.
107.
Bioremediation has been shown to be an effective means of treating petroleum‐contaminated soils in cold areas, although the conditions required to maximize bioremediation in cold region (cryic) soils are not well documented. A laboratory study was conducted to investigate the effects of nitrogen and phosphorus levels and temperature on petroleum bioremediation. A cryic entisol contaminated with diesel fuel was treated with nitrogen (0, 400, 800, or 1200 mg/kg of soil) and phosphorus (0, 60, 120, or 180 mg/kg of soil) and incubated at two temperatures (10 and 20°C). At 10°C, bioremediation rates were not affected by fertility treatments. At 20°C, reaction rates were increased by the addition of P, but unaffected by N. Regardless of fertility regime, the rate of diesel loss was much greater in soil incubated at 20°C than in soil incubated at 10°C. 相似文献
108.
Diana P. Trebec‐Reynolds Irina Voronov Johan N.M. Heersche Morris F. Manolson 《Journal of cellular biochemistry》2010,109(5):975-982
Interleukin 1 (IL‐1) is a proinflammatory cytokine upregulated in conditions such as rheumatoid arthritis and periodontal disease. Both isoforms, IL‐1α and IL‐1β, have been shown to activate osteoclasts (OCs), the cells responsible for resorbing bone. Inflammatory conditions are also characterized by increased bone loss and by the presence of large OCs (10+ nuclei). We and others have previously shown that large OCs are more likely to be resorbing compared to small OCs (2–5 nuclei). Moreover, large OCs express higher levels of the IL‐1 activating receptor IL‐1RI, integrins αv and β3, RANK, and TNFR1, while small OCs have higher levels of the decoy receptor IL‐1RII. We hypothesized that IL‐1 would have different effects on large and small OCs due to these distinct receptor expression patterns. To test this hypothesis, RAW 264.7 cells were differentiated into populations of small and large OCs and treated with IL‐1α or IL‐1β (1 and 10 ng/ml). In the presence of sRANKL, both IL‐1α and IL‐1β increased total OC number and resorptive activity of large OCs. IL‐1α stimulated formation of large OCs and increased the number of resorption pits, while IL‐1β changed the morphology of large OCs and integrin‐β3 phosphorylation. No effects were seen in small OCs in response to either IL‐1 isoform. These results demonstrate that IL‐1 predominantly affects large OCs. The dissimilarity of responses to IL‐1α and IL‐1β suggests that these isoforms activate different signaling pathways within the two OC populations. J. Cell. Biochem. 109: 975–982, 2010. © 2010 Wiley‐Liss, Inc. 相似文献
109.
Adam R. Boyko Pascale Quignon Lin Li Jeffrey J. Schoenebeck Jeremiah D. Degenhardt Kirk E. Lohmueller Keyan Zhao Abra Brisbin Heidi G. Parker Bridgett M. vonHoldt Michele Cargill Adam Auton Andy Reynolds Abdel G. Elkahloun Marta Castelhano Dana S. Mosher Nathan B. Sutter Gary S. Johnson John Novembre Melissa J. Hubisz Adam Siepel Robert K. Wayne Carlos D. Bustamante Elaine A. Ostrander 《PLoS biology》2010,8(8)
Domestic dogs exhibit tremendous phenotypic diversity, including a greater
variation in body size than any other terrestrial mammal. Here, we generate a
high density map of canine genetic variation by genotyping 915 dogs from 80
domestic dog breeds, 83 wild canids, and 10 outbred African shelter dogs across
60,968 single-nucleotide polymorphisms (SNPs). Coupling this genomic resource
with external measurements from breed standards and individuals as well as
skeletal measurements from museum specimens, we identify 51 regions of the dog
genome associated with phenotypic variation among breeds in 57 traits. The
complex traits include average breed body size and external body dimensions and
cranial, dental, and long bone shape and size with and without allometric
scaling. In contrast to the results from association mapping of quantitative
traits in humans and domesticated plants, we find that across dog breeds, a
small number of quantitative trait loci (≤3) explain the majority of
phenotypic variation for most of the traits we studied. In addition, many
genomic regions show signatures of recent selection, with most of the highly
differentiated regions being associated with breed-defining traits such as body
size, coat characteristics, and ear floppiness. Our results demonstrate the
efficacy of mapping multiple traits in the domestic dog using a database of
genotyped individuals and highlight the important role human-directed selection
has played in altering the genetic architecture of key traits in this important
species. 相似文献
110.
Drosophila perlecan modulates FGF and hedgehog signals to activate neural stem cell division 总被引:3,自引:0,他引:3
Park Y Rangel C Reynolds MM Caldwell MC Johns M Nayak M Welsh CJ McDermott S Datta S 《Developmental biology》2003,253(2):247-257
Mutations in the Drosophila trol gene cause cell cycle arrest of neuroblasts in the larval brain. Here, we show that trol encodes the Drosophila homolog of Perlecan and regulates neuroblast division by modulating both FGF and Hh signaling. Addition of human FGF-2 to trol mutant brains in culture rescues the trol proliferation phenotype, while addition of a MAPK inhibitor causes cell cycle arrest of the regulated neuroblasts in wildtype brains. Like FGF, Hh activates stem cell division in the larval brain in a Trol-dependent fashion. Coimmunoprecipitation studies are consistent with interactions between Trol and Hh and between mammalian Perlecan and Shh that are not competed with heparin sulfate. Finally, analyses of mutations in trol, hh, and ttv suggest that Trol affects Hh movement. These results indicate that Trol can mediate signaling through both of the FGF and Hedgehog pathways to control the onset of stem cell proliferation in the developing nervous system. 相似文献