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1.  Inhibition of CXCR4–CXCL12 chemotaxis in melanoma by AMD11070 
British Journal of Cancer  2013;108(8):1634-1640.
Background:
Despite intensive research and novel adjuvant therapies, there is currently no cure for metastatic melanoma. The chemokine receptor CXCR4 controls metastasis to sites such as the liver; however, the therapeutic blockade with the existing agents has proven difficult.
Methods:
AMD11070, a novel orally bioavailable inhibitor of CXCR4, was tested for its ability to inhibit the migration of melanoma cells compared with the commonly described antagonist AMD3100.
Results:
AMD11070 abrogated melanoma cell migration and was significantly more effective than AMD3100. Importantly for the clinical context, the expression of B-RAF-V600E did not the affect the sensitivity of AMD11070.
Conclusion:
Liver-resident myofibroblasts excrete CXCL12, which is able to promote the migration of CXCR4-expressing tumour cells from the blood into the liver. Blockade of this axis by AMD11070 thus represents a novel therapeutic strategy for both B-RAF wild-type and mutated melanomas.
doi:10.1038/bjc.2013.124
PMCID: PMC3668477  PMID: 23538388
chemokine; melanoma; metastasis; CXCR4; B-RAF; AMD11070
2.  Effects of Extreme Obliquity Variations on the Habitability of Exoplanets 
Astrobiology  2014;14(4):277-291.
Abstract
We explore the impact of obliquity variations on planetary habitability in hypothetical systems with high mutual inclination. We show that large-amplitude, high-frequency obliquity oscillations on Earth-like exoplanets can suppress the ice-albedo feedback, increasing the outer edge of the habitable zone. We restricted our exploration to hypothetical systems consisting of a solar-mass star, an Earth-mass planet at 1 AU, and 1 or 2 larger planets. We verified that these systems are stable for 108 years with N-body simulations and calculated the obliquity variations induced by the orbital evolution of the Earth-mass planet and a torque from the host star. We ran a simplified energy balance model on the terrestrial planet to assess surface temperature and ice coverage on the planet's surface, and we calculated differences in the outer edge of the habitable zone for planets with rapid obliquity variations. For each hypothetical system, we calculated the outer edge of habitability for two conditions: (1) the full evolution of the planetary spin and orbit and (2) the eccentricity and obliquity fixed at their average values. We recovered previous results that higher values of fixed obliquity and eccentricity expand the habitable zone, but we also found that obliquity oscillations further expand habitable orbits in all cases. Terrestrial planets near the outer edge of the habitable zone may be more likely to support life in systems that induce rapid obliquity oscillations as opposed to fixed-spin planets. Such planets may be the easiest to directly characterize with space-borne telescopes. Key Words: Exoplanets—Habitable zone—Energy balance models. Astrobiology 14, 277–291.
doi:10.1089/ast.2013.1129
PMCID: PMC3995117  PMID: 24611714
3.  Novel Therapies for the Treatment of Advanced Prostate Cancer 
Opinion statement
In recent years, great success has been achieved on many fronts in the treatment of men with metastatic castration-resistant prostate cancer (CRPC), including novel chemotherapeutics, immunotherapies, bone microenvironment-targeted agents, and hormonal therapies. Numerous agents are currently in early-phase clinical trial development for the treatment of advanced prostate cancer. These novel therapies target several areas of prostate tumor biology, including the upregulation of androgen signaling and biosynthesis, critical oncogenic intracellular pathways, epigenetic alterations, and cancer immunology. Importantly, the characterization of the prostate cancer genome offers the potential to exploit conserved genetic alterations, which may increase the efficacy of these targeted therapies. Predictive and prognostic biomarkers are urgently needed to maximize therapeutic efficacy and safety of these promising new treatments options in prostate cancer.
doi:10.1007/s11864-012-0222-4
PMCID: PMC3591460  PMID: 23322116
Prostate cancer; Novel; Treatments; Castration-resistant; Androgen receptor; Metastatic; PI3 kinase inhibitors; Androgen synthesis inhibitors; Immunotherapies; Epigenetic; Epithelial mesenchymal transition
4.  Among-sibling differences in the phenotypes of juvenile fish depend on their location within the egg mass and maternal dominance rank 
We investigated whether among-sibling differences in the phenotypes of juvenile fish were systematically related to the position in the egg mass where each individual developed during oogenesis. We sampled eggs from the front, middle and rear thirds of the egg mass in female brown trout of known dominance rank. In the resulting juveniles, we then measured traits that are related to individual fitness: body size, social status and standard metabolic rate (SMR). When controlling for differences among females in mean egg size, siblings from dominant mothers were initially larger (and had a lower mass-corrected SMR) if they developed from eggs at the rear of the egg mass. However, heterogeneity in the size of siblings from different positions in the egg mass diminished in lower-ranking females. Location of the egg within the egg mass also affected the social dominance of the resulting juvenile fish, although the direction of this effect varied with developmental age. This study provides the first evidence of a systematic basis for among-sibling differences in the phenotypes of offspring in a highly fecund organism.
doi:10.1098/rspb.2012.2441
PMCID: PMC3574412  PMID: 23193132
maternal effects; unpredictable environments; maternal fitness
5.  A simulator for spatially extended kappa models 
Bioinformatics  2013;29(23):3105-3106.
Summary: Spatial Kappa is a simulator of models written in a variant of the rule-based stochastic modelling language Kappa, with spatial extensions.
Availability: The spatial kappa simulator is an open-source project licensed under the LGPLv3, with Java source, binaries and manual available at http://github.com/lptolik/SpatialKappa.
Contact: oksana.sorokina@ed.ac.uk
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btt523
PMCID: PMC3834793  PMID: 24021382
6.  Evolutionary expansion and anatomical specialization of synapse proteome complexity 
Nature neuroscience  2008;11(7):799-806.
Understanding the origins and evolution of synapses may provide insight into species diversity and organisation of the brain. Using comparative proteomics and genomics we examined the evolution of the postsynaptic density (PSD) and MAGUK associated signalling complexes (MASCs) underlying learning and memory. PSD/MASC orthologues found in yeast perform basic cellular functions regulating protein synthesis and structural plasticity. Striking changes in signalling complexity were observed at the yeast:metazoan and invertebrate:vertebrate boundaries, with expansion of key synapse components, notably receptors, adhesion/cytoskeletal and scaffold proteins. Proteomic comparison of Drosophila and mouse MASCs revealed species-specific adaptation with greater signalling complexity in mouse. Although synapse components were conserved amongst diverse vertebrate species, mapping mRNA and protein expression within the mouse brain showed vertebrate-specific components preferentially contributed to differences between brain regions. We propose that evolution of synapse complexity around a core proto-synapse has contributed to invertebrate–vertebrate differences and to brain specialisation.
doi:10.1038/nn.2135
PMCID: PMC3624047  PMID: 18536710
7.  Mutations in the EXT1 and EXT2 genes in Spanish patients with multiple osteochondromas 
Scientific Reports  2013;3:1346.
Multiple osteochondromas is an autosomal dominant skeletal disorder characterized by the formation of multiple cartilage-capped tumours. Two causal genes have been identified, EXT1 and EXT2, which account for 65% and 30% of cases, respectively. We have undertaken a mutation analysis of the EXT1 and EXT2 genes in 39 unrelated Spanish patients, most of them with moderate phenotype, and looked for genotype-phenotype correlations. We found the mutant allele in 37 patients, 29 in EXT1 and 8 in EXT2. Five of the EXT1 mutations were deletions identified by MLPA. Two cases of mosaicism were documented. We detected a lower number of exostoses in patients with missense mutation versus other kinds of mutations. In conclusion, we found a mutation in EXT1 or in EXT2 in 95% of the Spanish patients. Eighteen of the mutations were novel.
doi:10.1038/srep01346
PMCID: PMC3581825  PMID: 23439489
8.  NMDA receptor-dependent regulation of miRNA expression and association with Argonaute during LTP in vivo 
microRNAs (miRNAs) are major regulators of protein synthesis in the brain. A major goal is to identify changes in miRNA expression underlying protein synthesis-dependent forms of synaptic plasticity such as long-term potentiation (LTP). Previous analyses focused on changes in miRNA levels in total lysate samples. Here, we asked whether changes in total miRNA accurately reflect changes in the amount of miRNA bound to Argonaute protein within the miRNA-induced silencing complex (miRISC). Ago2 immunoprecipitation was used to isolate RISC-associated miRNAs following high-frequency stimulation (HFS)-induced LTP in the dentate gyrus of anesthetized rats. Using locked-nucleic acid-based PCR cards for high-throughput screening and independent validation by quantitative TaqMan RT-PCR, we identified differential regulation of Ago2-associated and total miRNA expression. The ratio of Ago2/total miRNA expression was regulated bidirectionally in a miRNA-specific manner and was largely dependent on N-methyl-D-aspartate receptor (NMDA) activation during LTP induction. The present results identify miRNA association with Ago2 as a potential control point in activity-dependent synaptic plasticity in the adult brain. Finally, novel computational analysis for targets of the Ago2-associated miRNAs identifies 21 pathways that are enriched and differentially targeted by the miRNAs including axon guidance, mTOR, MAPK, Ras, and LTP.
doi:10.3389/fncel.2013.00285
PMCID: PMC3888942  PMID: 24454279
synaptic plasticity; microRNA; RNA-induced silencing complex; Argonaute; microRNA target prediction; gene expression; protein synthesis; hippocampus
9.  What causes intraspecific variation in resting metabolic rate and what are its ecological consequences? 
Individual differences in the energy cost of self-maintenance (resting metabolic rate, RMR) are substantial and the focus of an emerging research area. These differences may influence fitness because self-maintenance is considered as a life-history component along with growth and reproduction. In this review, we ask why do some individuals have two to three times the ‘maintenance costs’ of conspecifics, and what are the fitness consequences? Using evidence from a range of species, we demonstrate that diverse factors, such as genotypes, maternal effects, early developmental conditions and personality differences contribute to variation in individual RMR. We review evidence that RMR is linked with fitness, showing correlations with traits such as growth and survival. However, these relationships are modulated by environmental conditions (e.g. food supply), suggesting that the fitness consequences of a given RMR may be context-dependent. Then, using empirical examples, we discuss broad-scale reasons why variation in RMR might persist in natural populations, including the role of both spatial and temporal variation in selection pressures and trans-generational effects. To conclude, we discuss experimental approaches that will enable more rigorous examination of the causes and consequences of individual variation in this key physiological trait.
doi:10.1098/rspb.2011.1778
PMCID: PMC3189380  PMID: 21957133
standard metabolic rate; resting metabolic rate; basal metabolic rate; maternal effects; metabolism; energetics
10.  SynSysNet: integration of experimental data on synaptic protein–protein interactions with drug-target relations 
Nucleic Acids Research  2012;41(D1):D834-D840.
We created SynSysNet, available online at http://bioinformatics.charite.de/synsysnet, to provide a platform that creates a comprehensive 4D network of synaptic interactions. Neuronal synapses are fundamental structures linking nerve cells in the brain and they are responsible for neuronal communication and information processing. These processes are dynamically regulated by a network of proteins. New developments in interaction proteomics and yeast two-hybrid methods allow unbiased detection of interactors. The consolidation of data from different resources and methods is important to understand the relation to human behaviour and disease and to identify new therapeutic approaches. To this end, we established SynSysNet from a set of ∼1000 synapse specific proteins, their structures and small-molecule interactions. For two-thirds of these, 3D structures are provided (from Protein Data Bank and homology modelling). Drug-target interactions for 750 approved drugs and 50 000 compounds, as well as 5000 experimentally validated protein–protein interactions, are included. The resulting interaction network and user-selected parts can be viewed interactively and exported in XGMML. Approximately 200 involved pathways can be explored regarding drug-target interactions. Homology-modelled structures are downloadable in Protein Data Bank format, and drugs are available as MOL-files. Protein–protein interactions and drug-target interactions can be viewed as networks; corresponding PubMed IDs or sources are given.
doi:10.1093/nar/gks1040
PMCID: PMC3531074  PMID: 23143269
11.  Delayed presentation of vernix caseosa peritonitis 
INTRODUCTION
Vernix caseosa peritonitis (VCP) is a rare and poorly recognised condition resulting from a sustained foreign body reaction to the vernix caseosa of the baby. This case-based review aims to highlight its importance for any medical team managing patients with peritonitis who have undergone a recent Caesarean section.
CASE REPORT
A 31-year-old woman presented 5 weeks after a Caesarean section with symptoms and signs of peritonitis.
CONCLUSIONS
Laparotomy and peritoneal lavage is the mainstay of treatment for VCP. Knowledge of the condition may stop inadvertent resection of normal intra-abdominal organs. Greater awareness of VCP is required to ensure earlier recognition as patients can recover well following timely operative intervention.
doi:10.1308/003588412X13373405385296
PMCID: PMC3954279  PMID: 23131223
Vernix caseosa peritonitis; Caesarean section; Laparotomy
12.  Temporal and spatial patterns of sea lice levels on sea trout in western Scotland in relation to fish farm production cycles 
Biology Letters  2010;6(4):548-551.
The relationship between aquaculture and infestations of sea lice on wild sea trout (Salmo trutta) populations is controversial. Although some authors have concluded that there is a link between aquaculture and lice burdens on wild fish, others have questioned this interpretation. Lice levels have been shown to be generally higher on Atlantic salmon farms during the second years of two-year production cycles. Here we investigate whether this pattern relates to lice burdens on wild fish across broad temporal and spatial axes. Within Loch Shieldaig across five successive farm cycles from 2000 to 2009, the percentage of sea trout with lice, and those above a critical level, were significantly higher in the second year of a two-year production cycle. These patterns were mirrored in 2002–2003 across the Scottish west coast. The results suggest a link between Atlantic salmon farms and sea lice burdens on sea trout in the west of Scotland.
doi:10.1098/rsbl.2009.0872
PMCID: PMC2936189  PMID: 20164079
Lepeophtheirus; Salmo trutta; aquaculture
13.  Bio::Homology::InterologWalk - A Perl module to build putative protein-protein interaction networks through interolog mapping 
BMC Bioinformatics  2011;12:289.
Background
Protein-protein interaction (PPI) data are widely used to generate network models that aim to describe the relationships between proteins in biological systems. The fidelity and completeness of such networks is primarily limited by the paucity of protein interaction information and by the restriction of most of these data to just a few widely studied experimental organisms. In order to extend the utility of existing PPIs, computational methods can be used that exploit functional conservation between orthologous proteins across taxa to predict putative PPIs or 'interologs'. To date most interolog prediction efforts have been restricted to specific biological domains with fixed underlying data sources and there are no software tools available that provide a generalised framework for 'on-the-fly' interolog prediction.
Results
We introduce Bio::Homology::InterologWalk, a Perl module to retrieve, prioritise and visualise putative protein-protein interactions through an orthology-walk method. The module uses orthology and experimental interaction data to generate putative PPIs and optionally collates meta-data into an Interaction Prioritisation Index that can be used to help prioritise interologs for further analysis. We show the application of our interolog prediction method to the genomic interactome of the fruit fly, Drosophila melanogaster. We analyse the resulting interaction networks and show that the method proposes new interactome members and interactions that are candidates for future experimental investigation.
Conclusions
Our interolog prediction tool employs the Ensembl Perl API and PSICQUIC enabled protein interaction data sources to generate up to date interologs 'on-the-fly'. This represents a significant advance on previous methods for interolog prediction as it allows the use of the latest orthology and protein interaction data for all of the genomes in Ensembl. The module outputs simple text files, making it easy to customise the results by post-processing, allowing the putative PPI datasets to be easily integrated into existing analysis workflows. The Bio::Homology::InterologWalk module, sample scripts and full documentation are freely available from the Comprehensive Perl Archive Network (CPAN) under the GNU Public license.
doi:10.1186/1471-2105-12-289
PMCID: PMC3161927  PMID: 21767381
14.  Dietary Salt Levels Affect Salt Preference and Learning in Larval Drosophila 
PLoS ONE  2011;6(6):e20100.
Drosophila larvae change from exhibiting attraction to aversion as the concentration of salt in a substrate is increased. However, some aversive concentrations appear to act as positive reinforcers, increasing attraction to an odour with which they have been paired. We test whether this surprising dissociation between the unconditioned and conditioned response depends on the larvae's experience of salt concentration in their food. We find that although the point at which a NaCl concentration becomes aversive shifts with different rearing experience, the dissociation remains evident. Testing larvae using a substrate 0.025M above the NaCl concentration on which the larvae were reared consistently results in aversive choice behaviour but appetitive reinforcement effects.
doi:10.1371/journal.pone.0020100
PMCID: PMC3105986  PMID: 21687789
15.  Clustered Coding Variants in the Glutamate Receptor Complexes of Individuals with Schizophrenia and Bipolar Disorder 
PLoS ONE  2011;6(4):e19011.
Current models of schizophrenia and bipolar disorder implicate multiple genes, however their biological relationships remain elusive. To test the genetic role of glutamate receptors and their interacting scaffold proteins, the exons of ten glutamatergic ‘hub’ genes in 1304 individuals were re-sequenced in case and control samples. No significant difference in the overall number of non-synonymous single nucleotide polymorphisms (nsSNPs) was observed between cases and controls. However, cluster analysis of nsSNPs identified two exons encoding the cysteine-rich domain and first transmembrane helix of GRM1 as a risk locus with five mutations highly enriched within these domains. A new splice variant lacking the transmembrane GPCR domain of GRM1 was discovered in the human brain and the GRM1 mutation cluster could perturb the regulation of this variant. The predicted effect on individuals harbouring multiple mutations distributed in their ten hub genes was also examined. Diseased individuals possessed an increased load of deleteriousness from multiple concurrent rare and common coding variants. Together, these data suggest a disease model in which the interplay of compound genetic coding variants, distributed among glutamate receptors and their interacting proteins, contribute to the pathogenesis of schizophrenia and bipolar disorders.
doi:10.1371/journal.pone.0019011
PMCID: PMC3084736  PMID: 21559497
16.  The Gene Regulatory Cascade Linking Proneural Specification with Differentiation in Drosophila Sensory Neurons 
PLoS Biology  2011;9(1):e1000568.
Temporal expression profiling of sensory precursor cells reveals how the atonal proneural transcription factor regulates a specialized neuronal differentiation pathway.
In neurogenesis, neural cell fate specification is generally triggered by proneural transcription factors. Whilst the role of proneural factors in fate specification is well studied, the link between neural specification and the cellular pathways that ultimately must be activated to construct specialised neurons is usually obscure. High-resolution temporal profiling of gene expression reveals the events downstream of atonal proneural gene function during the development of Drosophila chordotonal (mechanosensory) neurons. Among other findings, this reveals the onset of expression of genes required for construction of the ciliary dendrite, a key specialisation of mechanosensory neurons. We determine that atonal activates this cellular differentiation pathway in several ways. Firstly, atonal directly regulates Rfx, a well-known highly conserved ciliogenesis transcriptional regulator. Unexpectedly, differences in Rfx regulation by proneural factors may underlie variations in ciliary dendrite specialisation in different sensory neuronal lineages. In contrast, fd3F encodes a novel forkhead family transcription factor that is exclusively expressed in differentiating chordotonal neurons. fd3F regulates genes required for specialized aspects of chordotonal dendrite physiology. In addition to these intermediate transcriptional regulators, we show that atonal directly regulates a novel gene, dilatory, that is directly associated with ciliogenesis during neuronal differentiation. Our analysis demonstrates how early cell fate specification factors can regulate structural and physiological differentiation of neuronal cell types. It also suggests a model for how subtype differentiation in different neuronal lineages may be regulated by different proneural factors. In addition, it provides a paradigm for how transcriptional regulation may modulate the ciliogenesis pathway to give rise to structurally and functionally specialised ciliary dendrites.
Author Summary
Early during development, cells differentiate and take on specialized forms and functions. This requires the activation of specific genes for different cellular pathways. Our study addresses how this activation is regulated in the developing Drosophila nervous system. In this model, it is well known that proneural transcription factors are involved in directing cells to differentiate into various types of neurons. However, the mechanism by which they choreograph the activation of genes for neuronal differentiation is not clear. In this study, we focused on events leading to differentiation of mechanosensory neurons, which have specialized dendritic processes that mediate sensory perception. In these developing neurons we profiled the time course of gene expression that is triggered by the proneural factor atonal. Our analysis revealed the activation of genes required for the formation of these specialized dendrites, called cilia. We then identified several ways in which atonal regulated these genes. First, it activates intermediate transcription factors that regulate different subsets of differentiation genes. Second, in at least one case, atonal activates a differentiation gene directly, one that is involved in the formation of cilia (ciliogenesis). These findings offer new insight into how proneural factors regulate specialized neuronal differentiation pathways.
doi:10.1371/journal.pbio.1000568
PMCID: PMC3023811  PMID: 21283833
17.  Merged consensus clustering to assess and improve class discovery with microarray data 
BMC Bioinformatics  2010;11:590.
Background
One of the most commonly performed tasks when analysing high throughput gene expression data is to use clustering methods to classify the data into groups. There are a large number of methods available to perform clustering, but it is often unclear which method is best suited to the data and how to quantify the quality of the classifications produced.
Results
Here we describe an R package containing methods to analyse the consistency of clustering results from any number of different clustering methods using resampling statistics. These methods allow the identification of the the best supported clusters and additionally rank cluster members by their fidelity within the cluster. These metrics allow us to compare the performance of different clustering algorithms under different experimental conditions and to select those that produce the most reliable clustering structures. We show the application of this method to simulated data, canonical gene expression experiments and our own novel analysis of genes involved in the specification of the peripheral nervous system in the fruitfly, Drosophila melanogaster.
Conclusions
Our package enables users to apply the merged consensus clustering methodology conveniently within the R programming environment, providing both analysis and graphical display functions for exploring clustering approaches. It extends the basic principle of consensus clustering by allowing the merging of results between different methods to provide an averaged clustering robustness. We show that this extension is useful in correcting for the tendency of clustering algorithms to treat outliers differently within datasets. The R package, clusterCons, is freely available at CRAN and sourceforge under the GNU public licence.
doi:10.1186/1471-2105-11-590
PMCID: PMC3002369  PMID: 21129181
18.  Presence of a conspecific causes divergent changes in resting metabolism, depending on its relative size 
It is well established that the average metabolism of many species of fish varies with group size. However, it is not clear whether all individuals respond in the same way. Here, we use a newly calibrated method of measuring the metabolic rate of fish from opercular (ventilatory) movements that allows for the first-time estimation of changes in resting metabolic rate (RMR) of each individual within different social groups and when alone. The presence of a conspecific had divergent effects on the RMR of juvenile Atlantic salmon Salmo salar, depending on its relative body size: the presence of a smaller fish caused a 40 per cent reduction, whereas the presence of a slightly larger fish approximately doubled RMR. These effects occurred in the absence of activity and were sustained at lower magnitude in the case of the relatively smaller conspecific even if a transparent barrier prevented any physical interactions between fish. Changes in RMR were mirrored by changes in eye colour that indicate they were linked to stress levels. These contrasting and strong responses show that even the nearby presence of a conspecific can have profound and variable effects on an individual's energy budget; they also highlight the complex trade-offs involved in social interactions.
doi:10.1098/rspb.2009.1219
PMCID: PMC2825787  PMID: 19710067
Salmo salar; resting metabolism; salmon; body size; social behaviour; stress
19.  NFAT signalling is a novel target of oncogenic BRAF in metastatic melanoma 
British Journal of Cancer  2009;101(8):1448-1455.
Background:
Metastatic melanoma is the most deadly form of skin cancer and with an overall 5-year survival rate of <11%, there is an acute need for novel therapeutic strategies. Activating mutations in the BRAF oncogene are present in 50–70% of cases and contribute to tumourigenesis, thus, defining downstream targets of oncogenic BRAF may help define novel targets for therapeutic intervention. The Ca2+/calcineurin-regulated transcription factor, Nuclear factor of activated T-cells (NFAT), is important in the pathogenesis of several human cancers, target genes of which are also known to contribute to melanoma progression. One such NFAT target gene is COX-2, increased expression of which correlates with poor prognosis; however, upstream regulators of COX-2 in melanoma remain undefined. Therefore, the aim of this study was to evaluate NFAT expression and activity in metastatic melanoma and establish whether or not oncogenic BRAF signalling modulates NFAT activity and determine if NFAT is a key upstream regulator of COX-2 in melanoma.
Methods:
Nuclear factor of activated T-cells transcriptional activity and protein expression were determined in three human metastatic melanoma cell lines with differing B-RAF mutational status. NFAT activation by oncogenic BRAFV600E was explored by BRAFV600E overexpression and application of the specific MEK inhibitor PD98059. Regulation of COX-2 expression by NFAT was investigated using NFAT-targeted siRNA, calcineurin inhibitors cyclosporin A and FK506, in addition to COX-2 luciferase reporter vectors that selectively lacked NFAT binding sites.
Results:
NFAT transcriptional activity was increased in BRAF-mutated melanoma cells compared with wild-type cells. Furthermore, in wild-type cells, overexpression of BRAFV600E increased NFAT activity, which was blocked by the MEK inhibitor PD98059. Using calcineurin inhibitors and siRNA-mediated knockdown of NFAT2 and 4, we show NFAT is required for COX-2 promoter activation and protein induction in metastatic melanoma cells.
Conclusion:
NFAT2 and 4 are expressed in human metastatic melanoma cell lines and are activated by oncogenic BRAFV600E via MEK/ERK signalling. NFAT is an important upstream regulator of COX-2 in metastatic melanoma. Furthermore, as the BRAF/MEK/ERK pathway is hyperactive in other malignancies and MEK/ERK are also activated by oncogenic RAS in 30% of all human cancers, the potential to exploit NFAT signalling for therapeutic benefit warrants further investigation.
doi:10.1038/sj.bjc.6605277
PMCID: PMC2768445  PMID: 19724275
B-RAF; NFAT; melanoma; COX-2
20.  A neural circuit mechanism integrating motivational state with memory expression in Drosophila 
Cell  2009;139(2):416-427.
Motivational states are important determinants of behavior. In fruit flies appetitive memory expression is constrained by satiety and promoted by hunger. Here we identify a neural mechanism that integrates the motivational state of hunger and memory. We show that stimulation of neurons that express Neuropeptide F (dNPF), an ortholog of mammalian NPY, mimicks food-deprivation and promotes memory performance in satiated flies. Robust appetitive memory performance requires the dNPF receptor in six dopaminergic neurons that innervate a distinct region of the mushroom bodies. Blocking these dopaminergic neurons releases memory performance in satiated flies whereas stimulation suppresses memory performance in hungry flies. Therefore dNPF and dopamine provide a motivational switch in the mushroom body that controls the output of appetitive memory.
doi:10.1016/j.cell.2009.08.035
PMCID: PMC2780032  PMID: 19837040
21.  Juvenile salmon with high standard metabolic rates have higher energy costs but can process meals faster 
Basal or standard metabolic rate (SMR) has been found to exhibit substantial intraspecific variation in a range of taxa, but the consequences of this variation are little understood. Here we explore how SMR is related to the energy cost of processing food, known as apparent specific dynamic action or the heat increment of feeding. Using juvenile Atlantic salmon Salmo salar, we show that fishes with a higher SMR had a higher peak and a greater total energy expenditure when digesting a given size of meal. However, the duration over which their metabolism was elevated after consuming the meal was shorter. The greater energy costs they incur for processing food may be related to their assimilation efficiency. These relationships are likely to have implications for feeding strategies and growth rates, since individuals with a higher SMR have higher routine costs of living but recover more quickly following feeding and so may have a greater potential for processing food.
doi:10.1098/rspb.2009.0080
PMCID: PMC2677234  PMID: 19324750
metabolic rate; energetics; fish; digestion; growth
22.  BrainTrap: a database of 3D protein expression patterns in the Drosophila brain 
Protein-trap strains of Drosophila melanogaster provide a very useful tool for examining the 3D-expression patterns of proteins and purification of protein complexes. Here we present BrainTrap, available at http://fruitfly.inf.ed.ac.uk/braintrap, an online database of 3D confocal datasets showing reporter gene expression and protein localization in the adult brain of Drosophila. Full size images throughout the volume of the entire brain can be viewed interactively in a web browser. The database includes searchable annotations linked to the FlyBase Drosophila anatomy ontology. Anatomical search criteria can be specified using automatic completion and a hierarchical browser for the ontology. The provenance of all annotation is retained and the location where the annotator made the conclusion can be highlighted.
Database URL: http://fruitfly.inf.ed.ac.uk/braintrap
doi:10.1093/database/baq005
PMCID: PMC2911840  PMID: 20624714
23.  Circadian Control of Mouse Heart Rate and Blood Pressure by the Suprachiasmatic Nuclei: Behavioral Effects Are More Significant than Direct Outputs 
PLoS ONE  2010;5(3):e9783.
Background
Diurnal variations in the incidence of events such as heart attack and stroke suggest a role for circadian rhythms in the etiology of cardiovascular disease. The aim of this study was to assess the influence of the suprachiasmatic nucleus (SCN) circadian clock on cardiovascular function.
Methodology/Principal Findings
Heart rate (HR), blood pressure (BP) and locomotor activity (LA) were measured in circadian mutant (Vipr2−/−) mice and wild type littermates, using implanted radio-telemetry devices. Sleep and wakefulness were studied in similar mice implanted with electroencephalograph (EEG) electrodes. There was less diurnal variation in the frequency and duration of bouts of rest/activity and sleep/wake in Vipr2−/− mice than in wild type (WT) and short “ultradian” episodes of arousal were more prominent, especially in constant conditions (DD). Activity was an important determinant of circadian variation in BP and HR in animals of both genotypes; altered timing of episodes of activity and rest (as well as sleep and wakefulness) across the day accounted for most of the difference between Vipr2−/− mice and WT. However, there was also a modest circadian rhythm of resting HR and BP that was independent of LA.
Conclusions/Significance
If appropriate methods of analysis are used that take into account sleep and locomotor activity level, mice are a good model for understanding the contribution of circadian timing to cardiovascular function. Future studies of the influence of sleep and wakefulness on cardiovascular physiology may help to explain accumulating evidence linking disrupted sleep with cardiovascular disease in man.
doi:10.1371/journal.pone.0009783
PMCID: PMC2842429  PMID: 20339544
24.  Letting the family know: balancing ethics and effectiveness when notifying relatives about genetic testing for a familial disorder 
Journal of Medical Genetics  2005;43(8):665-670.
Objective
To increase the awareness among at risk relatives of the availability of genetic testing for a familial disorder while respecting their autonomy and privacy.
Methods
This was a comparison of preintervention and postintervention cohorts of families carried out in a state wide clinical service providing genetic counselling and testing for people at risk of familial adult onset cancer. Unaffected relatives who were not clients of the service in 74 kindreds with familial mutations causing familial breast and ovarian cancer, hereditary non‐polyposis colorectal cancer, or Cowden syndrome were included in the study. In the baseline cohort (41 kindreds), family members who were clients of the clinical service and had been shown to be carriers of mutations were asked to advise relatives that genetic testing was available. In the intervention cohort (33 kindreds), the clinical service obtained consent to advise at risk relatives by letter that genetic testing was available. The main outcome measures were: (a) proportion of unaffected first and second degree relatives of the proband in each family whose genetic status was clarified within 2 years of the mutation being identified in the family, and (b) concerns regarding privacy and autonomy voiced by relatives receiving these letters.
Results
In the baseline cohort, the average proportion of relatives in each family whose genetic status was clarified was 23%. In the intervention cohort, the average proportion of relatives in each family whose genetic status was clarified was 40% (p = 0.001). None of the relatives in the intervention cohort complained of a breach of privacy or autonomy.
Conclusion
Clinical services can take an effective and proactive approach to notifying relatives who are not their clients of the availability of genetic testing without compromising principles of privacy and autonomy.
doi:10.1136/jmg.2005.039172
PMCID: PMC2564590  PMID: 16371501
ethics; privacy; risk notification; genetic testing
25.  Alveolar haemorrhage in anti‐glomerular basement membrane disease without detectable antibodies by conventional assays 
Thorax  2006;61(7):636-639.
Anti‐glomerular basement membrane (anti‐GBM) disease represents the spectrum of disease attributable to circulating anti‐GBM antibodies. While active anti‐GBM disease in the absence of circulating anti‐GBM antibodies has been described, it is considered rare with the use of current routinely available assays. We report four subjects with features consistent with active anti‐GBM antibody disease without detectable antibodies by routinely available enzyme linked immunosorbent assay (ELISA) and immunoblot techniques. All were smokers who presented with diffuse alveolar haemorrhage, minimal renal involvement, and undetectable anti‐GBM antibodies. Seronegative anti‐GBM disease with predominant pulmonary involvement may be more common than previously appreciated and should be part of the differential diagnosis for otherwise unexplained diffuse alveolar haemorrhage. Renal biopsy with immunofluorescent studies should be considered in the diagnostic evaluation of such subjects, including those with idiopathic pulmonary haemosiderosis.
doi:10.1136/thx.2004.028985
PMCID: PMC2104660  PMID: 16807392
anti‐glomerular basement membrane disease; alveolar haemorrhage

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