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    ABSTRACT: Mascara is a mild irritant that causes a range of medical problems. Animal models to predict ocular irritation have, however, been questioned at a number of levels, and there is a continued need to develop in vitro testing methods. We assess changes in an easily quantifiable attribute, ciliated protozoan growth rate, as a sensitive, sub-lethal measure. We provide evidence that two easily cultured protozoa (Paramecium caudatum, Blepharisma japonicum) should be considered as models to assess ocular irritancy (and possibly cosmetics in general) and establish the groundwork for such studies to be applied at a more commercial level. We do this by developing a bioassay for mascara toxicity and indicate the low-cost (after equipment is purchase, on the order of $100s) and the ease of performing such tests (able to be conducted by undergraduate students), as a consideration for their future commercial application. Specifically, we test six, randomly chosen, commercial mascara products against a control (as treatments) and reveal through ANOVA (n = 6, α=0.05) significant differences in the specific growth rate to treatments (for both protozoa): we first examined dose-dependence of responses, revealing that there was a need to conduct preliminary work to determine appropriate levels for sub-lethal responses. We then show that some products resulted in mortality at high concentrations, others decreased growth rate by >50% (compared to the control), while others had no significant effect, compared to the control. Now that we have provided a novel, quick, and inexpensive means to assess mascara, the next step is to validate these ciliate-bioassays by comparison with animal testing and epidemiological studies, which is beyond the scope of this fundamental "proof-of-concept" study. This article is protected by copyright. All rights reserved.
    International journal of cosmetic science 11/2013;
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    ABSTRACT: AMPLE is a program developed for clustering and truncating ab initio protein structure predictions into search models for molecular replacement. Here, it is shown that its core cluster-and-truncate methods also work well for processing NMR ensembles into search models. Rosetta remodelling helps to extend success to NMR structures bearing low sequence identity or high structural divergence from the target protein. Potential future routes to improved performance are considered and practical, general guidelines on using AMPLE are provided.
    Acta Crystallographica Section D Biological Crystallography 11/2013; 69(Pt 11):2194-201.
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    ABSTRACT: In multicellular organisms, tight regulation of gene expression ensures appropriate tissue and organismal growth throughout development. Reversible phosphorylation of the RNA Polymerase II (RNAPII) C-terminal domain (CTD) is critical for the regulation of gene expression states, but how phosphorylation is actively modified in a developmental context remains poorly understood. Protein phosphatase 1 (PP1) is one of several enzymes that has been reported to dephosphorylate the RNAPII CTD. However, PP1's contribution to transcriptional regulation during animal development and the mechanisms by which its activity is targeted to RNAPII have not been fully elucidated. Here we show that the Drosophila orthologue of the PP1 Nuclear Targeting Subunit (dPNUTS) is essential for organismal development and is cell autonomously required for growth of developing tissues. The function of dPNUTS in tissue development depends on its binding to PP1, which we show is targeted by dPNUTS to RNAPII at many active sites of transcription on chromosomes. Loss of dPNUTS function or specific disruption of its ability to bind PP1 results in hyperphosphorylation of the RNAPII CTD in whole animal extracts and on chromosomes. Consistent with dPNUTS being a global transcriptional regulator, we find that loss of dPNUTS function affects the expression of the majority of genes in developing 1(st) instar larvae, including those that promote proliferative growth. Together, these findings shed light on the in vivo role of the PNUTS-PP1 holoenzyme and its contribution to the control of gene expression during early Drosophila development.
    PLoS Genetics 10/2013; 9(10):e1003885.
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    ABSTRACT: The availability of thousands of genome sequences of bacterial pathogens poses a particular challenge because each genome contains hundreds of genes of unknown function (FUN). How can we easily discover which FUN genes encode important virulence factors? One solution is to combine two different functional genomic approaches. First, transcriptomics identifies bacterial FUN genes that show differential expression during the process of mammalian infection. Second, global mutagenesis identifies individual FUN genes that the pathogen requires to cause disease. The intersection of these datasets can reveal a small set of candidate genes most likely to encode novel virulence attributes. We demonstrate this approach with the Salmonella infection model, and propose that a similar strategy could be used for other bacterial pathogens.
    Current opinion in microbiology 09/2013;
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    ABSTRACT: Queuing up: Molecular orientation within macroscopically aligned nanotubes of the peptide AAAAAAK can be studied by solid-state NMR and IR spectroscopy. Line shape analysis of the NMR spectra indicates that the peptide NH bonds are tilted 65-70° relative to the nanotube long axis. Re-evaluation of earlier X-ray fiber diffraction data suggests that the peptide molecules are hydrogen-bonded in a helical arrangement along the nanotube axis.
    Angewandte Chemie International Edition 08/2013;
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    ABSTRACT: The giant cytoskeletal kinases of the titin-like family are emerging as key mediators of stretch-sensing in muscle. It is thought that their elastic conformational deformation during muscle function regulates both their catalysis and the recruitment of regulatory proteins to signalosomes that assemble in their vicinity. In the present article, we discuss the speciation of mechanosensory mechanisms in titin-like kinases, their scaffolding properties and the kinase/pseudokinase domain variations that define a rich functional diversity across the family.
    Biochemical Society Transactions 08/2013; 41(4):1066-71.
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    ABSTRACT: Recent studies of proteins containing kinase-like domains that lack catalytic residue(s) classically required for phosphotransfer, termed pseudokinases, have uncovered important roles in cell signalling across the kingdoms of life. Additionally, mutations within pseudokinase domains are known to underlie human diseases, suggesting that these proteins may represent new and unexplored therapeutic targets. To date, few pseudokinases have been studied in intricate detail, but as described in the present article and in the subsequent papers in this issue of Biochemical Society Transactions, several new studies have provided an advanced template and an improved framework for interrogating the roles of pseudokinases in signal transduction. In the present article, we review landmarks in the establishment of this field of study, highlight some experimental challenges and propose a simple scheme for definition of these domains based on their primary sequences, rather than experimentally defined nucleotide-binding or catalytic activities.
    Biochemical Society Transactions 08/2013; 41(4):969-74.
  • EMBO Reports 07/2013;
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    ABSTRACT: The Proteomics Standards Initiative has recently released the mzIdentML data standard for representing peptide and protein identification results, for example created by a search engine. When a new standard format is produced, it is important that software tools are available that make it straightforward for laboratory scientists to use it routinely, and for bioinformaticians to embed support in their own tools. Here we report the release of several open source Java-based software packages, based around mzIdentML: ProteoIDViewer, mzidLibrary and mzidValidator. The ProteoIDViewer is a desktop application allowing users to visualise mzIdentML-formatted results originating from any appropriate identification software, supporting visualisation of all the features of the mzIdentML format. The mzidLibrary is a software library, containing routines for importing data from external search engines, post-processing identification data (such as false discovery rate calculations), combining results from multiple search engines, performing protein inference, setting identification thresholds and exporting results from mzIdentML to plain text files. The mzidValidator is able to process files and report warnings or errors if files are not correctly formatted or contain some semantic error. We anticipate that these developments will simplify adoption of the new standard in proteomics laboratories and integration of mzIdentML into other software tools. All three tools are freely available in the public domain from: http://code.google.com/p/mzidentml-viewer/ (ProteoIDViewer), http://code.google.com/p/mzidentml-lib/ (mzidLibrary) and http://code.google.com/p/psi-pi/downloads/list (mzidValidator).
    Molecular &amp Cellular Proteomics 06/2013;
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    ABSTRACT: Extended breath-hold endurance enables the exploitation of the aquatic niche by numerous mammalian lineages and is accomplished by elevated body oxygen stores and adaptations that promote their economical use. However, little is known regarding the molecular and evolutionary underpinnings of the high muscle myoglobin concentration phenotype of divers. We used ancestral sequence reconstruction to trace the evolution of this oxygen-storing protein across a 130-species mammalian phylogeny and reveal an adaptive molecular signature of elevated myoglobin net surface charge in diving species that is mechanistically linked with maximal myoglobin concentration. This observation provides insights into the tempo and routes to enhanced dive capacity evolution within the ancestors of each major mammalian aquatic lineage and infers amphibious ancestries of echidnas, moles, hyraxes, and elephants, offering a fresh perspective on the evolution of this iconic respiratory pigment.
    Science 06/2013; 340(6138):1234192.
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