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    ABSTRACT: In our recent paper, we demonstrated that the hypervirulence exhibited by a lineage of the fatal fungal pathogen Cryptococcus gattii is associated with its mitochondrial gene expression and an unusual mitochondrial morphology. As an important organelle, the mitochondrion has been linked to various cellular activities, but its role in modulating virulence of pathogens remains unclear. In this addendum, the potential role of mitochondria in determining virulence in eukaryotic pathogens is discussed along with future experiments that may lead to an improved understanding of this topic.
    Virulence 10/2014; 1(3):197-201. DOI:10.4161/viru.1.3.11053
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    ABSTRACT: Currently, there are relatively few tasks suitable for testing planned problem solving in children. We presented 4- to 10-year-old children (N = 172) with two planning tasks (sequential planning and advance planning) using the paddle-box apparatus, which was originally designed to investigate the planning skills of nonhuman apes. First, we were interested in the development of children’s performance in the two tasks and whether the strategies children used to succeed differed among age groups. Performance improved significantly across age groups in both tasks. Strategies for success in the advance planning task differed among age groups, with 4- and 5-year-olds performing more excess actions, and a greater proportion of irrelevant excess actions, than older children. Findings are discussed in relation to the development of performance in tower tasks, which are a commonly used test of planning ability in humans. Second, based on previous findings with apes, we predicted that introducing measures to reduce the inhibitory demands of the advance planning task would improve children’s performance. Therefore, in this study we introduced two methodological alterations that have been shown to improve children’s performance in other tasks with inhibitory demands: (a) imposing a short delay before a child is allowed to act and (b) replacing reward items with symbolic tokens. Surprisingly, neither of these measures improved the performance of children in any of the age groups, suggesting that, contrary to our prediction, inhibitory control might not be a key performance-limiting factor in the advance planning paddle-box task.
    Journal of Experimental Child Psychology 09/2014; 125. DOI:10.1016/j.jecp.2014.02.006
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    ABSTRACT: The common Ser326Cys polymorphism in the base excision repair protein 8-oxoguanine glycosylase 1 is associated with a reduced capacity to repair oxidative DNA damage particularly under conditions of intracellular oxidative stress and there is evidence that Cys326-OGG1 homozygous individuals have increased susceptibility to specific cancer types. Indirect biochemical studies have shown that reduced repair capacity is related to OGG1 redox modification and also possibly OGG1 dimer formation. In the current study we have used bimolecular fluorescence complementation to study for the first time a component of the base excision repair pathway and applied it to visualise accumulation of Cys326-OGG1 protein complexes in the native cellular environment. Fluorescence was observed both within and around the cell nucleus, was shown to be specific to cells expressing Cys326-OGG1 and only occurred in cells under conditions of cellular oxidative stress following depletion of intracellular glutathione levels by treatment with buthionine sulphoximine. Furthermore, OGG1 complex formation was inhibited by incubation of cells with the thiol reducing agents β-mercaptoethanol and dithiothreitol and the antioxidant dimethylsulfoxide indicating a causative role for oxidative stress in the formation of OGG1 cellular complexes. In conclusion, this study has provided for the first time evidence of redox sensitive Cys326-OGG1 protein accumulation in cells under conditions of intracellular oxidative stress that may be related to the previously reported reduced repair capacity of Cys326-OGG1 specifically under conditions of oxidative stress.
    Biochemical and Biophysical Research Communications 03/2014; 447(1). DOI:10.1016/j.bbrc.2014.03.044
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    ABSTRACT: The common Ser326Cys polymorphism in the base excision repair protein 8-oxoguanine glycosylase 1 isassociated with a reduced capacity to repair oxidative DNA damage particularly under conditions of intracellular oxidative stress and there is evidence that Cys326-OGG1 homozygous individuals have increased susceptibility to specific cancer types. Indirect biochemical studies have shown that reduced repair capacity is related to OGG1 redox modification and also possibly OGG1 dimer formation. In the current study we have used bimolecular fluorescence complementation to study for the first time a component of the base excision repair pathway and applied it to visualise the accumulation of Cys326-OGG1 protein complexes in the native cellular environment. Fluorescence was observed both withinand around the cell nucleus,was shown to be specific to cells expressing Cys326-OGG1 and only occurred in cells under conditions of cellular oxidative stress following depletion of intracellular glutathionelevels by treatment with BSOFurthermore, OGG1 complex formation was inhibited by incubation of cells with the thiol reducing agents β-mercaptoethanol and dithiothreitol and the antioxidant dimethylsulfoxide indicating a causative role for oxidative stress in the formation of OGG1 cellular complexes. In conclusion, this study has provided for the first time evidence of redox sensitive Cys326-OGG1 proteinaccumulation in cells under conditions of intracellular oxidative stress that may be related to the previously reported reduced repair capacity of Cys326-OGG1 specifically under conditions of oxidative stress.
    Biochemical and Biophysical Research Communications 01/2014;
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    ABSTRACT: We know that even young children are proficient tool users, but until recently, little was known about how they make tools. Here, we will explore the concepts underlying tool making, and the kinds of information and putative cognitive abilities required for children to manufacture novel tools. We will review the evidence for novel tool manufacture from the comparative literature and present a growing body of data from children suggesting that innovation of the solution to a problem by making a tool is a much more challenging task than previously thought. Children's difficulty with these kinds of tasks does not seem to be explained by perseveration with unmodified tools, difficulty with switching to alternative strategies, task pragmatics or issues with permission. Rather, making novel tools (without having seen an example of the required tool within the context of the task) appears to be hard, because it is an example of an 'ill-structured problem'. In this type of ill-structured problem, the starting conditions and end goal are known, but the transformations and/or actions required to get from one to the other are not specified. We will discuss the implications of these findings for understanding the development of problem-solving in humans and other animals.
    Philosophical Transactions of The Royal Society B Biological Sciences 11/2013; 368(1630):20120409. DOI:10.1098/rstb.2012.0409
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    ABSTRACT: Flavonoids are group of plant-derived hydroxylated polycyclic molecules found in fruit and vegetables. They are known to bio-accumulate within humans and are believed to have beneficial health effects including cancer chemo-protection. One mechanism that has been proposed to explain this is that they are able to induce apoptosis in cancer cells by inhibiting a variety of kinases and also the Ca(2+) ATPase. An investigation into the mechanism of inhibition of 3 flavonoids, quercetin, galangin and 3,6 dihydroxyflavone (3,6-DHF) was undertaken. Each inhibited the Ca(2+) ATPase with Ki values of 8.7 μM, 10.3 μM and 5.4 μM, respectively, showing cooperative inhibition with n~2. Given their similar structures, the flavonoids showed several differences in their mechanisms of inhibition. All three flavonoids stabilized the ATPase in the E1 conformation and reduced [(32) P]-ATP binding. However, both galangin and 3,6-DHF increased Ca(2+) affinity to the ATPase by decreasing the Ca(2+) -dissociation rate constant, while quercetin had little effect. Ca(2+) -induced changes in tryptophan fluorescence levels were reduced in the presence of 3,6-DHF and galangin (but not with quercetin), indicating that Ca(2+) -associated changes within the transmembrane helices are altered. Both galangin and quercetin reduced the rates of ATP-dependent phosphorylation and dephosphorylation, while 3,6-DHF did not. Modelling studies suggest that flavonoids could potentially bind to two sites, one directly where nucleotides bind within ATP binding site and the other at a site close by. We hypothesise that interactions of these two neighbouring sites may account for both the cooperative inhibition and the multimode mechanisms of action seen with related flavonoids. This article is protected by copyright. All rights reserved.
    FEBS Journal 11/2013; 281(3). DOI:10.1111/febs.12621
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    ABSTRACT: The production of recombinant proteins is crucial for both the development of new protein drugs and the structural determination of drug targets. As such, recombinant protein production has a major role in drug development. Bacterial hosts are commonly used for the production of recombinant proteins, accounting for approximately 30% of current biopharmaceuticals on the market. In this review, I introduce fundamental concepts in recombinant protein production in bacteria, from drug development to production scales. Recombinant protein production processes can often fail, but how can this failure be minimised to deliver rapidly maximum yields of high-quality protein and so accelerate drug discovery?
    Drug discovery today 11/2013; 19(5). DOI:10.1016/j.drudis.2013.11.008
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    ABSTRACT: There is now considerable evidence that climate change is disrupting the phenology of key pollinator species. The recently reported UK winter activity of the bumblebee Bombus terrestris brings a novel set of thermal challenges to bumblebee workers that would typically only be exposed to summer conditions. Here we assess the ability of workers to survive acute and chronic cold stress (via lower lethal temperatures and lower lethal times at 0°C), the capacity for rapid cold hardening (RCH) and the influence of diet (pollen versus nectar consumption) on supercooling points (SCP). Comparisons are made with chronic cold stress indices and SCPs in queen bumblebees. Results showed worker bees were able to survive acute temperatures likely to be experienced in a mild winter, with queens significantly more tolerant to chronic cold temperature stress. The first evidence of RCH in any Hymenoptera is shown. In addition, dietary manipulation indicated the consumption of pollen significantly increased SCP temperature. These results are discussed in the light of winter active bumblebees and climate change.
    PLoS ONE 11/2013; 8(11):e80061. DOI:10.1371/journal.pone.0080061
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    ABSTRACT: Progress in microbiology has always been driven by technological advances, ever since Antonie van Leeuwenhoek discovered bacteria by making an improved compound microscope. Yet until very recently, we have not been able to identify microbes and record their mostly invisible activities such as nutrient consumption or toxin production on the level of the single cell, not even in the laboratory. This is now changing with the rapid rise of exciting new technologies for single-cell microbiology (1, 2), which enables microbiologists to do what plant and animal ecologists have been doing for a long time: observe who does what, when, where and next to whom. Single cells taken from the environment can be identified and even their genome sequenced. Ex situ, their size, elemental and biochemical composition, and other characteristics, can be measured with high-throughput and cells sorted accordingly. Even better, individual microbes can be observed in situ with a range of novel microscopic and spectroscopic methods, enabling localization, identification or functional characterization of cells in a natural sample, combined with detecting uptake of labeled compounds. Alternatively, they can be placed into fabricated microfluidic environments, where they can be positioned, exposed to stimuli, monitored, and their interactions controlled "in microfluido". By introducing genetically engineered reporter cells into a fabricated landscape or a microcosm taken from nature, their reproductive success or activity can be followed, or their sensing of their local environment recorded.
    Proceedings of the National Academy of Sciences 11/2013; 110(45):18027-8. DOI:10.1073/pnas.1317472110
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    ABSTRACT: Phytoplankton exudates play an important role in pelagic ecology and biogeochemical cycles of elements. Exuded compounds fuel the microbial food web and often encompass bioactive secondary metabolites like sex pheromones, allelochemicals, antibiotics, or feeding attractants that mediate biological interactions. Despite this importance, little is known about the bioactive compounds present in phytoplankton exudates. We report a stable-isotope metabolic footprinting method to characterise exudates from aquatic autotrophs. Exudates from 13C-enriched alga were concentrated by solid phase extraction and analysed by high-resolution Fourier transform ion cyclotron resonance mass spectrometry. We used the harmful algal bloom forming dinoflagellate Alexandrium tamarense to prove the method. An algorithm was developed to automatically pinpoint just those metabolites with highly 13C-enriched isotope signatures, allowing us to discover algal exudates from the complex seawater background. The stable-isotope pattern (SIP) of the detected metabolites then allowed for more accurate assignment to an empirical formula, a critical first step in their identification. This automated workflow provides an effective way to explore the chemical nature of the solutes exuded from phytoplankton cells and will facilitate the discovery of novel dissolved bioactive compounds.
    Marine Drugs 11/2013; 11(11):4158-75. DOI:10.3390/md11114158
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