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51.
Mohamed S. Gomaa Andrew S.T. Lim S.C. Wilson Lau Ann-Marie Watts Nicola A. Illingworth Caroline E. Bridgens Gareth J. Veal Christopher P.F. Redfern Andrea Brancale Jane L. Armstrong Claire Simons 《Bioorganic & medicinal chemistry》2012,20(20):6080-6088
The role of all-trans-retinoic acid (ATRA) in the development and maintenance of many epithelial and neural tissues has raised great interest in the potential of ATRA and related compounds (retinoids) as pharmacological agents, particularly for the treatment of cancer, skin, neurodegenerative and autoimmune diseases. The use of ATRA or prodrugs as pharmacological agents is limited by a short half-life in vivo resulting from the activity of specific ATRA hydroxylases, CYP26 enzymes, induced by ATRA in liver and target tissues. For this reason retinoic acid metabolism blocking agents (RAMBAs) have been developed for treating cancer and a wide range of other diseases.The synthesis, CYP26A1 inhibitory activity and molecular modeling studies of novel methyl 3-[4-(arylamino)phenyl]-3-(azole)-2,2-dimethylpropanoates are presented. From this series of compounds clear SAR can be derived for 4-substitution of the phenyl ring with electron-donating groups more favourable for inhibitory activity. Both the methylenedioxyphenyl imidazole (17, IC50 = 8 nM) and triazole (18, IC50 = 6.7 nM) derivatives were potent inhibitors with additional binding interactions between the methylenedioxy moiety and the CYP26 active site likely to be the main factor. The 6-bromo-3-pyridine imidazole 15 (IC50 = 5.7 nM) was the most active from this series compared with the standards liarozole (IC50 = 540 nM) and R116010 (IC50 = 10 nM). 相似文献
52.
Abdel Ayadi Marie-Christine Birling Joanna Bottomley James Bussell Helmut Fuchs Martin Fray Valérie Gailus-Durner Simon Greenaway Richard Houghton Natasha Karp Sophie Leblanc Christoph Lengger Holger Maier Ann-Marie Mallon Susan Marschall David Melvin Hugh Morgan Guillaume Pavlovic Ed Ryder William C. Skarnes Mohammed Selloum Ramiro Ramirez-Solis Tania Sorg Lydia Teboul Laurent Vasseur Alison Walling Tom Weaver Sara Wells Jacqui K. White Allan Bradley David J. Adams Karen P. Steel Martin Hrabě de Angelis Steve D. Brown Yann Herault 《Mammalian genome》2012,23(9-10):600-610
Two large-scale phenotyping efforts, the European Mouse Disease Clinic (EUMODIC) and the Wellcome Trust Sanger Institute Mouse Genetics Project (SANGER-MGP), started during the late 2000s with the aim to deliver a comprehensive assessment of phenotypes or to screen for robust indicators of diseases in mouse mutants. They both took advantage of available mouse mutant lines but predominantly of the embryonic stem (ES) cells resources derived from the European Conditional Mouse Mutagenesis programme (EUCOMM) and the Knockout Mouse Project (KOMP) to produce and study 799 mouse models that were systematically analysed with a comprehensive set of physiological and behavioural paradigms. They captured more than 400 variables and an additional panel of metadata describing the conditions of the tests. All the data are now available through EuroPhenome database (www.europhenome.org) and the WTSI mouse portal (http://www.sanger.ac.uk/mouseportal/), and the corresponding mouse lines are available through the European Mouse Mutant Archive (EMMA), the International Knockout Mouse Consortium (IKMC), or the Knockout Mouse Project (KOMP) Repository. Overall conclusions from both studies converged, with at least one phenotype scored in at least 80?% of the mutant lines. In addition, 57?% of the lines were viable, 13?% subviable, 30?% embryonic lethal, and 7?% displayed fertility impairments. These efforts provide an important underpinning for a future global programme that will undertake the complete functional annotation of the mammalian genome in the mouse model. 相似文献
53.
Ann-Marie?MallonEmail author Vivek?Iyer David?Melvin Hugh?Morgan Helen?Parkinson Steve?D.?M.?Brown Paul?Flicek William?C.?Skarnes 《Mammalian genome》2012,23(9-10):641-652
The International Mouse Phenotyping Consortium (IMPC) (http://www.mousephenotype.org) will reveal the pleiotropic functions of every gene in the mouse genome and uncover the wider role of genetic loci within diverse biological systems. Comprehensive informatics solutions are vital to ensuring that this vast array of data is captured in a standardised manner and made accessible to the scientific community for interrogation and analysis. Here we review the existing EuroPhenome and WTSI phenotype informatics systems and the IKMC portal, and present plans for extending these systems and lessons learned to the development of a robust IMPC informatics infrastructure. 相似文献
54.
Michelle M. Simon Ann-Marie Mallon Gareth R. Howell Laura G. Reinholdt 《Mammalian genome》2012,23(9-10):499-513
Phenotype-driven approaches in mice are powerful strategies for the discovery of genes and gene functions and for unravelling complex biological mechanisms. Traditional methods for mutation discovery are reliable and robust, but they can also be laborious and time consuming. Recently, high-throughput sequencing (HTS) technologies have revolutionised the process of forward genetics in mice by paving the way to rapid mutation discovery. However, successful application of HTS for mutation discovery relies heavily on the sequencing approach employed and strategies for data analysis. Here we review current HTS applications and resources for mutation discovery and provide an overview of the practical considerations for HTS implementation and data analysis. 相似文献
55.
A single gamma-carboxyglutamic acid residue in a novel cysteine-rich secretory protein without propeptide 总被引:1,自引:0,他引:1
Gamma-glutamyl carboxylase catalyzes the modification of specific glutamyl residues to gamma-carboxyglutamyl (Gla) residues in precursor proteins that possess the appropriate gamma-carboxylation recognition signal within the propeptide region. We describe the immunopurification and first biochemical characterization of an invertebrate high molecular weight Gla-containing protein with homologues in mammals. The protein, named GlaCrisp, was isolated from the venom of the marine cone snail Conus marmoreus. GlaCrisp gave intense signals in Western blot experiments employing the Gla-specific antibody M3B, and the presence of Gla was chemically confirmed by amino acid analysis after alkaline hydrolysis. Characterization of a full-length cDNA clone encoding GlaCrisp deduced a precursor containing an N-terminal signal peptide but, unlike other Gla-containing proteins, no apparent propeptide. The predicted mature protein of 265 amino acid residues showed considerable sequence similarity to the widely distributed cysteine-rich secretory protein family and closest similarity (65% identity) to the recently described substrate-specific protease Tex31. In addition, two cDNA clones encoding the precursors of two isoforms of GlaCrisp were identified. The predicted precursor isoforms differed at three amino acid positions (-6, 9, and 25). Analysis by Edman degradation and nanoelectrospray ionization mass spectrometry, before and after methyl esterfication, identified a Gla residue at amino acid position 9 in GlaCrisp. This is the first example of a Gla-containing protein without an obvious gamma-carboxylation recognition site. The results define a new class of Gla proteins and support the notion that gamma-carboxylation of glutamyl residues is phylogenetically older than blood coagulation and the vertebrate lineage. 相似文献
56.
The immune response affects learning and memory in insects. Given this and the known fitness costs of both the immune system and learning, does an evolutionary trade-off exist between these two systems? We tested this by measuring the learning ability of 12 bumble-bee (Bombus terrestris) colonies in a free-flying paradigm. We then tested their immune response using the zone of inhibition assay. We found a positive relationship between colony learning performance and immune response, that is, fast-learning colonies also show high levels of antimicrobial activity. We conclude that there is no a priori reason to demand an evolutionary relationship between two traits that are linked physiologically. 相似文献
57.
Nicola J. Lawrence Liang Song Jennifer Doig Ann-Marie Ritchie David G. Brownstein David W. Melton 《DNA Repair》2009,8(5):664-671
Topical application of thymidine dinucleotides (pTpT) provides some protection against the effects of UV on the skin, however, many details of the protective mechanism have yet to be elucidated. We have used mice with an epidermis-specific knockout for the nucleotide excision repair gene, Ercc1, to investigate the mechanisms of protection. pTpT offered no protection against the pronounced UV-induced short-term erythema and skin thickening responses that are characteristic of DNA repair-deficient skin. It also had no effect on UV-induced apoptosis in Ercc1-deficient cultured keratinocytes. However, in these short-term experiments in both skin and keratinocyte culture pTpT did cause a slight reduction in proliferation. pTpT application during a chronic UV irradiation protocol provided some protection from UVB-induced skin carcinogenesis in epidermis-specific Ercc1 knockout mice. The median tumour free survival time was increased in the pTpT-treated group and treated animals had fewer tumours. In addition, pTpT-treated animals developed fewer large inwardly growing skin lesions than untreated animals. Furthermore, the proliferation response was reduced in chronically irradiated, non-lesional pTpT-treated skin. We conclude that cancer protection by pTpT in our mice is not modulated by an upregulation of DNA repair, as protection appears to be independent of a functional nucleotide excision repair pathway. We hypothesise instead that protection by pTpT is due to a reduction in epidermal proliferation. 相似文献
58.
Ann-Marie Rajalin Piia Aarnisalo 《Biochemical and biophysical research communications》2010,396(2):477-5738
The orphan nuclear receptor estrogen-related receptor-α (ERRα) has been reported to have both a positive and a negative regulatory role in osteoblastic and adipocytic differentiation. We have studied the role of ERRα in osteoblastic and adipogenic differentiation of mesenchymal stem cells. Bone marrow mesenchymal stem cells were isolated from ERRα deficient mice and their differentiation capacities were compared to that of the wild-type cells. ERRα deficient cultures displayed reduced cellular proliferation, osteoblastic differentiation, and mineralization. In the complementary experiment, overexpression of ERRα in MC3T3-E1 cells increased the expression of osteoblastic markers and mineralization. Alterations in the expression of bone sialoprotein (BSP) may at least partially explain the effects on mineralization as BSP expression was reduced in ERRα deficient MSCs and enhanced upon ERRα overexpression in MC3T3-E1 cells. Furthermore, a luciferase reporter construct driven by the BSP promoter was efficiently transactivated by ERRα. Under adipogenic conditions, ERRα deficient cultures displayed reduced adipocytic differentiation. Our data thus propose a positive role for ERRα in osteoblastic and adipocytic differentiation. The variability in the results yielded in the different studies implies that ERRα may play different roles in bone under different physiological conditions. 相似文献
59.
Metalloproteins require soluble metal ions such as zinc to properly fold into their native and active state to maintain stability and biological activity. When protein products are produced during microbial fermentations, metals are made available to the metalloproteins via nutrient supplements. During the production at the manufacturing-scale of a recombinant product that required zinc as a cofactor, an insoluble precipitate formed in the preparation tank after steam sterilization of the nutrient feed containing methionine, glycerophosphate, and zinc sulfate (MGZ). The precipitated nutrient feed was believed to be the cause for not enough zinc delivered to the production fermentor, leading to poor product assembly and stabilization. This article explores several analytical techniques such as capillary zone electrophoresis, inductively coupled plasma and phosphate molybdate assays to identify and quantify the composition of the precipitate. Our results show that the glycerophosphate component of the combined MGZ nutrient feed contains inorganic phosphate, which precipitates zinc from the feed media. 相似文献
60.
Graciela Diap John Amuasi Isaac Boakye Ann-Marie Sevcsik Bernard Pecoul 《Malaria journal》2010,9(Z1):S1
At a recent meeting (Sept 18, 2009) in which reasons for the limited access to artemisinin-based combination therapy (ACT) in sub-Saharan Africa were discussed, policy and market surveys on anti-malarial drug availability and accessibility in Burundi and Sierra Leone were presented in a highly interactive brainstorming session among key stakeholders across private, public, and not-for-profit sectors. The surveys, the conduct of which directly involved the national malaria control programme managers of the two countries, provides the groundwork for evidence-based policy implementation. The results of the surveys could be extrapolated to other countries with similar socio-demographic and malaria profiles. The meeting resulted in recommendations on key actions to be taken at the global, national, and community level for better ACT accessibility.At the global level, both public and private sectors have actions to take to strengthen policies that lead to the replacement of loose blister packs with fixed-dose ACT products, develop strategies to ban inappropriate anti-malarials and regulate those bans, and facilitate technology and knowledge transfer to scale up production of fixed-dose ACT products, which should be readily available and affordable to those patients who are in the greatest need of these medicines.At the national level, policies that regulate the anti-malarial medicines market should be enacted and enforced. The public sector, including funding donors, should participate in ensuring that the private sector is engaged in the ACT implementation process. Research similar to the surveys discussed is important for other countries to develop and evaluate the right incentives at a local level.At the community level, community outreach and education about appropriate preventive and treatment measures must continue and be strengthened, with service delivery systems developed within both public and private sectors, among other measures, to decrease access to ineffective and inappropriate anti-malarial medicines.What was clear during the meeting is that continuing commitment, strengthened interaction and transparency among various stakeholders, with focus on communities, national governments, and evidence-based policy and action are the only way to sustainably address the control of malaria, a disease which continues to have a significant health and socio-economic impact worldwide, particularly in sub-Saharan Africa.Details on the methodology employed in carrying out the studies discussed at this meeting, as well as more detailed results, data analysis and discussion of the studies are soon to be published. 相似文献