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51.
Slater MJ Andrews DM Baker G Bethell SS Carey S Chaignot H Clarke B Coomber B Ellis M Good A Gray N Hardy G Jones P Mills G Robinson E 《Bioorganic & medicinal chemistry letters》2002,12(23):3359-3362
Using a pyrrolidine-5,5-trans-lactam template, we have designed small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease. Compound 11a, with an alpha-ethyl P1 substituent and a Boc-valine substituent at the pyrrolidine nitrogen, has an IC(50)=30 microM. 相似文献
52.
A Jain M Sundriyal S Roshnibala R Kotoky PB Kanjilal HB Singh RC Sundriyal 《Journal of ethnobiology and ethnomedicine》2011,7(1):29
Background
The wetlands of the North East India fall among the global hotspots of biodiversity. However, they have received very little attention with relation to their intrinsic values to human kind; therefore their conservation is hardly addressed. These wetlands are critical for the sustenance of the tribal communities.Methods
Field research was conducted during 2003 to 2006 in seven major wetlands of four districts of Manipur state, Northeast India (viz. Imphal-East, Imphal-West, Thoubal, and Bishnupur). A total of 224 wetland-plant-collectors were interviewed for the use and economics of species using semi-structured questionnaires and interview schedules. Imphal, Bishenpur and Thoubal markets were investigated in detail for influx and consumption pattern of these plants. The collectors were also inquired for medicinal use of wetland species. Nutritive values of 21 species were analyzed in laboratory. The vouchers were collected for all the species and deposited in the CSIR-NEIST (Formerly Regional Research Laboratory), Substation, Lamphelpat, Imphal, Manipur, India.Results
We recorded 51 edible wetland species used by indigenous people for food and medicinal purposes. Thirty eight species had high medicinal values and used in the traditional system to treat over 22 diseases. At least 27 species were traded in three markets studied (i.e. Imphal, Thoubal and Bishenpur), involving an annual turnover of 113 tons of wetland edible plants and a gross revenue of Rs. 907, 770/- (US$1 = Rs. 45/-). The Imphal market alone supplies 60% of the total business. Eighty per cent of the above mentioned species are very often used by the community. The community has a general opinion that the availability of 45% species has depleted in recent times, 15 species need consideration for conservation while another 7 species deserved immediate protection measures. The nutrient analysis showed that these species contribute to the dietary balance of tribal communities.Conclusions
Considering the importance of wild wetland plants in local sustenance, it is suggested to protect their habitats, develop domestication protocols of selected species, and build programs for the long-term management of wetland areas by involving local people. Some medicinal plants may also be used to develop into modern medicines.53.
54.
Richa Singh Alexander J Mackay Anant RC Patel Davinder S Garcha Beverly S Kowlessar Simon E Brill Louise E Donnelly Peter J Barnes Gavin C Donaldson Jadwiga A Wedzicha 《Respiratory research》2014,15(1)
Background
There has been increasing interest in the use of newer, culture-independent techniques to study the airway microbiome of COPD patients. We investigated the relationships between the three common potentially pathogenic microorganisms (PPMs) Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis, as detected by quantitative PCR (qPCR), and inflammation and health status in stable patients in the London COPD cohort.Methods
We prospectively collected sputum, serum and plasma samples for analysis of airway bacterial presence and load, and airway and systemic inflammation from 99 stable COPD patients between January 2011 and October 2012. Health status was measured with St George’s Respiratory Questionnaire and COPD Assessment Test.Results
Airway inflammation and plasma fibrinogen, but not C-reactive protein, were greater in samples with PPM detection (p < 0.001, p = 0.049 and p = 0.261, respectively). Increasing total bacterial load was associated with increasing airway (p < 0.01) but not systemic inflammation (p > 0.05). Samples with high total bacterial loads had significantly higher airway inflammation than both samples without PPM detection and those with lower loads. Haemophilus influenzae presence was associated with significantly higher levels of airway but not systemic inflammation for all given pathogen loads (p < 0.05), and was significantly greater than with other PPMs. No association was observed between inflammation and health status (p > 0.05).Conclusions
Airway and systemic inflammation, as measured by fibrinogen, is greater in stable COPD patients with PPMs detected using the culture-independent qPCR technique. The airway, but not systemic inflammatory response, appears to have a total pathogen-load threshold and appears attributable to Haemophilus influenzae. However, discordance between inflammation and health status was observed.Electronic supplementary material
The online version of this article (doi:10.1186/s12931-014-0114-1) contains supplementary material, which is available to authorized users. 相似文献55.
Clint A. James Patrick DeRoy Martin Duplessis Paul J. Edwards Teddy Halmos Joannie Minville Louis Morency Sébastien Morin Bruno Simoneau Martin Tremblay Richard Bethell Michael Cordingley Jianmin Duan Louie Lamorte Alex Pelletier Daniel Rajotte Patrick Salois Sonia Tremblay Claudio F. Sturino 《Bioorganic & medicinal chemistry letters》2013,23(9):2781-2786
56.
Chan L Pereira O Reddy TJ Das SK Poisson C Courchesne M Proulx M Siddiqui A Yannopoulos CG Nguyen-Ba N Roy C Nasturica D Moinet C Bethell R Hamel M L'Heureux L David M Nicolas O Courtemanche-Asselin P Brunette S Bilimoria D Bédard J 《Bioorganic & medicinal chemistry letters》2004,14(3):797-800
Further SAR studies on the thiophene-2-carboxylic acids are reported. These studies led to the identification of a series of tertiary amides that show inhibition of both HCV NS5B polymerase in vitro and HCV subgenomic RNA replication in Huh-7 cells. Structural insights about the bioactive conformation of this class of molecules were deduced from a combination of modeling and transferred NOE (trNOE) studies. 相似文献
57.
Catalytic and framework mutations in the neuraminidase active site of influenza viruses that are resistant to 4-guanidino-Neu5Ac2en. 总被引:7,自引:3,他引:4
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Here we report the isolation of influenza virus A/turkey/Minnesota/833/80 (H4N2) with a mutation at the catalytic residue of the neuraminidase (NA) active site, rendering it resistant to the novel NA inhibitor 4-guanidino-Neu5Ac2en (GG167). The resistance of the mutant stems from replacement of one of three invariant arginines (Arg 292-->Lys) that are conserved among all viral and bacterial NAs and participate in the conformational change of sialic acid moiety necessary for substrate catalysis. The Lys292 mutant was selected in vitro after 15 passages at increasing concentrations of GG167 (from 0.1 to 1,000 microM), conditions that earlier gave rise to GG167-resistant mutants with a substitution at the framework residue Glu119. Both types of mutants showed similar degrees of resistance in plaque reduction assays, but the Lys292 mutant was more sensitive to the inhibitor in NA inhibition tests than were mutants bearing a substitution at framework residue 119 (Asp, Ala, or Gly). Cross-resistance to other NA inhibitors (4-amino-Neu5Ac2en and Neu5Ac2en) varied among mutants resistant to GG167, being lowest for Lys292 and highest for Asp119. All GG167-resistant mutants demonstrated markedly reduced NA activity, only 3 to 50% of the parental level, depending on the particular amino acid substitution. The catalytic mutant (Lys292) showed a significant change in pH optimum of NA activity, from 5.9 to 5.3. All of the mutant NAs were less stable than the parental enzyme at low pH. Despite their impaired NA activity, the GG167-resistant mutants grew as well as parental virus in Madin-Darby canine kidney cells or in embryonated chicken eggs. However, the infectivity in mice was 500-fold lower for Lys292 than for the parental virus. These findings demonstrate that amino acid substitution in the NA active site at the catalytic or framework residues, followed by multiple passages in vitro, in the presence of increasing concentrations of the NA inhibitor GG167, generates GG167-resistant viruses with reduced NA activity and decreased infectivity in animals. 相似文献
58.
The estimation of the amount of evolutionary divergence that has taken
place between two DNA coding sequences depends strongly on the degree of
constraint on amino acid replacements. If amino acid replacements are
relatively unconstrained, the individual nucleotide is the appropriate unit
of analysis and the method of Tajima and Nei can be used. If amino acid
replacements are constrained, however, this method is shown to be
inapplicable. For sequences with strong amino acid constraints, a method is
outlined analogous to the Tajima and Nei method using codons as the unit of
analysis. Only synonymous substitutions are used. Codon usage data can be
employed to estimate the necessary parameters of the calculation, or a
priori models of substitution may be employed. Sequences with significant
but intermediate constraints on amino acid replacements are, in principle,
unanalyzable.
相似文献
59.
A new synthetic route to adenosine 5'-([gamma(R)-17O,18O]-gamma-thiotriphosphate) is described which combines chemical methods for introducing the heavy oxygen isotopes and enzymic methods for achieving the enantiospecificity. This material was used as a substrate for the activation of glutamate catalyzed by glutamine synthetase from Salmonella typhimurium. Analysis of the chirality of the [16O,17O,18O]thiophosphate produced showed that the reaction proceeds with inversion of configuration on phosphorus. This result, taken together with the positional isotope exchange studies of Midelfort and Rose [Midelfort, C. F., & Rose, I.A. (1976) J. Biol. Chem. 251, 5881-5887], demonstrates that the activation of glutamate to form gamma-glutamyl phosphate proceeds by a direct "in-line" transfer of the phosphoryl group. 相似文献
60.
Ans Timmermans Melanie C. Melendrez Youry Se Ilin Chuang Nou Samon Nichapat Uthaimongkol Chonticha Klungthong Wudtichai Manasatienkij Butsaya Thaisomboonsuk Stuart D. Tyner Sareth Rith Viseth Srey Horm Richard G. Jarman Delia Bethell Nitima Chanarat Julie Pavlin Tippa Wongstitwilairoong Piyaporn Saingam But Sam El Mark M. Fukuda Sok Touch Ly Sovann Stefan Fernandez Philippe Buchy Lon Chanthap David Saunders 《PloS one》2016,11(3)